title: Blockade of CD47-mediated cathepsin S/protease-activated receptor 2 signaling provides a therapeutic target for hepatocellular carcinoma.
abstract: 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(+) 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.
  
  
  CONCLUSIONS
  These data suggest that CD47 may be an attractive therapeutic target for HCC therapy.
authors: State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong; Departments of Pathology, The University of Hong Kong, Pokfulam, Hong Kong.
authors: Terence Kin-Wah
authors: TK
authors: Lee
authors: Vincent Chi-Ho
authors: VC
authors: Cheung
authors: Ping
authors: P
authors: Lu
authors: Eunice Yuen Ting
authors: EY
authors: Lau
authors: Stephanie
authors: S
authors: Ma
authors: Kwan Ho
authors: KH
authors: Tang
authors: Man
authors: M
authors: Tong
authors: Jessica
authors: J
authors: Lo
authors: Irene Oi Lin
authors: IO
authors: Ng
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D051928:CD47 Antigen / Q000235:genetics* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy*; D002403:Cathepsins / Q000378:metabolism*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D060172:Morpholinos / Q000494:pharmacology; D014411:Neoplastic Stem Cells / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D051928:CD47 Antigen; C497894:CD47 protein, human; D060172:Morpholinos; D044464:Receptor, PAR-2; D004317:Doxorubicin; D002403:Cathepsins; C028217:cathepsin S