title: Sympathetic nervous system promotes hepatocarcinogenesis by modulating inflammation through activation of alpha1-adrenergic receptors of Kupffer cells.
abstract: The sympathetic nervous system (SNS) is known to play a significant role in tumor initiation and metastasis. Hepatocellular carcinoma (HCC) frequently occurs in cirrhotic livers after chronic inflammation, and the SNS is hyperactive in advanced liver cirrhosis. However, it remains unclear whether the SNS promotes hepatocarcinogenesis by modulating chronic liver inflammation. In this study, a retrospective pathological analysis and quantification of sympathetic nerve fiber densities (tyrosine hydroxylase, TH+) in HCC patients, and diethylnitrosamine (DEN)-induced hepatocarcinogenesis in rats were performed. Our data showed that high density of sympathetic nerve fibers and α1-adrenergic receptors (ARs) of Kupffer cells (KCs) were associated with a poor prognosis of HCC. Sympathetic denervation or blocking of α1-ARs decreased DEN-induced HCC incidence and tumor development. In addition, synergistic effects of interleukin-6 (IL-6) and transforming growth factor-beta (TGF-β) in hepatocarcinogenesis were observed. The suppression of the SNS reduced IL-6 and TGF-β expression, which suppressed hepatocarcinogenesis, and KCs play a key role in this process. After the ablation of KCs, IL-6 and TGF-β expression and the development of HCC were inhibited. This study demonstrates that sympathetic innervation is crucial for hepatocarcinogenesis and that the SNS promotes hepatocarcinogenesis by activating α1-ARs of KCs to boost the activation of KCs and to maintain the inflammatory microenvironment. These results indicate that sympathetic denervation or α1-ARs blockage may represent novel treatment approaches for HCC.
authors: Institute of Hepatobiliary Surgery, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors: Hong-Bo
authors: HB
authors: Huan
authors: Institute of Hepatobiliary Surgery, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors: Xu-Dong
authors: XD
authors: Wen
authors: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, and Key Laboratory of Tumor Immunology and Pathology of Ministry of Education China, Chongqing, China.
authors: Xue-Jiao
authors: XJ
authors: Chen
authors: Institute of Hepatobiliary Surgery, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors: Lin
authors: L
authors: Wu
authors: Institute of Hepatobiliary Surgery, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors: Li-Li
authors: LL
authors: Wu
authors: Institute of Hepatobiliary Surgery, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors: Liang
authors: L
authors: Zhang
authors: Institute of Hepatobiliary Surgery, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors: Da-Peng
authors: DP
authors: Yang
authors: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, and Key Laboratory of Tumor Immunology and Pathology of Ministry of Education China, Chongqing, China.
authors: Xia
authors: X
authors: Zhang
authors: Institute of Hepatobiliary Surgery, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors: Ping
authors: P
authors: Bie
authors: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, and Key Laboratory of Tumor Immunology and Pathology of Ministry of Education China, Chongqing, China.
authors: Cheng
authors: C
authors: Qian
authors: Institute of Hepatobiliary Surgery, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China. Electronic address: txzzxf@163.com.
authors: Feng
authors: F
authors: Xia
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D063646:Carcinogenesis / Q000473:pathology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D015850:Interleukin-6 / Q000378:metabolism; D007728:Kupffer Cells; D008113:Liver Neoplasms / Q000139:chemically induced / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009412:Nerve Fibers / Q000473:pathology; D011379:Prognosis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1; D012189:Retrospective Studies; D013564:Sympathetic Nervous System / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D018340:Receptors, Adrenergic, alpha-1; D016212:Transforming Growth Factor beta
keywords: Alpha1-adrenergic receptor; Hepatocellular carcinoma; Kupffer cell; Sympathetic nervous system