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mTOR expression in primary colorectal cancer and corresponding liver metastases. A and b. Samples from two patients who showed low expression of mTOR in primary tumor, but high expression in liver metastatic specimens. c. mTOR expression was higher in liver metastases than in the primary tumor; P = 0.009.
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Liver metastasis is common in patients diagnosed with colorectal cancer (CRC), and is also correlated with poor outcome. In this study we screened the different expression profiles of microRNAs (miRNAs) on the development of liver metastasis in CRC patients. miR-99b-5p was found to be more than 6-fold higher in primary tumors than in matched liver...
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Context 1
... evaluate the correlation between mTOR and miR-99b-5p, the protein expression of mTOR and its down-stream pathway genes were examined by immunohistochemistry. Our results showed that the expression of miR-99b-5p was negatively associated with mTOR expression level in the 23 CRC patients with liver metastases (P = 0.01) (Figure 4, Table 3). We also found that the down-regulated expression of mTOR in the primary tumor tissues was comparable with that of the corresponding liver metastases ( Figure 5). However, correlation of mTOR in the primary tumor and overall survival was not observed. Higher expression of mTOR in liver metastases showed a poorer trend for survival, although a P value was not reached ( Figure ...
Citations
... From this point of view, understanding the precise and detailed crosstalk between chemotherapy methods and microRNAs function may provide more efficient methods in breast cancer treatment. In recent years, in addition to the reports of modification in miR-99-5P and miR-100-5p expression levels in some human cancers like prostate and colon cancers, their vital role in proliferation, migration and invasion of tumors has been highlighted as well as their tumor suppressor role [12][13][14]. The issue that makes them a great choice for cancer therapy research. ...
... Therefore, the investigation of their functions is of particular importance in diagnosing and treatment of breast cancer [7,37]. Recent studies have shown the impact of two microRNAs, miR-99b-5p and miR-100-5p in several human cancers [12][13][14]. Since less is known about miR-99b-5p and miR-100-5p influence from anti-breast cancer drugs like tamoxifen, we investigated their modification in breast cancer cell lines. ...
... Earlier, a relationship between decrease in mTOR gene expression and higher miR-100-5p activity in prostate cancer was reported [14]. Also, it has been reported that miR-99-5p inhibits mTOR gene expression and affects colon cancer [12]. Another similar study has recently indicated that the decrease in mTOR gene expression increases the success possibility of a breast cancer treatment [40]. ...
Background: Breast cancer treatment has always been an important challenge in medicine. Recent studies have revealed the
importance of microRNAs miR-99b-5p and miR-100-5p in breast cancer treatment. Moreover, however not fully understood,
the impact of exosomal microRNAs in human cancer progress or inhibition has been highlighted yet. The present study aimed
to investigate the effects of one of the most prescribed drugs in breast cancer chemotherapy, tamoxifen, on expression level of
miR-99b- 5p, miR-100-5p and also mTOR gene in MCF-7 cell lines.
Methods: MCF-7 cells were treated with 30 µM tamoxifen while being in a 70% surface density, then the expression level of
mentioned microRNAs and mTOR gene were investigated in RNA extracts of the cells and their exosomes.
Results: Results indicated the presence of a significant increase (P <0.01) in both miR-99b-5p and miR- 100-5p expression
levels in cell lines following tamoxifen treatment. Also, the evaluation of mTOR gene expression in the same cells after
treatment with tamoxifen showed significant (P <0.05) expression reduction.
Conclusions: Interestingly, the decrease in mTOR expression level was completely consistent with increase in the expression
of exosomal microRNAs level, which seems to be reasonable considering the targeting of the mTOR gene by the two mentioned
microRNAs. The results of this study suggest that the therapeutic effects of tamoxifen on breast cancer cells, can be justified
not only by its direct effect on cancer cells, but also by indirect impact on elements like microRNAs expression.
... Further enrichment analysis of GSVA in immune cells suggested that LM of colorectal cancer was associated with the activation of cancer progression-related pathways such as HALLMARK EPITHELIAL MESENCHYMAL TRANSITION, HALLMARK APOPTOSIS, and HALLMARK MTORC1 SIGNALING. 28,29 Further exploration of the cell origin of pCRC and LM groups through CNV and pseudotime analyses revealed distinct differentiation patterns between primary tumors and liver metastases. Additionally, substantial heterogeneity was observed among tumor samples, highlighting the importance of identifying shifting risk factors. ...
