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环状 RNA 0005105 通过靶向 miR-20a-3p 激活 COL11A1 促进胰腺导管腺癌进展。

Circ-0005105 activates COL11A1 by targeting miR-20a-3p to promote pancreatic ductal adenocarcinoma progression.

机构信息

Department of Pancreatic-Biliary Surgery, First Hospital of China Medical University, Shenyang, China.

出版信息

Cell Death Dis. 2021 Jun 28;12(7):656. doi: 10.1038/s41419-021-03938-8.

Abstract

Growing evidence indicates that circular RNAs (circRNAs) are closely involved in tumorigenesis, but the association between circRNAs and pancreatic ductal adenocarcinoma (PDAC) is far from clear. Here, we focused on the functional investigation of circ-0005105, a newly identified circRNA, in PDAC progression. In the present study, we assessed circ-0005105 expression in PDAC tissues and cell lines with quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The biological functions of circ-0005105 in cellular proliferation and invasion were identified through gain- and loss-of-function experiments in vitro and in vivo. The interaction between circ-0005105 and the microRNA (miR)-20a-3p-COL11A1 (collagen type XI alpha 1) axis was examined using luciferase reporter and RNA immunoprecipitation assays. We found that circ-0005105 expression was upregulated in both PDAC tissues and cell lines. Higher circ-0005105 expression correlated positively with the malignant clinical phenotype and poor prognosis of patients with PDAC. Gain- and loss-of-function analysis showed that circ-0005105 facilitated both in vitro and in vivo cellular proliferation and invasion. Mechanistically, circ-000510 served as a competing endogenous RNA (ceRNA) of miR-20a-3p and indirectly modulated COL11A1 expression, leading to activation of epithelial-mesenchymal transition (EMT). Rescue experiments suggested that the oncogenic activity of circ-0005105 was dependent on the modulation of the miR-20a-3p-COL11A1 axis. More importantly, COL11A1 overexpression was significantly associated with poor prognosis in PDAC, and silencing COL11A1 reduced PDAC cell tumorigenicity and metastasis. Taken together, our findings confirm for the first time that circ-0005105 has critical functions by regulating the miR-20a-3p-COL11A1 axis. In the clinic, circ-0005105 can act as a potential prognostic marker and therapeutic target in PDAC.

摘要

越来越多的证据表明,环状 RNA(circRNAs)与肿瘤发生密切相关,但 circRNAs 与胰腺导管腺癌(PDAC)的关联还远不清楚。在这里,我们专注于研究新鉴定的 circRNA circ-0005105 在 PDAC 进展中的功能。在本研究中,我们通过定量逆转录-聚合酶链反应(qRT-PCR)评估了 PDAC 组织和细胞系中 circ-0005105 的表达。通过体外和体内的功能获得和功能丧失实验,确定了 circ-0005105 在细胞增殖和侵袭中的生物学功能。通过荧光素酶报告和 RNA 免疫沉淀测定研究了 circ-0005105 与 microRNA(miR)-20a-3p-COL11A1(胶原 XI alpha 1)轴之间的相互作用。我们发现,circ-0005105 在 PDAC 组织和细胞系中均上调表达。circ-0005105 的高表达与 PDAC 患者恶性临床表型和不良预后呈正相关。功能获得和功能丧失分析表明,circ-0005105 促进了体外和体内细胞的增殖和侵袭。机制上,circ-000510 作为 miR-20a-3p 的竞争性内源性 RNA(ceRNA),间接调节 COL11A1 的表达,导致上皮-间质转化(EMT)的激活。挽救实验表明,circ-0005105 的致癌活性依赖于对 miR-20a-3p-COL11A1 轴的调节。更重要的是,COL11A1 的过表达与 PDAC 的不良预后显著相关,沉默 COL11A1 降低了 PDAC 细胞的致瘤性和转移能力。总之,我们的研究结果首次证实,circ-0005105 通过调节 miR-20a-3p-COL11A1 轴发挥关键功能。在临床上,circ-0005105 可作为 PDAC 的潜在预后标志物和治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06f9/8239051/9c00ab4baa14/41419_2021_3938_Fig1_HTML.jpg

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