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miR663a-TTC22V1 轴抑制结肠癌转移。

miR663a‑TTC22V1 axis inhibits colon cancer metastasis.

机构信息

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Division of Etiology, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China.

出版信息

Oncol Rep. 2019 Mar;41(3):1718-1728. doi: 10.3892/or.2019.6969. Epub 2019 Jan 16.

Abstract

An increasing number of studies have demonstrated that microRNAs (miRs) may act as oncogenes or anti‑oncogenes in various types of cancer, including colon cancer (CC). However, the clinical and biological significance of miR663a in the prognosis of CC and its underlying molecular mechanisms remain unknown. Using the reverse transcription‑quantitative polymerase chain reaction on CC and surgical margin tissue samples from 172 patients with CC, it was identified that miR663a was significantly downregulated in CC (P<0.001), particularly in metastatic CC (P=0.044). miR663a overexpression inhibited the proliferation and migration/invasion of CC cells in vitro, and also tumor growth and metastasis of CC cells in vivo. Additionally, miR663a target genes were analyzed. Inverse changes in tetratricopeptide repeat domain 22 variant 1 (TTC22V1) in response to alterations in miR663a expression were observed. miR663a decreased the reporter activity of the wild‑type TTC22V1‑3' untranslated region (UTR), but did not decrease that of a 3'UTR mutant. miR663a completely abolished cell migration/invasion induced by TTC22V1 containing the wild‑type 3'UTR sequence, but not that induced by TTC22V1 containing the 3'UTR mutant. An inverse correlation between miR663a and TTC22 mRNA levels was observed in CC tissues. These results suggest that TTC22V1 mRNA is a crucial miR663a target that directly promotes cell migration/invasion. TTC22, which, to the best of our knowledge, has rarely been investigated, is located in the nuclei of epithelial cells in colon stem cell niches at crypt bases, and is significantly downregulated in CC, particularly in non‑metastatic CC. High TTC22V1 expression is a significant poor survival factor for patients with CC. Collectively, the results of the present study suggested that TTC22V1 may be a metastasis‑associated gene and that the miR663a‑TTC22V1 axis inhibited CC metastasis.

摘要

越来越多的研究表明,微小 RNA(miRs)在包括结肠癌(CC)在内的多种类型癌症中可能作为癌基因或抑癌基因发挥作用。然而,miR663a 在 CC 预后中的临床和生物学意义及其潜在的分子机制尚不清楚。本研究通过逆转录定量聚合酶链反应(RT-qPCR)检测了 172 例 CC 患者的 CC 组织和手术切缘组织样本,发现 miR663a 在 CC 中显著下调(P<0.001),特别是在转移性 CC 中(P=0.044)。miR663a 的过表达抑制了 CC 细胞在体外的增殖和迁移/侵袭能力,并且还抑制了 CC 细胞在体内的肿瘤生长和转移。此外,分析了 miR663a 的靶基因。观察到 TTC22V1 变体 1(TTC22V1)的 tetratricopeptide repeat domain 22 基因在 miR663a 表达变化时的反向变化。miR663a 降低了野生型 TTC22V1-3'非翻译区(UTR)报告基因的活性,但不降低 3'UTR 突变体的活性。miR663a 完全消除了含有野生型 3'UTR 序列的 TTC22V1 诱导的细胞迁移/侵袭,但对含有 3'UTR 突变体的 TTC22V1 诱导的细胞迁移/侵袭没有影响。在 CC 组织中观察到 miR663a 和 TTC22 mRNA 水平之间的负相关。这些结果表明,TTC22V1 mRNA 是 miR663a 的一个关键靶基因,直接促进细胞迁移/侵袭。TTC22 在我们的知识范围内很少被研究,位于结肠干细胞巢隐窝底部的上皮细胞核内,在 CC 中显著下调,特别是在非转移性 CC 中。TTC22V1 高表达是 CC 患者生存不良的显著因素。总之,本研究结果表明,TTC22V1 可能是一个与转移相关的基因,miR663a-TTC22V1 轴抑制了 CC 的转移。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869f/6365692/df0cc03adb74/OR-41-03-1718-g00.jpg

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