Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cancer Med. 2020 Oct;9(19):6972-6983. doi: 10.1002/cam4.3331. Epub 2020 Aug 10.
Sorafenib has become the only FDA-approved first-line therapy for advanced hepatocellular carcinoma (HCC) for more than 10 years, but there is still no validated predictive or prognostic marker. Peptidase inhibitor 16 (PI16) is a functionally unknown gene in cancer research. This study aimed to determine the exact function of PI16 in HCC and whether it can represent as a biomarker for sorafenib response. We found that PI16 was over expressed in HCC tissues vs paired normal tissues. PI16 knockdown sensitize HCC cells to sorafenib treatment both in vitro and in vivo, whereas ectopic PI16 expression produced the opposite effect. Mechanistically, PI16 could suppress p38 MAPK/caspase-dependent apoptosis in this process, and p38 MAPK inhibitor reversed the sorafenib sensitive phenotype caused by PI16 inhibition. Clinically, immunohistochemistry was used to detect PI16 levels in resected patients with HCC prior to sorafenib treatment. We showed that high PI16 levels represented an independent risk factor for disease progression in patients treated with sorafenib. Patients with low PI16 showed significantly better progression free survival and overall survival after sorafenib therapy. In conclusion, PI16 attenuates response to sorafenib treatment in HCC, and may be a helpful prognostic biomarker of sorafenib treatment.
索拉非尼已成为 10 多年来唯一获得 FDA 批准用于晚期肝细胞癌（HCC）的一线治疗药物，但仍没有经过验证的预测或预后标志物。肽酶抑制剂 16（PI16）是癌症研究中一个功能未知的基因。本研究旨在确定 PI16 在 HCC 中的确切功能，以及它是否可以作为索拉非尼反应的标志物。我们发现，PI16 在 HCC 组织中表达高于配对的正常组织。PI16 敲低使 HCC 细胞对索拉非尼治疗在体外和体内均敏感，而异位 PI16 表达则产生相反的效果。在机制上，PI16 可以抑制这个过程中的 p38 MAPK/半胱天冬酶依赖性细胞凋亡，而 p38 MAPK 抑制剂则逆转了由 PI16 抑制引起的索拉非尼敏感表型。临床上，在接受索拉非尼治疗前，使用免疫组织化学检测接受 HCC 手术切除患者的 PI16 水平。我们发现，PI16 水平高是索拉非尼治疗患者疾病进展的独立危险因素。PI16 水平低的患者在接受索拉非尼治疗后，无进展生存期和总生存期明显改善。总之，PI16 减弱了 HCC 对索拉非尼治疗的反应，可能是索拉非尼治疗的一个有帮助的预后生物标志物。
