Steroid Receptor Coactivator 1 Promotes Human Hepatocellular Carcinoma Progression by Enhancing Wnt/β-Catenin Signaling
Steroid Receptor Coactivator 1 Promotes Human Hepatocellular Carcinoma Progression by Enhancing Wnt/β-Catenin Signaling
复制标题
DOI：
10.1074/jbc.m115.640490
复制
发表时间：
2015-07-24
影响因子：
4.8
通讯作者：
Yu, Chundong
中科院分区：
文献类型：
--
作者：
Tong, Zhangwei;Li, Ming;Yu, Chundong
类固醇受体共激活因子1（SRC-1）不仅是类固醇受体（如雄激素受体和雌激素受体）的转录共激活因子，而且也是其他转录因子的转录共激活因子。SRC-1已被证明在乳腺癌和前列腺癌的进展中起重要作用。然而，其在肝癌进展中的作用仍然未知。在这项研究中，我们报告SRC-1过表达25（62.5%）的40人肝细胞癌（HCC）标本。SRC-1的下调降低了HCC细胞的增殖，并损害了HCC异种移植物中的肿瘤维持。SRC-1的敲低降低了增殖标记物增殖细胞核抗原（PCNA）和癌基因c-Myc的蛋白水平。SRC-1基因敲除可降低二乙基亚硝胺/四氯化碳诱导的肝脏肿瘤形成以及c-Myc和PCNA在肝脏肿瘤中的表达。SRC-1至少部分通过直接与β-连环蛋白相互作用以增强Wnt/β-连环蛋白信号传导来促进c-Myc表达。与这些结果一致，SRC-1的表达与PCNA的表达在人HCC标本中呈正相关，并且SRC-1阳性HCC标本中c-Myc的表达水平高于SRC-1阴性HCC标本。此外，SRC-1和SRC-3在47.5%的HCC标本中共过表达，它们协同促进HCC细胞增殖。同时下调SRC-1和SRC-3显著抑制HCC细胞增殖。我们的研究结果表明SRC-1通过增强Wnt/β-catenin信号促进HCC进展，并表明SRC-1是HCC的潜在治疗分子靶点。
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 beta-catenin to enhance Wnt/beta-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/beta-catenin signaling and suggest that SRC-1 is a potential therapeutic molecular target for HCC.