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Blockade of CD47-mediated cathepsin S/protease-activated receptor 2 signaling provides a therapeutic target for hepatocellular carcinoma
- Source :
- Hepatology. 60:179-191
- Publication Year :
- 2014
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2014.
-
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. Conclusion: These data suggest that CD47 may be an attractive therapeutic target for HCC therapy. (Hepatology 2014;60:179–191)
- Subjects :
- Male
Carcinoma, Hepatocellular
Population
Mice, Nude
CD47 Antigen
Tumor initiation
Biology
Morpholinos
Metastasis
Mice
Cell Line, Tumor
medicine
Animals
Humans
Receptor, PAR-2
Progenitor cell
education
Protease-activated receptor 2
Cell Line, Transformed
Cathepsin S
Mice, Inbred BALB C
education.field_of_study
Antibiotics, Antineoplastic
Hepatology
CD47
Liver Neoplasms
Cancer
Genetic Therapy
Middle Aged
medicine.disease
Cathepsins
Xenograft Model Antitumor Assays
Doxorubicin
Neoplastic Stem Cells
Cancer research
Female
Signal Transduction
Subjects
Details
- ISSN :
- 02709139
- Volume :
- 60
- Database :
- OpenAIRE
- Journal :
- Hepatology
- Accession number :
- edsair.doi.dedup.....914741e33696187544a297c53a54fb4d