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

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-kappa B 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-kappa B 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-kappa B signaling. These outcomes foreboded that CASC2 could be a novel therapeutic target for further study of HCC-related diseases.

Automated summary

The tumor-suppressive lncRNA CASC2 is downregulated in hepatocellular carcinoma (HCC) and its low expression is associated with shorter overall survival. CASC2 overexpression inhibits HCC cell proliferation and induces cell apoptosis. CASC2 regulates TRAIL-sensitive HCC cells through the miR-24/caspase-8 and miR-221/caspase-3 axes and caspase cascades, while in TRAIL-resistant HCC cells, it regulates cell growth through the miR-18a/RIPK1 axis and the NF-kappa B signaling.