Telomere Length, TERT and Shelterin Complex Protein Expression in Hepatocellular Carcinomas with Stemness-Related Marker Expression.
Haeryoung Kim, Jai Young Cho, Hye Seung Lee, Ja June Jang, Sook Hyang Jeong, Young Nyun Park. Seoul National University Bundang Hospital, Seongnam, Korea; Seoul National University College of Medicine, Korea; Yonsei University Health System, Seoul, Korea
Background: Hepatocellular carcinomas (HCCs) with expression of stemness-related proteins have been recently associated with aggressive biological behavior and poor prognosis. We examined the relationship between stemness-related protein expression in HCCs and the telomere length, hTERT and shelterin complex protein expression in order to search for any differences in telomere dynamics of these tumors compared to conventional HCCs.
Design: Tissue microarrays were constructed from 139 surgically resected HCCs, and subjected to quantitative fluorescent in situ hybridization for telomere length, immunohistochemistry for stemness-related proteins (K19, EpCAM, CD133 and c-kit), AFP, anti-hepatocyte, hTERT, TRF2 and TPP1, and TUNEL assay for evaluation of apoptotic rate.
Results: The telomere lengths were significantly increased in HCCs expressing stemness-related proteins (K19: p<0.001, EpCAM: p=0.003, c-kit: p=0.040, CD133: p=0.003). K19-expressing HCCs demonstrated more frequent expression of hTERT (p=0.002) and TRF2 (p=0.028) proteins and higher TPP1-labeling indices (p=0.008) compared to K19-negative HCCs. Lower apoptotic rates were seen in HCCs expressing CD133 and c-kit (p=0.014 and p=0.067, respectively), and in HCCs expressing 2 or more stemness-related proteins (p=0.025). HCCs expressing anti-hepatocyte antigen showed shorter telomeres (p=0.014), decreased TPP1-labeling indices and lower Ki-67 labeling indices (p=0.002). Univariable analysis demonstrated a significant relationship between decreased overall survival and expression of at least 2 stemness-related proteins (p=0.035). In addition, a TPP1-labeling index exceeding half of the tumor cells was also associated with a significant poor overall survival compared to HCCs expressing TPP1 protein in less than half of the tumor population (p=0.035).
Conclusions: HCCs with expression of stemness-related proteins are characterized by increased expression of hTERT, TRF2 and TPP1 proteins, increased telomere lengths and decreased apoptosis compared to conventional HCCs.
Category: Liver & Pancreas
Tuesday, March 1, 2011 9:30 AM
Poster Session III # 258, Tuesday Morning