CD133-positive hepatocellular carcinoma in an area endemic for hepatitis B virus infection.
BACKGROUND
CD133 was detected in several types of cancers including hepatocellular carcinoma (HCC), which raised the possibility of stem cell origin in a subset of cancers. However, reappearance of embryonic markers in de-differentiated malignant cells was commonly observed. It remained to be elucidated whether CD133-positive HCCs were indeed of stem cell origin or they were just a group of poorly differentiated cells acquiring an embryonic marker. The aim of this study was to investigate the significance of CD133 expression in HCC in an area endemic for hepatitis B virus (HBV) infection to gain insights on this issue.


METHODS
154 HCC patients receiving total removal of HCCs were included. 104 of them (67.5%) were positive for HBV infection. The cancerous and adjacent non-cancerous liver tissues were subjected for Western blot and immunohistochemistry analysis for CD133 expression. The data were correlated with clinical parameters, patient survivals, and p53 expression.


RESULTS
Of 154 patients, 24 (15.6%) had CD133 expression in HCC. Univariate and multivariate logistic regression analysis revealed that CD133 expression was negatively correlated with the presence of hepatitis B surface antigen (HBsAg). The unadjusted and adjusted odds ratios were 0.337 (95%CI 0.126 - 0.890) and 0.084 (95%CI 0.010 - 0.707), respectively. On the other hand, p53 expression was positively associated with the presence of HBsAg in univariate analysis. The unadjusted odds ratio was 4.203 (95%CI 1.110 - 18.673). Survival analysis indicated that both CD133 and p53 expression in HCC predicted poor disease-free survival (P = 0.009 and 0.001, respectively), whereas only CD133 expression predicted poor overall survival (P = 0.001). Cox proportional hazard model showed that p53 and CD133 expression were two independent predictors for disease-free survival. The hazard ratios were 1.697 (95% CI 1.318 - 2.185) and 2.559 (95% CI 1.519 - 4.313), respectively (P < 0.001 for both).


CONCLUSIONS
In area where HBV infection accounts for the major attributive risk of HCC, CD133 expression in HCC was negatively associated with the presence of HBsAg, implicating a non-viral origin of CD133-positive HCC. Additionally, CD133 expression predicted poor disease-free survival independently of p53 expression, arguing for two distinguishable hepatocarcinogenesis pathways.
Yeh
Chau-Ting
CT
Liver Research Unit, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Taipei, Taiwan, ROC. chautingy@gmail.com
Kuo
Chia-Jung
CJ
Lai
Ming-Wei
MW
Chen
Tse-Ching
TC
Lin
Chun-Yen
CY
Yeh
Ta-Sen
TS
Lee
Wei-Chen
WC
D000071916:AC133 Antigen; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D018572:Disease-Free Survival; D019353:Endemic Diseases; D005260:Female; D015870:Gene Expression; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006509:Hepatitis B / Q000150:complications* / Q000453:epidemiology / Q000378:metabolism; D006514:Hepatitis B Surface Antigens / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; D006514:Hepatitis B Surface Antigens; C000606023:PROM1 protein, human; D010455:Peptides; D016159:Tumor Suppressor Protein p53