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Oncomir MicroRNA-346 Is Upregulated in Colons of Patients With Primary Sclerosing Cholangitis.
Clinical and Translational Gastroenterology ( IF 3.6 ) Pub Date : 2020-01-01 , DOI: 10.14309/ctg.0000000000000112
Agnieszka Kempinska-Podhorodecka 1 , Malgorzata Blatkiewicz 1 , Ewa Wunsch 2 , Lukasz Krupa 3 , Krzysztof Gutkowski 3 , Piotr Milkiewicz 2, 4 , Malgorzata Milkiewicz 1
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INTRODUCTION Primary sclerosing cholangitis (PSC) is a cholestatic liver disorder that is frequently associated with ulcerative colitis (UC). Patients with PSC and UC (PSC-UC) have a higher risk of colorectal neoplasia compared with patients with UC. The oncogenic properties of microRNA-346 (miR-346) have been recently reported. We investigated the expression of miR-346 and its 2 target genes, the receptor of vitamin D (VDR), and the tumor necrosis factor-α (TNF-α), which are known to modulate carcinogenesis. METHODS Ascending and sigmoid colon biopsies were obtained from patients with PSC, PSC and UC (PSC-UC), UC, and healthy controls (n = 10 in each group). Expressions of VDR, TNF-α, 18S RNA, p27, miR-346, and reference microRNA, miR-191, were evaluated by real-time PCR using human TaqMan Gene Expression and TaqMan MicroRNA Assays. Functional studies with miR-346 mimic and inhibitor were conducted in HepG2 and Caco-2 cells. The effect of ursodeoxycholic acid on miR-346 expression was examined in Caco-2 cells. RESULTS An increased expression of miR-346 in the ascending colon of PSC-UC was observed (P < 0.001 vs all groups). In patients with UC, an exceptionally low colonic expression of miRNA-346 was accompanied by the extensive upregulation of VDR and TNF-α genes. A functional in vitro analysis demonstrated that inhibition of miR-346 resulted in the upregulation of VDR and TNF-α, whereas the induction of miR-346 activity suppressed VDR, TNF-α, and p27. DISCUSSION The upregulation of miRNA-346 in the colon of patients with PSC may be responsible for the disturbance of VDR and TNF-α signaling pathway, which could result in an inadequate suppression of neoplasia.

中文翻译:

Oncomir MicroRNA-346 在原发性硬化性胆管炎患者的结肠中上调。

引言 原发性硬化性胆管炎 (PSC) 是一种胆汁淤积性肝病,通常与溃疡性结肠炎 (UC) 相关。与 UC 患者相比,PSC 和 UC (PSC-UC) 患者发生结直肠肿瘤的风险更高。最近报道了 microRNA-346 (miR-346) 的致癌特性。我们研究了 miR-346 及其 2 个靶基因的表达,即维生素 D 受体 (VDR) 和肿瘤坏死因子-α (TNF-α),已知它们可调节致癌作用。方法 升结肠和乙状结肠活检取自 PSC、PSC 和 UC (PSC-UC)、UC 患者和健康对照(每组 n = 10)。VDR、TNF-α、18S RNA、p27、miR-346 和参考 microRNA、miR-191 的表达通过实时 PCR 使用人 TaqMan 基因表达和 TaqMan MicroRNA Assays 进行评估。在 HepG2 和 Caco-2 细胞中进行了 miR-346 模拟物和抑制剂的功能研究。在 Caco-2 细胞中检测了熊去氧胆酸对 miR-346 表达的影响。结果观察到 miR-346 在 PSC-UC 的升结肠中表达增加(与所有组相比,P < 0.001)。在 UC 患者中,miRNA-346 的异常低结肠表达伴随着 VDR 和 TNF-α 基因的广泛上调。体外功能分析表明,抑制 miR-346 会导致 VDR 和 TNF-α 的上调,而诱导 miR-346 活性则抑制 VDR、TNF-α 和 p27。讨论 PSC 患者结肠中 miRNA-346 的上调可能是导致 VDR 和 TNF-α 信号通路紊乱的原因,这可能导致对肿瘤形成的抑制不足。
更新日期:2020-01-15
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