Blockade of CD47 mediated CTSS-PAR2 signaling provides a therapeutic target for hepatocellular carcinoma

The identification of therapeutic targets against tumor-initiating cells (T-ICs) is a priority in the development of new therapeutic paradigms against cancer. We enriched T-IC population capable of tumor initiation and self-renewal via serial passages of hepatospheres with chemotherapeutic agents. In the chemoresistant hepatospheres, CD47 was found to be up-regulated when compared with differentiated progenies. CD47 is preferentially expressed in liver T-ICs which contributed to tumor initiation, self-renewal and metastasis, and significantly affected patients' clinical outcome. Knockdown of CD47 suppressed the stem/progenitor cell characteristics. CD47+ HCC cells preferentially secreted Cathepsin S (CTSS), which regulates liver T-ICs through the CTSS/PAR2 loop. Suppression of CD47 by morpholino approach suppressed the growth of HCC in vivo and exerted chemosensitization effect through blockade of CTSS/PAR2 signaling. These data suggest that CD47 may be an attractive therapeutic target for HCC therapy.