lncRNA DUXAP8 Facilitates Multiple Malignant Phenotypes and Resistance to PARP Inhibitor in HCC via Upregulating FOXM1.

ABSTRACT

In this study, we examined the clinical significance and molecular mechanisms of a long non-coding RNA (lncRNA), double homeobox A pseudogene 8 (DUXAP8) in hepatocellular carcinoma (HCC). DUXAP8 expression was compared using quantitative real-time PCR in HCC versus adjacent tissues and in HCC cell lines versus normal hepatic epithelial cells. The correlations between DUXAP8 level and clinicopathological features were analyzed. Assays including MTT, colony-forming analysis, Transwell assay, western blot, xenograft formation, experimental metastasis, luciferase assay, RNA pull-down, and RNA immunoprecipitation were used to examine DUXAP8-induced malignant phenotypes, its regulation on forkhead box protein M1 (FOXM1), and the importance of FOXM1 in mediating DUXAP8 phenotypes. Our results showed that DUXAP8 was significantly upregulated in HCC tissues or cell lines associated with tumors of advanced grades, tumors that were positive for lymph node metastasis, and patients with poor overall survival. DUAXP8 was essential in maintaining multiple malignant phenotypes (including resistance to olaparib) both in vitro and in vivo. Mechanistically, DUXAP8 upregulated FOXM1 expression by sponging miR-485-5p and interacting with the RNA-binding protein Fused in Sarcoma (FUS). Functionally, FOXM1 essentially mediated the oncogenic phenotypes of DUXAP8. Collectively, DUXAP8 acts through two distinct mechanisms to upregulate FOXM1 and becomes a pleotropic oncogenic lncRNA in HCC.