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IC50 of cisplatin-resistant lung cancer cells A549/DPP and the parental lung cancer cell line A549 for cisplatin. b Real-time PCR analysis of the relative expression of miR-451 normalized to U6 RNA in A549 and A549/DPP cells. Western blot c and real-time PCR d analysis of the expression levels of Mcl-1 in A549 and A549/DPP cells. Each bar represents the mean ± SEM. The results shown were repeated in three independent experiments. **P < 0.01, ***P < 0.001
Source publication
As one of the most widely used chemotherapy drugs for lung cancer, chemoresistance of cisplatin (DPP) is one of the major hindrances in treatment of this malignancy. The microRNAs (miRNAs) have been identified to mediate chemotherapy drug resistance. MiR-451 as a tumor suppressor has been evaluated its potential effect on the sensitivity of cancer...
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Background
Protein disulfide isomerase A6 (PDIA6), a member of the disulfide isomerase (PDI) family, has been reported to be closely associated with progression of various cancers. However, the specific effects of PDIA6 on gastric cancer (GC) remain unclear. In this study, we investigated the expression pattern and biological functions of PDIA6 in...
Gliomas, the most prevalent cancer in the central nervous system, are characterized by high morbidity and mortality, emphasizing the need to understand their etiology. Here, we report that cyclin‐dependent kinase‐like 5 (CDKL5) is highly expressed in gliomas, and CDKL5 over‐expression promotes invasion, proliferation, migration, and drug (β‐lapacho...
Background:
Gallbladder cancer (GBC) is a malignant tumor highly resistant to chemotherapy. MicroRNAs (miRNAs) are found extensively involved in modulation of carcinogenesis and chemoresistance. This study aimed to investigate cisplatin (DDP)-susceptibility regulated by expression of the miRNAs and underlying pathways in GBC.
Results:
The microR...
Objective To examine the effects of pachyman in combination with vinorelbine and cisplatin on tumor growth and the expression of epidermal growth factor receptor (EGFR) and K-ras in a mouse model of lung cancer induced using the human lung cancer cell line A549, and to investigate the molecular mechanisms underlying the antitumor effects of pachyma...
The resistance of cancer cells to the anti-cancer drugs is the most important reason that affecting the efficacy of the non-small cell lung cancer (NSCLC) chemotherapy; thus, to explore the underlying mechanism of drug resistance of NSCLC medications is urgently needed for improving the therapeutic efficacy of current anti-NSCLC chemotherapies. The...
Citations
... MiR-363-3p suppresses migration, invasion, and EMT by targeting NEDD9 and SOX4 in NSCLC [86]. MiR-451 inhibits NSCLC tumor cell growth and migration by targeting LKB1/AMPK [87] and ATF2 [88] and sensitizes NSCLC cells to cisplatin by regulating Mcl-1 [89]. MiR-99a suppresses EMT and stemness through the inhibition of two oncogenic proteins, E2F2 and EMR2 [90], and enhances radiation sensitivity by targeting mTOR in NSCLC [91]. ...
Simple Summary
This study identified a set of 73 microRNAs (miRNAs) that can accurately detect lung cancer tumors from normal lung tissues. Based on the consistent expression patterns associated with patient survival outcomes and in tumors vs. normal lung tissues, 10 miRNAs were considered to be putatively tumor suppressive and 4 miRNAs were deemed as oncogenic in lung cancer. From the list of genes that were targeted by the 73 diagnostic miRNAs, DGKE and WDR47 had significant associations with responses to both systemic therapies and radiotherapy in lung cancer. Based on our identified miRNA-regulated network, we discovered three drugs—BX-912, daunorubicin, and midostaurin—that can be repositioned to treat lung cancer, which was not known before.
