Dataset Information

MicroRNA-423 enhances the invasiveness of hepatocellular carcinoma via regulation of BRMS1.

ABSTRACT: Tumor metastasis portrayed the most serious challenges of cancer as it is the major cause of mortality in patients with solid tumors, including hepatocellular carcinoma (HCC). In this regard, anti-metastatic genes have a great potential for metastasis inhibition. Recent evidence pointed to a role of Breast cancer metastasis suppressor 1 (BRMS1) in suppression of metastasis of several types of cancers, whereas the regulation of BRMS1 in HCC remains unknown. Here, we used bioinformatics analyses to predict BRMS1-targeting microRNAs (miRNAs), and evaluated the functional binding of miRNAs to BRMS1 mRNA using a dual luciferase reporter assay. Among all BRMS1-targeting miRNAs, we only detected significant expression of miR-626, miR-1289 and miR-423 in HCC specimens. Specifically, we found that only miR-423 significantly inhibited protein translation of BRMS1 via specific binding to 3'-UTR of the BRMS1 mRNA. Moreover, we detected significantly lower levels of BRMS1 and significantly higher levels of miR-423 in the HCC specimens, relative to paired adjacent non-tumor liver tissue. Furthermore, BRMS1 and miR-423 levels were correlated inversely. Overexpression of miR-423 significantly decreased BRMS1 levels and promoted HCC cell invasion, while depletion of miR-423 significantly increased BRMS1 levels and inhibited HCC cell invasion. This study sheds light on miR-423 as a crucial factor that enhances HCC cell invasiveness, and suggests miR-423 as a promising therapeutic target for HCC treatment.

SUBMITTER: Sun X

PROVIDER: S-EPMC5752907 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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MicroRNA-423 enhances the invasiveness of hepatocellular carcinoma via regulation of BRMS1.

Sun Xiangjun X Wang Mingchun M Liu Haiyan H Wang Jian J

American journal of translational research 20171215 12

Tumor metastasis portrayed the most serious challenges of cancer as it is the major cause of mortality in patients with solid tumors, including hepatocellular carcinoma (HCC). In this regard, anti-metastatic genes have a great potential for metastasis inhibition. Recent evidence pointed to a role of Breast cancer metastasis suppressor 1 (BRMS1) in suppression of metastasis of several types of cancers, whereas the regulation of BRMS1 in HCC remains unknown. Here, we used bioinformatics analyses t ...[more]

PMID: 29312509

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Project description:Rational: Patients with hepatocellular carcinoma (HCC) have a poor prognosis mostly due to intrahepatic as well as distal metastasis. Vasodilator-stimulated phosphoprotein (VASP), a regulator of actin cytoskeleton and cell migration, is overexpressed in HCC and correlated with its malignant features and poor prognosis. Very little is known about its function in HCC. Methods: qRT-PCR, Western blot and IHC were used to detect the VASP expression in tissues and cells. Transwell and wound healing assays were used to measure the migration and invasion of HCC cells. Immunoblotting and immunofluorescence were used for detection of epithelial-to-mesenchymal transition (EMT) progression in HCC cells. A lung metastasis mouse model was used to evaluate metastasis of HCC in vivo. The putative targets of miR-204 were disclosed by public databases and a dual-luciferase reporter assay. IP was used to show the interaction between VASP and CRKL. ChIP was used to analyze the binding of HIF-1? to VASP promoter region. Results: Our data involving both gain- and loss-of-function studies revealed that VASP activated AKT and ERK signaling and promoted HCC migration and invasion in vitro and in vivo by altering the EMT phenotype and expression of MMPs. We investigated the positive correlation between VASP and an adapter protein, CRKL. VASP dynamically co-localized at the SH3N domain of CRKL and mediated its function. Mechanistically, VASP overexpression at the transcriptional level was mediated by HIF-1? through direct binding to two hypoxia response elements (HRE) in the VASP promoter region. Furthermore, we identified hypoxia-induced down-regulation of miR-204, which functioned as the regulator of VASP overexpression at the post-transcriptional level. Also, hypoxia-activated p-Smad3 dependent TGF-? signaling indirectly promoted VASP expression. Conclusion: A variety of hypoxia-induced molecular mechanisms contributed to the upregulation of VASP at transcriptional and post-transcriptional levels. These mechanisms involved CRKL, HIF-1?, miR-204, and TGF-? activating the AKT and ERK signaling to promote EMT and expression of MMPs. Taken together, our results defined VASP as an oncogene of HCC pathogenesis and metastasis with the potential to serve as a prognostic biomarker.

Project description:BackgroundHepatocellular carcinoma (HCC) remains a major public health problem worldwide. The identification of effective chemotherapeutic targets for advanced HCC patients is urgently required. In this study, we investigated the role of protein phosphatase 2A-B55δ subunit (PP2A-B55δ, encoded by the PPP2R2D gene) and related mechanisms affecting chemotherapy sensitivity of HCC.MethodsExperimental approaches for measuring the levels of PPP2R2D mRNA and B55δ protein in HCC included bioinformatics analyses, quantitative real-time polymerase chain reaction (qRT-PCR), western blotting (WB), immunofluorescence and immunohistochemistry assays. Cell cycle, migration, colony formation, apoptosis, and cell proliferation assays in stable PPP2R2D-knockdown and -overexpression cell lines in vitro, and tumorigenicity assays in vivo, were performed to explore the function of B55δ in cisplatin (cDDP) chemotherapy of HCC. Bioinformatics prediction, luciferase reporter assays, qRT-PCR, WB, and cell cycle analyses were used to reveal the regulatory relationship between microRNA-133b (miR-133b) and PPP2R2D expression. miR-133b mimic and inhibitor were used to elucidate the regulatory mechanism.ResultsOur studies showed that PPP2R2D expression was down-regulated in both HCC tumors and HCC cell lines. Treatment with cDDP increased the amount of B55δ protein. Artificially increasing the expression of B55δ counteracted cyclin-dependent kinase 1 activation, modulated transitions of the cell cycle, and increased the suppressive effect of cDDP on cell migration, colony formation, apoptosis, and proliferation in vitro and tumor growth in vivo, thus enhancing therapeutic efficiency. In contrast, knockdown of B55δ partially inhibited the effect of cDDP chemotherapy. miR-133b was shown to regulate PPP2R2D expression by binding to the 3'-untranslated region of PPP2R2D mRNA. The miR-133b/PPP2R2D signaling pathway affects the effectiveness of cDDP chemotherapy.ConclusionsPP2A-B55δ, regulated by miR-133b, enhances the sensitivity of HCC to cDDP chemotherapy. Our data indicate that PP2A-B55δ might be a novel and attractive target for increasing chemotherapy sensitivity of HCC.

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MicroRNA-423 enhances the invasiveness of hepatocellular carcinoma via regulation of BRMS1.

Publications

MicroRNA-423 enhances the invasiveness of hepatocellular carcinoma via regulation of BRMS1.

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