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Steroid Receptor Coactivator 1 Promotes Human Hepatocellular Carcinoma Progression by Enhancing Wnt/?-Catenin Signaling.

ABSTRACT: Steroid receptor coactivator 1 (SRC-1) is a transcriptional coactivator not only for steroid receptors, such as androgen receptor and estrogen receptor, but also for other transcription factors. SRC-1 has been shown to play an important role in the progression of breast cancer and prostate cancer. However, its role in liver cancer progression remains unknown. In this study, we report that SRC-1 was overexpressed in 25 (62.5%) of 40 human hepatocellular carcinoma (HCC) specimens. Down-regulation of SRC-1 decreased HCC cell proliferation and impaired tumor maintenance in HCC xenografts. Knockdown of SRC-1 reduced protein levels of the proliferation marker proliferating cell nuclear antigen (PCNA) and the oncogene c-Myc. Knockout of SRC-1 in mice reduced diethylnitrosamine/CCl4-induced tumor formation in the liver and the expression of c-Myc and PCNA in liver tumors. SRC-1 promoted c-Myc expression, at least in part, by directly interacting with ?-catenin to enhance Wnt/?-catenin signaling. Consistent with these results, the expression of SRC-1 was positively correlated with PCNA expression in human HCC specimens, and the expression levels of c-Myc in SRC-1-positive HCC specimens were higher than in SRC-1-negative HCC specimens. In addition, SRC-1 and SRC-3 were co-overexpressed in 47.5% of HCC specimens, and they cooperated to promote HCC cell proliferation. Simultaneous down-regulation of SRC-1 and SRC-3 dramatically inhibited HCC cell proliferation. Our results demonstrate that SRC-1 promotes HCC progression by enhancing Wnt/?-catenin signaling and suggest that SRC-1 is a potential therapeutic molecular target for HCC.

SUBMITTER: Tong Z

PROVIDER: S-EPMC4513118 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Steroid Receptor Coactivator 1 Promotes Human Hepatocellular Carcinoma Progression by Enhancing Wnt/β-Catenin Signaling.

Tong Zhangwei Z Li Ming M Wang Wei W Mo Pingli P Yu Li L Liu Kun K Ren Wenjing W Li Wengang W Zhang Hao H Xu Jianming J Yu Chundong C

The Journal of biological chemistry 20150616 30

Steroid receptor coactivator 1 (SRC-1) is a transcriptional coactivator not only for steroid receptors, such as androgen receptor and estrogen receptor, but also for other transcription factors. SRC-1 has been shown to play an important role in the progression of breast cancer and prostate cancer. However, its role in liver cancer progression remains unknown. In this study, we report that SRC-1 was overexpressed in 25 (62.5%) of 40 human hepatocellular carcinoma (HCC) specimens. Down-regulation ...[more]

PMID: 26082485

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Project description:BackgroundHepatocellular carcinoma is a widespread cancer worldwide, ranking as the fifth most frequent cancer and the fourth leading cause of cancer-related deaths. According to comprehensive research, TLK2, a phosphorylated kinase, has been discovered to play a crucial role in promoting tumor development. However, the prognostic significance and influence of TLK2 on hepatocellular carcinoma tumor cells and the immune microenvironment remain unexplored, warranting further investigation. The aim of this study was to investigate the role of TLK2 in promoting the development of hepatocellular carcinoma.MethodsThe present study utilized The Cancer Genome Atlas (TCGA) database and other databases as training sets to examine the expression of TLK2 and its prognostic significance. The findings were subsequently validated through cell proliferation assays and cell colony assays. Gene set enrichment analysis (GSEA) was employed to investigate the tumor-related biological processes associated with TLK2 in hepatocellular carcinoma, while the relationship between TLK2 expression and Wnt/β-catenin signaling pathway was analyzed via TCGA dataset analysis. Western blotting and immunofluorescence assays were used to confirm the experimental results.ResultsTLK2 showed higher expression levels in tumor tissues than in normal tissues. Alpha fetoprotein (AFP), T stage, pathological stage, and histological grade were significantly associated with TLK2 expression. High TLK2 expression correlated with worse overall survival (OS) [hazard ratio (HR) =1.62, 95% confidence interval (CI): 1.14-2.29, P=0.007], progression-free survival (PFS) (HR =1.88, 95% CI: 1.40-2.52, P<0.001) and disease specific survival (DSS) (HR =1.86, 95% CI: 1.18-2.93, P=0.007) in the training and validation sets. Both univariate and multivariate analyses showed that TLK2 was an independent prognostic factor. GSEA showed that TLK2 was significantly enriched in tumor-related biological processes. TLK2 induced the activation of β-catenin signaling, resulting in sustained tumor growth. Methyl thiazolyl tetrazolium (MTT) and colony formation assays demonstrated that TLK2 could promote hepatocellular carcinoma progression. Furthermore, TLK2 showed a significant association with β-catenin in the Wnt pathway.ConclusionsTLK2 represents an independent prognostic factor in hepatocellular carcinoma and can promote cancer progression via the β-catenin signaling pathway.

Dataset Information

Steroid Receptor Coactivator 1 Promotes Human Hepatocellular Carcinoma Progression by Enhancing Wnt/?-Catenin Signaling.

Publications

Steroid Receptor Coactivator 1 Promotes Human Hepatocellular Carcinoma Progression by Enhancing Wnt/β-Catenin Signaling.

Similar Datasets

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