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REVIEW
Phytochemicals mediated modulation of microRNAs and long
non-coding RNAs in cancer prevention and therapy
Luis M. Ruiz-Manriquez
1
| Carolina Estrada-Meza
1
| Javier A. Benavides-Aguilar
1
|
S. Janin Ledesma-Pacheco
1
| Andrea Torres-Copado
1
| Francisco I. Serrano-Cano
1
|
Anindya Bandyopadhyay
2,3
| Surajit Pathak
4
| Samik Chakraborty
5
|
Aashish Srivastava
6
| Ashutosh Sharma
1
| Sujay Paul
1
1
Tecnologico de Monterrey, School of
Engineering and Sciences, Campus Queretaro,
San Pablo, Mexico
2
C4 Rice Center, International Rice Research
Institute, Manila, Philippines
3
Synthetic Biology, Biofuel and Genome
Editing R&D, Reliance Industries Ltd, Navi
Mumbai, India
4
Department of Medical Biotechnology,
Faculty of Allied Health Sciences, Chettinad
Hospital and Research Institute (CHRI),
Chettinad Academy of Research and
Education (CARE), Kelambakkam, Chennai,
India
5
Division of Nephrology, Boston Children's
Hospital, Harvard Medical School, Boston,
Massachusetts, USA
6
Department of Clinical Science, University of
Bergen, Bergen, Norway
Correspondence
Sujay Paul and Ashutosh Sharma, Tecnologico
de Monterrey, School of Engineering and
Sciences, Campus Queretaro, Av. Epigmenio
Gonzalez, No. 500 Fracc., San Pablo, 76130
Queretaro, Mexico.
Email: spaul@tec.mx (S. P.) and asharma@tec.
mx (A. S.)
Abstract
MicroRNAs (miRNAs) and long noncoding RNAs (lncRNAs) are two main categories
of noncoding RNAs (ncRNAs) that can influence essential biological functions in vari-
ous ways, as well as their expression and function are tightly regulated in physiologi-
cal homeostasis. Additionally, the dysregulation of these ncRNAs seems to be crucial
to the pathogenesis of human diseases. The latest findings indicate that ncRNAs exe-
cute vital roles in cancer initiation and progression, and the cancer phenotype can be
reversed by modulating their expression. Available scientific discoveries suggest that
phytochemicals such as polyphenols, alkaloids, terpenoids, and organosulfur com-
pounds can significantly modulate multiple cancer-associated miRNAs and lncRNAs,
thereby inhibiting cancer initiation and development. However, despite promising
outcomes of experimental research, only a few clinical trials are currently being con-
ducted to evaluate the therapeutic effectiveness of these compounds. Nevertheless,
understanding phytochemical-mediated ncRNA regulation in cancer and the underly-
ing molecular mechanisms on tumor pathophysiology can aid in the development of
novel therapeutic strategies to combat this deadly disease.
KEYWORDS
cancer, chemoprevention, gene regulation, lncRNAs, microRNA, phytochemicals, therapeutics
1|INTRODUCTION
Cancer is one of the deadliest chronic disorders, and according to the
recent statistics of the World Health Organization (WHO), it is the
world's second leading cause of mortality after ischemic heart disease.
Cancer is responsible for around 1 in 6 deaths globally, accounting for
an estimated 9.6 million deaths in 2018. The most frequent causes of
death from cancer are lung cancer (1.76 million deaths), followed by
colorectal cancer (862,000 deaths), stomach cancer (783,000 deaths),
liver cancer (782,000 deaths), and breast cancer (627,000 deaths)
(WHO, 2019). Moreover, based on statistics compiled by the Interna-
tional Agency for Research on Cancer (IARC) for the year 2018, the
global number of new cancer cases was 18.1 million, and it has been
speculated that the global cancer incidence by the year 2040 will
increase to 29.5 million (International Agency for Research on
Cancer, 2018).
Cancer is categorized as a multistage disease that can be concep-
tually separated into initiation, promotion, conversion, progression,
and subsequent invasion and metastasis stages (Koh, Ho, &
Pan, 2020). Given the disease's high profile and complex nature, the
search for an effective treatment has been exhaustive, yet with rela-
tively little success. Surgical removal and radiation therapy, usually
accompanied by systematic chemotherapy, are currently available
cancer treatment choices (Choudhari, Mandave, Deshpande,
Received: 5 July 2021 Revised: 7 October 2021 Accepted: 4 November 2021
DOI: 10.1002/ptr.7338
Phytotherapy Research. 2021;1–25. wileyonlinelibrary.com/journal/ptr © 2021 John Wiley & Sons Ltd. 1
Ranjekar, & Prakash, 2020). However, chemotherapeutic medications
have several drawbacks, including high cost, cancer recurrence, drug
resistance, and adverse effects on nontargeted tissues, all of which
can hinder the use of anticancer drugs and thus reduce patient quality
of life (Choudhari et al., 2020). Besides, cancer is nowadays one of the
most critical financial challenges for affected families as healthcare
becomes advanced and new cancer treatment methods are costly and
sophisticated. The WHO (2019) reported that a staggering 1.16 tril-
lion USD was the cumulative economic cost of cancer for 2010.
Hence, exploring alternative cost-effective promising anticancer
agents with greater effectiveness and minor side effects is the current
key research arena of medical science. In this context, phytochemicals
and plant derivatives might be the most promising ones (Dhupal &
Chowdhury, 2020).
Phytochemicals are plant-derived metabolites found in a wide
range of fruits, vegetables, and herbs (Tsuji, Galinn, & Hartman, 2016).
Due to favorable safety profiles and bioavailability, polyphenols, alka-
loids, terpenoids, and organosulfur compounds are well-known phyto-
chemical groups with excellent health-promoting effects such as
anticancer properties and have been used for years to prevent or treat
different types of cancers based on traditional medicinal practices
(Abbasi et al., 2018; Budisan et al., 2017; Chiou, Li, Ho, & Pan, 2018;
Izzo, Hoon-Kim, Radhakrishnan, & Williamson, 2016; Kaur
et al., 2018). According to the scientific evidence, phytochemicals
have substantial anticarcinogenic effects, and about half of all licensed
anticancer drugs between 1940 and 2014 come from natural products
or are extracted explicitly from them (Newman & Cragg, 2016). Many
of these phytochemicals display their anticancer properties through
multiple mechanisms, and the corresponding contribution varies with
the stage of cancer (Shukla, Meeran, & Katiyar, 2014; Singh, Arora,
Ansari, & Sharma, 2019).
In the last couple of decades, several studies have found that the
dysregulation of the central dogma can result in the progress of many
diseases such as cancer. Even though less than 2% of the genome
codes for proteins, they represent the primary functional end-product
of genetic information (J. Wang et al., 2019). It has also been shown
that functional products encoded by the genome are not limited to
proteins but include a variety of unique RNAs. Fortunately, advance-
ments in sequencing technologies have led to the discovery of multi-
ple ncRNA species, including well-studied miRNAs and lncRNAs
(Anastasiadou, Jacob, & Slack, 2018). They are explicated as key regu-
lators in major cellular processes such as development, differentiation,
proliferation, transcription, posttranscriptional modifications, apopto-
sis, and cell metabolism (J. Wang, Zhu, et al., 2019). Interestingly,
recent evidence suggests that a variety of phytochemicals significantly
control the expression of different ncRNAs, which might be crucial in
carcinogenesis.
miRNAs are short endogenous noncoding RNA molecules (20–24
nucleotides) that perform vital roles in the posttranscriptional gene
regulation to fine-tune the normal cellular physiology, and their
expression is tissue- or developmental stage-specific (Paul
et al., 2020; Paul et al., 2021; Vishnoi & Rani, 2017). Since Lee,
Feinbaum, and Ambros (1993) discovered miRNAs in Caenorhabditis
elegans, it has been shown that they are commonly distributed in most
eukaryotes, including humans (T. X. Lu & Rothenberg, 2018). It has
been documented that miRNAs regulate approximately 60% of human
protein-coding genes (Shu, Silva, Gao, Xu, & Cui, 2017), and there are
currently 2,654 distinct human mature miRNAs annotated in miRbase
(http://www.mirbase.org/), indicating that miRNAs are involved in
complex regulatory networks (De La Fuente Jiménez, Sharma, &
Paul, 2020; Yi et al., 2020). Biogenesis and processing of miRNAs
(Figure 1) start in the nucleus when RNA polymerase II transcribes
miRNAs genes as long hairpin structures called primary miRNAs tran-
scripts (pri-miRNA). Subsequently, the microprocessor complex inte-
grated by Drosha and DGCR8 processes the pri-miRNA to produce a
precursor miRNA (pre-miRNA) with a shorter stem–loop structure.
Afterward, the pre-miRNAs are exported to the cytoplasm by inter-
acting with Exportin 5, where it is processed once more by the RNase
III dicer and the trans-activation responsive RNA-binding protein
(TRBP) to produce the mature miRNA/miRNA* duplex. Later, the
duplex is separated by a helicase, and one of the miRNA strands
(guide strand) of the processed duplex is loaded onto the RNA-
induced silencing complex (RISC) coupled with the Argonaute (AGO)
protein family to interact with the target mRNA. Finally, the miRNA–
mRNA interaction leads to different pathways based on the nucleo-
tides complementarity; a partial interaction results in translational
repression, while a complete match leads to mRNA degradation (Paul
et al., 2021; Paul, Reyes, Garza, & Sharma, 2019; Treiber, Treiber, &
Meister, 2019). A number of noncanonical pathways have also been
reported following the elucidation of the core features of canonical
miRNA biogenesis (Abdelfattah, Park, & Choi, 2014).
Moreover, their aberrant expression is significantly linked to
developing different pathogenic conditions (Vishnoi & Rani, 2017). In
this context, phytochemical-mediated modulation of oncomiRs and
tumor suppressor miRNAs (miRNAs involved in carcinogenesis) has
also been reported (Srivastava, Arora, Averett, Singh, & Singh, 2015).
Furthermore, the ability of anticancer agents to target miRNAs/mRNA
pathways has become a leading field of research as they are the key
players in cell differentiation, apoptosis, DNA damage repair, and
intercellular communication (B. Liu, Shyr, Cai, & Liu, 2019).
On the other hand, lncRNAs are a group of noncoding RNAs com-
posed of >200 nucleotides that play key roles in regulating chromatin
remodeling, gene transcription, and epigenetic modification (R. Zhang,
Xia, Lu, Zhang, & Zhu, 2016). Studies have demonstrated that dys-
function of lncRNAs is significantly associated with cancer progres-
sion as they regulate cell proliferation, apoptosis, migration, invasion,
and maintenance of stemness (X. Huang et al., 2016; M.-C. Jiang, Ni,
Cui, Wang, & Zhuo, 2019). Recent investigations have elucidated that
lncRNAs could be a potential prognostic biomarker and therapeutic
target for different types of cancer (R. Zhang et al., 2016).
