Inactivation of Transcriptional Repressor Capicua Confers Sorafenib Resistance in Human Hepatocellular Carcinoma.

Inactivation of Transcriptional Repressor Capicua Confers Sorafenib Resistance in Human Hepatocellular Carcinoma.

Cellular and molecular gastroenterology and hepatology (2020-03-15)

Tomomi Hashiba, Taro Yamashita, Hikari Okada, Kouki Nio, Takehiro Hayashi, Yoshiro Asahina, Tomoyuki Hayashi, Takeshi Terashima, Noriho Iida, Hajime Takatori, Tetsuro Shimakami, Kazunori Kawaguchi, Kuniaki Arai, Yoshio Sakai, Tatsuya Yamashita, Eishiro Mizukoshi, Hiroyuki Takamura, Tetsuo Ohta, Masao Honda, Shuichi Kaneko

PMID32169577

摘要

Sorafenib is a multireceptor tyrosine kinase inhibitor that can prolong overall survival in patients with advanced hepatocellular carcinoma (HCC). Although most HCC patients who receive sorafenib ultimately show disease progression, it still is unclear whether and how HCC cells acquire chemoresistance during sorafenib treatment in human beings. We analyzed surgically resected HCC tissues from a patient who received sorafenib for prevention of HCC recurrence after surgery (Adjuvant Sorafenib for Hepatocellular Carcinoma after Resection or Ablation trial) and established patient-derived HCC cells. Whole-exome sequence analysis was performed to detect mutations in sorafenib-resistant clones. We examined 30 advanced HCC cases immunohistochemically and 140 HCC cases enrolled in the Adjuvant Sorafenib for Hepatocellular Carcinoma after Resection or Ablation trial using microarray analysis to evaluate the association of Capicua Transcriptional Repressor (CIC) status with sorafenib treatment response. We found a CIC mutation in recurrent HCC specimens after sorafenib. CIC encodes Capicua, a general sensor of receptor tyrosine kinase signaling. HCC cells established from the recurrent tumor specimen showed chemoresistance to sorafenib in vitro and in vivo. Established sorafenib-resistant Huh1 and Huh7 cell lines showed reduced expression of Capicua without mutations. Immunohistochemical analysis showed that HCC patients with low Capicua expression showed poor overall survival. Microarray analysis showed that the CIC gene signature could predict the preventive effect of adjuvant sorafenib treatment on HCC recurrence. Intriguingly, although CIC knockdown induced sorafenib resistance in HCC cell lines, regorafenib suppressed growth of sorafenib-resistant, Capicua-inactivated HCC cells and inhibited extracellular signal-regulated kinase phosphorylation. Evaluation of Capicua status may be pivotal to predict response to sorafenib, and regorafenib treatment could be effective to treat HCC with functional Capicua impairment.