Background
Colorectal cancer (CRC) is one of the deadliest causes of death by cancer worldwide. Liver metastasis (LM) is the main cause of death in patients with CRC. Therefore, identification of patients with the greatest risk of liver metastasis is critical for early treatment and reduces the mortality of patients with colorectal cancer liver metastases.
Methods
Initially, we characterized cell composition through single-cell transcriptome analysis. Subsequently, we employed copy number variation (CNV) and pseudotime analysis to delineate the cellular origins of LM and identify LM-related epithelial cells (LMECs). The LM-index was constructed using machine learning algorithms to forecast the relative abundance of LMECs, reflecting the risk of LM. Furthermore, we analyzed drug sensitivity and drug targeted gene expression in LMECs and patients with a high risk of LM. Finally, functional experiments were conducted to determine the biological roles of metastasis-related gene in vitro.
Results
Single-cell RNA sequencing analysis revealed different immune landscapes between primary CRC and LM tumor. LM originated from chromosomal variants with copy number loss of chr1 and chr6p and copy number gain of chr7 and chr20q. We identified the LMECs cluster and found LM-associated pathways such as Wnt/beta-catenin signaling and KRAS signaling. Subsequently, we identified ten metastasis-associated genes, including SOX4, and established the LM-index, which correlates with poorer prognosis, higher stage, and advanced age. Furthermore, we screened two drugs as potential candidates for treating LM, including Linsitinib_1510, Lapatinib_1558. Immunohistochemistry results demonstrated significantly elevated SOX4 expression in tumor samples compared to normal samples. Finally, in vitro experiments verified that silencing SOX4 significantly inhibited tumor cell migration and invasion.
Conclusion
This study reveals the possible cellular origin and driving factors of LM in CRC at the single cell level, and provides a reference for early detection of CRC patients with a high risk of LM.
... The miR-99 family members may act as oncomiRs or TS miRNAs in different types of cancer. For instance, miR-99 family members can promote leukemic stem cells (LSCs) self-renewal in acute myeloid leukaemia (AML) by suppressing cell differentiation [621], but also suppress tumour growth in lung cancer [622], colorectal cancer [623], and glioma [624]. ...
Tumour suppressor genes play a cardinal role in the development of a large array of human cancers, including lung cancer, which is one of the most frequently diagnosed cancers worldwide. Therefore, extensive studies have been committed to deciphering the underlying mechanisms of alterations of tumour suppressor genes in governing tumourigenesis, as well as resistance to cancer therapies. In spite of the encouraging clinical outcomes demonstrated by lung cancer patients on initial treatment, the subsequent unresponsiveness to first-line treatments manifested by virtually all the patients is inherently a contentious issue. In light of the aforementioned concerns, this review compiles the current knowledge on the molecular mechanisms of some of the tumour suppressor genes implicated in lung cancer that are either frequently mutated and/or are located on the chromosomal arms having high LOH rates (1p, 3p, 9p, 10q, 13q, and 17p). Our study identifies specific genomic loci prone to LOH, revealing a recurrent pattern in lung cancer cases. These loci, including 3p14.2 (FHIT), 9p21.3 (p16INK4a), 10q23 (PTEN), 17p13 (TP53), exhibit a higher susceptibility to LOH due to environmental factors such as exposure to DNA-damaging agents (carcinogens in cigarette smoke) and genetic factors such as chromosomal instability, genetic mutations, DNA replication errors, and genetic predisposition. Furthermore, this review summarizes the current treatment landscape and advancements for lung cancers, including the challenges and endeavours to overcome it. This review envisages inspired researchers to embark on a journey of discovery to add to the list of what was known in hopes of prompting the development of effective therapeutic strategies for lung cancer.
... Aspirin inhibits COX-2 and activates EP1-4 prostaglandin receptors while preventing the synthesis of prostaglandin E2. EP1-4 prostaglandin receptor activation results in colonic tumorigenesis and invasion [85,86]. In colon cancer cells, β-catenin is activated by EP2, which is part of the Wnt/βcatenin pathway, and plays a role in CRC induction, invasion and growth. ...
