RUNX3 regulates hepatocellular carcinoma cell metastasis via targeting miR-186/E-cadherin/EMT pathway

Gou, Yuli; Zhai, Feifei; Zhang, Liang; Cui, Lan

doi:10.18632/oncotarget.18424

Cited by 27 publications

(28 citation statements)

References 37 publications

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“…In HCC, aberrant CpG methylation could also contribute to RUNX3 downregulation . RUNX3 represses epithelial‐mesenchymal transition, and suppresses HCC metastasis . RUNX3 leads to dysregulated cell cycle distribution, apoptosis and angiogenesis .…”

Section: Discussionmentioning

confidence: 99%

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circLARP4 induces cellular senescence through regulating miR‐761/RUNX3/p53/p21 signaling in hepatocellular carcinoma

Chen

Zuo

et al. 2019

Cancer Science

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Circular RNAs (circRNAs), a novel class of non‐coding RNAs, have emerged as indispensable modulators in human malignancies. Aberrant cellular senescence is a phenotype observed in various cancers. The association of circRNAs with cellular senescence in tumors is yet to determined. Here, we investigated the role of circLARP4 in cellular senescence and cell proliferation in hepatocellular carcinoma (HCC). Downregulated circLARP4 level was observed in HCC tissues and cell lines. Low expression level of circLARP4 independently predicted poor survival outcome. Gain‐of‐function and loss‐of‐function assays demonstrated that circLARP4 suppressed HCC cell proliferation, mediated cell cycle arrest and induced senescence in vitro. Levels of p53 and p21, 2 key regulatory molecules in cellular senescence, were increased in circLARP4‐overexpressed HCC cells and decreased in circLARP4‐silenced HCC cells. In vivo experiments further confirmed the tumor‐suppressing activity of circLARP4. Further mechanistic studies showed that circLARP4 dampened HCC progression by sponging miR‐761, thereby promoting the expression level of RUNX3 and activating the downstream p53/p21 signaling. Our study revealed the role of circLARP4/miR‐761/RUNX3/p53/p21 signaling in HCC progression, providing a potential survival predictor and therapeutic candidate for HCC.

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Section: Discussionmentioning

confidence: 99%

“…40,41 RUNX3 represses epithelial-mesenchymal transition, and suppresses HCC metastasis. 42 RUNX3 leads to dysregulated cell cycle distribution, apoptosis and angiogenesis. 43,44 RUNX3 induces ARF to stabilize p53, thereby exerting a persistent anti-tumor effect.…”

Section: Discussionmentioning

confidence: 99%

circLARP4 induces cellular senescence through regulating miR‐761/RUNX3/p53/p21 signaling in hepatocellular carcinoma

Chen

Zuo

et al. 2019

Cancer Science

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“…For instance, miR-125b inhibits the expression of MMP13 and suppresses CSCC cell proliferation, migration and invasion (11). miR-186 is an important member of cancer-associated miRs and has been reported to generally serve a tumour suppressive role in various types of human cancer, including chronic myeloid leukaemia (12), colorectal cancer (13), gastrointestinal stromal tumour (14), lung cancer (15), liver cancer (16), cervical cancer (17), and gastric cancer (18). miR-186 inhibits the proliferation, metastasis and epithelial-to-mesenchymal transition of colorectal cancer cells by targeting ZEB1 (13).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‑186 promotes cell proliferation and inhibits cell apoptosis in cutaneous squamous cell carcinoma by targeting RETREG1

Liu

et al. 2019

Exp Ther Med

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MicroRNAs (miRs), a class of small non-coding RNAs, have been demonstrated to be involved in the development and progression of human malignancies, including cutaneous squamous cell carcinoma (CSCC). miR-186 serves a suppressive role in certain common types of human cancer; however, its exact function in CSCC has not been reported previously. In the present study, the expression of miR-186 was significantly increased in CSCC tissues compared with adjacent non-tumour tissues. Overexpression of miR-186 significantly promoted CSCC cell proliferation while inhibiting cell apoptosis. Reticulophagy regulator 1 (RETREG1), a gene that is significantly downregulated in CSCC tissues and cell lines, was identified as a novel target of miR-186. In addition, the expression of RETREG1 was inversely correlated with miR-186 expression in CSCC tissues. Furthermore, the expression of RETREG1 was negatively regulated by miR-186 in CSCC cells, and restoration of RETREG1 attenuated the effects of miR-186 on CSCC cells. Taken together, the results of the current study suggest that miR-186 serves an oncogenic role in CSCC and may be used as a potential therapeutic target for the treatment of this disease.

