Hypoxia upregulates Rab11-family interacting protein 4 through HIF-1α to promote the metastasis of hepatocellular carcinoma
Hypoxia upregulates Rab11-family interacting protein 4 through HIF-1α to promote the metastasis of hepatocellular carcinoma
复制标题
缺氧通过HIF-1α上调Rab11家族相互作用蛋白4促进肝细胞癌转移
DOI：
10.1038/onc.2015.49
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发表时间：
2015-12-03
期刊：
影响因子：
8
通讯作者：
Qin, W.
中科院分区：
文献类型：
--
作者：
Hu, F.;Deng, X.;Qin, W.
低氧微环境是肝细胞癌（HCC）侵袭转移的强大驱动力。缺氧诱导因子1 α (HIF-1 α)作为缺氧转录反应的重要调节因子，可诱导参与HCC转移过程不同步骤的多个靶基因的表达。寻找与缺氧转移相关的靶基因对于揭示肝癌转移的分子机制具有重要意义。在本研究中，我们发现缺氧可以诱导rab11家族相互作用蛋白4 （Rab11-FIP4）上调，并通过HIF-1a激活Rab11-FIP4启动子。Rab11-FIP4过表达显著增强了肝癌细胞在体外的迁移和侵袭能力，也促进了肝癌细胞在体内的远处肺转移，而Rab11-FIP4沉默则降低了肝癌细胞在体外的迁移和侵袭能力，抑制了肝癌细胞在体内的肺转移。Rab11-FIP4通过磷酸化PRAS40促进HCC转移，并受mTOR调控。此外，Rab11-FIP4在HCC组织中的表达水平显著升高，Rab11-FIP4的高表达与HCC患者血管侵犯及预后不良密切相关。在HCC组织中Rab11-FIP4与HIF-1 α的表达呈显著正相关，Rab11-FIP4与HIF-1 α的联合表达是HCC患者预后不良的更有价值的预测因子。综上所述，Rab11-FIP4是HIF-1 α的靶基因，在HCC中具有促转移作用，提示Rab11-FIP4可能是HCC治疗的一个有希望的候选靶点。
Hypoxic microenvironment is a powerful driving force for the invasion and metastasis of hepatocellular carcinoma (HCC). Hypoxia-inducible factor 1 alpha (HIF-1 alpha), as a crucial regulator of transcriptional responses to hypoxia, induces the expression of multiple target genes involved in different steps of HCC metastatic process. It is critical to find target genes associated with metastasis under hypoxia for shedding new light on molecular mechanism of HCC metastasis. In this study, we uncovered that hypoxia could induce the upregulation of Rab11-family interacting protein 4 (Rab11-FIP4) and activation of Rab11-FIP4 promoter by HIF-1a. The overexpression of Rab11-FIP4 significantly enhanced the mobility and invasiveness of HCC cells in vitro, also contributed to distant lung metastasis in vivo, whereas silencing of Rab11-FIP4 decreased the ability of migration and invasion in HCC cells in vitro and suppressed lung metastasis in vivo. Rab11-FIP4 facilitated HCC metastasis through the phosphorylation of PRAS40, which was regulated by mTOR. Furthermore, the expression level of Rab11-FIP4 was significantly increased in HCC tissues and high expression of Rab11-FIP4 was closely correlated with vascular invasion and poor prognosis in HCC patients. A markedly positive correlation between the expression of Rab11-FIP4 and HIF-1 alpha was observed in HCC tissues and combination of Rab11-FIP4 and HIF-1 alpha was a more valuable predictor of poor prognosis for HCC patients. In conclusion, Rab11-FIP4 is a target gene of HIF-1 alpha and has a pro-metastatic role in HCC, suggesting that Rab11-FIP4 may be a promising candidate target for HCC treatment.