CYP3A5 Functions as a Tumor Suppressor in Hepatocellular Carcinoma by Regulating mTORC2/Akt Signaling
CYP3A5 Functions as a Tumor Suppressor in Hepatocellular Carcinoma by Regulating mTORC2/Akt Signaling
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DOI：
10.1158/0008-5472.can-14-1589
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发表时间：
2015-04-01
期刊：
影响因子：
11.2
通讯作者：
Wang, Hong-Yang
中科院分区：
文献类型：
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作者：
Jiang, Feng;Chen, Lei;Wang, Hong-Yang
CYP 3A 5是一种细胞色素P450蛋白，在许多致癌物和抗癌药物的肝脏代谢中发挥作用。然而，它并没有被认为直接影响癌症的进展。在这项研究中，我们通过证明CYP 3A 5在许多肝细胞癌（HCC）中下调来挑战这一观点，其中它作为肿瘤抑制因子拮抗恶性表型具有重要作用。CYP 3A 5在检测的多个人HCC队列中下调。较低的CYP 3A 5水平与更侵袭性的血管浸润、分化差、治疗后疾病复发时间较短和患者总体生存率较差相关。机制研究表明，CYP 3A 5过表达限制MMP 2/9的功能，并通过抑制AKT信号转导抑制HCC的迁移和侵袭。值得注意的是，在CYP 3A 5过表达的HCC细胞中，Ser 473处的AKT磷酸化受到抑制，这一事件需要mTORC 2而不是Rictor/mTOR复合物的形成。发现CYP 3A 5诱导的ROS蓄积是mTORC 2活性的关键上游调节因子，这与大多数转移能力降低的临床HCC标本中GSH氧化还原活性降低的证据一致。综上所述，我们的研究结果将CYP 3A 5定义为HCC发病机制和转移的抑制因子，具有作为预后生物标志物的潜在效用。（C）2015年AACR。
CYP3A5 is a cytochrome P450 protein that functions in the liver metabolism of many carcinogens and cancer drugs. However, it has not been thought to directly affect cancer progression. In this study, we challenge this perspective by demonstrating that CYP3A5 is downregulated in many hepatocellular carcinomas (HCC), where it has an important role as a tumor suppressor that antagonizes the malignant phenotype. CYP3A5 was downregulated in multiple cohorts of human HCC examined. Lower CYP3A5 levels were associated with more aggressive vascular invasion, poor differentiation, shorter time to disease recurrence after treatment, and worse overall patient survival. Mechanistic investigations showed that CYP3A5 over-expression limited MMP2/9 function and suppressed HCC migration and invasion in vitro and in vivo by inhibiting AKT signaling. Notably, AKT phosphorylation at Ser473 was inhibited in CYP3A5-overexpressing HCC cells, an event requiring mTORC2 but not Rictor/mTOR complex formation. CYP3A5-induced ROS accumulation was found to be a critical upstream regulator of mTORC2 activity, consistent with evidence of reduced GSH redox activity in most clinical HCC specimens with reduced metastatic capacity. Taken together, our results defined CYP3A5 as a suppressor of HCC pathogenesis and metastasis with potential utility a prognostic biomarker. (C)2015 AACR.