Understanding the biogenesis of lncRNAs leads to deciphering its
functional significance rather than differentiating it from other types
of RNAs. The biogenesis of lncRNAs is cell type- and stage-specific,
which is controlled by cell type–and stage-specific stimuli (Dahariya
et al., 2019). Several distinct classes of lncRNAs are transcribed from
different DNA elements, including promoters, enhancers, and
2RUIZ-MANRIQUEZ ET AL.
intergenic regions in eukaryotic genomes (H. Wu, Yang, &
Chen, 2017). Moreover, various mechanisms have been elucidated in
lncRNA biogenesis, such as cleavage by ribonuclease P (RNase P) to
generate mature ends, formation of small nucleolar RNA, and protein
complex caps at their ends (Dahariya et al., 2019). In addition, unique
protein-rich nuclear organelles built around a specific lncRNA scaffold
known as “paraspeckles”have been identified among specific
lncRNAs during their biogenesis. Once formed, paraspeckles influence
gene regulation through sequestration of component proteins and
RNAs (Fox, Nakagawa, Hirose, & Bond, 2018).
The general mechanisms by which lncRNAs act to regulate vari-
ous cellular functions include epigenetic regulations such as chromatin
remodeling or histone modification, interfering with the transcrip-
tional machinery to alter gene expression, inducing alternative splic-
ing, activating Dicer due to sense–antisense hybridization and
subsequent production of siRNAs in the cells, as well as binding to the
specific protein to alter its cellular localization or activity
(Rathinasamy & Velmurugan, 2018).
Although the mechanism of lncRNAs function varies under differ-
ent conditions, it has been noticed that lncRNAs and miRNAs can
potentially cross-talk during carcinogenesis. More recently, a number
of phytochemicals have been demonstrated to affect lncRNA expres-
sion either directly or indirectly through the involvement of miRNAs
and other proteins, suggesting that this modulation can produce ther-
apeutic effects in some types of cancer (Mishra et al., 2019).
TheexpressionprofilesofmiRNAsandlncRNAshavebeenwell
studied for their possible use as diagnostic or prognostic markers in vari-
ous cancers (Khan et al., 2019; Rupaimoole & Slack, 2017). Besides, sev-
eral researchers have identified novel phytochemical-modulated ncRNAs
target transcripts and studied their possible use in miRNA-mediated
therapeutic approaches (Arora, Sharma, & Tollefsbol, 2019). This review
focuses on the most recent information about the phytochemical-
mediated modulation of miRNAs and lncRNAs in humans and their func-
tional implications inhibiting cancer cell growth, which might be useful in
developing specific and efficient anticancer drugs as well as to design
preventive medicine for multiple cancer types.
FIGURE 1 miRNA biogenesis pathway. Canonical miRNAs biogenesis initiates in the nucleus when Pol II transcribes miRNA genes into pri-
miRNA. The microprocessor complex, which includes the enzymes Drosha and DGCR8, processes pri-miRNA to pre-miRNA, which is then
translocated from the nucleus to the cytoplasm by Exportin 5. Afterward, the RNase III dicer and the RNA-binding protein TRBP work together to
process pre-miRNA into mature miRNA/miRNA* duplexes. The duplex is then separated by a helicase, and the resulting guide strand is integrated
into RISC with the guidance of Argonaute2 (AGO2). Finally, the RISC–miRNA complex recognizes specific mRNAs based on sequence
complementarity, causing mRNA degradation or translational inhibition. The figure was created using BioRender.com and exported under a paid
subscription [Colour figure can be viewed at wileyonlinelibrary.com]
RUIZ-MANRIQUEZ ET AL.3
2|PHYTOCHEMICALS MEDIATED
MODULATION OF DIFFERENT miRNAs IN
CANCER
The cancer hallmarks include six biological capabilities acquired during
the multistep development of tumorigenesis and carcinogenesis,
including evading growth suppressors, sustaining proliferative signal-
ing, resisting cell death, enabling replicative immortality, inducing
angiogenesis, and activating invasion and metastasis (Fouad &
Aanei, 2017; X. Zhang et al., 2019). In this context, cellular pathways,
especially those controlling cell proliferation, differentiation, and sur-
vival, have been shown to be regulated by miRNAs (Paul et al., 2021;
Paul, Bravo Vázquez, Pérez Uribe, Roxana Reyes-Pérez, &
Sharma, 2020; Treiber et al., 2019). In almost all cancer types, dys-
regulation of miRNA expression has been reported (Khan et al., 2019).
Interestingly, recent evidence has elucidated that miRNAs can act as
oncogenic or tumor suppressors (Vanacore et al., 2017; H. Z. Zhu
et al., 2020). Oncogenic miRNAs upregulations lead to the inhibition
and degradation of tumor suppressor gene products that modulate
cell growth; in contrast, tumor-suppressor miRNAs are associated
with inhibiting oncogenes' primary transcripts that promote cell prolif-
eration (Svoronos, Engelman, & Slack, 2016). This strengthens the
notion that intervention in multiple targets is better than targeting a
single gene or signaling pathway (Ahmed et al., 2020), leading to new
cancer therapeutics options.
A range of investigations has been elucidated that numerous
plant-derived bioactive compounds can regulate the expression of
several oncogenic and tumor-suppressive miRNAs (Figure 2) (Table 1)
(De La Parra et al., 2016; Hargraves et al., 2015; Kapinova
et al., 2018; Sayeed et al., 2017); however, the explicit molecular
mechanism underlying the phytochemical mediated modulation of
miRNAs and their impact on carcinogenesis are yet to be thoroughly
elucidated. Nonetheless, growing evidence suggests that the dys-
regulation of miRNAs occurs through various mechanisms, including
the activation or deletion of miRNA genes, irregular transcription of
miRNAs, abnormal epigenetic changes, and defective miRNA biogene-
sis pathways (Figure 3) (Kang, 2019; Srivastava et al., 2015). In this
context, Baselga-Escudero et al. (2014) stated that polyphenols could
directly bind to the mature miRNAs and influence their expression.
Using 1H NMR spectroscopic studies, they observed that resveratrol
FIGURE 2 Phytochemicals mediated regulation of miRNAs in different cancers. Red (downregulated) and green (upregulated) dots indicate
differential expression of each miRNA [Colour figure can be viewed at wileyonlinelibrary.com]
4RUIZ-MANRIQUEZ ET AL.
TABLE 1 Phytochemicals mediated regulation of miRNAs and their targets in cancer
miRNA Compound
Effect in miRNA
expression
pattern Target gene Biological mechanism Sample Reference
Oncogenic miRNAs
miR-21 Curcumin #PDCD4 Inhibition of tumor
development and progression
RKO and HCT-116 cells Mudduluru et al. (2011)
#Notch-1 Inhibition of cell proliferation
and colony formation
TE-7 and TE-10 cells, ESO-1
mouse cells
Subramaniam et al. (2012)
#PTEN Antiproliferative and
proapoptotic activities
A549 cells W. Zhang, Bai, and
Zhang (2013)
#PTEN Inhibition of cell viability
Promotion of apoptosis
MCF-7 cells X. Wang et al. (2017)
Curcumin and
PD98059
#PTEN Promotion of apoptosis MGC-803 cells Qiang et al. (2019)
EF24 #PTEN, PDCD4 Promotion of apoptosis DU145 cells and B16 murine
cells
C. H. Yang, Yue, Sims, and
Pfeffer (2013)
Difluorinated
curcumin
#PTEN Inhibition of cell growth
Promotion of apoptosis
HCT116 and HT-29
chemoresistant cells
Roy, Yu, Padhye, Sarkar, and
Majumdar (2013)
Sulforaphane #hTERT Antiproliferative activity RKO cells Martin, Kala, and
Tollefsbol (2018)
I3C and gemcitabine #PDCD4 Improved chemosensitivity of
cancer cells
Promotion of apoptosis
Panc-1 cells Paik et al. (2013)
I3C #PTEN Antiproliferative and
proapoptotic activities
HCC xenograft model, HCC cell
culture
X. Wang et al. (2015)
#PTEN, PDCD4, RECK Inhibition of tumor
development and progression
VC-treated mouse lung tissues,
A549 cells
Melkamu, Zhang, Tan, Zeng,
and Kassie (2010)
Gemcitabine and
garcinol
#TGF-β, MAPK, STAT, VEGF,
notch, mTOR
Inhibition of cell proliferation
Promotion of apoptosis
Panc-1 cells Parasramka et al. (2013)
Resveratrol #Bcl-2 Promotion of apoptosis Panc-1, CFPac-1, and MIA
Paca-2 cells, rat C6 glioma
cells
P. Liu et al. (2013); X. Wang
et al. (2015)
#STAT3 Reduction of tumorigenesis DU145 and LNCaP cells Al Aameri et al. (2017)
Berberine #ALDH1 Inhibition of cell self-renewal,
migration, and invasion
OSCC-CSC mice model Lin et al. (2017)
#IL6, STAT3 Inhibition of cell proliferation
Promotion of apoptosis
RPMI-8266 and U226 cells Luo et al. (2014)
Nimbolide #RECK Inhibition of tumor
development and progression
HBP carcinogenesis model Kowshik et al. (2017)
(Continues)
RUIZ-MANRIQUEZ ET AL.5
TABLE 1 (Continued)
miRNA Compound
Effect in miRNA
expression
pattern Target gene Biological mechanism Sample Reference
α-Solanine #PTEN, RECK Inhibition of cell proliferation
Promotion of apoptosis
PC-3 cells Shen et al. (2014)
Isoliquiritigenin #RECK Inhibition of tumor
development and progression
Hs-578 T and MDA-MB-231
cells
Ning et al. (2016)
#STAT3 Breast cancer cells Ning et al. (2017)
Silibinin #SNAIL, ZEB, N-cadherin Reversal of erlotinib resistance Erlotinib-resistant NSCLC
xenografts
Cufí et al. (2013)
#BID, CASP-9 Inhibition of cell proliferation
Promotion of apoptosis
MCF-7 cells Zadeh, Motamed, Ranji, Majidi,
and Falahi (2016)
3,6-Dihydroxyflavone #Notch-1, PTEN Inhibition of tumor
development and progression
Promotion of apoptosis
1-MNU induced mouse
xenografts
Hui et al. (2012); Peng
et al. (2015)
miR-200 RM
a
"
b,c,d
GATA4, BCL-2, ZEB1 Promotion of apoptosis
Inhibition of cell invasion
HCT 116 cells Ayan, Çetinkaya, Dursun, and
Süntar (2020)
HT-29 cells
RM and 5-FU HCT 116 cells
HT-29 cells
Resveratrol #
d
BCL2, XIAP, CDK6, CDK4,
CDK2
Promotion of apoptosis MDA-MB-231 cells Venkatadri, Muni, Iyer, Yakisich,
and Azad (2016)
TCRV "
b,c,d
E-cadherin, N-cadherin,
Vimentin, Zeb1
Promotion of apoptosis
Inhibition of cell proliferation,
survival, and invasion
AsPC-1 and Panc-1 cells J. Fu, Shrivastava, Shrivastava,
Srivastava, and
Shankar (2019)
miR-155 Oleuropein #TP53INP1, FADD Inhibition of cell proliferation
Promotion of apoptosis
MCF-7 cells Abtin et al. (2018)
Genistein #FOXO3, PTEN, CK1αPromotion of apoptosis
Inhibition of cell viability
MDA-MB-435 and Hs578t cells De La Parra et al. (2016)
miR-224 Luteolin #MMP-2, MMP-9, Vimentin,
cyclin D1, cyclin E, Bc12, E-
cadherin
Regulation of GC cell cycle,
proliferation, colony
formation, migration,
invasion, and apoptosis
MKN45 and BGC823 cells Pu et al. (2018)
miR-17 Resveratrol #PTEN Inhibition of cell proliferation
Promotion of apoptosis
DU145 and 22Rv1 cells,
xenografts models
Kumar, Rimando, and
Levenson (2017)
miR-92a-
1-5p
EPRE #EP4/Notch1 Inhibition of cell proliferation SNU-16 cells M. G. Jang, Ko, and Kim (2018);
Shin et al. (2018)
miR-18a Ginsenoside Rd #Smad2, TGFβ1 Antimetastatic effects 4 T1 cells, tumors in breast
cancer cell line
P. Wang et al. (2016)
6RUIZ-MANRIQUEZ ET AL.
