Dataset Information

A SOX9-AS1/miR-5590-3p/SOX9 positive feedback loop drives tumor growth and metastasis in hepatocellular carcinoma through the Wnt/?-catenin pathway.

ABSTRACT: Hepatocellular carcinoma (HCC) is a prevalent solid tumor with a high global death rate. SRY box 9 (SOX9) has been reported as an oncogene in HCC by several studies, but the underlying mechanism remains largely unexplored. Here, we confirmed upregulation of SOX9 in HCC tissues and cell lines and validated that SOX9 facilitates proliferation, migration and invasion in HCC. We subsequently identified that the long non-coding RNA (lncRNA) SOX9 antisense RNA 1 (SOX9-AS1) is a neighbor gene to SOX9; SOX9-AS1 is also upregulated in HCC, and its expression is positively correlated with that of SOX9. In addition, SOX9-AS1 appears to have prognostic significance in HCC patients. We showed that SOX9-AS1 aggravates HCC progression and metastasis in vitro and in vivo. We demonstrated that SOX9-AS1 sponges miR-5590-3p to elevate SOX9 expression, and that SOX9 in turn transcriptionally activates SOX9-AS1. Moreover, we verified that SOX9-AS1 regulates SOX9 and its known downstream Wnt/?-catenin pathway so as to facilitate epithelial-to-mesenchymal transition. The results of our rescue assays suggest that SOX9-AS1 regulates HCC progression through SOX9 and the Wnt/?-catenin pathway. In conclusion, our study demonstrates that a SOX9-AS1/miR-5590-3p/SOX9 positive feedback loop drives tumor growth and metastasis in HCC through the Wnt/?-catenin pathway, suggesting SOX9-AS1 as a novel potential prognostic and treatment target for HCC.

SUBMITTER: Zhang W

PROVIDER: S-EPMC6763786 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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A SOX9-AS1/miR-5590-3p/SOX9 positive feedback loop drives tumor growth and metastasis in hepatocellular carcinoma through the Wnt/β-catenin pathway.

Zhang Wei W Wu Yanhui Y Hou Bingwu B Wang Yadong Y Deng Dongfeng D Fu Zhihao Z Xu Zongquan Z

Molecular oncology 20190831 10

Hepatocellular carcinoma (HCC) is a prevalent solid tumor with a high global death rate. SRY box 9 (SOX9) has been reported as an oncogene in HCC by several studies, but the underlying mechanism remains largely unexplored. Here, we confirmed upregulation of SOX9 in HCC tissues and cell lines and validated that SOX9 facilitates proliferation, migration and invasion in HCC. We subsequently identified that the long non-coding RNA (lncRNA) SOX9 antisense RNA 1 (SOX9-AS1) is a neighbor gene to SOX9; ...[more]

PMID: 31402556

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Project description:The Wnt/?-catenin pathway is constitutively active and promotes multiple tumor processes, including breast cancer metastasis. However, the underlying mechanism by which the Wnt/?-catenin pathway is constitutively activated in breast cancer metastasis remains unclear. Inhibition of Wnt antagonists is important for Wnt/?-catenin signaling activation, and post-transcriptional regulation of these antagonists by microRNAs (miRNAs) might be a possible mechanism underlying signaling activation. Regulation of nuclear pre-mRNA domain-containing 1A (RPRD1A) is a known inhibitor of cell growth and Wnt/?-catenin signaling activity, but the function and regulatory mechanism of RPRD1A in breast cancer have not been clarified. The aim of this study was to understand how regulators of the Wnt/?-catenin pathway may play a role in the metastasis of this cancer. Methods: RPRD1A expression and its association with multiple clinicopathological characteristics was analyzed immunohistochemically in human breast cancer specimens. miR-454-3p expression was analyzed using real-time PCR. RPRD1A or miR-454-3p knockdown and overexpression were used to determine the underlying mechanism of their functions in breast cancer cells. Xenografted tumor model, 3D invasive culture, cell migration and invasion assays and sphere formation assay were used to determine the biofunction of RPRD1A and miR-454-3p in breast cancer. Electrophoretic mobility shift assay (EMSA), luciferase reporter assay, and RNA immunoprecipitation (RIP) were performed to study the regulation and underlying mechanisms of RPRD1A and miR-454-3p expression and their correlation with the Wnt/?-catenin pathway in breast cancer. Results: The Wnt/?-catenin signaling antagonist RPRD1A was downregulated and its upstream regulator miR-454-3p was amplified and overexpressed in metastatic breast cancer, and both were correlated with overall and relapse-free survival in breast cancer patients. The suppression by miR-454-3p on RPRD1A was found to activate Wnt/?-catenin signaling, thereby promoting metastasis. Simultaneously, three other negative regulators of the Wnt/?-catenin pathway, namely, AXIN2, dickkopf WNT signaling pathway inhibitor (DKK) 3 and secreted frizzled related protein (SFRP) 1, were also found to be targets of miR-454-3p and were involved in the signaling activation. miR-454-3p was found to be involved in early metastatic processes and to promote the stemness of breast cancer cells and early relapse under both in vitro and in vivo conditions. Conclusions: The findings indicate that miR-454-3p-mediated suppression of Wnt/?-catenin antagonist RPRD1A, as well as AXIN2, DKK3 and SFRP1, sustains the constitutive activation of Wnt/?-catenin signaling; thus, miR-454-3p and RPRD1A might be potential diagnostic and therapeutic targets for breast cancer metastasis.

Dataset Information

A SOX9-AS1/miR-5590-3p/SOX9 positive feedback loop drives tumor growth and metastasis in hepatocellular carcinoma through the Wnt/?-catenin pathway.

Publications

A SOX9-AS1/miR-5590-3p/SOX9 positive feedback loop drives tumor growth and metastasis in hepatocellular carcinoma through the Wnt/β-catenin pathway.

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