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Section: Up-regulated Mirs Mediating Metastasismentioning

confidence: 99%

“…miR-186 is repressed by metastasis inhibiting runt-related transcription factor 3 (RUNX3) and inhibits E-cadherin (CDH1) expression by binding to the 3'-UTR of its mRNA (73). miR-186 mimics reduced the expression of CDH1 in HCC cell lines HepG2 and Hep3B (73). RUNX3 suppressed migration, invasion and angiogenesis of human renal cell carcinoma (74) and the gene encoding RUNX3 is methylated in various types of cancer (75).…”

Section: Up-regulated Mirs Mediating Metastasismentioning

confidence: 99%

MicroRNAs Involved in Metastasis of Hepatocellular Carcinoma: Target Candidates, Functionality and Efficacy in Animal Models and Prognostic Relevance

Weidle

Schmid

Birzele

et al. 2019

Cancer Genomics Proteomics

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Hepatocellular carcinoma (HCC) is responsible for the second-leading cancer-related death toll worldwide. Although sorafenib and levantinib as frontline therapy and regorafenib, cabazantinib and ramicurimab have now been approved for second-line therapy, the therapeutic benefit is in the range of only a few months with respect to prolongation of survival. Aggressiveness of HCC is mediated by metastasis. Intrahepatic metastases and distant metastasis to the lungs, lymph nodes, bones, omentum, adrenal gland and brain have been observed. Therefore, the identification of metastasis-related new targets and treatment modalities is of paramount importance. In this review, we focus on metastasis-related microRNAs (miRs) as therapeutic targets for HCC. We describe miRs which mediate or repress HCC metastasis in mouse xenograft models. We discuss 18 metastasis-promoting miRs and 35 metastasis-inhibiting miRs according to the criteria as outlined. Six of the metastasispromoting miRs (miR-29a,-219-5p,-331-3p, 425-5p,-487a and-1247-3p) are associated with unfavourable clinical prognosis. Another set of six down-regulated miRs (miR-101,-129-3p,-137,-149,-503, and-630) correlate with a worse clinical prognosis. We discuss the corresponding metastasisrelated targets as well as their potential as therapeutic modalities for treatment of HCC-related metastasis. A subset of up-regulated miRs-29a,-219-5p and-425-5p and downregulated miRs-129-3p and-630 were evaluated in orthotopic metastasis-related models which are suitable to mimic HCC-related metastasis. Those miRNAs may represent prioritized targets emerging from our survey. Hepatocellular carcinoma (HCC) is the second-leading cause of cancer-related death worldwide (1). In the next couple of years, an annual incidence of one million cases is expected (1). Risk factors for HCC are non-alcohol steatohepatitis, hepatitis B and C virus (HBV/HCV), alcohol and aflatoxin (2). In Asia and Africa, 60% of HCC cases are associated with HBV, 20% are related to HCV (2). Patients with early-and intermediatestage HCC are treated with locoreginal therapies, those with advanced disease receive systemic treatment (3). Sorafenib, a multikinase tyrosine kinase inhibitor was the only approved agent between 2007 and 2016 (4). This agent gives rise to only marginal therapeutic benefit. Recently, therapeutic benefit was shown with multikinase inhibitors levantinib as frontline therapy, and regorafenib, cabazantinib and ramucirumab, a monoclonal antibody directed against vascular endothelial growth factor receptor 2, as second-line therapies (4). In addition, nivolumab, a monoclonal antibody directed against programmed cell death protein 1 (PD1) has been granted accelerated approval by the Food and Drug Administration for treatment of HCC and other checkpoint inhibitors are undergoing phase III clinical trials for this indication (5). Unsupervised clustering has revealed three subtypes of HCC based on transcriptional profiling (6) and immune phenotyping with respect to lymphocyte infiltration has discov...

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RUNX3 regulates hepatocellular carcinoma cell metastasis via targeting miR-186/E-cadherin/EMT pathway

Cited by 27 publications

References 37 publications

circLARP4 induces cellular senescence through regulating miR‐761/RUNX3/p53/p21 signaling in hepatocellular carcinoma

circLARP4 induces cellular senescence through regulating miR‐761/RUNX3/p53/p21 signaling in hepatocellular carcinoma

MicroRNA‑186 promotes cell proliferation and inhibits cell apoptosis in cutaneous squamous cell carcinoma by targeting RETREG1

MicroRNAs Involved in Metastasis of Hepatocellular Carcinoma: Target Candidates, Functionality and Efficacy in Animal Models and Prognostic Relevance

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