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

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

doi:10.3389/fonc.2021.726622

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

Front Oncol. 2022 Jan 25:11:726622. doi: 10.3389/fonc.2021.726622. eCollection 2021.

Authors

Jichun Sun¹, Hongbo Xu², Zhao Lei¹, Zhiqiang Li¹, Hongwei Zhu¹, Zhen Deng¹, Xiao Yu¹, Xiaoxin Jin³, Zhi Yang^{4

5}

Affiliations

¹ Department of Hepatobiliary and Pancreatic Surgery, The Third Xiangya Hospital, Central South University, Changsha, China.
² Department of Vascular Surgery, The Third Xiangya Hospital, Central South University, Changsha, China.
³ Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, China.
⁴ Department of Colorectal & Anal Surgery, General Surgery, Xiangya Hospital, Central South University, Changsha, China.
⁵ National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.

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.

Keywords: TNF-related apoptosis-inducing ligand (TRAIL); hepatocellular carcinoma; lncRNA CASC2; miR-18a; receptor-interacting serine/threonine-protein kinase 1 (RIPK1); the NF-κB signaling.