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

Xiaomin Ma,Kun Mu,Tao Li,Pengbo Guo,Yumin Qiu,Lihui Han,Lihui Zhu,Wei Zhao

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.

Highlights

Hepatocellular carcinoma (HCC) is the most frequent and aggressive primary tumor of the liver and has limited treatment options
Immunohistochemical staining showed that Absent in melanoma 2 (AIM2) signal was stained in yellow and brown, and it was mostly expressed in the cytoplasm of hepatocellular carcinoma (HCC) cells and hepatocytes
These data indicated that loss of AIM2 expression in liver cancer cells contributed to the disease progression of HCC patients

Summary

INTRODUCTION

Hepatocellular carcinoma (HCC) is the most frequent and aggressive primary tumor of the liver and has limited treatment options. Surgical resection is considered as one of the standard curative therapy and provides a long-term survival of patients, but HCC still shows high postsurgical recurrence, rapid progression and extremely poor prognosis It is in critical need of defining its molecular mechanism and identifying new therapeutic target for manipulation of this disease. Further studies support the tumor suppressor role of AIM2 in several types of tumors, including colon cancer [5,6,7,8], breast cancer [9], and prostate cancer [10] It indicated that innate immune DNA sensor AIM2 was implicated as a potential tumor suppressor, whereas its mechanism is not fully understood. Our data surprisingly indicated that loss of AIM2 in HCC cells contributed to disease progression via mammalian target of rapamycin (mTOR)-S6K1 pathway activation, which may pave a new avenue to treat AIM2 deficient cancer by suppression of mTOR

RESULTS

Low High

MATERIALS AND METHODS

CONFLICTS OF INTEREST