The lncRNA CASC2 Modulates Hepatocellular Carcinoma Cell Sensitivity and Resistance to TRAIL Through Apoptotic and Non-Apoptotic Signaling.

Hongwei Zhu,Jichun Sun,Xiao Yu,Zhi Yang,Zhao Lei,Hongbo Xu,Zhiqiang Li,Xiaoxin Jin,Zhen Deng

doi:10.3389/fonc.2021.726622

Abstract

The immune cytokine tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been widely concerned as a tumor therapy because of its ability of selective triggering cancer cell apoptosis; nevertheless, hepatocellular carcinoma (HCC) exhibits acquired resistance to TRAIL-induced apoptosis. In the present study, tumor-suppressive lncRNA cancer susceptibility candidate 2 (CASC2) was downregulated in HCC tissues and cell lines; HCC patients with lower CASC2 expression predicted a shorter overall survival rate. In vitro, CASC2 overexpression dramatically repressed HCC cell proliferation and inhibited cell apoptosis; in vivo, CASC2 overexpression inhibited subcutaneous xenotransplant tumor growth. CASC2 affected the caspase cascades and NF-κB signaling in TRAIL-sensitive [Huh-7 (S) and HCCLM3 (S)] or TRAIL-resistant cell lines [Huh-7 (R) and HCCLM3 (R)] in different ways. In Huh-7 (S) and HCCLM3 (S) cells, CASC2 affected cell apoptosis through the miR-24/caspase-8 and miR-221/caspase-3 axes and the caspase cascades. miR-18a directly targeted CASC2 and RIPK1. In Huh-7 (R) and HCCLM3 (R) cells, CASC2 affected cell proliferation through the miR-18a/RIPK1 axis and the NF-κB signaling. RELA bound to CASC2 promoter region and inhibited CASC2 transcription. In conclusion, CASC2 affects cell growth mainly via the miR-24/caspase-8 and miR-221/caspase-3 axes in TRAIL-sensitive HCC cells; while in TRAIL-resistant HCC cells, CASC2 affects cell growth mainly via miR-18a/RIPK1 axis and the NF-κB signaling. These outcomes foreboded that CASC2 could be a novel therapeutic target for further study of HCC-related diseases.

Highlights

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, and its high fatality rate and high incidence are a serious threat to public health [1]
All hepatocellular carcinoma (HCC) patients were free from other viral infections, such as Human Immunodeficiency Virus (HIV), hepatitis virus
Given the tumor-suppressive role of cancer susceptibility candidate 2 (CASC2) in HCC by our and other groups’ studies [26, 40,41,42], the expression of CASC2 was first validated in collected clinical tissue samples and cell lines

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, and its high fatality rate and high incidence are a serious threat to public health [1]. On the other hand, activated caspase-8 promotes the expression of RIPK1 (receptor-interacting serine/ threonine-protein kinase 1), inhibits the activation of NF-kB pathway, and inhibits the proliferation of tumor cells [12]. Since death receptors showed to be expressed ubiquitously in both cancer and non-cancerous cells [13, 14], HCC exhibits acquired resistance to TRAIL-induced apoptosis [15,16,17,18]. In TRAIL-resistant cell lines [9,10,11], TRAIL recruits TNF receptor 1 associated death domain protein (TRADD)/TNF receptor-associated factors (TRAFs) through the receptor DR4/ DR5 receptor to activate the NF-kB pathway and promote cell proliferation, while activated NF-kB targeted and inhibited the caspase pathway, thereby inhibiting tumor cell apoptosis.

Methods

Results

Conclusion