Circ-PGAM1 promotes malignant progression of epithelial ovarian cancer through regulation of the miR-542-3p/CDC5L/PEAK1 pathway.,Cancer Medicine

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Circ-PGAM1 promotes malignant progression of epithelial ovarian cancer through regulation of the miR-542-3p/CDC5L/PEAK1 pathway.
Cancer Medicine ( IF 2.9 ) Pub Date : 2020-03-13 , DOI: 10.1002/cam4.2929
Chunmei Zhang ₁ , Yang Li ₁ , Wancheng Zhao ₁ , Guipeng Liu ₁ , Qing Yang ₁

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BACKGROUND Epithelial ovarian cancer (EOC) is the most common ovarian malignant cancer. Circular RNA is a type of endogenous noncoding RNA and is considered as a novel regulatory molecule in the development and progression of tumors. This study investigated the expression and functions of a circular RNA, circular-phosphoglycerate mutase 1 (circ-PGAM1), in EOC tissues and cells. METHODS The expression of circ-PGAM1 and miR-542-3p in EOC was analyzed using quantitative RT-PCR. Immunohistochemistry and western blot were performed to confirm the localization and expression of cell division cycle 5-like (CDC5L) and pseudopodium enriched atypical kinase 1 (PEAK1) in EOC tissues. Cell lines (CAOV3 and OVCAR3) overexpressing or silencingcirc-PGAM1 and miR-542-3p were established to explore the functions of circ-PGAM1 and miR-542-3p in ovarian cancer cells. Furthermore, dual-luciferase reporter assay was performed to study the interactions between circ-PGAM1 and miR-542-3p and between miR-542-3p and CDC5L. CCK-8, transwell, and flow cytometry were used to study the effect of circ-PGAM1 and miR-542-3p on cell biological behaviors including proliferation, migration, invasion, and apoptosis. The interaction between CDC5L and the PEAK1 gene promoter was confirmed using chromatin immunoprecipitation (ChIP). RESULTS Circ-PGAM1 was upregulated in EOC tissues, whereas linear PGAM1 was not deregulated in EOC tissues. Silencing of circ-PAGM1 inhibited proliferation, migration, and invasion of ovarian cancer cells and promoted cell apoptosis. MiR-542-3p was downregulated in EOC tissues, and miR-542-3p overexpression inhibited malignant progression of ovarian cancer cells. Circ-PGAM1 directly interacted with miR-542-3p, with mutual negative feedback between them. CDC5L was a direct target of miR-542-3p and played an oncogenic role in ovarian cancer cells. Furthermore, the CDC5L protein binds directly to the PEAK1 promoter to promote its transcription. PEAK1 overexpression activated ERK1/2 and JAK2 signaling pathways and promoted malignant biological behaviors of ovarian cancer cells. Circ-PAGM1 silencing combined with miR-542-3p overexpression played the greatest anticancer role in vivo. CONCLUSION The circ-PGAM1/miR-542-3p/CDC5L/PEAK1 pathway played an important role in the progression of ovarian cancer and might be a novel therapeutic target for ovarian cancer.

中文翻译：

Circ-PGAM1 通过调控 miR-542-3p/CDC5L/PEAK1 通路促进上皮性卵巢癌的恶性进展。

背景上皮性卵巢癌（EOC）是最常见的卵巢恶性肿瘤。环状RNA是一种内源性非编码RNA，被认为是肿瘤发生发展的新型调控分子。本研究调查了环状 RNA、环状磷酸甘油酸变位酶 1 (circ-PGAM1) 在 EOC 组织和细胞中的表达和功能。方法使用定量RT-PCR分析circ-PGAM1和miR-542-3p在EOC中的表达。进行免疫组织化学和蛋白质印迹以确认 EOC 组织中细胞分裂周期 5 样 (CDC5L) 和富含假足的非典型激酶 1 (PEAK1) 的定位和表达。建立过表达或沉默circ-PGAM1和miR-542-3p的细胞系（CAOV3和OVCAR3）以探索circ-PGAM1和miR-542-3p在卵巢癌细胞中的功能。此外，还进行了双荧光素酶报告基因检测以研究 circ-PGAM1 和 miR-542-3p 之间以及 miR-542-3p 和 CDC5L 之间的相互作用。采用CCK-8、transwell和流式细胞术研究circ-PGAM1和miR-542-3p对细胞增殖、迁移、侵袭和凋亡等生物学行为的影响。使用染色质免疫沉淀 (ChIP) 证实了 CDC5L 和 PEAK1 基因启动子之间的相互作用。结果 Circ-PGAM1 在 EOC 组织中上调，而线性 PGAM1 在 EOC 组织中未解除调节。circ-PAGM1 的沉默抑制增殖、迁移、和侵袭卵巢癌细胞，促进细胞凋亡。MiR-542-3p 在 EOC 组织中下调，miR-542-3p 过表达抑制卵巢癌细胞的恶性进展。Circ-PGAM1 直接与 miR-542-3p 相互作用，它们之间相互负反馈。CDC5L 是 miR-542-3p 的直接靶标，并在卵巢癌细胞中发挥致癌作用。此外，CDC5L 蛋白直接与 PEAK1 启动子结合以促进其转录。PEAK1过表达激活ERK1/2和JAK2信号通路，促进卵巢癌细胞的恶性生物学行为。Circ-PAGM1 沉默结合 miR-542-3p 过表达在体内发挥了最大的抗癌作用。

更新日期：2020-03-13

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