Dataset Information

MiR-642 serves as a tumor suppressor in hepatocellular carcinoma by regulating SEMA4C and p38 MAPK signaling pathway.

ABSTRACT: Hepatocellular carcinoma (HCC) is a malignant tumor with high incidence and high risk. Study of the role and mechanism of miRNAs are a hot spot of research providing new treatment ideas in malignant tumors. The effect of miR-642a on HCC progression and the underlying molecular mechanism were investigated. Expression of miR-642a and SEMA4C was measured by western blot analysis and RT-PCR. miR-642a expression was elevated while SEMA4C expression was attenuated in HCC tissues and cells. Results of luciferase reporter and western blot analyses show that miR-642a modulated SEMA4C expression by binding to its 3'UTR. Moreover, miR-642a negatively regulated SEMA4C expression. HCC cell migration and invasion was tested by Transwell assays. The findings revealed that the number of migrated and invaded cells were reduced by miR-642a mimic and raised by miR-642a inhibitor, indicating that miR-642a showed a suppression effect on HCC cell migration and invasion. Additionally, the migration and invasion of HCC cells were inhibited by SEMA4C siRNA, and SEMA4C reversed miR-642a effect on HCC migration and invasion. Furthermore, p38 MAPK signaling pathway was proven to be inhibited by miR-642a mimic, whereas facilitated by miR-642a inhibitor and SEMA4C siRNA could overturn the promotion effect of miR-642a inhibitor. Briefly, miR-642a targeted SEMA4C to repress HCC cell migration and invasion through p38 MAPK signaling pathway providing a new strategy for treatment of HCC patients.

SUBMITTER: Yu Z

PROVIDER: S-EPMC7436928 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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miR-642 serves as a tumor suppressor in hepatocellular carcinoma by regulating SEMA4C and p38 MAPK signaling pathway.

Yu Zaijun Z Du Yuehe Y Li Hongying H Huang Jichao J Jiang Deqing D Fan Jilong J Shen Yuelan Y Zhang Lingling L Yu Xiujuan X Xu Na N Ke Qungang Q

Oncology letters 20200730 4

Hepatocellular carcinoma (HCC) is a malignant tumor with high incidence and high risk. Study of the role and mechanism of miRNAs are a hot spot of research providing new treatment ideas in malignant tumors. The effect of miR-642a on HCC progression and the underlying molecular mechanism were investigated. Expression of miR-642a and SEMA4C was measured by western blot analysis and RT-PCR. miR-642a expression was elevated while SEMA4C expression was attenuated in HCC tissues and cells. Results of ...[more]

PMID: 32863907

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Project description:Extensive changes of circRNA expression underscore their essential contributions to multiple hallmarks of cancers; however, their functions and mechanisms of action in esophageal squamous cell carcinoma (ESCC) remain undetermined. Here, we adopted a three-stage approach by first screening for significantly differentially expressed circRNAs in ESCC and performing an external validation study, followed by the functional analyses. The properties of circRNAs were evaluated using Sanger sequencing, RNase R digestion, actinomycin D treatment, subcellular localization analysis, and fluorescence in situ hybridization. Target transcripts were predicted using online tools and verified by dual-luciferase, RNA immunoprecipitation, qRT-PCR, and western blot. Biotin-labeled RNA-protein pull-down, mass spectrometry, and RNA immunoprecipitation were employed to identify proteins interacting with circRNAs. Gain- and loss-of-function experiments were performed to uncover the roles of circRNAs, their target genes, and binding proteins in the proliferation, metastasis, and invasion. We observed that circFAM120B (hsa_circ_0001666) was frequently downregulated in cancer tissues and patient plasma, and its expression level was related to overall survival in ESCC patients. Overexpression of circFAM120B inhibited the proliferation, metastasis, and invasion of ESCC while silencing it enhanced malignant phenotypes. Mechanistically, circFAM120B was predominantly located in the cytoplasm, guarantying its sponging for miR-661 to restore the expression of PPM1L, a tumor suppressor. We observed that circFAM120B could reduce the stability of RNA-dependent protein kinase (PKR) by promoting its ubiquitination-dependent degradation and subsequently regulating the p38 MAPK signaling pathway, resulting in the repression of EMTs in ESCC cells. Our findings suggest that circFAM120B is a promising biomarker of ESCC, which acts as a tumor suppressor via the circFAM120B/miR-661/PPM1L axis and PKR/p38 MAPK/EMT pathway, supporting its significance as a candidate therapeutic target.

Project description:Background: Hypoxia plays an important role in the lung metastasis of hepatocellular carcinoma (HCC). However, the process by which hypoxia promotes the formation of a pre-metastatic niche (PMN) and its underlying mechanism remain unclear. Methods: Exosomes derived from normoxic and hypoxic HCC cells were collected to induce fibroblast activation in vitro and PMN formation in vivo. The micro RNA (miR) profiles of the exosomes were sequenced to identify differentially expressed miRNAs. Gain- and loss-of-function analyses were performed to investigate miR-4508 function. Dual-luciferase, western blotting, and real-time reverse transcription-PCR analyses were used to identify the direct targets of miR-4508 and its downstream signaling pathways. To demonstrate the roles of hypoxic tumor-derived exosomes (H-TDEs) and miR-4508 in the lung metastasis of liver cancer, H22 tumor cells were injected through the tail vein of mice. Blood plasma-derived exosomes from patients with HCC who underwent transarterial chemoembolization (TACE) were applied to determine clinical correlations. Results: We demonstrated that H-TDEs activated lung fibroblasts and facilitated PMN formation, thereby promoting lung metastasis in mice. Screening for upregulated exosomal miRNAs revealed that miR-4508 and its target, regulatory factor X1 (RFX1), were involved in H-TDE-induced lung PMN formation. Moreover, miR-4508 was significantly upregulated in plasma exosomes derived from patients with HCC after TACE. We confirmed that the p38 MAPK-NF-κB signaling pathway is involved in RFX1 knockdown-induced fibroblast activation and PMN formation. In addition, IL17A, a downstream target of RFX1, was identified as a link between RFX1 knockdown and p38 MAPK activation in fibroblasts. Conclusion: Hypoxia enhances the release of TDEs enriched with miR-4508, thereby promoting lung PMN formation by targeting the RFX1-IL17A-p38 MAPK-NF-κB pathway. These findings highlight a novel mechanism underlying hypoxia-induced pulmonary metastasis of HCC.

Dataset Information

MiR-642 serves as a tumor suppressor in hepatocellular carcinoma by regulating SEMA4C and p38 MAPK signaling pathway.

Publications

miR-642 serves as a tumor suppressor in hepatocellular carcinoma by regulating SEMA4C and p38 MAPK signaling pathway.

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