Lnc-PDZD7 contributes to stemness properties and chemosensitivity in hepatocellular carcinoma through EZH2-mediated ATOH8 transcriptional repression
Lnc-PDZD7 contributes to stemness properties and chemosensitivity in hepatocellular carcinoma through EZH2-mediated ATOH8 transcriptional repression
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Lnc-PDZD7 通过 EZH2 介导的 ATOH8 转录抑制促进肝细胞癌的干性特性和化疗敏感性
DOI：
10.1186/s13046-019-1106-2
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发表时间：
2019-02-20
影响因子：
11.3
通讯作者：
He, Songqing
中科院分区：
文献类型：
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作者：
Zhang, Yi;Tang, Bo;He, Songqing
背景具有干细胞特征的肝细胞癌在肿瘤的发生、化疗耐药和进展中起着关键作用。长的非编码RNA参与了肝细胞癌干细胞特性的调节；然而，其机制仍很不清楚。在此，我们发现LNC-PDZD7是一个潜在的癌基因。我们系统地分析了LNC-PDZD7在干性和化疗敏感性调节方面的临床意义和机制。方法采用QRT-PCR和原位杂交技术分析LNC-PDZD7在肝癌组织和细胞系中的表达水平。通过功能获得和功能丧失实验，研究了LNC-PDZD7在茎和化学敏感性调节中的生物学功能。结果LNC-PDZD7在肝细胞癌组织中表达上调；染色质免疫沉淀法、亚硫酸氢盐基因组测序和Western印迹法检测EZH2抑制ATOH8的机制。LNC-PDZD7高表达的患者预后较差，对辅助TACE治疗的反应较差。LNC-PDZD7在体内外均能增强肝癌细胞的干性特征，抑制肿瘤细胞对抗癌药物的敏感性。从机制上讲，LNC-PDZD7作为miR-101的分子海绵，拮抗其抑制EZH2表达的能力。结论Lnc-PDZD7通过miR-101/EZH2/ATOH8途径促进干细胞特性，抑制化疗敏感性，为肝癌的诊断提供了新的生物标志物和潜在的药物靶点。
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.