Upregulation of miR-501-5p activates the wnt/β-catenin signaling pathway and enhances stem cell-like phenotype in gastric cancer

Fan, Daiming; Ren, Baoqi; Yang, Xiaojun; Liu, Jia; Zhang, Zhengzheng

doi:10.1186/s13046-016-0432-x

Cited by 79 publications

(72 citation statements)

References 33 publications

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“…Based on this observation, it is tempting to speculate that TERT , a crucial gene for life, regulates and is regulated by miRNAs of the same cluster. In line with this speculation, MIR500A and all downstream miRNAs of the cluster, act as oncomiRs and are related to different cancer types: MIR500A in hepatocellular carcinoma, gastric and breast cancer (26-28), MIR362 in chronic myeloid leukemia (29), MIR501 in gastric cancer (30), MIR660 in breast cancer (31) and MIR502 in colorectal and prostate cancer (32, 33). Conversely, the miRNAs located upstream MIR500A act as tumor suppressors: MIR532 inhibits the expression of TERT in ovarian cancer, resulting in decreased cell proliferation and invasion capacity (34), and MIR188 is down-regulated in oral squamous cell carcinoma (35).…”

Section: Discussionmentioning

confidence: 69%

TERT-mediated induction of MIR500A contributes to tumor invasiveness by targeting Hedgehog pathway

Bernabé-García

Martínez‐Balsalobre²,

García‐Moreno³

et al. 2020

Preprint

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19The classical activity of telomerase (TERT) is to maintain telomere homeostasis, 20 ensuring chromosome stability and cellular proliferation. However, increasing 21 evidences of telomere-independent human TERT functions have been lastly obtained. 22 We report here that TERT directly binds to the TCF binding elements (TBE) located 23 upstream the oncomiR MIR500A inducing its expression and promoting cancer 24 invasiveness. This function is independent of telomerase activity, since catalytic 25 inactive TERT also induces MIR500A expression and telomerase inhibitors directed 26 2 against TERT, but not to its RNA component TERC, inhibit telomerase-induced 27 MIR500A expression and cancer invasiveness. Mechanistically, telomerase-induced 28 MIR500A down-regulates key genes of the Hedgehog signaling pathway, namely 29 patched 1 (PTCH1), Gli family zinc finger 3 (GLI3) and cullin 3 (CUL3), increasing 30 tumor invasiveness. Our results show a crucial role of the TERT/MIR500A/Hedgehog 31 axis is tumor aggressiveness, pointing out to the relevance of inhibiting the 32 extracurricular functions of telomerase to fight cancer.33 34 35 36 37 38 39 40 41 42 43 44 45 48 TERT by the homologous recombination (HR)-mediated alternative lengthening of 49 telomeres (ALT) pathway (1). Increasing evidences are revealing non-canonical roles of 50 TERT not only in cancer, but also in several essential cellular functions, via 51 mechanisms independent of telomere maintenance. These novel roles of TERT may 52 provide transformed cells with specific capacities at multiple stages of tumor 53 development (2). Among the numerous non-telomeric biological functions of TERT, it 54has been demonstrated that TERT acts as a regulatory molecule modulating gene 55 transcription (3-6). However, the non-canonical roles of TERT in cancer and their 56 relevance in its progression and response to therapy remain poorly understood. 57miRNAs are endogenous non-coding small RNAs (~22 nucleotides) that cause 58 post-transcriptional repression or cleavage of target messenger RNAs (mRNAs) by 59 binding to their 3'UTR. Around 50% of all miRNA genes are located within 50 kb in 60 length on the genome and transcribed together as a cluster and frequently shows similar 61 sequence homology in the seed sequence, the region for target recognition, resulting in 62 identical targets for a miRNA cluster (7). Different studies estimated that each miRNA 63 can regulate more than 200 genes (8, 9), implying that miRNAs regulates a large 64 number of biological processes that are frequently altered in many human diseases. 65Over the past 15 years, a lot of evidence has shown that aberrant miRNAs expression is 66 involved not only in tumorigenesis and metastasis (10) but, in addition, the miRNA 67 expression profile is unique for each cancer type, so blood-based miRNA expression 68 patterns can be used as a non-invasive method for cancer diagnosis (11). In 2014, 69Drevytska and colleagues showed a positive correlation between the expression of 70 TERT and several miRNA (12)....

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Section: Discussionmentioning

confidence: 69%

TERT-mediated induction of MIR500A contributes to tumor invasiveness by targeting Hedgehog pathway

Bernabé-García

Martínez‐Balsalobre²,

García‐Moreno³

et al. 2020

Preprint

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“…The VEGF receptor is required in response to VEGF-dependent cell survival via EMT in colon carcinoma cell lines [40,41]. Additionally, miR-200 families are well-known miRNAs that regulate Wnt/β-catenin signaling [34] and also directly regulate EMT by targeting transcriptional repressors of ZEB1 and ZEB2, which regulate CDH1 expression [42,43]. These results indicate that the miRNAs we identified may play an important role in both high-and low-risk subtypes.…”

