Abstract 341: The role of telomere protective protein TPP1 in hepatocellular carcinoma
Authors: Jiang Zou, Ru Sun, Jingruo Xia, Dan Xiao, Chang Liu, Hebin Liao, Lei Xu, Qiang Ma, Yan Cai, Jingdong Li, Xiaolan Guo
Journal: Cancer Research (2018)

Abstract Hepatocellular carcinoma (HCC) is a worldwide malignancy. To date, surgery is still the most effective treatment with curative potential, but only about 20% of patients with HCC are eligible for surgical intervention. Therefore exploring the pathogenesis of liver cancer, looking for molecules targeting therapy, is very important. Telomeres, the chromosome extremities, are protected by specific proteins, such as POT1, RAP1, TIN2, TRF1, TRF2,and TPP1. More and more findings have discovered that TPP1 plays an important role in the tumorigenesis. However, the mechanism of TPP1 in HCC remains unknown. The purpose of this study is to explore the role of TPP1 in HCC. Currently 42 cases of HCC patients were recruited in this study. First, the patients' tumor tissue, adjacent tissue and normal tissue were analyzed by Western blot. The results showed that TPP1 expression in patients' adjacent tissue and normal tissue was lower than that in tumor tissue, respectively (P&amp;lt;0.05; P&amp;lt;0.05). Furthermore, investigation on the protein expression levels of TPP1 with clinicopathologic characteristics discovered that the higher TPP1 in patients' tumor tissue was correlated with the tumor clinical stages, demonstrating that those patients who were in earlier stages (I + II) showed lower TPP1 protein levels than those in later or advanced stages (III + IV) (P&amp;lt;0.05). More importantly, the survival analysis showed that the overall survival was significantly shorter in patients with high TPP1 expression than in others (P&amp;lt;0.05). To further study the role of telomere protective protein TPP1 in HCC, we used lentiviral shRNA embedding TPP1 to knock down the expression of TPP1 in HepG2 and SK-Hep1 cells. The cell growth curve results showed that knockdown of TPP1 could inhibit the growth and proliferation of the above cells. Meanwhile we found that the migration and invasion abilities of the cells were significantly reduced by knocking down the expression of TPP1 compared with the cells transfected with the control lentiviral shRNA. Through scratch test and cell invasion transwell chamber test, TPP1 depletion dramatically suppressed the colony formation on soft agar, which indicated that TPP1 loss could reduce the transformation ability of HCC. More interestingly, we found that ATM pathway was activated after knockdown of TPP1, resulting in γ-H2AX and phosphorylated ATM(p-ATM) upregulation. On the other hand, removal of TPP1 initiated mTOR pathway activation, which resulted in phosphorylated mTOR (p-mTOR) augmentation, followed by the increase of p70S6K and 4EBP1 phosphorylation. Eventually the autophagy marker LC3 I/II conversion and p62 declined obviously by depletion of TPP1 in HepG2 and SK-Hep1 cells. Taken together, TPP1 could be a potential predictor of hepatocellular carcinoma staging and overall survival, and targeting TPP1 might be a therapeutic approach for HCC. Citation Format: Jiang Zou, Ru Sun, Jingruo Xia, Dan Xiao, Chang Liu, Hebin Liao, Lei Xu, Qiang Ma, Yan Cai, Jingdong Li, Xiaolan Guo. The role of telomere protective protein TPP1 in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 341.