Identification of WDR12 as a novel oncogene involved in hepatocellular carcinoma propagation.
Identification of WDR12 as a novel oncogene involved in hepatocellular carcinoma propagation.
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WDR12 被鉴定为参与肝细胞癌增殖的新型癌基因
DOI：
10.2147/cmar.s176268
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发表时间：
2018
影响因子：
3.3
通讯作者：
Li M
中科院分区：
文献类型：
--
作者：
Yin Y;Zhou L;Zhan R;Zhang Q;Li M
背景肝细胞癌（Hepatocellular carcinoma，HCC）是世界范围内最常见的恶性肿瘤之一。重要的是，导致HCC致病性的确切机制仍然未知。潜在癌基因的鉴定对于寻找新的肝癌治疗靶点具有重要意义。目的WDR 12（WD repeat protein 12）是WD repeats家族的成员，在核糖体生物合成途径中发挥重要作用。然而，WDR 12是否有助于HCC的发展仍然未知。本研究的目的是阐明WDR 12在HCC发展中的作用。方法从GEO数据库中检测WDR 12在肝癌组织及癌旁组织中的表达水平。RT-PCR和Western blot检测肝癌细胞系中WDR 12的表达水平。Kaplan-Meier分析WDR 12水平对HCC患者总生存期和无病生存期的影响。为了检测WDR 12是否支持HCC的发展，我们通过使用编码shRNA的慢病毒系统抑制WDR 12的表达。评估了WDR 12敲除对细胞生长、细胞增殖和细胞迁移的影响。Western blot分析其对肝癌细胞生长、增殖和迁移的影响。结果肝癌组织中WDR 12的表达水平与肝癌患者血清AFP水平、肿瘤血管浸润程度、组织学分级及TNM分期有关。此外，WDR 12的表达上调与HCC患者的总生存期和复发时间短显著相关。shRNA介导的WDR 12表达的敲低导致HepG 2和Huh-7细胞的增殖和迁移减少。值得注意的是，WDR 12的抑制导致AKT、mTOR和S6 K1的磷酸化降低。结论WDR 12参与了肝癌的增殖，抑制WDR 12可能是治疗肝癌的一个潜在策略。
Background Hepatocellular carcinoma (HCC) is one of the most common malignant cancer worldwide. Importantly, the precise mechanisms causing HCC pathogenicity are still unknown. The identification of potential oncogenes plays significant roles in finding novel therapeutic targets for human HCC. Purpose WDR12 (WD repeat protein 12), a member of WD repeats family, plays crucial roles in the ribosome biogenesis pathway. However, Whether WDR12 contributes to HCC development remains unknown. The objective of this study was to elucidate the role of WDR12 in HCC development. Methods The expression level of WDR12 in HCC tissues and adjacent non-tumor tissues were detected form Gene Expression Omnibus (GEO) database. The expression level of WDR12 in HCC cell lines were examined by RT-PCR and western blot. Kaplan-Meier analysis were used to analyze the effect of WDR12 level on overall and disease-free survival of HCC patients. To examine whether WDR12 supports development of HCC, we inhibited expression of WDR12 by using an shRNA-encoding lentivirus system. Effects of WDR12 knockdown were evaluated on cell-growth, cell-proliferation and cell-migration. The mechanisms involved in HCC cells growth, proliferation and migration were analyzed by western blot assay. Results In silico analysis of HCC data sets showed that elevated expression of WDR12 correlated with high serum AFP level, high vascular invasion, high histologic grade and high TNM stage in HCC patients. Furthermore, up-regulated expression of WDR12 significantly correlated with the short overall survival and recurrence time of HCC patients. The shRNA-mediated knockdown of WDR12 expression resulted in reduced proliferation and migration of HepG2 and Huh-7 cells. Notably, inhibition of WDR12 resulted in decreased phosphorylation of AKT, mTOR and S6K1. Conclusion Our study indicates that WDR12 contributes to HCC propagation, and indicates that suppression of WDR12 may be a potential strategy for human HCC treatment.