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食管鳞状细胞癌的分子发病机制:miR-145-3p 对基因调控的抗肿瘤作用鉴定。

Molecular pathogenesis of esophageal squamous cell carcinoma: Identification of the antitumor effects of miR‑145‑3p on gene regulation.

机构信息

Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima 890‑8520, Japan.

Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba 260‑8670, Japan.

出版信息

Int J Oncol. 2019 Feb;54(2):673-688. doi: 10.3892/ijo.2018.4657. Epub 2018 Dec 6.

DOI:10.3892/ijo.2018.4657
PMID:30535463
Abstract

Although miR‑145‑5p (the guide strand of the miR‑145 duplex) is established as a tumor suppressive microRNA (miRNA or miR), the functional significance of miR‑145‑3p (the passenger strand of the miR‑145 duplex) in cancer cells and its targets remains obscure. In our continuing analysis of esophageal squamous cell carcinoma (ESCC) pathogenesis, the aim of the present study was to identify important oncogenes and proteins that are controlled by miR‑145‑3p. Overexpression of miR‑145‑3p significantly reduced cancer cell proliferation, migration and invasive abilities, and further increased apoptotic abilities. In ESCC cells, 30 possible oncogenic targets were identified that might be regulated by miR‑145‑3p. Among these targets, dehydrogenase/reductase member 2 (DHRS2) and myosin IB (MYO1B) were focused on to investigate their functional roles in ESCC cells. DHRS2 and MYO1B were directly regulated by miR‑145‑3p in ESCC cells by dual luciferase reporter assays. Aberrantly expressed DHRS2 and MYOIB were detected in ESCC clinical specimens, and their overexpression enhanced cancer cell aggressiveness. Genes regulated by antitumor miR‑145‑3p were closely associated with the molecular pathogenesis of ESCC. The approach based on antitumor miRNAs may contribute to the understanding of ESCC molecular pathogenesis.

摘要

虽然 miR-145-5p(miR-145 双链体的指导链)已被确定为肿瘤抑制性 microRNA(miRNA 或 miR),但 miR-145-3p(miR-145 双链体的过客链)在癌细胞中的功能意义及其靶标仍不清楚。在我们对食管鳞状细胞癌(ESCC)发病机制的持续分析中,本研究旨在确定受 miR-145-3p 调控的重要癌基因和蛋白。miR-145-3p 的过表达显著降低了癌细胞的增殖、迁移和侵袭能力,并进一步增加了细胞凋亡能力。在 ESCC 细胞中,鉴定出 30 个可能的致癌靶标,这些靶标可能受 miR-145-3p 调控。在这些靶标中,醛还原酶成员 2(DHRS2)和肌球蛋白 IB(MYO1B)被作为重点来研究它们在 ESCC 细胞中的功能作用。DHRS2 和 MYO1B 通过双荧光素酶报告基因检测在 ESCC 细胞中受 miR-145-3p 的直接调控。在 ESCC 临床标本中检测到异常表达的 DHRS2 和 MYO1B,它们的过表达增强了癌细胞的侵袭能力。受抗肿瘤 miR-145-3p 调控的基因与 ESCC 的分子发病机制密切相关。基于抗肿瘤 miRNA 的方法可能有助于理解 ESCC 的分子发病机制。

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