Section: Gsea Kegg Pathway Analysis and Go Analysismentioning

confidence: 65%

“…KEGG pathway analysis showed that fatty acid metabolism, oxidative phosphorylation, valine, leucine, and isoleucine degradation pathways were significantly different. For the miRNA, miR-501 that activates Wnt/β-catenin signaling in gastric cancer and colorectal cancer [34,35] and tumor suppressor miR-26 that has been reported to regulate the Wnt/β-catenin signaling in prostate cancer and cholangiocarcinoma [36] were significance between subtypes. Intriguingly, miR-26 is also known to contribute TGF-β-induced EMT [37] and inflammation response [38], which could be associated with the low-risk subtype.…”

Section: Gsea Kegg Pathway Analysis and Go Analysismentioning

confidence: 96%

Uncovering Prognosis-Related Genes and Pathways by Multi-Omics Analysis in Lung Cancer

et al. 2020

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Lung cancer is one of the leading causes of death worldwide. Therefore, understanding the factors linked to patient survival is essential. Recently, multi-omics analysis has emerged, allowing for patient groups to be classified according to prognosis and at a more individual level, to support the use of precision medicine. Here, we combined RNA expression and miRNA expression with clinical information, to conduct a multi-omics analysis, using publicly available datasets (the cancer genome atlas (TCGA) focusing on lung adenocarcinoma (LUAD)). We were able to successfully subclass patients according to survival. The classifiers we developed, using inferred labels obtained from patient subtypes showed that a support vector machine (SVM), gave the best classification results, with an accuracy of 0.82 with the test dataset. Using these subtypes, we ranked genes based on RNA expression levels. The top 25 genes were investigated, to elucidate the mechanisms that underlie patient prognosis. Bioinformatics analyses showed that the expression levels of six out of 25 genes (ERO1B, DPY19L1, NCAM1, RET, MARCH1, and SLC7A8) were associated with LUAD patient survival (p < 0.05), and pathway analyses indicated that major cancer signaling was altered in the subtypes.

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“…Another study by Lin et al [137] demonstrate that nanoformulation of miR-34a successfully removes BCSCs via targeting C22ORF28 (chromosome 22 open reading frame 28), which act as a direct and functional target of TV-miR-34a. By using hTERT promoter-driven VISA delivery of miR-34a plasmid, they further showed TV-miR-34a markedly suppressed tumor-initiating properties of BCSC in vitro and in vivo and also reported that TV-miR-34a plasmid synergizes with docetaxel for eradicating BCSC by targeting C22ORF28 [96]. miR-628, another important miRNA deregulated in human cancer pathogenesis, has been shown to suppresses BCSC stemness features by targeting Ras/Rac guanine nucleotide exchange factor 1 (SOS1) [138].…”

Section: Breast Cancermentioning

confidence: 96%

Role of miRNA-Regulated Cancer Stem Cells in the Pathogenesis of Human Malignancies

Khan

Ahmed

Elareer

et al. 2019

Cells

226

168

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Recent biomedical discoveries have revolutionized the concept and understanding of carcinogenesis, a complex and multistep phenomenon which involves accretion of genetic, epigenetic, biochemical, and histological changes, with special reference to MicroRNAs (miRNAs) and cancer stem cells (CSCs). miRNAs are small noncoding molecules known to regulate expression of more than 60% of the human genes, and their aberrant expression has been associated with the pathogenesis of human cancers and the regulation of stemness features of CSCs. CSCs are the small population of cells present in human malignancies well-known for cancer resistance, relapse, tumorigenesis, and poor clinical outcome which compels the development of novel and effective therapeutic protocols for better clinical outcome. Interestingly, the role of miRNAs in maintaining and regulating the functioning of CSCs through targeting various oncogenic signaling pathways, such as Notch, wingless (WNT)/β-Catenin, janus kinases/ signal transducer and activator of transcription (JAK/STAT), phosphatidylinositol 3-kinase/ protein kinase B (PI3/AKT), and nuclear factor kappa-light-chain-enhancer of activated B (NF-kB), is critical and poses a huge challenge to cancer treatment. Based on recent findings, here, we have documented the regulatory action or the underlying mechanisms of how miRNAs affect the signaling pathways attributed to stemness features of CSCs, such as self-renewal, differentiation, epithelial to mesenchymal transition (EMT), metastasis, resistance and recurrence etc., associated with the pathogenesis of various types of human malignancies including colorectal cancer, lung cancer, breast cancer, head and neck cancer, prostate cancer, liver cancer, etc. We also shed light on the fact that the targeted attenuation of deregulated functioning of miRNA related to stemness in human carcinogenesis could be a viable approach for cancer treatment.

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Upregulation of miR-501-5p activates the wnt/β-catenin signaling pathway and enhances stem cell-like phenotype in gastric cancer

Cited by 79 publications

References 33 publications

TERT-mediated induction of MIR500A contributes to tumor invasiveness by targeting Hedgehog pathway

TERT-mediated induction of MIR500A contributes to tumor invasiveness by targeting Hedgehog pathway

Uncovering Prognosis-Related Genes and Pathways by Multi-Omics Analysis in Lung Cancer

Role of miRNA-Regulated Cancer Stem Cells in the Pathogenesis of Human Malignancies

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