Upregulator of cell proliferation predicts poor prognosis in hepatocellular carcinoma and contributes to hepatocarcinogenesis by downregulating FOXO3a.
Upregulator of cell proliferation predicts poor prognosis in hepatocellular carcinoma and contributes to hepatocarcinogenesis by downregulating FOXO3a.
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细胞增殖上调可预测肝细胞癌的不良预后，并通过下调 FOXO3a 促进肝癌发生
DOI：
10.1371/journal.pone.0040607
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Gao ZL
中科院分区：
文献类型：
--
作者：
Xie C;Song LB;Wu JH;Li J;Yun JP;Lai JM;Xie DY;Lin BL;Yuan YF;Li M;Gao ZL
目的探讨细胞增殖上调因子（URGCP/URG 4）的表达水平与肝细胞癌（HCC）预后的关系，探讨URGCP/URG 4在HCC发生发展中的生物学作用，进一步了解其在肝癌发生发展中的分子机制。设计使用免疫组织化学（MHC）和蛋白质印迹分析（WB）在15个肝癌细胞系、278个存档的石蜡包埋肝癌切片以及10对新鲜肝癌肿瘤和癌旁非癌组织中分析了URGCP/URG 4表达。在体外和体内检查URGCP/URG 4对细胞增殖和肿瘤发生的影响。WB和荧光素酶报告基因分析，以确定URGCP/URG 4-过表达或-敲低对细胞周期调控因子的表达和FOXO 3a的转录活性的影响。结果与正常肝细胞和癌旁组织相比，所有肝癌细胞系和新鲜肝癌组织中URGCP/URG 4表达均上调。URGCP/URG 4在278份存档HCC标本中的122份（43.8%）中也以高水平表达。URGCP/URG 4的表达水平与研究队列和各种临床亚组中HCC的临床分期和患者生存率低显著相关。引人注目的是，URGCP/URG 4的异位表达诱导HCC细胞的增殖和锚定非依赖性生长，而URGCP/URG 4的沉默具有相反的效果。此外，肝癌细胞中URGCP/URG 4的过表达增加了细胞进入G1/S过渡期，与p27 Kip 1和p21 Cip 1的下调和细胞周期蛋白D1的上调有关。这些作用伴随着Akt活性增强和FOXO 3a转录活性降低。结论URGCP/URG 4在促进肝癌细胞增殖和肿瘤发生中起重要作用，可能成为肝癌新的预后标志物和治疗靶点。
Objective The goal of the present study was to investigate the potential correlation between the expression level of upregulator of cell proliferation (URGCP/URG4) and the prognosis of hepatocellular carcinoma (HCC), and to examine the biological function of URGCP/URG4 in the progression of HCC, to better understand its underlying molecular mechanism in hepatic tumorigenesis. Design URGCP/URG4 expression was analyzed in 15 HCC cell lines, in 278 archived paraffin-embedded HCC sections, and in 10 pairs of fresh HCC tumor and para-tumor non-cancerous tissues using immunohistochemistry (IHC) and Western blotting analysis (WB). The effect of URGCP/URG4 on cell proliferation and tumorigenesis was examined in vitro and in vivo. WB and luciferase reporter analyses were performed to identify the effects of URGCP/URG4-overexpression or -knockdown on expression of cell cycle regulators and transcriptional activity of FOXO3a. Results IHC results revealed an upregulation of URGCP/URG4 in all HCC cell lines and fresh HCC samples as compared with normal liver cells and para-tumor tissues, respectively. URGCP/URG4 was also expressed at a high level in 122 of the 278 (43.8%) archived HCC specimens. The expression level of URGCP/URG4 was significantly correlated with clinical staging and poor patient survival of HCC in the study cohort, and in various clinical subgroups. Strikingly, ectopic expression of URGCP/URG4 induced proliferation and anchorage-independent growth of HCC cells, while silencing of URGCP/URG4 had the opposite effect. Furthermore, URGCP/URG4 overexpression in HCC cells increased cellular entry into the G1/S transitional phase, associated with downregulation of p27Kip1 and p21Cip1 and upregulation of cyclin D1. These effects were accompanied by enhanced Akt activity and reduced FOXO3a transcriptional activity. Conclusions URGCP/URG4 plays an important role in promoting proliferation and tumorigenesis of HCC and may represent a novel prognostic biomarker and therapeutic target for this disease.
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