TABLE 1 (Continued)
miRNA Compound
Effect in miRNA
expression
pattern Target gene Biological mechanism Sample Reference
Tumor supressor miRNAs
miR-34c Resveratrol "p53 Inhibition of cell viability
Promotion of apoptosis
Cell cycle arrest
HCT-116 and HT-29 cells S. Yang et al. (2015)
mir-34a "E2F3, Sirt1 Promotion of apoptosis DLD-1, SW480 and COLO20
cells, and drug-resistant DLD-
1/5FU and DLD-1/OXA
Kumazaki et al. (2013)
"p53 Proliferation suppression MDA-MB-231 and MCF7 cells Otsuka, Yamamoto, and
Ochiya (2018)
"p-STAT3 Inhibition of hypoxia-induced
migration and invasion
U87 and U251 cells H. Wang, Feng, and
Zhang (2016)
Curcumin and
emodin
"mir-34a Bcl-2, Bmi-1 Inhibition of cell proliferation,
survival, and invasion
MDA-MB-231 and MDA-MB-
435 cells
Guo et al. (2013)
Curcumin and AKBA "mir-34a cMyc, cyclin D1, CDK4, CDK6,
and Bcl-2
Inhibition of tumor growth HCT116, RKO, SW480,
SW620, HT29, Caco2 and
HCT116p53/cells and
mouse models
Toden et al. (2015)
mir-34a
mir-34c
CDF "Notch-1 Inhibition of cell growth
Promotion of apoptosis
SW620, HCT116wt, HCT116
chemoresistant,
HCT116p53/cells.
Roy, Levi, Majumdar, and
Sarkar (2012)
mir-34a Luteolin "Bcl-2 Inhibition of cell proliferation
Promotion of apoptosis
Gastric cancer tumor tissue H. Wu, Huang, Liu, Shu, and
Liu (2015)
Artemisinin "CDK4 Inhibition of cell proliferation,
survival, and invasion
Modulates chemotherapy
resistance
Disruption metastasis
Promotion of apoptosis
MCF-7 and T47D cells Deng et al. (2014); Hargraves,
He, and Firestone (2015); X.
J. Li et al. (2012); MacKiewicz
et al. (2011); C. H. Yang
et al. (2013)
DADS "SRC Inhibition of cell proliferation,
survival, and invasion
MDA-MB-231 cells and
xenografts model
Xiao et al. (2014)
Thymoquinone ΔTWIST1, ZEB1 Repression of tumor growth
and migration
BT-549 cells Imani et al. (2017)
Honokiol "Wnt1 MTA1, β-catenin Inhibition of cell growth Leptin-induced MCF-7, MDA-
MB-231, MDA- MB-468, and
T47D cells, mouse models
Avtanski et al. (2015)
(Continues)
RUIZ-MANRIQUEZ ET AL.7
TABLE 1 (Continued)
miRNA Compound
Effect in miRNA
expression
pattern Target gene Biological mechanism Sample Reference
Genistein "Notch-1 Promotion of apoptosis
Inhibition of growth, invasion,
and self-renewal capacity of
cancer stem cells
AsPC-1 and MiaPaCa-2 cells Xia et al. (2012)
"HOTAIR Inhibition of cell migration,
proliferation and invasion
Promotion of apoptosis
Cell cycle arrest
PC3 and DU145 cells, mouse
models
Chiyomaru et al. (2013)
Capsaicin "Bcl-2 Promotion of apoptosis A549 cells Chakraborty et al. (2014)
Ellagic acid "p53 Antiproliferative activity EJ and RUBE cells Zhou et al. (2015)
let-7a Quercetin and GTC "K-ras Inhibition of colony formation
Promotion of apoptosis
MIA-PaCa2, BxPC-3, and
PacaDD-183 cells
Appari, Babu, Kaczorowski,
Gross, and Herr (2014)
let-7b Epigallocatechin-
3-gallate
"67LR Inhibition of tumor growth B16 cells Yamada et al. (2016)
let-7c Quercetin "Numbl Inhibition of cell proliferation
Suppression of tumors
AsPC-1, ASANPaCa and Panc-1
cells
Nwaeburu et al. (2016)
let-7b, let-
7c, let-
7d, let-
7e
Diindolylmethane "ZEB1 Modulation of EMT and
chemosensitivity
Gemcitabine-resistant
pancreatic cancer cells
Y. Li et al. (2009)
Isoflavone G2535
let-7f-1 Lycopene "AKT2 Inhibition of proliferation cell
Promotion of apoptosis
PC3 cells D. Li, Chen, Zhao, Hao, and
An (2016)
let-7b
Let-7i
Acetyl-11-keto-
β-boswellic acid
"CDK6, vimentin Inhibition of cell proliferation
and migration
Promotion of apoptosis
HCT116, HT29, SW480, and
SW620 cells
Takahashi et al. (2012)
miR-218 Andrographolide "Bmi1 Inhibition of cell proliferation
and invasion
OCSC Yamamoto et al. (2013); P. Y.
Yang et al. (2017)
miR-
122-5p
Resveratrol "Bcl-2, XIAP Promotion of apoptosis
Inhibition of cell viability
MDA-MB-231 cells Venkatadri et al. (2016)
Dualistic role of miRNAs—Tumor supressors and oncogenic miRNAs
miR-16 Curcumin "Bcl-2 Promotion of apoptosis
Inhibition of cell proliferation
MCF-7 cells J. Yang, Cao, Sun, and
Zhang (2010)
"WT1 K562 and HL-60 cells Gao et al. (2012)
Epigallocatechin-
3-gallate
"Bcl-2 HepG2 cells Tsang and Kwok (2010)
"IKKαPrevention of survival and
proliferation of tumor cells
4 T1 murine breast cancer cells
and tumor exosomes
J. Y. Jang, Lee, Jeon, and
Kim (2013)
8RUIZ-MANRIQUEZ ET AL.
TABLE 1 (Continued)
miRNA Compound
Effect in miRNA
expression
pattern Target gene Biological mechanism Sample Reference
Resveratrol "AGO2 Inhibition of stem-cell-like
features
Breast cancer cells Hagiwara et al. (2012)
"BLC2 Promotion of apoptosis CCRF-CEM cells Azimi et al. (2015)
Quercetin "Claudin-2 Prevention of tumorigenesis A549 cells Sonoki et al. (2015)
Paeoniflorin "MMP-9 Inhibition of cell proliferation
Promotion of apoptosis
U87 cells W. Li et al. (2015)
miR-221
miR-222
Genistein "Not reported Not reported 8505C cells Allegri et al. (2018)
#SW1736 cells
Resveratrol "8505C cells
#SW1736 cells
Curcumin #8505C and SW1736 cells
SAHA ad EGCG #ERαLimitation of cell growth and
proliferation
MDA-MB-157 and HCC1806
cells
Lewis, Jordan, and
Tollefsbol (2019)
miR-221 EGCG #Not reported Not reported SW1736 and 8505C cells Allegri et al. (2018)
miR-20a Pterostilbene #PTEN Inhibition of cell proliferation
Promotion of apoptosis
DU145 and 22Rv1 cells,
xenografts models
Kumar et al. (2017)
miR-186
e
Curcumin #Caspase-10, myc, bc19, P2X7 Inhibition of cell proliferation
Promotion of apoptosis
A549 cells J. Zhang et al. (2010)
Note:ΔSynergistic effect.
a
Showed better results than the combination.
b
miR-200a.
c
miR-200b.
d
miR-200c.
e
Partially suppressed.
RUIZ-MANRIQUEZ ET AL.9
and epigallocatechin-3-gallate (EGCG) directly bind to miR-33a and
miR-122. Additionally, phytochemicals have been shown to affect
miRNA levels by regulating different associated transcription factors
and consequently modulate the cancer pathology. For example, treat-
ment with EGCG promotes the binding of hypoxia-inducible factor-1
(HIF-1) to the hypoxia response element present in the promoter
region of miR-210, resulting in transcriptional activation of miR-210 in
lung cancer (Hong Wang, Bian, & Yang, 2011).
Moreover, Pan et al. (2017) demonstrated that resveratrol could
regulate the expression of c-Myc, a transcriptional activator of miR-
17, leading to the suppression of oncogenic miR-17 levels in breast
cancer cells. Besides, supporting evidence suggests that epigenetic
modification, like aberrant CpG methylation, contributes to the dys-
regulation of miRNA expression in tumor cells. Precisely, Saini
et al. (2011) provided evidence that curcumin treatment resulted in
the hypomethylation of miR-203 promoter and subsequent
upregulation of miR-203 in bladder cancer cells. Finally, phytochemi-
cals could alter miRNA processing regulation at various steps, which
might increase or decrease the level of miRNAs. Hagiwara et al. (2012)
noticed that resveratrol treatment significantly increased the expres-
sion of Ago2 and resulted in enhanced levels of tumor suppressor
miRNAs such as miR-16, miR- 141, miR-143, and miR-200c in breast
cancer cells.
