Blockade of CD47-Mediated Cathepsin S/Protease-Activated Receptor 2 Signaling Provides a Therapeutic Target for Hepatocellular Carcinoma
Blockade of CD47-Mediated Cathepsin S/Protease-Activated Receptor 2 Signaling Provides a Therapeutic Target for Hepatocellular Carcinoma
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阻断 CD47 介导的组织蛋白酶 S/蛋白酶激活受体 2 信号传导为肝细胞癌提供了治疗靶点
DOI：
10.1002/hep.27070
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发表时间：
2014-07-01
期刊：
影响因子：
13.5
通讯作者：
Ng, Irene Oi Lin
中科院分区：
文献类型：
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作者：
Lee, Terence Kin-Wah;Cheung, Vincent Chi-Ho;Ng, Irene Oi Lin
识别针对肿瘤起始细胞（TICs）的治疗靶点是开发新的癌症治疗范式的首要任务。我们通过用化疗药物连续传代肝球来富集能够引发肿瘤和自我更新的TIC群体。在化学抗性肝球，CD 47被发现是上调，与分化后代相比。CD 47在肝脏TIC中优先表达，这有助于肿瘤的发生、自我更新和转移，并显著影响患者的临床结局。CD 47的敲低抑制干/祖细胞特性。CD 47 - 1肝细胞癌（HCC）细胞优先分泌组织蛋白酶S（CTSS），其通过CTSS/蛋白酶激活受体2（PAR 2）环调节肝TIC。通过morpholino方法抑制CD 47可抑制体内HCC的生长，并通过阻断CTSS/PAR 2信号传导发挥化疗增敏作用。结论：CD 47可能成为肝癌治疗的一个有吸引力的靶点。
Identification of therapeutic targets against tumor-initiating cells (TICs) is a priority in the development of new therapeutic paradigms against cancer. We enriched a TIC population capable of tumor initiation and self-renewal by serial passages of hepatospheres with chemotherapeutic agents. In chemoresistant hepatospheres, CD47 was found to be up-regulated, when compared with differentiated progenies. CD47 is preferentially expressed in liver TICs, which contributed to tumor initiation, self-renewal, and metastasis and significantly affected patients' clinical outcome. Knockdown of CD47 suppressed stem/progenitor cell characteristics. CD47 1 hepatocellular carcinoma (HCC) cells preferentially secreted cathepsin S (CTSS), which regulates liver TICs through the CTSS/protease-activated receptor 2 (PAR2) loop. Suppression of CD47 by morpholino approach suppressed growth of HCC in vivo and exerted a chemosensitization effect through blockade of CTSS/PAR2 signaling. Conclusion: These data suggest that CD47 may be an attractive therapeutic target for HCC therapy.