Uganda is a developing low-income country with a low incidence of colorectal cancer, which is steadily increasing. Ugandan colorectal cancer (CRC) patients are young and present with advanced-stage disease. In our population, there is a scarcity of genetic oncological studies, therefore, we investigated the mutational status of CRC tissues, focusing in particular on the adenomatous polyposis coli (APC), phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), and SMAD4 genes. Our objective was to determine whether there were any differences between other populations and Ugandan patients. We performed next-generation sequencing on the extracted DNA from formalin-fixed paraffin-embedded adenocarcinoma samples from 127 patients (mean (SD) age: 54.9 (16.0) years; male: female sex ratio: 1.2:1). Most tumours were located in the rectum 56 (44.1%), 14 (11%) tumours were high grade, and 96 (75.6%) were moderate grade CRC. Stage III+IV CRC tumours were found in 109 (85.8%) patients. We identified 48 variants of APC, including 9 novel APC mutations that were all pathogenic or deleterious. For PIK3CA, we found 19 variants, of which 9 were deleterious or pathogenic. Four PIK3CA novel pathogenic or deleterious variants were included (c.1397C>G, c.2399_2400insA, c.2621G>C, c.2632C>G). Three SMAD4 variants were reported, including two pathogenic or deleterious variants (c.1268G>T, c.556dupC) and one tolerant (c.563A>C) variant. One novel SMAD4 deleterious mutation (c.1268G>T) was reported. In conclusion, we provide clinicopathological information and new genetic variation data pertinent to CRC in Uganda.
... Furthermore, the upregulation of several groups of miR-135b-5p has been observed to promote tumorigenic metastasis in other types of cancer, including lung cancer, and head and neck squamous cell carcinoma. 17,18 Li et al. 13 reported that miR-135b-5p may be a promising non-invasive biomarker for diagnosing CRC patients with TNM stage III/IV, and a potential candidate for developing an intervention strategy for CRC. ...
... The mucinous component, lymphovascular involvement, and neural involvement rates were 39.1%, 70.4%, and 67.4%, respectively. The median number of surgically removed LNs was 16 (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). However, the rate of lymph node positivity was only 76.1% ( Table 1). ...
... 11,12 The miR-99 family plays an essential role in CRC. MiR-99 family members, acting as TSmiRs, can generally prevent cancer metastasis 14,15,17 In a study of 56 primary CRC clinical samples and related LVMs, Li et al. 13 showed that miR-99b-5p downregulation in CRC was a common event during LVM. MiR-99b-5p overexpression inhibits mTOR, indicating that miR-99b-5p blocks CRC metastasis by targeting Mtor. ...
Aim:
This study aimed to evaluate the expression levels of miR-99b and miR-135b in peritoneal carcinoma and liver metastases associated with Colorectal Cancer (CRC), assess their association with the intracellular signaling pathway proteins Kirsten Rat Sarcoma Virus (KRAS) and Akt, and investigate their effects on survival.
Materials and methods:
Changes in the KRAS gene and Akt proteins, expression levels of miR-99b and miR-135b, and factors affecting survival were compared between colorectal cancer-associated peritoneal carcinomatosis and liver metastasis.
Results:
The expression levels of miR-99b and miR-135b and the immunohistochemical grade classification score of Akt were higher in colorectal cancer, peritoneal carcinomatosis, and liver metastasis than in normal tissues (p < 0.05). MiR-99b expression was highest in CRC, whereas miR-135b expression was highest in peritoneal carcinomatosis (p < 0.05). The expression level of miR-99b decreased and that of miR-135b increased in peritoneal and liver metastases compared with that in the tumor tissue. MiR-99b, Akt, and recurrence were risk factors that affected the overall survival rate in the model of clinical predictions (p = 0.045, p = 0.006, and p = 0.012, respectively).
Conclusion:
While the expression of miR-99b was highest in the primary tumor, its decrease in liver metastasis and peritoneal carcinomatosis suggests that miR-99b has a protective effect against liver metastasis and peritoneal carcinomatosis. However, the detection of miR-135b expression was highest in peritoneal carcinomatosis and liver metastasis compared with that in the colorectal cancer tissues suggesting that it facilitates peritoneal carcinomatosis and liver metastasis. Furthermore, miR-99b, KRAS mutations, and Akt are risk factors for the overall survival of colorectal cancer.
... Another tumor-suppressive miRNA, miR-99b, belongs to the miR-125a-let-7e cluster. MiR-99b-5p is frequently downregulated and was found to regulate differentiation, proliferation, invasion, and migration in PCa, cervical, breast, esophageal, gastric, and colon cancers [59][60][61][62][63][64]. Members of miR-99 were downregulated in advanced PCa compared to the normal prostate epithelium. ...