The most common cancer-associated miRNAs and their modula-
tion during different well-known phytochemical-based treatments
against cancer reported so far are discussed as follows:
2.1 |Oncogenic miRNAs
2.1.1 | miR-21
One of the earliest miRNAs identified in mammals was miR-21. Its
chromosomal position in Homo sapiens is located at 17q23.2 in the
eleventh intron of the transmembrane protein (49TMEM49) gene, a
precursor of vacuole membrane protein 1 (VMP1) (Bautista-Sánchez
et al., 2020; Najjary et al., 2020). miR-21 overexpression has been
associated with several types of cancer, such as lung, stomach, pros-
tate, ovarian, breast, thyroid, colon, pancreas, and gliomas, where it
targets critical tumor suppressor genes as well as genes involved in
carcinogenesis, including phosphate and tensin homolog (PTEN),
programmed cell death 4 (PDCD4) and reversion-inducing cysteine-
rich protein with Kazal motifs (RECK) (Bautista-Sánchez et al., 2020;
J. Liu et al., 2020; Melkamu et al., 2010). Due to its potential onco-
genic role, miR-21 is currently one of the most studied target miRNAs
in cancer therapeutic research (Figure 4) (Najjary et al., 2020).
Curcumin (a yellow polyphenol, which is the main active compo-
nent of Curcuma longa) has the ability to reduce the expression of the
oncogenic miR-21 in RKO and HCT-116 colon cancer cells leading to
reduced tumor growth and metastasis formation by enhanced expres-
sion of PDCD4 (Mudduluru et al., 2011; J. Yang et al., 2010). While
Subramaniam et al. (2012) reported that curcumin negatively regulates
Notch signaling and Notch-1-specific miRNAs expressions, including
miR-21 in TE-7, TE-10 human esophageal cancer cells, and ESO-1
mouse esophageal adenocarcinoma cancer cells, leading to an inhibi-
tion of proliferation and colony formation of these cell lines. Interest-
ingly, W. Zhang et al. (2013) demonstrated that curcumin exhibits
proapoptotic and antiproliferative properties in human non-small-cell
lung cancer (NSCLC) A549 cells, primarily mediated by PTEN
upregulation through inhibition of its repressor miR-21. Likewise,
curcumin-mediated downregulation of miR-21 expression in human
breast cancer MCF-7 cells with the PTEN/Akt signaling pathway's
upregulation was also noticed (X. Wang et al., 2017). More recently,
Qiang et al. (2019) reported that curcumin acts synergistically with
PD98059 flavonoid, a potent and selective inhibitor of mitogen-
activated protein kinase (MAPK), repressing the expression of miR-21
and p-Akt while increasing the expression of the PTEN protein,
resulting in an efficient induction of apoptosis in human gastric cancer
FIGURE 3 Overview of miRNA
regulation mechanisms induced by
phytochemicals. Phytochemicals influence
miRNA expression via activating or
deleting miRNA genes, modulating
transcription factors, causing epigenetic
alterations, and interfering with miRNA
biogenesis pathways, which in turn
increases the expression of tumor
suppressors miRNAs and decreases the
expression of oncogenic miRNAs
promoting the anticancer effects [Colour
figure can be viewed at
wileyonlinelibrary.com]
10 RUIZ-MANRIQUEZ ET AL.
MGC-803 cells. Curcumin analogs such as EF24 displayed enhanced
anticancer activity over curcumin. EF24 inhibits the NF-kB signaling
pathway in DU145 human prostate cancer cells and B16 murine mela-
noma cells and triggers apoptosis apparently by the inhibition of miR-
21 expression, enhancing the expression of its target genes, PTEN and
PDCD4 (C. H. Yang et al., 2013). Similarly, difluorinated curcumin
(CDF), a synthetic analog of curcumin, exhibited greater bioavailability
than actual curcumin. CDF has been shown to inhibit cellular growth
and induce apoptosis in chemoresistant colon cancer cells HCT116
and HT-29 by downregulating miR-21 and reinstating PTEN expres-
sion (Roy et al., 2013).
Sulforaphane (SFN), one of the most potent active anticancer
compounds found in cruciferous vegetables such as cabbage, kale,
and brussels sprouts, causes significant inhibition of mir-21 in RKO
human colorectal cancer (CRC) cells and subsequently downregulates
epigenetically regulated highly cancer-associated human telomerase
reverse transcriptase (hTERT) gene expression, which might be due to
the inhibition of p-Akt pathways by mir-21 induced overexpression of
the tumor suppressor PTEN (Martin et al., 2018).
Similarly, indole-3-carbinol (I3C), a phytochemical derived from
cruciferous vegetables, in combination with gemcitabine (chemother-
apy drug), enhanced apoptosis and improved chemosensitivity in
human pancreatic cancer cells (Panc-1). Such improvement could be
explained by the miR-21-induced upregulation of PDCD4 (Paik
et al., 2013). I3C-mediated downregulation of miR-21 was also
reported in the hepatocellular carcinoma (HCC) xenograft model and
HCC cell culture (X. Wang et al., 2015). Additionally, previous studies
evidenced that I3C can reverse the expression of miR-21 induced by
vinyl carbamate (VC) that were inversely correlated with the expres-
sion of PTEN, PDCD4, and RECK in mouse lung tissues and A549
human lung cancer cells (Melkamu et al., 2010).
Also, garcinol is a potent anticancer phytochemical derived from
the plants of the genus Garcinia, and when a combination of garcinol
and gemcitabine is applied to the pancreatic cancer cells (PaCa)
Panc-1, a synergistic effect via modulating the miR-21 was noticed
that causes the inhibition of cell proliferation and induce apoptosis
(Parasramka et al., 2013). Moreover, it was also demonstrated that
miR-21 target transcripts are involved in various cancer-associated
FIGURE 4 miR-21-mediated anticancer functions of phytochemicals. One of the most extensively studied oncogenic miRNAs, miRNA-21,
affects human health by modulating the mRNA expression of crucial cancer genes, while several phytochemicals exert anticancer effects by
modulating miR-21 expression levels [Colour figure can be viewed at wileyonlinelibrary.com]
RUIZ-MANRIQUEZ ET AL.11
pathways, including cytokine receptor, apoptosis, TGF-β, MAPK, Jak–
STAT signaling, VEGF, Notch, and mTOR, and focal adhesion path-
ways (Parasramka, Ho, Williams, & Dashwood, 2012).
Resveratrol (trans-3, 49, 5-trihydroxy-tilbene), a polyphenolic
antioxidant found in grapes, red wine, and peanuts (Ko et al., 2017;
Samec et al., 2019), can downregulate the oncogenic miR-21 in
Panc-1, CFPac-1, and MIA Paca-2 pancreatic cancer cells, and rat C6
glioma cells exerting enhanced apoptosis induction via suppression of
the antiapoptotic Bcl-2 protein (P. Liu et al., 2013; X. Wang
et al., 2015). Likewise, in DU145 and LNCaP, prostate cancer cells,
resveratrol can suppress the expression of miR-21, presumably by
inhibiting STAT3; more precisely, by interfering with the STAT3/miR-
21 pathway resveratrol could block the IL-6-mediated down-
regulation of PDCD4 and prostate cancer-associated transcription
29/PCAT29 (a putative tumor suppressor gene), thus reducing tumori-
genesis (Al Aameri et al., 2017).
Berberine, a phenanthrene alkaloid isolated from the plants of the
genus Berberis, was documented to attenuate tumor growth in vivo in
the mice model (Lin et al., 2017). Further research showed that down-
regulating the miR-21 berberine can reduce the oncogenicity such as
self-renewal, migration, aldehyde dehydrogenase 1 (ALDH1) activity,
and invasion capabilities of oral squamous cell carcinomas (OSCC)-
cancer stem cells (CSC) (Lin et al., 2017). Thus, berberine manifests
the potential to serve as an adjunct to traditional chemotherapy to
enhance oral cancer treatment. Similarly, Luo et al. (2014) demon-
strated that berberine could inhibit cell proliferation and induce apo-
ptosis in multiple myeloma RPMI-8266 and U226 cells via the
regulation of miR-21 and IL6/STAT3 signaling pathway, which might
increase PDCD4 expression and suppress the p53 signaling pathway.
Nimbolide, a principal limonoid constituent of the neem tree
(Azadirachta indica), was reported to show chemotherapeutic effect
via triggering the RECK expression by targeting the miR-21 and HIF-
1α, which in turn results in the inhibition of tumor development and
progression by downregulating the expression of matrix
metalloproteinases (MMPs), a typical negative target for oncogenic
signals in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced ham-
ster buccal pouch (HBP) carcinogenesis model (Kowshik et al., 2017).
α-solanine, a naturally occurring steroidal glycoalkaloid obtained
from the nightshade (Solanum nigrum Linn.) plant, exhibited an inhibi-
tory effect on the human prostate cancer PC-3 cells in a dose-
dependent manner (Shen et al., 2014), accompanied by the reversal of
epithelial-mesenchymal transition (EMT) (a process in which epithelial
cells lose their cell polarity and cell–cell adhesion and acquire migra-
tory and invasive qualities, which might occur in the initiation of
metastasis) by upregulation of PTEN, and the induction of RECK
expression feasibly caused by the downregulation of miR-21.
Isoliquiritigenin (IS), a flavonoid found primarily in licorice root,
suppressed invasion of Hs-578T and MDA-MB-231 breast cancer
cells by upregulating RECK and downregulating miR-21 with the con-
sequent reduction in the expression and enzymatic activities of
MMP9 (Ning et al., 2016). IS was also documented to reduce the
expression of primary and mature miR-21 and decreased the signaling
activity of STAT3 in breast cancer cells (Ning et al., 2017).
Silibinin, a natural polyphenol and active component of milk this-
tle (Silybum marianum) fruit, was shown to suppress miR-21 expres-
sion in erlotinib-resistant NSCLC xenografts linked with a reversal of
EMT and repression of mesenchymal markers (SNAIL, ZEB, N-
cadherin) (Cufí et al., 2013). Silibinin has also been reported to signifi-
cantly decrease MCF-7 breast cancer cells' proliferation by down-
regulation of miR-21 and induced apoptosis of its targets such as BID
and CASP-9 through intrinsic and extrinsic pathways (Zadeh
et al., 2016).
The oral administration of Primula farinosa plant-derived com-
pound flavone 3,6-dihydroxyflavone (3,6-DHF) was found to inhibit
1-methyl-1-nitrosourea (MNU) induced breast carcinogenesis in mice
by downregulating the miR-21 (Hui et al., 2012). Further study rev-
ealed that miR-21 suppression significantly enhanced the effect of
3,6-DHF on Notch-1 and PTEN, consequently suppresses the PI3K/
Akt/mTOR signaling pathway in breast carcinogenesis (Peng
et al., 2015).
Evidence suggests that miR-21 is an oncogenic miRNA that con-
trols several cancer-related downstream effectors, and its over-
expression is linked to a variety of cancers. All the reports mentioned
above showed that a number of phytochemicals have the ability to
exert anticancer effects by modulating the dysregulated oncomiR-21.
Thus, it could be used as a diagnostic and prognostic biomarker for
various malignancies and a therapeutic target in the future.
2.1.2 | miR-200 family
The miR-200 family comprises five different miRNAs distributed into
two different clusters located in two different genomic regions. For
instance, cluster I includes miR-200b, miR-200a, and miR-429, and it
is located in an intergenic region along chromosome 1, while cluster II
consists of miR-200c and miR-141 and is located in chromosome
12 (Humphries & Yang, 2015). The expression of this mRNA family
can be controlled by alterations and interactions with their promoters.
