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硫氧还蛋白相互作用蛋白是 miR-125b 的首选靶标,通过 HIF1α 通路促进胰腺癌的转移和进展。

Thioredoxin-interacting protein is a favored target of miR-125b, promoting metastasis and progression of pancreatic cancer via the HIF1α pathway.

机构信息

Department of Gastroenterology, Xinxiang Central Hospital, Xinxiang, Henan, China.

Department of Endocrinology, Xinxiang Central Hospital, Xinxiang, Henan, China.

出版信息

J Biochem Mol Toxicol. 2021 Jul;35(7):e22782. doi: 10.1002/jbt.22782. Epub 2021 Apr 25.

Abstract

MicroRNAs (miRs) are vital in the development of pancreatic cancer (PC) targeting several cellular processes. This study was aimed at evaluating the function of miR-125b and the mechanism involved in PC. Cell migration, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), and Bromodeoxyuridine/5-bromo-2'-deoxyuridine (BrdU) study was done to establish the migration capability, cell viability, and cell proliferation, respectively. Binding sites for miR-125b were recognized by luciferase assay, and the expression of protein by Western blot and immunofluorescence assay. In vivo study was done by BALB/c nude xenograft mice for evaluating the function of miR-125b. The study showed that expression of miR-125b was elevated in PC cells and tissues and was correlated to proliferation and migration of cells. Also, overexpression of miR-125b encouraged migration, metastasis, and proliferation of BxPC-3 cells, and suppression reversed it. We also noticed that thioredoxin-interacting protein (TXNIP) was the potential target of miR-125b. The outcomes also suggested that miR-125b governed the expression of TXNIP inversely via directly attaching to the three prime untranslated region (3'-UTR) activating hypoxia-inducible factor 1α (HIF1α). Looking into the relation between HIF1α and TXNIP, we discovered that TXNIP caused the degradation and export of HIF1α by making a complex with it. The miR-125b-TXNIP-HIF1α pathway may serve as a useful strategy for diagnosing and treating PC.

摘要

微小 RNA(miRs)在胰腺癌(PC)的发展中起着至关重要的作用,靶向多个细胞过程。本研究旨在评估 miR-125b 的功能及其在 PC 中涉及的机制。细胞迁移、3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴盐(MTT)和溴脱氧尿苷/5-溴-2'-脱氧尿苷(BrdU)研究分别用于建立迁移能力、细胞活力和细胞增殖。通过荧光素酶测定法识别 miR-125b 的结合位点,通过 Western blot 和免疫荧光测定法检测蛋白的表达。通过 BALB/c 裸鼠异种移植小鼠进行体内研究,以评估 miR-125b 的功能。研究表明,miR-125b 在 PC 细胞和组织中的表达上调,与细胞的增殖和迁移相关。此外,miR-125b 的过表达促进了 BxPC-3 细胞的迁移、转移和增殖,而抑制则逆转了这一过程。我们还注意到,硫氧还蛋白相互作用蛋白(TXNIP)是 miR-125b 的潜在靶标。研究结果还表明,miR-125b 通过直接结合到三磷酸未翻译区(3'-UTR)来负调控 TXNIP 的表达,从而激活缺氧诱导因子 1α(HIF1α)。在研究 HIF1α 和 TXNIP 之间的关系时,我们发现 TXNIP 通过与 HIF1α 形成复合物导致 HIF1α 的降解和输出。miR-125b-TXNIP-HIF1α 通路可能成为诊断和治疗 PC 的一种有用策略。

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