Abstract
The majority of lung cancer patients are diagnosed with metastatic disease. This study identified a set of 73 microRNAs (miRNAs) that classified lung cancer tumors from normal lung tissues with an overall accuracy of 96.3% in the training patient cohort (n = 109) and 91.7% in unsupervised classification and 92.3% in supervised classification in the validation set (n = 375). Based on association with patient survival (n = 1016), 10 miRNAs were identified as potential tumor suppressors (hsa-miR-144, hsa-miR-195, hsa-miR-223, hsa-miR-30a, hsa-miR-30b, hsa-miR-30d, hsa-miR-335, hsa-miR-363, hsa-miR-451, and hsa-miR-99a), and 4 were identified as potential oncogenes (hsa-miR-21, hsa-miR-31, hsa-miR-411, and hsa-miR-494) in lung cancer. Experimentally confirmed target genes were identified for the 73 diagnostic miRNAs, from which proliferation genes were selected from CRISPR-Cas9/RNA interference (RNAi) screening assays. Pansensitive and panresistant genes to 21 NCCN-recommended drugs with concordant mRNA and protein expression were identified. DGKE and WDR47 were found with significant associations with responses to both systemic therapies and radiotherapy in lung cancer. Based on our identified miRNA-regulated molecular machinery, an inhibitor of PDK1/Akt BX-912, an anthracycline antibiotic daunorubicin, and a multi-targeted protein kinase inhibitor midostaurin were discovered as potential repositioning drugs for treating lung cancer. These findings have implications for improving lung cancer diagnosis, optimizing treatment selection, and discovering new drug options for better patient outcomes.
... In the present study, we measured the expression of Mcl-1 in both chemosensitive and chemoresistant CRC tissues and cell lines. Similar to previous studies, 31,50 we also confirmed that ...
Chemoresistance to 5-Fluorouracil (5-Fu)-based chemotherapy is one of the primary reasons for the failure of colorectal cancer (CRC) management. STAT3 can mediate tumor drug resistance through a variety of diverse mechanisms. Nonetheless, the underlying mechanisms of STAT3-induced 5-Fu resistance in CRC are still poorly understood. Here, we aimed to investigate the potential mechanism(s) of STAT3-induced 5-Fu resistance in CRC. Quantitative RT-PCR and Western blot were used to test the expression of STAT3 and Mcl-1 in chemosensitive and chemoresistant CRC tissues and cell lines. After overexpression or knockdown of STAT3 or Mcl-1, and/or treated with or without 5-Fu or chloroquine (CQ), we tested cell viability, inhibitory concentration 50% (IC50 ) value of 5-FU, cell apoptosis, proliferation, migration, and autophagy. STAT3 and Mcl-1 were significantly upregulated in the chemoresistant CRC tissues and cell lines, and STAT3 positively regulated Mcl-1. Functional studies demonstrated that STAT3 promoted 5-Fu resistance in CRC. Mechanistically, STAT3 triggered autophagy via Mcl-1 to induce cancer chemoresistance. Our results show that STAT3 regulates 5-Fu resistance in CRC by promoting Mcl-1-dependent cytoprotective autophagy. Our results provide a novel role of STAT3 and may offer a new approach for managing CRC 5-Fu resistance.
... Table 3. miRNAs regulating DDP-therapy response, confirmed in three different types of experiments (data based on DDP-resistance studies and extracted from Tables S1 and S2). miR-378 sCLU [78] miR-379 EIF4G2 [79] miR-381 NFkB [80] miR-451a MCL-1 [81][82][83] miR-486-5p TWF1 [84] miR-613 GJA1 [85,86] DDP-cisplatin; DDP-S miRNA-miRNA associated with DDP sensitivity; DDP-R miRNA-miRNA associated with DDP resistance. ...
Background:
Platinum-based chemotherapy, cisplatin (DDP) specifically, is the main strategy for treating lung cancer (LC). However, currently, there is a lack of predictive drug-resistance markers, and there is increased interest in the development of a reliable and sensitive panels of markers for DDP chemotherapy-effectiveness prediction. MicroRNAs represent a perspective pool of markers for chemotherapy effectiveness.
Objectives:
Data on miRNAs associated with LC DDP chemotherapy response are summarized and analyzed.
Materials and methods:
A comprehensive review of the data in the literature and an analysis of bioinformatics resources were performed. The gene targets of miRNAs, as well as their reciprocal relationships with miRNAs, were studied using several databases.
Results and discussion:
The complex analysis of bioinformatics resources and the literature indicated that the expressions of 12 miRNAs have a high predictive potential for LC DDP chemotherapy responses. The obtained information was discussed from the point of view of the main mechanisms of LC chemoresistance.
Conclusions:
An overview of the published data and bioinformatics resources, with respect to the predictive microRNA markers of chemotherapy response, is presented in this review. The selected microRNAs and gene panel have a high potential for predicting LC DDP sensitiveness or DDP resistance as well as for the development of a DDP co-therapy.
