Abstract
BackgroundHepatocellular carcinoma (HCC) with stemness features are pivotal for tumorigenesis, chemoresistance, and progression. Long non-coding RNAs have been implicated in the regulation of HCC stemness features; however, their mechanisms remain largely unknown. Here, we found that Lnc-PDZD7 is a potential oncogene. We systematically analyzed the clinical significance and mechanism of Lnc-PDZD7 in stemness and chemosensitivity regulation.MethodsWe analyzed the Lnc-PDZD7 expression levels in liver cancer tissues and cell line by qRT-PCR and In situ hybridization. Gain- and loss-of-function experiments were conducted to investigate the biological functions of Lnc-PDZD7 in stemness and chemosensitivity regulation. Bioinformatics analysis, dual-luciferase reporter assays were performed to validate that Lnc-PDZD7 competitively regulates EZH2, Moreover, chromatin immunoprecipitation assays, bisulfite genomic sequencing and Western blot were performed to evaluate the mechanisms of EZH2 repressing ATOH8.ResultsLnc-PDZD7 is frequently upregulated in HCC tissues. Patients with high Lnc-PDZD7 expression had poorer prognoses and a poor response to adjuvant TACE therapy. Lnc-PDZD7 could promote stemness features and suppress the sensitivity of HCC cells to anticancer drugs in vitro and in vivo. Mechanistically, Lnc-PDZD7 functioned as a molecular sponge for miR-101, antagonizing its ability to repress EZH2 expression. Subsequently, EZH2 can further inhibit the expression of the stemness regulator ATOH8 via elevating its H3K27 trimethylation and DNA methylation.ConclusionLnc-PDZD7 promotes stemness properties and suppresses chemosensitivity though the miR-101/EZH2/ATOH8 pathway, providing new biomarkers for diagnosis and potential drug targets for HCC.
Highlights
Hepatocellular carcinoma (HCC) with stemness features are pivotal for tumorigenesis, chemoresistance, and progression
We found that 26 Long noncoding RNA (lncRNA) were significantly upregulated in HCC tissues compared to para-tumorous tissues (P < 0.01 and fold change> 6, Additional file 1: Figure S1)
We analyzed Lnc-PDZD7 expression levels in liver tissues, and Quantitative real time RT-PCR (qRT-PCR) revealed that Lnc-PDZD7 expression was higher in HCC cases compared with peritumoral tissues (Fig. 1a)
Summary
Hepatocellular carcinoma (HCC) with stemness features are pivotal for tumorigenesis, chemoresistance, and progression. Long non-coding RNAs have been implicated in the regulation of HCC stemness features; their mechanisms remain largely unknown. Studies suggest that tumor cells with stemness features have strong self-renewal capacity and can be labeled by stemness-related genes, such as CD133, OCT4, NANOG and SOX2, which are pivotal for tumorigenesis, chemoresistance, and progression of HCC [2, 3]. HOTTIP mediated HOXA9 to enhance the Wnt/β-catenin pathway, which is critical for the maintenance of stemness properties in human pancreatic cancer [6]. These findings suggested that lncRNAs may be stemness regulators
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