2. Academic Validation
  3. CCL22 signaling contributes to sorafenib resistance in hepatitis B virus-associated hepatocellular carcinoma

CCL22 signaling contributes to sorafenib resistance in hepatitis B virus-associated hepatocellular carcinoma

  • Pharmacol Res. 2020 Jul;157:104800. doi: 10.1016/j.phrs.2020.104800.
Yanan Gao 1,  Xing Fan 1,  Nan Li 2,  Chengzhi Du 1,  Bin Yang 1,  Wenhao Qin 3,  Jing Fu 3,  Geoffrey J Markowitz 4,  Hongyang Wang 3,  Jianli Ma 5,  Shuqun Cheng 6,  Pengyuan Yang 7
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, 100101, China.
  • 2 Department of Hepatic Surgery I, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China.
  • 3 National Center for Liver Cancer, Second Military Medical University, Shanghai, 200433, China.
  • 4 Departments of Cardiothoracic Surgery and Cell and Developmental Biology, Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA.
  • 5 Department of Pharmacy, General Hospital of the Chinese People's Liberation Army (PLAGH), 100048, Beijing, China. Electronic address: jianli.ma@163.com.
  • 6 Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200433, China. Electronic address: chengshuqun@aliyun.com.
  • 7 CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, 100101, China. Electronic address: pyyang@ibp.ac.cn.
PMID: 32278046 DOI: 10.1016/j.phrs.2020.104800
Abstract

The HBV-initiated hepatocellular carcinoma (HCC) frequently develops from or accompanies long-term chronic hepatitis, inflammation, and cirrhosis, and has a poor prognosis. Sorafenib, an orally active multi-kinase inhibitor, currently the most common approved drug for first-line systemic treatment of advanced HCC, only improves overall survival of three months, suggesting the need for new therapeutic strategies. In this study, we identified that sorafenib selectively resisted in immune competent C57BL/6 mice but not nude mice. The chemokines CCL22 and CCL17 were upregulated by sorafenib, which elevated dramatically higher in HBV-associated HCC. Mechanically, sorafenib accelerates CCL22 expression via TNF-α-RIP1-NF-κB signaling pathway. Blocking CCL22 signaling with antagonist C-021 and sorafenib treated in combination can inhibit tumor growth and enhance the antitumor response, whereas no significant differences in tumor burden were observed in nude mice upon addition of C-021. These findings strongly suggest that CCL22 signaling pathway strongly contributes to sorafenib resistance in HBV-associated HCC, indicating a potential therapeutic strategy for immunological chemotherapy complementing first-line agents against HBV-associated HCC.

Keywords

CCL22 signaling; Chemokine; HBV; Hepatocellular carcinoma; Sorafenib resistance.

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