title: ADRB2 signaling promotes HCC progression and sorafenib resistance by inhibiting autophagic degradation of HIF1α.
abstract: Considerable evidence suggests that adrenergic signaling played an essential role in tumor progression. However, its role in hepatocellular carcinoma (HCC) and the underlying mechanisms remain unknown.
  
  
  
  The effect of adrenaline in hepatocarcinogenesis was observed in a classical diethylnitrosamine-induced HCC mouse model. Effects of ADRB2 signaling inhibition in HCC cell lines were analyzed in proliferation, apoptosis, colony formation assays. Autophagy regulation by ADRB2 was assessed in immunoblotting, immunofluorescence and immunoprecipitation assays. In vivo tumorigenic properties and anticancer effects of sorafenib were examined in nude mice. Expression levels of ADRB2 and hypoxia-inducible factor-1α (HIF1α) in 150 human HCC samples were evaluated by immunohistochemistry.
  
  
  
  We uncovered that adrenaline promoted DEN-induced hepatocarcinogenesis, which was reversed by the ADRB2 antagonist ICI118,551. ADRB2 signaling also played an essential role in sustaining HCC cell proliferation and survival. Notably, ADRB2 signaling negatively regulated autophagy by disrupting Beclin1/VPS34/Atg14 complex in an Akt-dependent manner, leading to HIF1α stabilization, reprogramming of HCC cells glucose metabolism, and the acquisition of resistance to sorafenib. Conversely, inhibition of ADRB2 signaling by ICI118,551, or knockdown ADRB2 expression, led to enhanced autophagy, HIF1α destabilization, tumor growth suppression, and improved anti-tumor activity of sorafenib. Consistently, ADRB2 expression correlated positively with HIF1α in HCC specimens and was associated with HCC outcomes.
  
  
  
  Our results uncover an important role of ADRB2 signaling in regulating HCC progression. Given the efficacy of ADRB2 modulation on HCC inhibition and sorafenib resistance, adrenoceptor antagonist appears to be a putative novel treatment for HCC and chemoresistance.
  
  
  
  ADRB2 signaling played an essential role in sustaining hepatocellular carcinoma cell proliferation and survival. ADRB2 signaling negatively regulated autophagy, leading to hypoxia-inducible factor-1α stabilization, reprogramming of hepatocellular carcinoma cells glucose metabolism, and the acquisition of resistance to sorafenib. Adrenoceptor antagonist appears to be a putative novel treatment for hepatocellular carcinoma and chemoresistance.
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, PR China.
authors.forename: Fu-Quan
authors.initials: FQ
authors.lastname: Wu
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, PR China.
authors.forename: Tian
authors.initials: T
authors.lastname: Fang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, PR China; National Center for Liver Cancer Research, Shanghai, PR China.
authors.forename: Le-Xing
authors.initials: LX
authors.lastname: Yu
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, PR China; National Center for Liver Cancer Research, Shanghai, PR China.
authors.forename: Gui-Shuai
authors.initials: GS
authors.lastname: Lv
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, PR China.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Lv
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, PR China.
authors.forename: Dong
authors.initials: D
authors.lastname: Liang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, PR China.
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, PR China.
authors.forename: Chang-Zheng
authors.initials: CZ
authors.lastname: Wang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, PR China; National Center for Liver Cancer Research, Shanghai, PR China.
authors.forename: Ye-Xiong
authors.initials: YX
authors.lastname: Tan
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, PR China; National Center for Liver Cancer Research, Shanghai, PR China.
authors.forename: Jin
authors.initials: J
authors.lastname: Ding
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, PR China; National Center for Liver Cancer Research, Shanghai, PR China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Chen
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, PR China; National Center for Liver Cancer Research, Shanghai, PR China.
authors.forename: Liang
authors.initials: L
authors.lastname: Tang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, PR China; National Center for Liver Cancer Research, Shanghai, PR China.
authors.forename: Lin-Na
authors.initials: LN
authors.lastname: Guo
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, PR China; National Center for Liver Cancer Research, Shanghai, PR China.
authors.forename: Shan-Hua
authors.initials: SH
authors.lastname: Tang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, PR China; National Center for Liver Cancer Research, Shanghai, PR China. Electronic address: woodeasy66@hotmail.com.
authors.forename: Wen
authors.initials: W
authors.lastname: Yang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, PR China; National Center for Liver Cancer Research, Shanghai, PR China; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, PR China. Electronic address: hywangk@vip.sina.com.
authors.forename: Hong-Yang
authors.initials: HY
authors.lastname: Wang
mesh_terms: D000818:Animals; D001343:Autophagy; D006528:Carcinoma, Hepatocellular; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008113:Liver Neoplasms; D051379:Mice; D008819:Mice, Nude; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D018343:Receptors, Adrenergic, beta-2; D015398:Signal Transduction; D000077157:Sorafenib
chemical_list: C553443:ADRB2 protein, human; D010671:Phenylurea Compounds; D018343:Receptors, Adrenergic, beta-2; D009536:Niacinamide; D000077157:Sorafenib
keywords: Autophagy; Beta-2 adrenergic receptor; Liver cancer; Sorafenib resistance