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MicroRNA-144-3p suppresses tumor growth and angiogenesis by targeting SGK3 in hepatocellular carcinoma.

ABSTRACT: In our previous studies, the Illumine Soledad massively parallel signature sequencing of miRNomes in non?tumor and hepatocellular carcinoma (HCC) tissues revealed that microRNA (miR)-144-3p was significantly downregulated in HCC, but its role in HCC development, especially angiogenesis, remains unclear. In this investigation, we found recovering miR?144?3p expression can significantly suppress the growth, migration and induced angiogenic capacity of HCC cells through both in vivo and in vitro experiments. Moreover, clinical correlation analysis showed that low expression of miR?144?3p was positively correlated to poor disease-free survival (DFS) of HCC patients. Mechanistically, serum and glucocorticoid kinase 3 (SGK3), the putative targets of miR?144?3p, was predicted by Target Scan database and identified to be suppressed by miR?144?3p so that inhibiting the activation of mTOR-VEGF downstream signals was activated by the phosphoinositide 3-kinase (PI3K)-independent pathway. Hence, we concluded that miR?144?3p, which is frequently downregulated in HCC, can inhibit proliferation, migration and repress angiogenesis by regulating SGK3 activation with PI3K independent signal pathway, and acts as a prognostic factor for HCC patients.

SUBMITTER: Wu M

PROVIDER: S-EPMC5652965 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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MicroRNA-144-3p suppresses tumor growth and angiogenesis by targeting SGK3 in hepatocellular carcinoma.

Wu Manya M Huang Chaoyuan C Huang Xinping X Liang Rong R Feng Yan Y Luo Xiaoling X

Oncology reports 20170811 4

In our previous studies, the Illumine Soledad massively parallel signature sequencing of miRNomes in non‑tumor and hepatocellular carcinoma (HCC) tissues revealed that microRNA (miR)-144-3p was significantly downregulated in HCC, but its role in HCC development, especially angiogenesis, remains unclear. In this investigation, we found recovering miR‑144‑3p expression can significantly suppress the growth, migration and induced angiogenic capacity of HCC cells through both in vivo and in vitro ex ...[more]

PMID: 28849156

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Project description:PurposeThe purpose of this study was to investigate the effects and mechanism of microRNA (miR)-92a-3p in retinal angiogenesis in vitro and in vivo.MethodsThe expression of miR-92a-3p was verified by real-time quantitative polymerase chain reaction (RT-qPCR). Agomir-92a-3p was intravitreally injected into the right eye on postnatal day 3 (P3), P5, and P8 in the mice, with the agomir-NC injected left eye as the control. At P7, P9, and P12, immunofluorescence was performed to examine the retinal superficial vascular plexus, deep vascular plexus, proliferation, and apoptosis in retinal vascular endothelial cells (ECs). Human retinal microvascular endothelial cells (HRMECs) were treated with mimic-NC and mimic-92a-3p, then the tube formation, cell migration, and wound healing assays were used to detect the effect of miR-92a-3p on retinal angiogenesis in vitro. Agomir-92a-3p was also intravitreally injected into the right eye of oxygen-induced retinopathy (OIR) mice at P12, with the agomir-NC injected left eye as the control, the neovascularization was observed by retinal flatmount staining with isolectin B4 at P17. Bioinformatics and high-throughput sequencing were performed to identify potential target genes of miR-92a-3p. RT-qPCR and Western blot were carried out to detect the expression of SGK3, p-GSK3β, GSK3β, Bcl-xL, and cleaved caspase-3 in the HRMECs and mouse retinas.ResultsThe overexpression of miR-92a-3p inhibited the development of retinal superficial vascular plexus and deep vascular plexus, decreased the expression of Ki67, and increased the expression of cleaved caspase-3 in isolectin B4-labeled retinal vascular ECs. In vitro, the overexpression of miR-92a-3p markedly suppressed the tube formation, cell migration, and wound healing of cultured ECs. Overexpression of miR-92a-3p inhibited both in vivo and in vitro physiological angiogenesis by downregulating the expression of SGK3, p-GSK3β/GSK3β, and Bcl-xL. In addition, agomir-92a-3p inhibited the pathological retinal neovascularization of OIR mice, by targeting SGK3, p-GSK3β/GSK3β, and Bcl-xL.ConclusionsThe miR-92a-3p could affect retinal angiogenesis by targeting SGK3 pathway, suggesting that miR-92a-3p may be a potential anti-angiogenic factor for retinal vascular disease.

Project description:PurposeHepatocellular carcinoma (HCC), a worldwide leading cause of morbidity and mortality, is the most frequent primary liver tumor. Most HCC patients are diagnosed with advanced liver cancer, resulting in a very low 5-year survival rate. Thus, there is an urgent need for the development of targeted therapies. In this study, we aimed to investigate the effect and mechanism of the miR-20a/EZH1 axis on the proliferation and metastasis of HCC and the inhibitory effect of the EZH1/EZH2 inhibitor UNC1999 on HCC.Materials and methodsThe expression of miR-20a in human HCC tissues and cell lines was detected using quantitative real-time PCR (qRT-PCR). The expressions of proteins were analyzed with immunohistochemistry and Western blotting. Luciferase assay was used to verify whether miR-20a targets EZH1 or EZH2. The effect of miR-20a on HCC progression was studied in vivo and in vitro. The tumor inhibitory effect of UNC1999 was confirmed in vivo. CCK8 assay, wound healing assay, cell migration and invasion assay were used to evaluate the synergistic effect of UNC1999 with sorafenib. RNA sequencing (RNA-seq) was performed to screen the differentially expressed genes in the Huh7 and SMMC7721 cell lines after UNC1999, sorafenib, and combination treatments.ResultsIn this study, miR-20a showed a lower expression in both HCC tissues and cell lines. MiR-20a inhibited the proliferation and migration of SMMC7721 and Huh7 cells. The results of the luciferase assay and Western blot analysis revealed that miR-20a directly targeted EZH1, a histone methyltransferase. We demonstrated that miR-20a negatively regulated the expression of EZH1 and inhibited the proliferation and metastasis of HCC by reducing H3K27 methylation. We found UNC1999 inhibited tumor cells proliferation and enhanced the inhibitory effect of sorafenib.ConclusionWe demonstrated that miR-20a suppresses the tumor proliferation and metastasis in HCC by directly targeting EZH1. UNC1999 can inhibit tumor proliferation in vivo and increase the sensitivity of hepatoma cell lines to sorafenib.

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MicroRNA-144-3p suppresses tumor growth and angiogenesis by targeting SGK3 in hepatocellular carcinoma.

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MicroRNA-144-3p suppresses tumor growth and angiogenesis by targeting SGK3 in hepatocellular carcinoma.

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