Inactivation of Transcriptional Repressor Capicua Confers Sorafenib Resistance in Human Hepatocellular Carcinoma
Inactivation of Transcriptional Repressor Capicua Confers Sorafenib Resistance in Human Hepatocellular Carcinoma
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DOI：
10.1016/j.jcmgh.2020.02.009
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发表时间：
2020-01-01
影响因子：
7.2
通讯作者：
Kaneko, Shuichi
中科院分区：
文献类型：
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作者：
Hashiba, Tomomi;Yamashita, Taro;Kaneko, Shuichi
背景与目的：索拉非尼是一种多受体酪氨酸激酶抑制剂，可延长晚期肝细胞癌（HCC）患者的总生存期。虽然大多数肝癌患者接受索拉非尼最终显示疾病进展，它仍然是不清楚的肝癌细胞是否以及如何获得索拉非尼治疗过程中的humanbeings.METHODS：我们分析了手术切除的肝癌组织从一个病人谁收到索拉非尼预防肝癌复发手术后（辅助索拉非尼肝细胞癌切除或消融试验），并建立患者来源的肝癌细胞。进行全外显子组序列分析以检测索拉非尼耐药克隆中的突变。我们检查了30个先进的肝癌病例免疫组化和140个肝癌病例参加了辅助索拉非尼肝细胞癌切除或消融试验后，使用微阵列分析，以评估与索拉非尼治疗respons.RESULTS的Capicua转录抑制因子（CIC）状态的关联：我们发现索拉非尼后复发的肝癌标本中的CIC突变。CIC编码Capicua，一种受体酪氨酸激酶信号传导的通用传感器。从复发肿瘤标本中建立的HCC细胞在体外和体内对索拉非尼表现出耐药性。已建立的索拉非尼耐药Huh 1和Huh 7细胞系显示Capicua表达减少，无突变。免疫组化分析显示，低表达Capicua的HCC患者总体生存率较差。芯片分析表明，CIC基因标签可以预测索拉非尼辅助治疗对肝癌复发的预防作用。有趣的是，虽然CIC敲低诱导索拉非尼在肝癌细胞系的耐药，regorafenib抑制索拉非尼耐药，Capicua失活的肝癌细胞的生长和抑制细胞外信号调节激酶phosphorylation.CONCLUSIONS：Capicua状态的评价可能是关键的预测索拉非尼的反应，regorafenib治疗可能是有效的治疗肝癌功能Capicua损害。
BACKGROUND & AIMS: 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.METHODS: 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.RESULTS: 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 fromthe 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.CONCLUSIONS: 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.