mTOR in viral hepatitis and hepatocellular carcinoma: function and treatment

Abstract

As the fifth most common cancer in men and the eighth most common cancer in women, hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide, with standard chemotherapy and radiation being minimally effective in prolonging survival. Virus hepatitis, particularly HBV and HCV infection is the most prominent risk factor for HCC development. Mammalian target of rapamycin (mTOR) pathway is activated in viral hepatitis and HCC. mTOR inhibitors have been tested successfully in clinical trials for their antineoplastic potency and well tolerability. Treatment with mTOR inhibitor alone or in combination with cytotoxic drugs or targeted therapy drug scan significantly reduces HCC growth and improves clinical outcome, indicating that mTOR inhibition is a promising strategy for the clinical management of HCC.

Figure 1

The structure of mTORC1 and mTORC2. The core mTOR machinery consists of mTOR, DEPTOR, and mLST8. The combination of core mTOR machinery with different proteins constitutes mTOR1 and mTORC2.

Figure 2

The regulation of mTOR. The activity of mTOR can be regulated by PI3K-Akt and LKB1-AMPK pathway. Activated mTOR regulates transcriptional activity of FOXO1-FOXO3a and protein translation by pS6 and eIF-4E.

Figure 3

Regulation and function of mTOR in viral hepatitis and HCC development. In HCV infection, NS5A can activate mTOR through PI3K/Akt pathway or impair the combination between mTOR and FKBP38. The complex formed by mTOR and NF-κB can downregulate the expression of PTEN. In HBV infection, pre-S1 can activate Akt/mTOR pathway through upregulation of VEGFR-2. YY1-HDAC1 complex can inhibit the transcription from the pre-S1 promoter as a negative feedback. HBx can increase the expression of mTOR and PI3K/Akt. S6K can activate PAK1 to regulate actin cytoskeleton and cell motility.