title: CYP3A5 Functions as a Tumor Suppressor in Hepatocellular Carcinoma by Regulating mTORC2/Akt Signaling.
abstract: 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 overexpression 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.
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China. Department of Thoracic Surgery, Cancer Hospital of Jiangsu Province, Cancer Institution of Jiangsu Province, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China. Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Cancer Hospital of Jiangsu Province, Nanjing, China.
authors: Feng
authors: F
authors: Jiang
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China. National Center for Liver Cancer, Shanghai, China.
authors: Lei
authors: L
authors: Chen
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
authors: Ying-Cheng
authors: YC
authors: Yang
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
authors: Xian-Ming
authors: XM
authors: Wang
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
authors: Ruo-Yu
authors: RY
authors: Wang
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
authors: Liang
authors: L
authors: Li
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
authors: Wen
authors: W
authors: Wen
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
authors: Yan-Xin
authors: YX
authors: Chang
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
authors: Cai-Yang
authors: CY
authors: Chen
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
authors: Jing
authors: J
authors: Tang
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
authors: Gao-Mi-Yang
authors: GM
authors: Liu
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
authors: Wen-Tao
authors: WT
authors: Huang
authors: Department of Thoracic Surgery, Cancer Hospital of Jiangsu Province, Cancer Institution of Jiangsu Province, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China. Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Cancer Hospital of Jiangsu Province, Nanjing, China. hywangk@vip.sina.com xulin_83@hotmail.com.
authors: Lin
authors: L
authors: Xu
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China. National Center for Liver Cancer, Shanghai, China. hywangk@vip.sina.com xulin_83@hotmail.com.
authors: Hong-Yang
authors: HY
authors: Wang
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000401:mortality / Q000556:secondary; D002465:Cell Movement; D051544:Cytochrome P-450 CYP3A / Q000502:physiology*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D008175:Lung Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000556:secondary; D000076225:Mechanistic Target of Rapamycin Complex 2; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D011379:Prognosis; D016016:Proportional Hazards Models; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D046912:Multiprotein Complexes; C560822:TIMP1 protein, human; C560823:TIMP2 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases