Occurrence of Biased mTOR Signaling in Hepatocellular Carcinoma

Background: mTOR signaling promotes cell growth and anabolic processes in all eukaryotes. Hyperactivation of mTOR signaling is associated with various cancers along with hepatocellular carcinoma (HCC). HCC is a highly lethal malignancy with multiple aetiologies such as viral infection, alcohol abuse, and metabolic dysfunction. Therapeutic options for HCC remain limited due to an incomplete understanding of oncogenic drivers and poorly characterized mechanisms of disease progression. Methods: Various regimens of DEN and CCl4 carcinogen dosage were investigated on C57BL/6J mice to induce HCC. The histological analysis for fibrosis and serum markers for liver function were performed. Molecular analyses of oncogenic drivers were performed in the HCC tissues obtained from mice and HCC patients. The impact of inhibition of mTOR signaling was assessed on HCC progression. Results: We established a rapid DEN+CCl4 induced (DCI) HCC model in C57BL/6 mice to study disease progression longitudinally. The molecular analysis revealed upregulation of MAPK and downregulation of mTORC1-S6K-S6 signaling in HCC. However, other branches of mTOR such as mTORC1-ULK1, mTORC1-4EBP1, and mTORC2-PKC were upregulated due to the increased expression. Similar observations were found in tissues derived from HCC patients. Furthermore, inhibition of mTORC1 alone by Rapamycin did not reduce HCC progression but Torin 1 mediated inhibition of both mTORC1 and mTORC2 significantly reduced HCC progression. Conclusions: We propose this biased mTOR signaling modulates mTOR activity towards specific downstream processes that are crucial for cancer cell growth and targeting both the mTOR complexes has better therapeutic potential in HCC.