title: FoxO3 inactivation promotes human cholangiocarcinoma tumorigenesis and chemoresistance through Keap1-Nrf2 signaling.
abstract: FoxO transcription factors have been reported to play pivotal roles in tumorigenesis and drug resistance. The mechanisms underlying the tumor suppression function of FoxOs in human cancers remain largely unknown. Aberrant expression and activation of Nrf2 often correlate with chemoresistance and poor prognosis. Here, we report that FoxO3 directs the basal transcription of Kelch-like ECH-associated protein 1 (Keap1), an adaptor protein that bridges Nrf2 to Cul3 for degradation. FoxO3 depletion resulted in Keap1 down-regulation, thereby activating Nrf2 signaling. We further demonstrated that inhibition of the FoxO3-Keap1 axis accounts for Nrf2 induction and activation induced by constitutively active AKT signaling or tumor necrosis factor α treatment. Unlike previous findings, FoxO3 silencing led to decreased reactive oxygen species production, therefore protecting cells from oxidative stress-induced killing in an Nrf2-dependent manner. Importantly, FoxO3 deficiency strongly potentiated tumor formation in nude mice and rendered cholangiocarcinoma xenografts resistant to cisplatin-induced cell death by activating Nrf2. Additionally, we found that clinical cholangiocarcinoma samples displayed FoxO3-Keap1 down-regulation and Nrf2 hyperactivation, underscoring the essential roles of these proteins in cholangiocarcinoma development.
  
  
  
  Our results unravel a unique mechanism underlying the tumor suppressor function of FoxO3 through constraining Nrf2 signaling. (Hepatology 2016;63:1914-1927).
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors: Li
authors: L
authors: Guan
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors: Lei
authors: L
authors: Zhang
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors: Zhicheng
authors: Z
authors: Gong
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors: Xiaonan
authors: X
authors: Hou
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors: Yuxiu
authors: Y
authors: Xu
authors: Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
authors: Xinhua
authors: X
authors: Feng
authors: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Shanghai, 225 Changhai Road Shanghai 200438, China.
authors: Hongyang
authors: H
authors: Wang
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors: Han
authors: H
authors: You
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000209:etiology* / Q000378:metabolism; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000209:etiology* / Q000378:metabolism; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005260:Female; D000071316:Forkhead Box Protein O3 / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000378:metabolism*; D008819:Mice, Nude; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011897:Random Allocation; D020239:Receptor Cross-Talk; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt