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miR-181b的表观遗传沉默通过靶向RASSF1A促进结直肠癌的致瘤性。

Epigenetic silencing of miR-181b contributes to tumorigenicity in colorectal cancer by targeting RASSF1A.

作者信息

Zhao Lun-De, Zheng Wei-Wei, Wang Gao-Xiang, Kang Xiao-Chun, Qin Lei, Ji Juan-Juan, Hao Sha

机构信息

Department of Emergency, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453100, P.R. China.

Department of General Surgery, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453100, P.R. China.

出版信息

Int J Oncol. 2016 May;48(5):1977-84. doi: 10.3892/ijo.2016.3414. Epub 2016 Mar 3.

Abstract

Aberrant microRNA expression is common in colorectal cancer and DNA methylation is believed to be responsible for this alteration. In this study, we performed evaluation in vivo and in vitro to determine the role of miR-181b as a potential diagnostic and prognostic biomarker in colorectal cancer. Ninety-seven pairs of colorectal cancer tissues and adjacent normal tissues were collected. The expression level and methylation status of miR-181b was determined in tissue samples and multiple colorectal cancer cell lines. RASSF1A, a predicted target gene of miR-181b, was investigated in vitro. Further mechanistic explorations were conducted. It was found that miR-181b expression was frequently downregulated in cancer samples. This lower expression level resulted from higher hypermethylation in cancer tissue and was closely related to TNM stage. Following artificial synthesis of miR-181b stimulation, colorectal cancer cell proliferation was greatly inhibited in CRC cells while apoptosis percentage markedly increased. miR-181b achieved the tumor suppressive effects via direct targeting of the RASSF1A gene. This study indicated the clinical significance of miR-181b and the influence of miR-181b promoter region in epigenetic silencing of tumorigenicity in colorectal cancer, and implied the possible usage of miR-181b as a diagnostic and prognostic biomarker in colorectal cancer.

摘要

异常的微小RNA表达在结直肠癌中很常见,DNA甲基化被认为是这种改变的原因。在本研究中,我们进行了体内和体外评估,以确定miR-181b作为结直肠癌潜在诊断和预后生物标志物的作用。收集了97对结直肠癌组织和相邻正常组织。测定了组织样本和多种结直肠癌细胞系中miR-181b的表达水平和甲基化状态。在体外研究了miR-181b的预测靶基因RASSF1A。进行了进一步的机制探索。发现癌样本中miR-181b表达经常下调。这种较低的表达水平是由于癌组织中较高的高甲基化所致,并且与TNM分期密切相关。人工合成miR-181b刺激后,结直肠癌细胞系中结直肠癌细胞增殖受到极大抑制,而凋亡百分比显著增加。miR-181b通过直接靶向RASSF1A基因实现肿瘤抑制作用。本研究表明了miR-181b的临床意义以及miR-181b启动子区域对结直肠癌致瘤性表观遗传沉默的影响,并暗示了miR-181b作为结直肠癌诊断和预后生物标志物的可能用途。

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