Several studies have suggested that in cancer, the modifications to
the promoter regions of the miR-200 clusters might cause its loss of
expression. In the promoter region of cluster I, it has been shown to
be principally silenced through polycomb group-mediated histone
alterations, while the promoter region of cluster II has been demon-
strated to be hypermethylated (Lim et al., 2013). The miR-200 family
is another most commonly studied miRNAs in cancer due to its impli-
cations in initiation, metastasis, diagnosis, and treatment
(Humphries & Yang, 2015).
Ayan et al. (2020) conducted a study in order to demonstrate the
anticarcinogenic effects of bioactive compounds of Syrian rhubarb
(Rheum ribes L.) alone and in combination with the chemotherapeutic
agent 5-FU in two human colorectal cancer cell lines, HCT 116 and
HT-29, as well as its relationship with the miR-200 family. Their study
showed that among all the extracts that derived from Rheum ribes L.,
root methanol extract (RM) was the one with the highest phenolic and
flavonoid contents; therefore, they used it alone as well as in combi-
nation with 5-FU to observe the expression levels of miR-200a, miR-
12 RUIZ-MANRIQUEZ ET AL.
200b, and miR-200c. In HCT 116 cells, the highest levels of miR-200a
and miR200b were determined with the combination of RM +5-FU,
while in HT-29 cells, the highest levels of the three miRNAs were
observed with only the RM treatment. Besides, they investigated the
expression levels of the genes targeted by the miR-200 family and
other pathways associated with these genes, and they found that RM
treatment caused more obvious changes in cell cycle, apoptosis, and
EMT-correlated genes in HT-29 cells; on the other hand, in HCT
116 cells, RM and RM +5-FU treatments had similar changes in the
expression of the cell cycle, apoptosis, and EMT-related genes, while
RM treatment was the most effective in the suppression of TGF-β
pathway. Moreover, they observed a significant suppression of crucial
genes such as GATA4, BCL-2, and ZEB1, direct or indirect targets of
the miR-200 family. Finally, they concluded that cancer cells respond
better to only RM or RM +5-FU treatment than only 5-FU
treatment.
Venkatadri et al. (2016) also documented a significant down-
regulation of miR-200c-3p in the resveratrol-treated MDA-MB-231
breast cancer cells. Besides, they noticed a dose-dependent down-
regulation of antiapoptotic proteins, such as X-linked inhibitor of apo-
ptosis protein (XIAP) and Bcl-2, as well as cell cycle proteins that
include CDK6, CDK4, and CDK2. These findings demonstrated that
resveratrol exerts a key modulation of apoptotic miRNAs crucial in
breast cancer cell death. Similarly, due to the poor oral bioavailability
of resveratrol, J. Fu et al. (2019) conducted a study with resveratrol
derivative triacetyl resveratrol (TCRV) in two pancreatic cancer cell
lines (AsPC-1 and PANC-1) and searched for its relationship with the
miRNA-200 family. They found that in both cell lines, TCRV induced
apoptosis through caspase-3 activity. They also examined the molecu-
lar mechanisms behind the EMT process and found that TCRV increased
E-cadherin expression and simultaneously inhibited N-cadherin and
vimentin expression in both the cell lines. Additionally, TCRV treatment-
induced miR-200a, miR-200b, and miR-200c expression and inhibited
EMT-associated transcription factor Zeb1in AsPC-1 cells. These data
suggest that targeting the Zeb1-miR-200 feedback loop might be the
key strategy for a possible treatment of pancreatic cancer.
Although recent studies on the miR-200 family have yielded
encouraging results, additional research is needed to comprehend the
family's function in cancer fully. Future research into the miR-200
family may aid in a better understanding of how miR-200s impact can-
cer development, metastasis, and recurrence. Because so much
research has concentrated on the influence of entire clusters/groups
on metastasis, additional research on individual members of the miR-
200 family is needed better to understand their function in each stage
of carcinogenesis.
2.1.3 | miR-155
miR-155 is a common oncomiR that derives from the conserved
region of the MIR155HG gene of chromosome 21 locus and is usually
found upregulated in several types of cancers, including glioma, lung
cancer, colorectal cancer, breast cancer, bladder cancer, among others
(Bayraktar & Van Roosbroeck, 2018; H. Z. Zhu et al., 2020). Abtin
et al. (2018) found that in the MCF-7 cell line, olive-derived polyphe-
nol oleuropein can downregulate miR-155 expression leading to cell
proliferation and increment of apoptosis. The main target gene of
miR-155 is TP53INP1, which is known to play a significant role in cell
cycle arrest and p53-mediated apoptosis and whose downregulation
is associated with a poor prognosis, metastasis, and progression of
breast cancer. Additionally, FADD is an important apoptotic gene that
has been known to be downregulated in several types of cancers and
hence classified as a cancer driver gene. FADD is a direct target of
miR-155, and oleuropein-induced upregulation of FADD in breast
cancer cells indicated its possible regulation by miR-155. This study
suggested that the use of oleuropein as a preventive agent of breast
cancer is feasible; however, the application of this phytochemical as a
therapeutic agent needs to be further investigated (Abtin et al., 2018).
De la Parra et al. (2016) investigated the effect of soy isoflavone
genistein on MDA-MB-435 and Hs578t breast cancer cell lines, and
they noticed a significant downregulation of miR-155 expression,
which in turn negatively regulates its important target transcripts,
including the proapoptotic forkhead family transcription factor
(FOXO3), PTEN, and CK1αcausing an induction of apoptosis and
reduction of cell viability.
miR-155 has been shown to have a role in cancer therapy resis-
tance, including chemo and radiation, and its suppression by some
phytochemicals has been demonstrated to resensitize tumors to con-
ventional treatments. Taken together, miR-155 could be a promising
new target to treat a variety of human malignancies, and its role in
cancer therapy resistance makes it a good candidate for combination
treatments. Nevertheless, to support this idea, formal preclinical and
clinical research is required.
2.1.4 | miR-224
miR-224 is also considered one of the most common cancer-
associated miRNA or oncomiR, and its anomalous expression leads to
the development of human malignancies and tumorigenesis (D. Zhu
et al., 2014). It was demonstrated that miR-224 targets apoptosis
inhibitor 5 (API-5), whose downregulation increases the apoptosis of
Hep G2 cells (Y. Wang et al., 2008). Pu et al. (2018) conducted a study
to demonstrate the function of luteolin in regulating gastric cancer
(GC) cell migration, proliferation, and invasion and its role in the mod-
ulation of diverse signaling pathways and miRNAs. The results
showed that luteolin regulates the GC cell cycle, proliferation, colony
formation, migration, invasion, and apoptosis. Moreover, luteolin
inhibits MMP-2, MMP-9, vimentin, cyclin D1, cyclin E, and Bc12 and
promotes E-cadherin expression. It was also demonstrated that
luteolin treatment increased p-P38 signaling and decreased p-Akt, p-
STAT3, p-PI3K, Notch1, p-mTOR, and p-ERK involved in the biological
effects of MKN45 and BGC823 GC cells. Furthermore, after luteolin
treatment, the miR-224 expression was significantly downregulated,
indicating that luteolin regulates the expression of diverse miRNAs
associated with the biological function of GC.
RUIZ-MANRIQUEZ ET AL.13
2.1.5 | miR-17 cluster
miR-17 oncogenic family is a group of miRNAs and comprises six
miRNAs: miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1, and miR-
92a-1, implicated in all three cancer stages: tumor initiation, progres-
sion, and metastasis since it targets several tumor suppressor genes,
such as PTEN, ATG7, LKB1, CYP7B1, and PHLPP2 (Kumar
et al., 2017). Kumar et al. (2017) investigated the ability of resveratrol
and pterostilbene (natural analog of resveratrol found in grapes and
blueberries) to reverse the overexpressed miR-17-mediated inhibition
of PTEN in DU145 and 22Rv1 prostate cancer cells, and they found
that both resveratrol and pterostilbene can downregulate the expres-
sion of miR-17 and miR-20a, another member of the miR-17 92
cluster, and upregulate PTEN expression. Additionally, it was found
that pterostilbene treatment can reduce tumor growth in xenografts
by suppressing the expression of serum miR-17 leading to cell apopto-
sis (Kumar et al., 2017).
2.1.6 | miR-92a
Dysregulation of miR-92a targeting tumor suppressor proteins has
been found in several cancers, including gastric cancer (Shin
et al., 2018), indicating that miR-92a acts as an onco-miRNA. Sasa
quelpaertensis Nakai leaf phytochemicals were previously reported to
have the potential to suppress the proliferation of human gastric can-
cer cell lines such as MKN-74, MKN-45, SNU-1, and SNU-16
(M. G. Jang et al., 2018). Recently, M. G. Jang, Ko, and Kim (2020)
studied precisely the effect of ethyl acetate fraction (EPRE) of Sasa
quelpaertensis Nakai leaf in the miRNA profile of SNU-16 cells, and
they found a significant downregulation of miR-92a-1-5p that might
induce the anticancer effect by targeting EP4/Notch1 axis (Shin
et al., 2018).
2.1.7 | miR-18a
The association of miR-18a has been noticed in various types of can-
cers. P. Wang, Du, et al. (2016) demonstrated that Ginsenoside Rd
(Rd) found in Panax notoginseng possesses antimetastatic effects both
in cultured 4 T1 cells and in tumors related to this breast cancer cell
line. This assertion is supported since Rd treatment hampers 4 T1 cell
migration in vitro as well as in vivo. Additionally, it was shown that
Smad2, whose knockdown causes an aggressive metastatic process in
human breast cancer, is a direct target of miR-18a, and when Rd is
applied into 4 T1 cells, a downregulation of miR-18a has been noticed,
which negatively regulates the expression of Smad2 and diminishes
breast cancer metastasis. Furthermore, TGF-β1 expression, which is
known to be positively correlated to breast cancer's metastasis and
usually overexpressed in human breast cancer, was decreased by
Rd. These results open the possibility for future studies on Rd as a
therapeutic tool against breast cancer metastasis (P. Wang, Du,
et al., 2016).
2.2 |Tumor suppressor miRNAs
2.2.1 | miR-34
miR-34 is a tumor suppressor miRNA family comprised of three
members: miR-34a, miR-34b, and miR-34c (L. Zhang, Liao, &
Tang, 2019). Interestingly, its expression has been shown to drasti-
cally diminished in various cancer types, while its reactivation has
been reported to prevent cancerous activities (L. Zhang, Liao, &
Tang, 2019). miRNA-34 is reported to induce cell cycle arrest in the
G1 phase and improve apoptosis by suppressing cyclin E2, CDK4,
CDK6, c-Myc, E2F transcription factor 3 (E2F3), and BCL-2 (Otsuka
et al., 2018).
