Modulation of miR-155-5p signalling via 5-ASA for the prevention of high microsatellite instability: an in vitro study using human epithelial cell lines.

IF 3.7 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of physiology and biochemistry Pub Date : 2024-08-01 Epub Date: 2024-07-10 DOI:10.1007/s13105-024-01033-y
Monika Adamowicz, Joanna Abramczyk, Ewa Kilanczyk, Piotr Milkiewicz, Alicja Łaba, Malgorzata Milkiewicz, Agnieszka Kempinska-Podhorodecka
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Abstract

5-aminosalicylic acid (5-ASA) is a first-line treatment for maintaining colitis remission. It is a highly effective, safe, and well-tolerated drug with anti-inflammatory and chemo-preventive properties. While patients with primary sclerosing cholangitis (PSC) with concomitant ulcerative colitis are treated with 5-ASA, the molecular mechanisms underlying the drug's chemo-preventive effects are not entirely understood. We previously reported that bile acids and lipopolysaccharide-induced miR-155 expression was associated with downregulating mismatch repair (MMR) proteins in CACO-2 cell lines. Therefore, in this investigation, a set of in vitro functional studies was performed to show the possible mechanisms behind the epigenetic relationship between miR-155 and 5-ASA's prevention of high microsatellite instability (MSI-H). In transient transfection with miR-155Mimic, which behaves like endogenous miRNA, we confirmed the relationships between miR-155 and its target MMR in three human intestinal epithelial cell lines: CACO-2, NCM460D and HT-29. We have shown, for the first time, that 5-ASA modulates MLH1, MSH2, MSH6 in miR-155 transfected cells. These findings underline that chemoprotective 5-ASA therapy can effectively attenuate the expression of miR-155 and potentially prevent a development of MSI-H in a subset of colorectal cancers associated with PSC.

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通过 5-ASA 调节 miR-155-5p 信号以预防高微卫星不稳定性:一项利用人体上皮细胞系进行的体外研究。
5- 氨基水杨酸(5-ASA)是维持结肠炎缓解的一线治疗药物。它是一种高效、安全、耐受性良好的药物,具有抗炎和预防化疗的作用。虽然合并溃疡性结肠炎的原发性硬化性胆管炎(PSC)患者可以使用 5-ASA 进行治疗,但人们对该药物化学预防作用的分子机制还不完全清楚。我们曾报道,胆汁酸和脂多糖诱导的 miR-155 表达与 CACO-2 细胞系错配修复(MMR)蛋白的下调有关。因此,本研究进行了一系列体外功能研究,以显示 miR-155 与 5-ASA 预防高微卫星不稳定性(MSI-H)之间的表观遗传学关系背后的可能机制。通过瞬时转染 miR-155Mimic(其行为类似于内源性 miRNA),我们在三种人类肠上皮细胞系中证实了 miR-155 与其靶 MMR 之间的关系:CACO-2、NCM460D 和 HT-29。我们首次发现,在 miR-155 转染的细胞中,5-ASA 可调节 MLH1、MSH2 和 MSH6。这些研究结果表明,5-ASA 化学保护疗法能有效减少 miR-155 的表达,并有可能防止与 PSC 相关的部分结直肠癌发展成 MSI-H。
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来源期刊
Journal of physiology and biochemistry
Journal of physiology and biochemistry 生物-生化与分子生物学
CiteScore
6.60
自引率
0.00%
发文量
86
审稿时长
6-12 weeks
期刊介绍: The Journal of Physiology and Biochemistry publishes original research articles and reviews describing relevant new observations on molecular, biochemical and cellular mechanisms involved in human physiology. All areas of the physiology are covered. Special emphasis is placed on the integration of those levels in the whole-organism. The Journal of Physiology and Biochemistry also welcomes articles on molecular nutrition and metabolism studies, and works related to the genomic or proteomic bases of the physiological functions. Descriptive manuscripts about physiological/biochemical processes or clinical manuscripts will not be considered. The journal will not accept manuscripts testing effects of animal or plant extracts.
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