Loss of AIM2 expression promotes hepatocarcinoma progression through activation of mTOR-S6K1 pathway

Oncotarget. 2016 Jun 14;7(24):36185-36197. doi: 10.18632/oncotarget.9154.

Abstract

Absent in melanoma (AIM2) is a member of the interferon-inducible HIN-200 protein family and is recently recognized to play an important dual role in both innate immunity and tumor pathology. However, the role of AIM2 in the development of hepatocellular carcinoma (HCC) remains to be clarified. Here we showed that AIM2 expression was significantly decreased in liver cancer tissues, and loss of its expression was significantly correlated with more advanced tumor progression. Exogenous overexpression of AIM2 in HCC cells suppressed mammalian target of rapamycin (mTOR)-S6K1 pathway and further inhibited proliferation, colony formation and invasion of HCC cells. On the contrary, block of AIM2 in HCC cells induced (mTOR)-S6K1 pathway activation and thus promoted HCC progression. Treatment with mTOR pathway inhibitor rapamycin further verified its contribution to HCC progression in AIM2 absent HCC cells. Thus, these data suggested that AIM2 played a critical role as a tumor suppressor and might serve as a potential therapeutic target for future development of AIM2-based gene therapy for human liver cancer. This study also paves a new avenue to treat AIM2-deficient cancer by suppression of mTOR.

Keywords: absent in melanoma 2; hepatocellular carcinoma; inflammasome; mammalian target of rapamycin; tumor progression.

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Disease Progression
  • Female
  • Gene Expression Regulation, Neoplastic
  • Hep G2 Cells
  • Humans
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Male
  • Mice, Inbred BALB C
  • Mice, Nude
  • Middle Aged
  • RNA Interference
  • Ribosomal Protein S6 Kinases, 70-kDa / genetics*
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Signal Transduction / genetics
  • TOR Serine-Threonine Kinases / genetics*
  • TOR Serine-Threonine Kinases / metabolism
  • Transplantation, Heterologous

Substances

  • AIM2 protein, human
  • DNA-Binding Proteins
  • MTOR protein, human
  • Ribosomal Protein S6 Kinases, 70-kDa
  • TOR Serine-Threonine Kinases
  • ribosomal protein S6 kinase, 70kD, polypeptide 1