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Activation of androgen receptor induces ID1 and promotes hepatocellular carcinoma cell migration and invasion.

ABSTRACT: Androgen receptor (AR) activity is associated with cancer development and progression. In hepatocellular carcinoma (HCC), AR contributes to HCC incidence, but the role of AR in HCC cell migration and invasion remains largely unknown. In this study, we found that AR was expressed at high levels in a subgroup of HCC cell lines with high metastatic potential. Experiments using lentiviral overexpression or small hairpin RNA knockdown of AR as well as activation of AR by its ligand indicated that AR activation promoted HCC cell migration and invasion. We also found that AR activation enhanced the expression of a metastasis-promoting gene, ID1, which led to increased HCC cell migration and invasion. An AR antagonist was able to block this process, suggesting that AR activation in AR-positive HCC may be therapeutically inhibited as a potential intervention strategy.

SUBMITTER: Ao J

PROVIDER: S-EPMC5528389 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Activation of androgen receptor induces ID1 and promotes hepatocellular carcinoma cell migration and invasion.

Ao Junping J Meng Jiao J Zhu Lei L Nie Huizhen H Yang Chenchen C Li Jinjun J Gu Jianren J Lin Qiushi Q Long Weiwen W Dong Xiaoqun X Li Chao C

Molecular oncology 20120705 5

Androgen receptor (AR) activity is associated with cancer development and progression. In hepatocellular carcinoma (HCC), AR contributes to HCC incidence, but the role of AR in HCC cell migration and invasion remains largely unknown. In this study, we found that AR was expressed at high levels in a subgroup of HCC cell lines with high metastatic potential. Experiments using lentiviral overexpression or small hairpin RNA knockdown of AR as well as activation of AR by its ligand indicated that AR ...[more]

PMID: 22819717

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Project description:Dickkopf-1 (DKK1), an inhibitor of the most frequently impaired signaling pathway in hepatocellular carcinoma (HCC), the Wnt/beta-catenin pathway, seems to fulfill contradictory functions in the process of tumorigenesis, acting either as an oncogenic promoter of metastasis or as a tumor suppressor. Elevated serum levels of DKK1 have been reported in HCC; however, little is known about its functional significance. In the current study, we treated HepG2/C3A and PLC/PRF/5 with the recombinant protein DKK1. Cytotoxicity was first determined by the WST-8 assay. AFP expression was measured at both the mRNA and protein levels. Expression of the oncogenes MYC, CCND1, hTERT, and MDM2 and the tumor suppressor genes TP53, P21 and RB was assessed. Western blot analysis of non-phosphorylated ?-catenin and Sanger sequencing were performed to explain the functional differences between the two cell lines. Subsequently, inflammation, migration and invasion were evaluated by qPCR, ELISA, the Boyden chamber assay, zymography, and MMP-2 and MMP-9 western blot analysis. Knockdown of DKK1 and TGF-?1 were also performed. Our results suggest that DKK1 exerts an oncogenic effect on HepG2/C3A cell line by upregulating the expression of oncogenes and downregulating that of tumor suppressor genes, whereas the opposite effect was demonstrated in PLC/PRF/5 cells. This differential impact of DKK1 can be explained by the mutations that affect the canonical Wnt pathway that were detected in exon 3 of the CTNNB1 gene in the HepG2 cell line. We further confirmed that DKK1 promotes inflammation, tumor invasion and migration in both cell types. The canonical pathway was not responsible for the DKK1 proinvasive effect, as indicated by the active ?-catenin levels in the two cell lines upon DKK1 treatment. Interestingly, knockdown of TGF-?1 negatively affected the DKK1 proinvasive effect. Taken together, DKK1 appears to facilitate tumor invasion and migration through TGF- ?1 by remodeling the tumor microenvironment and inducing inflammation. This finding endorses the relevance of TGF-?1 as a therapeutic target.

Dataset Information

Activation of androgen receptor induces ID1 and promotes hepatocellular carcinoma cell migration and invasion.

Publications

Activation of androgen receptor induces ID1 and promotes hepatocellular carcinoma cell migration and invasion.

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