... However, miR-21 oncogenecity was further approved by identifying pancreatic cancer cells resistance to gemcitabine-induced apoptosis when it was expressed ectopically [188]. In cisplatin-resistant lung cancer cells, miR-451 was downregulated and simultaneously Mcl-1 was upregulated but an exogenous expression of miR-451 or knockdown of Mcl-1 improved the chemosensitivity [189]. miRNAs in cancer prognosis/diagnosis miRNAs are remarkably stable in the human body fluids since they reside in membrane bound vesicles and can escape from RNases mediated degradation [191][192][193]. ...
Till date, several groups have studied the mechanism of microRNA (miRNA) biogenesis, processing, stability, silencing, and their dysregulation in cancer. The miRNA coding genes recurrently go through abnormal amplification, deletion, transcription, and epigenetic regulation in cancer. Some miRNAs function as tumor promoters while few others are tumor suppressors based on the transcriptional regulation of target genes. A review of miRNAs and their target genes in a wide range of cancers is attempted in this article, which may help in the development of new diagnostic tools and intervention therapies. The contribution of miRNAs for drug sensitivity or resistance in cancer therapy and opportunities of miRNAs in cancer prognosis or diagnosis and therapy is also presented in detail.
... Low levels of the tumor-suppressive miR-451 were associated with poor prognosis in NSCLC patients [33]. Additionally, the tumor suppressor miR-451 was also shown to enhance cisplatin sensitivity via regulation of Mcl-1 expression, suggesting that novel therapeutic targets may be designed thereafter [34,35]. In a previous study from our group [13], levels of miR-451 were also reduced in the tumors of patients with LC, particularly in those with COPD. ...
Lung cancer (LC) risk increases in patients with chronic respiratory diseases (COPD). MicroRNAs and redox imbalance are involved in lung tumorigenesis in COPD patients. Whether systemic alterations of those events may also take place in LC patients remains unknown. Our objectives were to assess the plasma levels of microRNAs, redox balance, and cytokines in LC patients with/without COPD. MicroRNAs (RT-PCR) involved in LC, oxidized DNA, MDA-protein adducts, GSH, TEAC, VEGF, and TGF-beta (ELISA) were quantified in plasma samples from non-LC controls (n = 45), LC-only patients (n = 32), and LC-COPD patients (n = 91). In LC-COPD patients compared to controls and LC-only, MDA-protein adduct levels increased, while those of GSH decreased, and two patterns of plasma microRNA were detected. In both LC patient groups, miR-451 expression was downregulated, while those of microRNA-let7c were upregulated, and levels of TEAC and TGF-beta increased compared to the controls. Correlations were found between clinical and biological variables. A differential expression profile of microRNAs was detected in patients with LC. Moreover, in LC patients with COPD, plasma oxidative stress levels increased, whereas those of GSH declined. Systemic oxidative and antioxidant markers are differentially expressed in LC patients with respiratory diseases, thus implying its contribution to the pathogenesis of tumorigenesis in these patients.
... MiR-451 is one of the most conservative miRNAs with an essential clinical application value [9]. The evident difference of miR-451 expression has been reported in various cancers, such as renal cell carcinoma [10] and lung cancer [11]. Importantly, the inhibitive effects of miR-451 on HCC progression have also been demonstrated before [12,13]. ...
Objective: Exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs) expressing microRNAs (miRNAs) have been highlighted in human cancers. However, the detailed molecular mechanism of hucMSCs-derived exosomal miR-451a on hepatocellular carcinoma (HCC) remains further investigation. Our study aims to explore the impact of exosomal miR-451a on the progression of HCC.
Methods: Expression of miR-451a and a disintegrin and metalloprotease 10 (ADAM10) in HCC tissues and adjacent normal tissues was determined. The exosomes were extracted from hucMSCs and co-cultured with Hep3B and SMMC-7721 cell lines. After the treatment of relative exosomes or exosome inhibitor GW4869 in Hep3B and SMMC-7721 cells, the paclitaxel resistance and malignant phenotypes of HCC cells were measured. Moreover, effect of hucMSCs-derived exosomes on expression of miR-451a and ADAM10 in HCC cells was assessed. The targeting relationship between miR-451a and ADAM10 was verified to detect the impact of ADAM10-wild type and ADAM10-mutant type (MUT) on HCC cell processes.
