期刊
FRONTIERS IN ONCOLOGY
卷 9, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fonc.2019.01251
关键词
colorectal cancer; miR-4666-3p; miR-329; cancer stem cells; TGF-beta; smad
类别
资金
- Natural Science Foundation of Zhejiang Province [LY13H160039, LR19H160001]
- Natural Science Foundation of China [81772575, 81502463]
- key Research Project of Science Technology Department of Zhejiang Province [2015C33097]
- Key Project of Health Bureau of Zhejiang Province [20182747347, 2017KY233]
- CSCO Merck Serono Oncology Research Fund, SCORE [Y-MX2015-038]
Quiescent caner stem cells are identified as a subpopulation of colon cancer cells in dormant state and possess strong stem-cell like characteristics. Previously, we have identified this subpopulation in colorectal cancer (quiescent colon cancer stem cells, QCCSCs), and find QCCSCs are sensitive to the apoptotic effect of IFN-gamma, which is attributed to their high IFN-gamma R expression levels. Microarray and bioinformatic analysis indicate miR-4666-3p is low expressed in QCCSCs and target IFN-gamma R1/2, which is proved by luciferase assay and western-blot. Furthermore, we find miR-4666-3p could also target TGF-beta R1 to block the activation of TGF-beta 1/Smad pathway, therefore function as a tumor suppressor gene to inhibit the stemness of colon cancer cells. Besides, compared with QCCSCs, we find the TGF-beta 1 expression also decreased with the weakening of stemness properties. In terms of mechanism, our result reveal TGF-beta 1 is the target gene of miR-329, which is also high expressed in non-QCCSCs. Thereafter, we perform gain- and loss- function experiments to confirm the synergistic effect between miR-4666-3p and miR-329 in blocking the activation of TGF-beta/Smad pathway. Finally, we evaluate the expression of both miR-4666-3p and miR-329 in 73 tumor specimens and paired normal tissue, and find both two miRNAs are related to unfavorable prognosis and advanced tumor stage in colorectal cancer. Our study revealed a novel epigenetic regulation mechanism in colon cancer stem cells, which could be exploited as a novel therapeutic strategy for cancer treatment.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据