P-113 - Mammilian target of rapamycin (mTOR) and autophagy in hepatitis C virus-related hepatocellular carcinoma: relation to tumor progression

Date 04 July 2015
Event WorldGI 2015
Session Posters
Topics Hepatobiliary Cancers
Translational Research
Presenter H. El Aggan
Citation Annals of Oncology (2015) 26 (suppl_4): 1-100. 10.1093/annonc/mdv233
Authors H. El Aggan1, M. Helmy1, L. Younis1, E. Hassona2, S. Lashen1
  • 1University of Alexandria, Alexandria/EG
  • 2University of Alexandria, Alexandris/EG

Abstract

Introduction

Mammalian target of rapamycin (mTOR) is a key regulator of cell metabolism, growth and proliferation. Also, mTOR is a down-regulator of autophagy, the basic catabolic process by which cells degrade dysfunctional cellular components through the lysosomal machinery. The cross talk between mTOR and autophagy in hepatocellular carcinoma (HCC) is unknown. Therefore, the present study was designed to study the role of mTOR and autophagy in the development and progression of hepatitis C virus (HCV)-related HCC.

Methods

27 patients with HCV-related cirrhosis (13 patients without HCC and 14 patients with HCC who underwent surgical resection of the tumor) and 15 healthy subjects were included in the study. The severity of liver disease was graded according to Child-Pugh classification and the Model for End Stage Liver Disease (MELD) score. The staging of HCC was determined according to the Barcelona Clinic Liver Cancer (BCLC) staging system and the Cancer of the Liver Italian Program (CLIP). Quantitative measurement of mTOR protein levels in was determined using solid phase sandwich enzyme linked immunosorbent assay kit. The tumor histological grade was assessed according to Edmonson and Steiner's criteria. Immunohistochemical examination of HCC and the surrounding non-neoplastic cirrhotic tissues was performed using anti-human antibodies against mTOR and autophagy-related protein 5 (Atg5) as a marker of autophagy and the staining intensity was scored semi-quantitatively.

Results

The serum mTOR levels were significantly higher in cirrhotic patients with and without HCC than in healthy subjects and in patients with HCC than in patients without HCC (P < 0.001). By plotting receiver-operating characteristic (ROC) curve, the sensitivity and specificity of serum mTOR levels in discriminating cirrhotic patients with and without HCC were 92.9% and 100% respectively at a cut-off value of 4.55 ng/ml [Area under ROC curve (AUROC) = 0.970]. The mTOR expression showed a significant increase in HCV-related HCC tissues compared with the surrounding non-neoplastic cirrhotic tissues (P = 0.035) while Atg5 expression was significantly lower in HCCs than in the cirrhotic tissues. The serum mTOR levels and mTOR expression in HCCs showed significant positive correlations with serum AFP levels (P = 0.003 and P = 0.003 respectively), HCC maximum diameter (P = 0.018 and P = 0.032 respectively), CLIP stage (P = 0.032 and P = 0.002 respectively) and HCC histological grade (P = 0.003 and P = 0.025 respectively). The Atg5 expression in HCCs showed significant inverse correlations with serum mTOR levels (P = 0.005), mTOR expression (P < 0.001), serum AFP levels (P = 0.004), HCC maximum diameter (P < 0.001), BCLC stage (P = 0.002), CLIP stage (P< 0.001) and HCC histological grade (P < 0.001).

Conclusion

Activation of mTOR pathway plays an important role in the development and progression of HCV-related HCC, possibly, through inhibition of autophagy. Modulation of the mTOR pathway and/or autophagy could be a potential anti-cancer target in HCC therapy. Serum mTOR levels may represent a potential diagnostic biomarker for the development of HCC in chronic HCV infection and should be tested in the future.