Results: Low expression of miR-451a and high expression of ADAM10 indicated a poor prognosis of HCC patients. MiR-451a was up-regulated while ADAM10 was down-regulated in HCC cells after co-culture with HucMSC-derived exosomes. The exosomes elevated miR-451a and inhibited ADAM10 to suppress the paclitaxel resistance, cell cycle transition, proliferation, migration and invasion, and promote apoptosis of HCC cells. ADAM10 was verified to be a target gene of miR-451a. ADAM10-MUT promoted HCC process independent of miR-451a mimic.
Conclusion: HucMSC-derived exosomal miR-451a could restrict the epithelial-mesenchymal transition of HCC cells by targeting ADAM10, which might provide new targets for HCC treatment.
... [6][7][8][9][10] In addition, miRNAs are applied as the biomarkers, prognostic markers and therapeutic targets of many diseases, especially for cancers. [11][12][13] Several miRNAs have been identi ed to regulate the cisplatin chemosensitivity in NSCLC cells, such as miR-451, miR-379, and miR-185-5p. 1 [4][5][6][7][8][9][10][11][12][13][14][15][16] Besides, miR-382 and miR-381 inhibit cancer cell growth and metastasis in NSCLC. 17,18 It's reported that miR-221-3p promotes the dysfunction of endothelial cells by suppressing PGC-1α expression in progressed atherosclerosis. ...
Objective
The mortality rate of lung cancer ranks first in malignant tumors. Among them, non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancer patients. In this study, we explore part of the mechanism of development and progression of NSCLC.
Methods/ Results
Firstly, there was an increase in microRNA-221-3p (miR-221-3p) expression and a decrease in Axin2 expression in NSCLC tissues using real-time reverse transcription polymerase chain reaction. Further studies showed that miR-221-3p inhibited the expression of Axin2, which negatively regulated the Wnt signaling pathway. With the method of inhibiting and overexpressing the expression of miR-221-3p and/or Axin2 respectively in NSCLC cell lines A549 and H1975, we found that inhibiting the expression of miR-221-3p leaded to a decrease in cell proliferation, migration and invasion, just like the results of overexpressing Axin2. Relatively speaking, overexpression of miR-221-3P in NSCLC cell lines showed the increase of proliferation as well as the decrease of apoptosis. Thus, we knew that miR-221-3p promoted the migration and invasion of NSCLC cells in vitro. What’s more, according to western blot and EdU assay, we demonstrated that overexpression of miR-221-3p inhibited the expression of Axin2 and subsequently activate classical Wnt/β-catenin signaling pathway. At last, a series of methods were used to identify that miR-221-3p inhibited Axin2 expression, increased cell proliferation, invasion and migration, and decreased cell apoptosis.
Conclusion
Our results suggest that miR-221-3p inhibits the expression of Axin2 and indirectly activates the typical Wnt/β-catenin signaling pathway, thus promoting tumor proliferation and invasion in NSCLC.
... However, the specificity of the miRNAs towards a specific disease condition is questionable, as they can regulate the expression profiles of several types of mRNA. The human miRNA disease database was analysed to discover [192] miR-153 Arsenious acid Chronic myeloid leukaemia Bcl2 Downregulation [193] miR-126 Vincristine and Adriamycin Gastric cancer Directly targeting EZH2 [194] miR-200c Vincristine Cisplatin Cetuximab NSCLC BCL2 BCL2/ZEB1 ZEB1 [195] miR-451 Cisplatin Lung cancer Mcl-1 [196] miR-1 Doxorubicin Etoposide ...
Objectives
MicroRNAs (miRNAs) are a type of small noncoding RNA employed by the cells for gene regulation. A single miRNA, typically 22 nucleotides in length, can regulate the expression of numerous genes. Over the past decade, the study of miRNA biology in the context of cancer has led to the development of new diagnostic and therapeutic opportunities.
Key findings
MicroRNA dysregulation is commonly associated with cancer, in part because miRNAs are actively involved in the mechanisms like genomic instabilities, aberrant transcriptional control, altered epigenetic regulation and biogenesis machinery defects. MicroRNAs can regulate oncogenes or tumour suppressor genes and thus when altered can lead to tumorigenesis. Expression profiling of miRNAs has boosted the possibilities of application of miRNAs as potential cancer biomarkers and therapeutic targets, although the feasibility of these approaches will require further validation.
Summary
In this review, we will focus on how miRNAs regulate tumour development and the potential applications of targeting miRNAs for cancer therapy.
... MiRNAs were reported to be involved in regulating cancer development [7] and drug resistance [12,13]. It has been shown recently that many miRNAs play a significant role in overexpression suppressed the cytotoxic effect of cisplatin in HCC cells via targeting FASLG [9]. ...
