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Chronic hepatitis C virus (HCV) infection is a leading cause of end-stage liver diseases, such as fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Several cellular entities, including paraspeckles and their related components, are involved in viral pathogenesis and cancer progression. NEAT1 lncRNA is a major component of paraspeckles that has been linked to several malignancies. In this study, analysis of the Cancer Genome Atlas (TCGA) database and validation in HCV-induced HCC tissue and serum samples showed significantly high expression of NEAT1 in patients with liver cancer. Moreover, we found that NEAT1 levels increased upon HCV infection. To further understand the mechanism of NEAT1-induced HCC progression, we selected one of its targets, miR-9–5 p, which regulates BGH3 mRNA levels. Interestingly, miR-9–5 p levels were downregulated upon HCV infection, whereas BGH3 levels were upregulated. Additionally, partial NEAT1 knockdown increased miR-9–5 p levels and decreased BGH3 levels, corroborating our initial results. BGH3 levels were also upregulated in HCV-induced HCC and TCGA tissue samples, which could be directly correlated with NEAT1 levels. As a known oncogene, BGH3 is directly linked to HCC progression mediated by NEAT1. We also found that NEAT1 levels remained upregulated in serum samples from patients treated with direct-acting antivirals (DAA), indicating that NEAT1 might be a molecular trigger that promotes HCC development. Collectively, these findings provide molecular insights into HCV-induced HCC progression via the NEAT1-miR-9-BGH3 axis.

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Recently, we showed that Δ40p53, the translational isoform of p53, can inhibit cell growth independently of p53 by regulating microRNAs. Here, we explored the role of Δ40p53 in regulating the lncRNA-miRNA axis. Based on early research from our laboratory, we selected LINC00176 for further exploration. LINC00176 levels were affected by the overexpression and knockdown of Δ40p53. Further, under DNA damage, ER stress, and glucose deprivation, LINC00176 was upregulated in HCT116 p53-/- cells (harboring only Δ40p53) compared to HCT116 p53+/+ cells. Additionally, ChIP and RNA stability assays revealed that Δ40p53 transactivates LINC00176 transcriptionally and stabilizes it post-transcriptionally. We ectopically overexpressed and knocked down LINC00176 in HCT116 p53-/- cells, which affected proliferation, cell viability, and the expression of epithelial markers. Finally, RNA pulldown revealed that LINC00176 sequesters several putative miRNA targets. These results provide important insights into the pivotal role of Δ40p53 in regulating the lncRNA-miRNA axis.