MiR-942 decreases TRAIL-induced apoptosis through ISG12a downregulation and is regulated by AKT.

Nianli Liu,Tianran Chen,Jing Wang,Chaohui Zuo,Xiaohong Wang,Darong Yang,Haizhen Zhu

doi:10.18632/oncotarget.2067

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an attractive death ligand in targeted cancer therapy. Many cancer cells are refractory to TRAIL-induced cell death and the mechanisms underlying resistance are unclear. The molecular mechanisms of HCC and gastric cancer cells resistant to TRAIL-induced apoptosis were explored using molecular biological and immunological methods. In vivo experiments were conducted to study the effect of interferon stimulated gene 12a (ISG12a) on human liver cancer xenografts in mice. ISG12a decreases in TRAIL-resistant cancer cells. ISG12a regulates the sensitivity of cancer cells to TRAIL in vitro and in vivo. MicroRNA-942 (miR-942) is inversely correlated with ISG12a expression in cancer cells and tissues. Forced expression of miR-942 in TRAIL-sensitive cells significantly reduces endogenous ISG12a level and changes the TRAIL sensitive phenotype to a resistant one. Knockdown of miR-942 expression in TRAIL-resistant cells restores the expression of ISG12a and sensitizes the cells to TRAIL treatment. AKT control TRAIL resistance of cancer cells through downregulation of ISG12a by miR-942. Downregulation of ISG12a by miR-942 is needed to maintain the TRAIL-resistant phenotype of cancer cells and favors cancer cell survival. MiR-942 may offer a novel drug response marker with important implications in designing new therapeutics for TRAIL resistant tumors.

Highlights

Hepatocellular carcinoma (HCC) and gastric cancer (GC) are among the most common cancers worldwide [1]
To further explore the mechanisms of interferon stimulated gene 12a (ISG12a) in Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, we examined the expression of IFN-β in TRAIL-treated cancer cells
We examined the expression of miR-942 and ISG12a by real-time polymerase chain reaction (PCR) in primary liver cancer and gastric cancer tissue samples

Summary

Introduction

Hepatocellular carcinoma (HCC) and gastric cancer (GC) are among the most common cancers worldwide [1]. Sorafenib was recently approved for the treatment of advanced renal cell carcinoma and liver cancer patients [2, 3]. It can only improve the survival from 7.9 months to 10.7 months for HCC patients [4]. TRAIL-induced apoptosis of cancer cells is carried out by activation of mitochondria-independent and mitochondria-dependent intracellular death signaling pathways [9, 10]. Upon the binding of TRAIL, DR4 or DR5 oligomerizes and forms a death-inducing signaling complex (DISC) by recruiting the adaptor protein FADD together with caspase-8, and FLIP. For the mitochondria-dependent pathway, caspase8-mediated cleavage of BID leads to oligomerisation of Bax and Bak, resulting in the release of cytochrome c. Activated caspase-3 and caspase-7 provoke cellular destruction by cleaving several hundred cellular proteins including poly ADPribose polymerase (PARP)

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