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医学资料-hep27070.pdf

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HEPATOBILIARY MALIGNANCIES Blockade of CD47-Mediated Cathepsin S/Protease- Activated Receptor 2 Signaling Provides a Therapeutic Target for Hepatocellular Carcinoma Terence Kin-Wah Lee,1,2* Vincent Chi-Ho Cheung,1,2* Ping Lu,1,2 Eunice Yuen Ting Lau,1,2 Stephanie Ma,1,3 Kwan Ho Tang,2 Man Tong,3 Jessica Lo, 1,2 and Irene Oi Lin Ng1,2 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 popu- lation 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 metas- tasis and signiﬁcantly affected patients’ clinical outcome. Knockdown of CD47 sup- pressed stem/progenitor cell characteristics. CD471 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 b