In colorectal cancer cell lines HCT-116 and HT-29, resveratrol
has been demonstrated to inhibit cell viability and promote apoptosis
and cell-type-dependent cell cycle arrest via upregulating miR-34c
expression. HT-29 cells treated with resveratrol showed a prominent
induction of miR-34c and p53 and inactivation of PI3K/Akt signaling
(S. Yang et al., 2015). Similarly, Kumazaki et al. (2013) studied the
influence of resveratrol in human colon cancer cell lines DLD-1,
SW480, and COLO20, as well as two drug-resistant DLD-1 cell lines,
and their results revealed that miR-34a overexpression after resvera-
trol treatment negatively regulates the target genes E2F3 and Sirt1
and induce apoptosis even in the DLD-1 cell lines. Additionally,
Otsuka et al. (2018) demonstrated the role of resveratrol in
suppressing the proliferation of breast cancer MDA-MB-231 and
MCF7 cell lines by upregulating miR-34a via p53. Another study
stated that resveratrol inhibits hypoxia-induced migration and inva-
sion by upregulating miR-34a and perhaps altering the levels of phos-
phorylated signal transducer and activator of transcription 3 (p-
STAT3) in glioma U87 and U251 cell lines (H. Wang, Feng, &
Zhang, 2016).
Likewise, Guo et al. (2013) demonstrated that a combined admin-
istration of curcumin and emodin, an active component isolated from
Rheum palmatum, synergistically inhibits proliferation, survival, and
invasion of breast cancer cells MDA-MB-231 and MDA-MB-435 by
upregulating the miR-34a, which diminutions the expression levels of
Bcl-2 (an apoptosis regulator) and Bmi-1 (an apoptosis and self-
renewal of adult stem cells regulator) protein levels.
Toden et al. (2015) found that 3 acetyl-11-keto-b-boswellic acid
(AKBA), a potent anti-inflammatory compound derived from Boswellia
serrata, exerts a significant synergistic effect along with curcumin
against tumor growth through upregulating the miR-34a and
dysregulating its target genes such as cMyc, cyclin D1, CDK4, CDK6,
and Bcl-2 in HCT116, RKO, SW480, SW620, HT29, Caco2, and
HCT116p53/cells and mouse models. This suggested that due to
the heterogeneous nature of cancer, the combination of anti-
tumorigenic compounds might be the more effective cancer therapeu-
tic strategy (Toden et al., 2015). Interestingly, by using the same cell
lines, Roy et al. (2012) previously demonstrated that CDF resulted in
the highly effective re-expression of miR-34a and miR-34c, which
subsequently reduced the expression of its target gene Notch-1, thus
contributing to cancer treatment.
14 RUIZ-MANRIQUEZ ET AL.
Luteolin is a nontoxic flavonoid compound extracted from stems
and leaves of mignonette (Reseda odorata) known for its anti-
carcinogenesis properties (Ganai et al., 2021). Wu et al. (2015) docu-
mented that luteolin downregulates prosurvival Bcl-2 expression by
upregulating miR-34a in gastric cancer tissue, consequently inhibiting
proliferation and promoting apoptosis.
Similarly, Hargraves et al. (2015) discovered that the phytochemi-
cal artemisinin extracted from the sweet wormwood plant triggers the
miR-34a expression, which negatively regulates its target gene CDK4
in breast cancer MCF-7 (expressing wild-type p53) and T47D
(expressing mutant p53) cell lines. In the same study, they observed a
p53-independent mechanism that elevates miR-34 expression,
enlightening the possibility that miR-34a levels could be increased by
expressing a mutant or null phenotype of p53. Nevertheless, the
phytochemical-mediated regulation of miR-34a levels is highly rele-
vant since it has been associated with breast cancer cell proliferation
and migration, chemotherapy resistance, metastasis disruption, apo-
ptosis, and inhibition of target genes such as the receptor tyrosine
kinase AXL and transmembrane receptor Notch-1. (Deng et al., 2014;
X. J. Li et al., 2012; MacKiewicz et al., 2011; C. H. Yang et al., 2013).
Diallyl disulfide (DADS) is an organosulfur phytochemical found in
garlic that has been demonstrated to have antitumor effects in many
tumor cells types such as neuroblastoma, breast cancer, colon cancer,
skin cancer, and gastric cell lines (Xiao et al., 2014). A study by Xiao
et al. (2014) showed that DADS upregulates miR-34a expression
levels in the breast cancer MDA-MB-231 cell line and xenografts
models, inhibiting its target proto-oncogene SRC, which regulates key
cellular processes such as proliferation, survival, adhesion, motility,
and causes the suppression of Ras-GTP and phosphorylated-
extracellular signal-regulated kinase 1/2 (ERK1/2). This information
indicates that DADS might inhibit breast cancer cell migration and
invasion via miR-34a mediated SRC/Ras/ERK suppression.
Imani et al. (2017) noticed a synergistic effect of thymoquinone, a
molecular component of black seeds of Nigella sativa, and miR-34a in
metastatic breast cancer BT-549 cell line where these molecules
together inactivated the EMT signaling pathway by downregulating
and targeting TWIST1 and ZEB1. This information suggests a thera-
peutic potential of miR-34a and thymoquinone against tumor growth
and migrations.
Obesity has been related to breast cancer risk, progression, and
prognosis (Argolo, Hudis, & Iyengar, 2018). High levels of leptin asso-
ciated with obesity promote breast tumor growth and metastasis by
stimulating breast cancer cell proliferation, invasion, migration, and
angiogenesis (Samad & Rao, 2019). In this context, Avtanski
et al. (2015) studied the potency of honokiol (HNK), a natural phenolic
compound isolated from Magnolia grandiflora, inhibiting oncogenic
effects of highly-active leptin signaling related to obesity in MCF-7,
MDA-MB-231, MDA-MB-468, and T47D cell lines as well as in
mouse models. Results revealed that HNK inhibits the growth of
breast cancer cells induced by leptin, as it inhibits the expression of
leptin-induced Wnt1, MTA1, and β-catenin both in vivo and in vitro
through the upregulation of miR-34a.
Genistein is a natural isoflavone chemopreventive agent found in
soybeans and other plants (Q. Zhang et al., 2019). Xia et al. (2012)
revealed that pancreatic cancer (PC) cell lines AsPC-1 and MiaPaCa-2
treated with genistein displayed an overexpression of miR-34a, which
therefore downregulated Notch-1, leading to induction of apoptosis
and inhibition of cell growth, invasion, and induction self-renewal
capacity of cancer stem cells. Likewise, Chiyomaru et al. (2013) stud-
ied the influence of genistein in PC cells, using PC3 and DU145 and
nude mouse models, and they showed that HOX transcript antisense
RNA (HOTAIR) gene, which tends to be highly expressed in various
cancer types, was highly regulated by genistein, especially in
castration-resistant PC cells. The downregulation of HOTAIR was
associated with a decrease in cell migration, proliferation, and invasion
and an induction of apoptosis and cell cycle arrest. Interestingly,
genistein-induced miR-34a overexpression was thought to target and
downregulate HOTAIR expression directly.
Capsaicin, a homovanillic acid derivative in chili pepper, has been
reported to have in vitro anticancerous effects on several types of
cancer cells such as prostate, colon, gastric, hepatic, and leukemic
without harming healthy cells (Chakraborty et al., 2014). It was found
that capsaicin treatment in lung cancer A549 cell line leads to activa-
tion of p53, which in turn triggers the miR-34a expression. Conse-
quently, the upregulated miR-34 inhibits the expression of its target
gene Bcl-2 and thus decreases the survival advantage of NSCLC cells,
creating a proapoptotic environment by initiating a mitochondrial
death cascade that involves caspase-9 and -3. These findings suggest
that capsaicin might play an essential role in the therapy of human
drug–resistant NSCLCs.
Pomegranate (Punica granatum) has been reported to have antip-
roliferative and apoptosis ability against various tumor cells primarily
due to its ellagic acid (EA) content (Sayeed et al., 2017). Zhou
et al. (2015) investigated the effect of pomegranate rind extract (PRE)
on human bladder carcinoma EJ cell line as well as normal rat urinary
bladder epithelial (RUBE) cells, and they found that the expression of
p53 which is usually suppressed in bladder cancers was reversed after
PRE exposure along with the upregulation of miR-34a, suggesting that
EA induced miR-34a might inhibit cancer proliferation via induction of
p53 expression.
MiR-34 has been recognized as a novel diagnostic, prognostic,
and predictive biomarker for cancer. In addition, the restoration of
miR-34 levels may synergize with phytochemical-mediated treatment
to take advantage of both therapeutic approaches to improve cancer
treatment as well as achieve a more favorable clinical outcome in can-
cer patients.
2.2.2 | Let-7 family
Ten members of the let-7 family (let-7a, let-7b, let-7c, let-7d, let-7e,
let-7f, let-7g, let-7i, miR-98, and miR-202) have been identified in
humans (Thammaiah & Jayaram, 2016). Several cancer biologists have
demonstrated that the expression of let-7 is significantly down-
regulated or lost in different cancers, and it has been currently impli-
cated in a variety of approaches for therapy and diagnosis (Chirshev,
Oberg, Ioffe, & Unternaehrer, 2019). Many phytochemicals have been
shown to act on this family of miRNAs regulating its expression.
RUIZ-MANRIQUEZ ET AL.15
Nwaeburu et al. (2016) executed a miRNA profiling of pancreatic
ductal adenocarcinoma following quercetin treatment, and they found
that a significantly upregulated let-7c in AsPC-1, ASANPaCa, and
Panc-1 pancreatic cancer cells activates the Notch-inhibitor Numbl by
inhibiting the Notch as a target highlighting the anticancer functions
of quercetin as tumor suppression. Likewise, when used with green
tea catechins (GTC), quercetin was shown to enhance the expression
of let-7a in MIA-PaCa2, BxPC-3, and PacaDD-183 pancreatic cancer
cells, followed by K-ras inhibition and hindering the advancement of
pancreatic cancer (Appari et al., 2014). EGCG is also reported to
upregulate the expression of miRNA-let-7b and inhibit tumor growth
by activating 67 kDa laminin receptors (67LR) signaling in B16 mela-
noma cells (Yamada et al., 2016).
Likewise, Y. Li et al. (2009) reported that DIM and isoflavone
G2535 (a combination of genistein with other isoflavones) induces
the overexpression of let-7 family members (let-7b, let-7c, let-7d, let-
7e), which in turn downregulate the expression of ZEB1 leading to
EMT and enhanced chemosensitivity in gemcitabine-resistant pancre-
atic cancer cells. Additionally, lycopene, the most effective oxygen
radical reducing agent found in fruits and vegetables, constrains the
growth of various cancer cells (Ono, Takeshima, & Nakano, 2015).
D. Li et al. (2016) demonstrated that lycopene exerts an anticancer
effect against prostate cancer by upregulating the expression of miR-
let-7f-1 in PC3 cells and by downregulating the expression of AKT2.
