Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, Guangxi, 530021, People's Republic of China.
Department of General Surgery, Affiliated hospital of Xuzhou Medical University, Xuzhou, 221000, China.
J Exp Clin Cancer Res. 2019 Feb 20;38(1):92. doi: 10.1186/s13046-019-1106-2.
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; 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.
We 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.
Lnc-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.
Lnc-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.
具有干性特征的肝细胞癌（HCC）是肿瘤发生、化疗耐药和进展的关键。长链非编码 RNA 已被证明参与 HCC 干性特征的调节；然而，其机制在很大程度上仍然未知。在这里，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中的临床意义和机制。
我们通过 qRT-PCR 和原位杂交分析了肝癌组织和细胞系中 Lnc-PDZD7 的表达水平。通过增益和缺失功能实验研究了 Lnc-PDZD7 在干性和化疗敏感性调节中的生物学功能。生物信息学分析、双荧光素酶报告实验验证了 Lnc-PDZD7 竞争性调节 EZH2 的作用。此外，染色质免疫沉淀实验、亚硫酸氢盐基因组测序和 Western blot 实验评估了 EZH2 抑制 ATOH8 的机制。
Lnc-PDZD7 在 HCC 组织中频繁上调。高 Lnc-PDZD7 表达的患者预后较差，对辅助 TACE 治疗反应不佳。Lnc-PDZD7 可以在体外和体内促进 HCC 细胞的干性特征并抑制其对抗癌药物的敏感性。在机制上，Lnc-PDZD7 作为 miR-101 的分子海绵发挥作用，拮抗其抑制 EZH2 表达的能力。随后，EZH2 通过提高其 H3K27 三甲基化和 DNA 甲基化来进一步抑制干性调节因子 ATOH8 的表达。
Lnc-PDZD7 通过 miR-101/EZH2/ATOH8 通路促进干性特征并抑制化学敏感性，为 HCC 的诊断提供了新的生物标志物，并为 HCC 提供了潜在的药物靶点。