... Mcl-1 is a key antiapoptotic gene that regulates apoptotic cell death through regulating mitochondrial outer membrane permeability and degradation of other apoptotic proteins [39][40][41][42][43][44][45]. Mcl-1 is implicated in tumorigenesis in many cancers, such as lung cancer [46], multiple myeloma [47], breast cancer [48] and HCC [49], and significantly involved in chemotherapy resistance [12,13,[50][51][52]. Therefore, targeting Mcl-1 could be considered a potential approach to enhance chemosensitivity in HCC treatment. ...
Background
Doxorubicin (DOX) is the most common drugs used in cancer therapy, including Hepatocellular Carcinoma (HCC). Drug resistance, is one of chemotherapy’s significant problems. Emerging studies have shown that microRNAs (miRNAs) could participate in regulating this mechanism. Nevertheless, the impact of miRNAs on HCC chemoresistance is still enigmatic.
Objective
Investigating the role of miR-520c-3p in enhancement of anti-tumor effect of DOX against HepG2 cells.
Methods
Expression profile for liver related miRNAs (384 miRNAs) has been analyzed on HepG2 cells treated with DOX using qRT-PCR. miR-520c-3p, the most deregulated miRNA, was selected for combination treatment with DOX. Expression level for LEF1, CDK2, CDH1, VIM, Mcl-1 and TP53 was evaluated in miR-520c-3p transfected cells. Cell viability, colony formation, wound healing as well as apoptosis assays have been demonstrated. Furthermore, Mcl-1 protein level was measured using western blot technique.
Results
The present data indicated that miR-520c-3p overexpression could render HepG2 cells chemo-sensitive to DOX through enhancing its suppressive effects on proliferation, migration, and induction of apoptosis. The suppressive effect of miR-520c-3p involved altering the expression levels of some key regulators of cell cycle, proliferation, migration and apoptosis including LEF1, CDK2, CDH1, VIM, Mcl-1 and TP53. Interestingly, Mcl-1 was found to be one of the potential targets of miR-520c-3p, and its protein expression level was down-regulated upon miR-520c-3p overexpression.
Conclusion
Our data referred to the tumor suppressor function of miR-520c-3p that could modulate chemosensitivity of HepG2 cells toward DOX treatment, providing a promising therapeutic strategy in HCC.
... Erythropoietin-induced suppression of miR-451 in GBM led to increased cisplatin chemoresistance [73]. Overexpression of miR-451 sensitized lung cancer cells to cisplatin [76][77][78] and irradiation [79], breast cancer cells to tamoxifen and paclitaxel [80,81], and colorectal cancer cells to irinotecan [82]. We showed that GBM cells responded to TMZ treatment and irradiation by significant reduction of endogenous miR-451 expression by~3-fold (Figure 3a), while stable overexpression of miR-451 led to significant sensitization to both therapeutic regimens (Figure 3b). ...
Malignant glioblastoma (GBM, glioma) is the most common and aggressive primary adult brain tumor. The prognosis of GBM patients remains poor, despite surgery, radiation and chemotherapy. The major obstacles for successful remedy are invasiveness and therapy resistance of GBM cells. Invasive glioma cells leave primary tumor core and infiltrate surrounding normal brain leading to inevitable recurrence, even after surgical resection, radiation and chemotherapy. Therapy resistance allowing for selection of more aggressive and resistant sub-populations including GBM stem-like cells (GSCs) upon treatment is another serious impediment to successful treatment. Through their regulation of multiple genes, microRNAs can orchestrate complex programs of gene expression and act as master regulators of cellular processes. MicroRNA-based therapeutics could thus impact broad cellular programs, leading to inhibition of invasion and sensitization to radio/chemotherapy. Our data show that miR-451 attenuates glioma cell migration in vitro and invasion in vivo. In addition, we have found that miR-451 sensitizes glioma cells to conventional chemo- and radio-therapy. Our data also show that miR-451 is regulated in vivo by AMPK pathway and that AMPK/miR-451 loop has the ability to switch between proliferative and migratory pattern of glioma cells behavior. We therefore postulate that AMPK/miR-451 negative reciprocal feedback loop allows GBM cells/GSCs to adapt to tumor “ecosystem” by metabolic and behavioral flexibility, and that disruption of such a loop reduces invasiveness and diminishes therapy resistance.