Takahashi et al. (2012) reported that AKBA has an anticancer role in
HCT116, HT29, SW480, and SW620 colorectal cancer cells. In those
cells, AKBA inhibits cell viability, colony formation, proliferation, and
migration while increasing apoptosis. The regulation of let-7 miRNA
partly mediates this anticancer effect. Let-7b and let-7i expression are
increased by AKBA, while expression of relevant target genes impli-
cated in EMT, such as CDK6 and Vimentin, is decreased. As a result,
AKBA-mediated modulation of the let-7 family could be critical in
preventing colorectal cancer metastasis.
Due to a significant association between the let-7 family and car-
cinogenesis, this family could be a potent phytochemical-based
theranostic target for patients suffering from various cancers. How-
ever, to get a deeper insight into the therapeutic efficacy of this fam-
ily, a better understanding of the precise mechanism is required.
2.2.3 | miR-218
miR-218 is a tumor suppressor miRNA that is downregulated in can-
cer tissues compared to the adjacent healthy epithelium. miR-218 is a
vertebrate-specific intronic miRNA generated from two separated loci
located on chromosomes 4p15.31 and 5q35.1 (P. Y. Yang
et al., 2017). It has been reported that miR-218 targets oncogenic
genes, which leads to the inhibition of cell proliferation and invasion
(Yamamoto et al., 2013). P. Y. Yang et al. (2017) investigated the
effect of andrographolide, a diterpene lactone extracted from the
leaves of the Asian-native plant Andrographis paniculate, on miR-218
in oral cancer stem cells (OCSC), and they found that andrographolide
can trigger the expression of miR-218 in OCSC, which in turn
negatively regulates its oncogenic target gene B-cell-specific Moloney
murine leukemia virus integration site 1 (Bmi1).
2.2.4 | miR-122
miRNA-122-5p is a tumor-suppressive miRNA commonly down-
regulated in several types of cancer such as breast cancer, hepatic
cancer, gallbladder carcinoma, and bladder cancer (X. Xu et al., 2018).
miR-122-5p was reported to be significantly upregulated and have a
key role in MDA-MB-231 breast cancer cells in response to resvera-
trol, affecting apoptosis, cell viability, Bcl-2, XIAP proteins expression,
as well as cell cycle progression (Venkatadri et al., 2016).
2.3 |Dualistic role of miRNAs—Tumor suppressors
and oncogenic
2.3.1 | miR-16
miR-16 is an important miRNA located at chromosome 13q14, and its
aberrant expression is associated with different cancers (Cui, 2015).
Interestingly, depending on cancer types miR-16 acts either as the
tumor suppressor or as the promoter. For example, in lung cancer,
breast cancer, and glioma, miR-16 is noticeably downregulated and
acts as a suppressor, while in the case of renal cell carcinoma, gastric
cancer, and pancreatic cancer, it acts as an oncomiR to develop the
tumors (X. Fu et al., 2018; Jiao, Wang, & Wang, 2018).
J. Yang et al. (2010) reported that in curcumin-treated human
breast adenocarcinoma MCF-7 cells, the overexpressed miR-16 nega-
tively regulates its target Bcl-2 inducing apoptosis. Pure curcumin was
also reported to upregulate the expression of miR-16-1 in K562 and
HL-60 leukemic cells leading to the suppression of WT1 (Wilms'
tumor protein 1) and promoting the antiproliferation and antitumor
effect (Gao et al., 2012).
Similarly, EGCG, the primary polyphenol of green tea (Filippini
et al., 2020), was shown to induce apoptosis in the hepatocellular car-
cinoma HepG2 cell lines triggering the expression of miR-16 and
suppressing its target antiapoptotic protein Bcl-2 (Tsang &
Kwok, 2010). Likewise, J. Y. Jang et al. (2013) also found that EGCG
induces the upregulation of miR-16 in 4 T1 murine breast cancer cells
and tumor exosomes. It has been assumed that miR-16 might act as a
negative regulator of NF-κB by inhibiting IKKαexpression, which con-
tributes to the ability of miR-16 as a tumor suppressor miRNA
preventing the survival and proliferation of tumor cells (J. Y. Jang
et al., 2013).
According to Hagiwara et al. (2012), resveratrol stimulates the
activity of AGO2, a central RNA interference (RNAi) component,
which thus inhibits stem-cell-like features of breast cancer by enhanc-
ing the expression of several tumor-suppressive miRNAs, including
miR-16, in different breast cancer cell lines. Likewise, Azimi et al. (2015)
demonstrated that resveratrol induces apoptosis in a time and dose-
dependent manner in acute lymphoblastic leukemia CCRF-CEM cells
16 RUIZ-MANRIQUEZ ET AL.
by inducing the expression of miR-16-1 with BLC2 as the most crucial
target gene.
Quercetin, a flavonoid derived from fruits and vegetables, such as
berries, apples, onions, and broccoli, is a potential chemopreventive
agent with limited cytotoxicity in normal cells (Chirumbolo, 2013; Nam
et al., 2016; Russo et al., 2014). Sonoki et al. (2015) reported that quer-
cetin partially prevents tumorigenesis via upregulation of miR-16 and
suppression of claudin-2 in A549 lung adenocarcinoma cells.
Finally, paeoniflorin, one of the active ingredients extracted from
the medicinal plant Paeonia lactiflora, exhibits anticancer properties.
Paeoniflorin treatment significantly upregulated miR-16 expression
and reduced MMP-9 protein expression in U87 cells, exerting antican-
cer effects against human glioma cells, promoting the inhibition of cell
proliferation and accelerated cell apoptosis (W. Li et al., 2015).
Aberrant expression of the miR-16 family in several tumors has
recently been discovered, suggesting a link between miR-16 and cancer.
However, a number of phytochemicals were found to successfully mod-
ulate the expression of this family, leading to hinder cancer progression.
Nonetheless, more research and improvements are needed to substanti-
ate the clinical applicability of miR-16 profiling for cancer management.
2.3.2 | miR-221/222
miR-221/miR-222 cluster has been served both as a tumor suppressor
or oncogene, and their high expression has been associated with sev-
eral types of cancers (Abak, Amini, Sakhinia, & Abhari, 2018). Some of
the commonly reported targets of these miRNAs are KIT, p27(Kip1),
p57, and PTEN (Srivastava et al., 2015). Allegri et al. (2018) conducted
a study in order to know the effects of genistein, curcumin, EGCG,
and resveratrol in anaplastic thyroid carcinoma (ATC) cell lines
SW1736 and 8505C, as well as their effect on the expression levels
of miRNAs miR-221 and miR-222 since they are associated with thy-
roid cancer progression. EGCG was found to diminish miR-221
expression in both the cell lines, while resveratrol and genistein
induced both the miRNAs in 8505C and downregulate both in
SW1736. Interestingly, curcumin treatment showed a remarkable dec-
lination of both miR-221 and miR-222 in both cell lines, indicating it
as one of the best phytochemicals against thyroid carcinoma. Lewis
et al. (2019) conducted a study intending to know the molecular
crosstalk between suberoylanilide hydroxamic acid (SAHA) and miR-
221/222 cluster and their effects in triple-negative breast cancer
(TNBC) cells. SAHA is an FDA-approved histone deacetylase that is
commonly used in T cell lymphoma treatment. They noticed that
SAHA, in combination with EGCG, significantly reduced miR-221/222
expression in the MDA-MB-157 and HCC1806 cell lines and
upregulates estrogen receptor α(ERα) expression, which might lead to
limit the growth and proliferation in breast cancer cells.
2.3.3 | miR-186
miR-186 is another common cancer-associated miRNA located at the
chromosome band 1q31.1. Interestingly, miR-186 can either act as a
tumor suppressor or as an oncomiR and correlated to various tumor
biological behaviors, such as apoptosis, invasion, cell proliferation, cell
cycle, migration, intracellular metabolism, angiogenesis, and
lymphangiogenesis of tumors (Z. Wang, Sha, & Li, 2019). J. Zhang
et al. (2010) conducted a study to check the anticancer effects of cur-
cumin on A549 human lung adenocarcinoma cells, and they found
that curcumin represses A549 cell proliferation and induces apoptosis
in a time and quantity-manner via the downregulation of miR-186*
expression. Furthermore, they predicted three target genes (caspase-
10, myc, and bc19) for miR-186*, related to cell proliferation and apo-
ptosis. Nonetheless, caspase-10 was found to have a more significant
effect since its expression levels were increased in A549 cells trans-
fected with curcumin-treated miR-186. Besides, they also noticed that
miR-186 diminished the expression levels of the proapoptotic
purinergic receptor, P2X7. Therefore, it can be concluded that miR-
186* plays a crucial role in the apoptosis and growth of lung cancer
cells, indicating its importance in lung cancer development (J. Zhang
et al., 2010).
3|PHYTOCHEMICALS-MEDIATED
MODULATION OF DIFFERENT lncRNAs IN
CANCER
Dysregulation of lncRNAs also plays a crucial role in carcinogenesis
(P. Jiang, Wu, Wang, Huang, & Feng, 2016). Notably, recent studies
have shown a link between lncRNAs and tumor-associated proteins
regulated by herbal compounds, which might affect cancer incidence
and spread (Kalhori et al., 2021; Saghafi, Taheri, Parkkila, & Zolfaghari
Emameh, 2019). Moreover, phytochemicals have been found to signif-
icantly modulate several coding genes and lncRNAs by acting as epi-
genetic modifiers, which have a therapeutic and preventive action
against cancer (DNA methylation and histone modifications). Among
the most well-known lncRNAs reported to be influenced by phyto-
chemicals are ROR, MALAT1, PVT1, PANDAR, GAS5, PCAT29,
NEAT1, HOTAIR, H19, and MEG3 (Figure 5). Nevertheless, curcumin
is the most studied phytochemicals in lncRNA-associated cancer
research.
It has been revealed that when human prostate cancer stem cells
(HuPCaSC) were treated with curcumin, the expression of repro-
gramming regulator (ROR) and Oct4, a transcription factor that main-
tains proliferation and pluripotency, was inhibited by miR-145 (T. Liu
et al., 2017). The effect of curcumin relies on the “sponge effect”
made by lncRNA-ROR. The authors also stated that miR-145 has
binding sites on both ROR and Oct4 sequences and could effectively
hinder their expression, causing cell cycle arrest and hampering
HuPCaSCs proliferation and invasion (T. Liu et al., 2017).
Likewise, Shao et al. (2020) demonstrated how ROR controls the
suppressive effects of curcumin on HCC. They treated SMMC7721
and Huh-7 HCC cell lines with curcumin and observed a significant
downregulation of ROR expression, resulting in the inactivation of
Wnt/β-catenin signaling. It is well known that the Wnt/β-catenin
pathway plays a crucial role in organ formation, stem cell renewal, cell
proliferation, and cell survival, and its abnormal activation could lead
RUIZ-MANRIQUEZ ET AL.17
to tumorigenesis (Y. Zhang & Wang, 2020). Thus, curcumin showed
antiproliferative effects in HCC cells by inactivating the Wnt/β-
catenin pathway via ROR (Shao et al., 2020).
