Granulin-epithelin precursor and ATP-dependent binding cassette (ABC)B5 regulate liver cancer cell chemoresistance.
OBJECTIVE
Chemotherapy is used to treat unresectable liver cancer with marginal efficacy; this might result from hepatic cancer cells with stem cell and chemoresistant features. Gene expression profiling studies have shown that hepatic cancer cells express granulin-epithelin precursor (GEP); we investigated its role in hepatic cancer stem cell functions and chemoresistance.


METHODS
The effects of GEP and drug transporter signaling on chemoresistance were investigated in hepatic cancer stem cells. We analyzed the expression patterns of 142 clinical samples from liver tumors, adjacent nontumorous liver tissue, and liver tissue from patients who did not have cancer.


RESULTS
GEP regulated the expression of the adenosine triphosphate-dependent binding cassette (ABC)B5 drug transporter in liver cancer cells. Chemoresistant cells that expressed GEP had increased levels of ABCB5; suppression of ABCB5 sensitized the cells to doxorubicin uptake and apoptosis. Most cells that expressed GEP and ABCB5 also expressed the hepatic cancer stem cell markers CD133 and EpCAM; blocking ABCB5 reduced their expression. Expression levels of GEP and ABCB5 were correlated in human liver tumor samples. ABCB5 levels were increased in liver cancer cells compared with nontumor liver tissue from patients with cirrhosis or hepatitis, or normal liver tissue. ABCB5 expression was associated with the recurrence of hepatocellular carcinoma after partial hepatectomy.


CONCLUSIONS
Expression of GEP and ABCB5 in liver cancer stem cells is associated with chemoresistance and reduced survival times of patients with hepatocellular carcinoma. Reagents designed to target these proteins might be developed as therapeutics and given in combination with chemotherapy to patients with liver cancer.
Cheung
Siu Tim
ST
Department of Surgery, The University of Hong Kong, Hong Kong, China. stcheung@hku.hk
Cheung
Phyllis F Y
PF
Cheng
Christine K C
CK
Wong
Nicholas C L
NC
Fan
Sheung Tat
ST
D000071916:AC133 Antigen; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D015703:Antigens, CD / Q000032:analysis; D000951:Antigens, Neoplasm / Q000032:analysis; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D015815:Cell Adhesion Molecules / Q000032:analysis; D004317:Doxorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D000071858:Epithelial Cell Adhesion Molecule; D005500:Follow-Up Studies; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000032:analysis; D000077153:Progranulins; D014407:Tumor Cells, Cultured
C480744:ABCB5 protein, human; D000071916:AC133 Antigen; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; C492314:GRN protein, human; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C000606023:PROM1 protein, human; D010455:Peptides; D000077153:Progranulins; D004317:Doxorubicin