Simple Summary
Accumulating studies have highlighted the critical roles of microRNAs in tumorigenesis and cancer treatment responses. Here, we systematically review the scientific publications describing the roles of microRNAs in the development and progression of prostate cancer. Numerous studies have demonstrated that microRNAs target and regulate critical genes involved in prostate cancer aggressiveness and drug resistance. However, the molecular mechanisms underlying microRNA involvement in the advanced and treatment-resistant prostate cancers remain unclear. This review aims to highlight the current understanding and knowledge gap related to the deregulation of microRNAs in prostate cancer diseases. Furthermore, we summarize the promising progress on the development of microRNA-based diagnostic/prognostic biomarkers and therapies for prostate cancer.
Abstract
Prostate cancer (PCa) is the most frequently diagnosed cancer and the second leading cause of cancer deaths among American men. Complex genetic and epigenetic mechanisms are involved in the development and progression of PCa. MicroRNAs (miRNAs) are short noncoding RNAs that regulate protein expression at the post-transcriptional level by targeting mRNAs for degradation or inhibiting protein translation. In the past two decades, the field of miRNA research has rapidly expanded, and emerging evidence has revealed miRNA dysfunction to be an important epigenetic mechanism underlying a wide range of diseases, including cancers. This review article focuses on understanding the functional roles and molecular mechanisms of deregulated miRNAs in PCa aggressiveness and drug resistance based on the existing literature. Specifically, the miRNAs differentially expressed (upregulated or downregulated) in PCa vs. normal tissues, advanced vs. low-grade PCa, and treatment-responsive vs. non-responsive PCa are discussed. In particular, the oncogenic and tumor-suppressive miRNAs involved in the regulation of (1) the synthesis of the androgen receptor (AR) and its AR-V7 splice variant, (2) PTEN expression and PTEN-mediated signaling, (3) RNA splicing mechanisms, (4) chemo- and hormone-therapy resistance, and (5) racial disparities in PCa are discussed and summarized. We further provide an overview of the current advances and challenges of miRNA-based biomarkers and therapeutics in clinical practice for PCa diagnosis/prognosis and treatment.
... miR-99b-5p was expressed at a significantly higher level in CRC patients without metastasis when compared to patients with metastasis, which was particularly prominent in stage III. Higher expression was associated with increased survival, suggesting that it may help in preventing liver metastasis [74]. The expression of miRNA-10b in CRC tissues and adjacent tissues was studied by Jiang et al., who found the increased expression of miRNA-10b in CRC tissues and patients with liver metastasis. ...
Exosomes are extracellular vesicles that originate from endosomes and are released by all cells irrespective of their origin or type. They play an important role in cell communication and can act in an autocrine, endocrine, or paracrine fashion. They are 40–150 nm in diameter and have a similar composition to the cell of origin. An exosome released by a particular cell is unique since it carries information about the state of the cell in pathological conditions such as cancer. miRNAs carried by cancer-derived exosomes play a multifaceted role by taking part in cell proliferation, invasion, metastasis, epithelial–mesenchymal transition, angiogenesis, apoptosis, and immune evasion. Depending on the type of miRNA that it carries as its cargo, it can render cells chemo- or radiosensitive or resistant and can also act as a tumor suppressor. Since the composition of exosomes is affected by the cellular state, stress, and changes in the environment, they can be used as diagnostic or prognostic biomarkers. Their unique ability to cross biological barriers makes them an excellent choice as vehicles for drug delivery. Because of their easy availability and stability, they can be used to replace cancer biopsies, which are invasive and expensive. Exosomes can also be used to follow the progression of diseases and monitor treatment strategies. A better understanding of the roles and functions of exosomal miRNA can be used to develop noninvasive, innovative, and novel treatments for cancer.
... MiR-99a, miR-99b-5p, miR-199a3p, and miR-100 were found to target mTOR. The dysregulation of mTOR by the mentioned miRNAs affects liver metastasis and different stages of the hepatic cell cycle (83)(84)(85)(86). However, their expression patterns and their ability to impact the IS pathway of normal hepatic cells were the least experimented with. ...