Additionally, curcumin can influence lncRNA metastasis-related
lung adenocarcinoma transcript 1 (MALAT1), which is generally highly
expressed in colon cancer tissues and tightly linked to the migration
of SW480 colon cancer cells and lower chemotherapeutic resistance.
Despite that, curcumin was demonstrated to be one of the inhibitors
of β-catenin, c-myc, and cyclin D1 in the Wnt/ß-catenin pathway
leading to the suppression of SW480 cell proliferation and invasion
(Dai et al., 2019).
The use of curcumin has also been reported in the sensitization of
chemoresistant PDAC (pancreatic ductal adenocarcinoma) cells. Cur-
cumin improves chemosensitivity in cancer cells by decreasing the
expression of the EZH2 subunit of crucial epigenetic mediator of can-
cer stem cells PRC2 and its associated lncRNA PVT1, a well-known
drug resistance inducer in PDAC, in gemcitabine-resistant BxPC3 and
Panc1 PDAC cell lines. Interestingly, PVT1 participates in DNA
rearrangements and interacts with c-Myc in various malignancies.
Given that PVT1 regulates myc expression, curcumin is predicted to
inhibit the PRC2-PVT1-c-Myc axis, resulting in gemcitabine sensitiza-
tion in chemoresistant tumors (Yoshida, Toden, Ravindranathan,
Han, & Goel, 2017).
Other lncRNAs that are influenced by curcumin include PANDAR,
MEG3, and GAS5. The PANDAR is a lncRNA that promotes
proliferation and migration and has been upregulated in various can-
cer types including bladder and colorectal cancers (Mishra
et al., 2019). Chen, Yang, Wang, and He (2017) revealed repression in
PANDAR expression with low-dose curcumin in DLD-1 cells com-
pared to the control group. Moreover, the silencing of PANDAR in
these cells augmented apoptosis and decreased senescence, possibly
by stimulating the expression of the p53-upregulated modulator of
apoptosis (PUMA), a proapoptotic gene.
By acting as a demethylation agent, curcumin can restore MEG3,
a tumor-suppressive lncRNA that appeared in various cancers, to nor-
mal levels in cells and extracellular vesicles (EVs) (J. Zhang, Liu, Xu, &
Li, 2017). EVs play a vital role since they can be released as exosomes
by ovarian cancer cells containing lncRNAs derived from the cyto-
plasm of the donor chemoresistant cell and be absorbed by other cells
modulating the chemosensitivity of the recipient cells (Von Schulze &
Deng, 2020). Overexpression of MEG3 in ovarian cancer cells' EVs
inhibits miR-214, lowering drug resistance in the recipient cells. Cur-
cumin restored MEG3 in cells and EVs, which substantially reduced
miR-214 in A2780cp cells, making this miRNA a highly possible target
of MEG3 since it induces cell survival by targeting the PTEN/Akt
pathway (J. Zhang et al., 2017).
GAS5 upregulated by curcumin in breast cancer promotes metas-
tasis inhibition, cell cycle arrest, and apoptosis activation. In MCF7,
MDA-MB231, and SKBR3 breast cancer cell lines, curcumin
nanoparticles dendrosomal curcumin (DNC) activates GAS5 promoter
FIGURE 5 Phytochemicals mediated regulation of lncRNAs in cancer. The potential anticancer effect of phytochemicals via regulation of the
expression of lncRNAs is shown. Red (downregulated) and green (upregulated) arrows indicate differential expression of each lncRNAs [Colour
figure can be viewed at wileyonlinelibrary.com]
18 RUIZ-MANRIQUEZ ET AL.
and induces apoptosis by blocking oncogenic signaling pathways
including MAPK and PI3K/PKB (Esmatabadi, Motamedrad, &
Sadeghizadeh, 2018). An overexpression of GAS5 was also noticed in
bladder cancer by the effect of gambogic acid decreasing T24 and EJ
cancer cells' viability and inducing apoptosis. By directly interacting
with E2F4, GAS5 efficiently inhibits the EZH2 transcription, an essen-
tial factor in regulating cell biological activity in bladder cancer,
resulting in overexpression of miR-101, thus confirming a negative
correlation between the level of GAS5 and the bladder tumor
(M. Wang et al., 2018).
Although curcumin is the most studied phytochemical in lncRNA-
associated cancer research, different other phytochemicals have also
been shown to affect the expression of lncRNAs. The prostate
cancer–associated transcript 29 (PCAT-29) is a lncRNA and a putative
tumor-suppressive gene whose poor expression has been related to
the induction of prostate tumors (Y.-H. Xu, Deng, Wang, &
Zhu, 2019). A low expression of PCAT-29 was caused by decreased
levels of PDCD4 and STAT3, which are downstream targets of miR-
21. In DU145 and LNCaP prostate cancer cells, resveratrol down-
regulates miR-21 expression likely by suppressing STAT3 and restor-
ing PDCD4 regulation. As a result of interfering with the STAT3/miR-
21 pathway, resveratrol can defeat IL-6 signaling while increasing
PCAT-29 expression and promoting its antitumor properties
(Al Aameri et al., 2017). A quercetin treatment in prostate cancer cells
significantly reduced the MALAT1 expression. Moreover, during pros-
tate cancer development, quercetin reduced EMT, increased apopto-
sis, and disrupted the PI3K/Akt signaling pathway, regulating
metabolism and cell proliferation. Thus, MALAT1 could be an essential
cancer treatment target (X. Lu, Chen, Yang, & Xing, 2020).
lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) has an
essential function in a variety of tumors. EGCG positively regulates it,
thus increasing the accumulation of CTR1 (copper transporter 1),
which induces a greater sensitivity of treatment with chemotherapy
drug cisplatin in NSCLC (A549, H460, and H1299) cells, cDDP-
resistant A549 cells, and a nude mouse xenograft model. Notably,
according to computational research, NEAT1 has the mir-98-5p com-
plementary binding site, which was expected to be a potential CTR1
target. NEAT1 can thus function as a competitive endogenous
lncRNA, leading the mir-98-5p sponge to upregulate EGCG-induced
CTR1 expression (P. Jiang et al., 2016). A recent study demonstrated
that EGCG therapy could boost ROS levels involved in cell prolifera-
tion, the emergence of malignancies, and the organism's immunity. In
NSCLC cells, EGCG regulates CTR1 by exerting its pro-oxidant prop-
erties. Moreover, ROS could suppress ERK1/2 while increasing
NEAT1, both of which are essential regulators of cell proliferation, dif-
ferentiation, migration, and apoptosis. Furthermore, it has been found
that EGCG therapy increased ROS levels, CTR1 expression, and
NEAT1 expression in tumor tissue in a nude mice xenograft model.
These findings disclosed a potential mechanism for EGCG-mediated
ROS to modulate CTR1 expression via the ERK1/2/NEAT1 signaling
pathway, expanding the possibilities for EGCG as a natural adjuvant
medicine for lung cancer (A. Chen et al., 2020). The NEAT1, on the
other hand, has been demonstrated to be a lncRNA that is typically
overexpressed in multiple myeloma cells, while resveratrol reversed
its negative effect hindering the cancer-associated Wnt/β-catenin sig-
naling pathway (Geng et al., 2018).
A study by Y. Huang et al. (2018) revealed that MCF7 breast can-
cer cells treated with pterostilbene exhibited inhibition of cell prolifer-
ation and EMT, as well as increased apoptosis, autophagy, and
endoplasmic reticulum (ER) stress. Pterostilbene upregulated the
expression of lncRNAs MEG3 and H19 and downregulated HOTAIR.
While in ovarian cancer cells, Ginsenoside 20 (S) -Rg3 repressed the
Warburg effect (one of the main metabolic features for cancers) via
the lncRNA H19/miR-324-5p/PKM2 pathway (X. Zheng et al., 2018).
Silibinin has been demonstrated to exert an anticancer effect in blad-
der cancer via significantly suppressing oncogenic HOTAIR expression
(Imai-Sumida et al., 2017). HOTAIR has also been elevated in NSCLC
cells, while miR-34a-5p expression was decreased (F. Zheng
et al., 2020). The authors demonstrated that the combination of ber-
berine and gefitinib inhibits the EMT process via a miR-34a-5p and
HOTAIR-mediated interaction.
As lncRNAs are crucial regulators of human chronic diseases,
numerous approaches have been made to target these RNA molecules
for therapeutic purposes (Arun, Diermeier, & Spector, 2018); among
those, phytochemical-mediated lncRNAs modulation in cancer pre-
vention and therapy was found promising (Saghafi et al., 2019). How-
ever, further in-depth research is required to understand the precise
molecular mechanism through which phytochemicals regulate
lncRNAs (Garcia-Oliveira et al., 2021).
4|CONCLUSION AND FUTURE
PERSPECTIVES
Despite several limitations, significant progress has been made in devel-
oping novel cancer-fighting approaches providing hope to millions of
patients. In this context, phytochemicals extracted from medicinal
plants and dietary sources have shown great potential against cancer.
Moreover, combinatorial approaches have revealed additive and/or
synergistic effects in treating certain cancers. Therefore, to augment
cancer treatment, phytochemicals can be utilized for therapeutic strate-
gies combined with well-established drugs. Phytochemicals are demon-
strated to show anticancer effects by controlling the expression of
tumor suppressors and oncogenic ncRNAs, and since ncRNAs vary in
length and mode of action, it is essential to develop comprehensive
genomic and functional tools to understand their regulatory activities
better. However, despite the encouraging results of the experimental
research, only a few clinical trials to evaluate the anticancer therapeutic
efficacy of these compounds are currently underway; hence, it is essen-
tial to perform phytochemistry research with the same rigor as conven-
tional medical research and large-scale, well-controlled clinical trials of
potential phytochemicals are indispensable. Furthermore, substantial
standardization of potential phytochemicals in terms of techniques for
assessing their bioavailability, efficacy, safety, quality, composition,
manufacturing processes, regulatory, and approval standards must be
carried out to reach the international standard.
RUIZ-MANRIQUEZ ET AL.19
CONFLICT OF INTEREST
The authors declare that there are no conflicts of interest.
DATA AVAILABILITY STATEMENT
The datasets generated during and/or analyzed during the current
study are available from the corresponding author on reasonable
request.
ORCID
Sujay Paul https://orcid.org/0000-0001-5024-7261
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How to cite this article: Ruiz-Manriquez, L. M., Estrada-Meza,
C., Benavides-Aguilar, J. A., Ledesma-Pacheco, S. J.,
Torres-Copado, A., Serrano-Cano, F. I., Bandyopadhyay, A.,
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S. (2021). Phytochemicals mediated modulation of microRNAs
and long non-coding RNAs in cancer prevention and therapy.
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