The paradoxical action of insulin on hepatic glucose metabolism and lipid metabolism in the insulin-resistant state has been of much research interest in recent years. Generally, insulin resistance would promote hepatic gluconeogenesis and demote hepatic de novo lipogenesis. The underlying major drivers of these mechanisms were insulin-dependent, via FOXO-1-mediated gluconeogenesis and SREBP1c-mediated lipogenesis. However, insulin-resistant mouse models have shown high glucose levels as well as excess lipid accumulation. As suggested, the inert insulin resistance causes the activation of the FOXO-1 pathway promoting gluconeogenesis. However, it does not affect the SREBP1c pathway; therefore, cells continue de novo lipogenesis. Many hypotheses were suggested for this paradoxical action occurring in insulin-resistant rodent models. A “downstream branch point” in the insulin-mediated pathway was suggested to act differentially on the FOXO-1 and SREBP1c pathways. MicroRNAs have been widely studied for their action of pathway mediation via suppressing the intermediate protein expressions. Many in vitro studies have postulated the roles of hepato-specific expressions of miRNAs on insulin cascade. Thus, miRNA would play a pivotal role in selective hepatic insulin resistance. As observed, there were confirmations and contradictions between the outcomes of gene knockout studies conducted on selective hepatic insulin resistance and hepato-specific miRNA expression studies. Furthermore, these studies had evaluated only the effect of miRNAs on glucose metabolism and few on hepatic de novo lipogenesis, limiting the ability to conclude their role in selective hepatic insulin resistance. Future studies conducted on the role of miRNAs on selective hepatic insulin resistance warrant the understanding of this paradoxical action of insulin.
... We found an isomiR associated with breast cancer that is derived from the hsa-miR-99b-5p locus. This miRNA is reported to suppress liver metastasis in colorectal cancer by downregulating mTOR [39]. Additionally, it can target IGF-1R in gastric cancer [40] and suppress the fibroblast growth factor receptor 3 gene in lung cancer [41]. ...
The identification of expression quantitative trait loci (eQTL) is an important component in efforts to understand how genetic variants influence disease risk. MicroRNAs (miRNAs) are short noncoding RNA molecules capable of regulating the expression of several genes simultaneously. Recently, several novel isomers of miRNAs (isomiRs) that differ slightly in length and sequence composition compared to their canonical miRNAs have been reported. Here we present isomiR-eQTL, a user-friendly database designed to help researchers find single nucleotide polymorphisms (SNPs) that can impact miRNA (miR-eQTL) and isomiR expression (isomiR-eQTL) in 30 cancer types. The isomiR-eQTL includes a total of 152,671 miR-eQTLs and 2,390,805 isomiR-eQTLs at a false discovery rate (FDR) of 0.05. It also includes 65,733 miR-eQTLs overlapping known cancer-associated loci identified through genome-wide association studies (GWAS). To the best of our knowledge, this is the first study investigating the impact of SNPs on isomiR expression at the genome-wide level. This database may pave the way for researchers toward finding a model for personalised medicine in which miRNAs, isomiRs, and genotypes are utilised.
... Previous studies have shown that the tumor suppressive miR-99b-5p is downregulated in various cancers including PCa [15,[29][30][31][32]. In contrast, mTOR is upregulated in a variety of cancer types [15,16,33]. ...
Mammalian target of rapamycin (mTOR) regulates various fundamental cellular events including cell proliferation, protein synthesis, metabolism, apoptosis, and autophagy. Tumor suppressive miR-99b-5p has been implicated in regulating PI3K/AKT/mTOR signaling in a variety of types of cancer. Our previous study suggested the reciprocal miR-99b-5p/MTOR (downregulated/upregulated) pairing as a key microRNA-mRNA regulatory component involved in the prostate cancer (PCa) disparities. In this study, we further validated the expression profiles of mTOR and miR-99b-5p in the PCa, colon, breast, and lung cancer specimens and cell lines. The immunohistochemistry (IHC), immunofluorescence, Western blot, and RT-qPCR assays have confirmed that mTOR is upregulated while miR-99b-5p is downregulated in different patient cohorts and a panel of cancer cell lines. Intriguingly, elevated nuclear mTOR expression was observed in African American PCa and other advanced cancers. Transfection of the miR-99b-5p mimic resulted in a significant reduction in nuclear mTOR and androgen receptor (AR), while a slight/moderate to no decrease in cytoplasmic mTOR and AR in PCa and other cancer cells, suggesting that miR-99b-5p inhibits mTOR and AR expression and their nuclear translocation. Moreover, overexpression of miR-99b-5p targets/inhibits AR-mTOR axis, subsequently initiating cell apoptosis and sensitizing docetaxel-induced cytotoxicity in various cancers. In conclusion, our data suggest that reciprocal miR-99b-5p/nuclear mTOR pairing may be a more precise diagnostic/prognostic biomarker for aggressive PCa, than miR-99b-5p/MTOR pairing or mTOR alone. Targeting the AR-mTOR axis using miR-99b-5p has also been suggested as a novel therapeutic strategy to induce apoptosis and overcome chemoresistance in aggressive PCa.
