期刊
NATURE MEDICINE
卷 23, 期 11, 页码 1331-+出版社
NATURE PORTFOLIO
DOI: 10.1038/nm.4424
关键词
-
资金
- Vanderbilt University Cell Imaging, Chemical Biology Synthesis
- Flow Cytometry Shared Resources
- National Cancer Institute (NCI) [R01 CA046413, R35 CA197570, P50 CA095103]
- Natural Science Foundation of China (NSFC) [81430072, 81421003]
- National Key RD Program [2016YFC1303200]
- Emmy Noether-Programme of the German Research Foundation [KL 2374/2-1]
De novo and acquired resistance, which are largely attributed to genetic alterations, are barriers to effective anti-epidermal-growth-factor-receptor ( EGFR) therapy. To generate cetuximab-resistant cells, we exposed cetuximab-sensitive colorectal cancer cells to cetuximab in three-dimensional culture. Using whole-exome sequencing and transcriptional profiling, we found that the long non-coding RNA MIR100HG and two embedded microRNAs, miR-100 and miR-125b, were overexpressed in the absence of known genetic events linked to cetuximab resistance. MIR100HG, miR-100 and miR-125b overexpression was also observed in cetuximab-resistant colorectal cancer and head and neck squamous cell cancer cell lines and in tumors from colorectal cancer patients that progressed on cetuximab. miR-100 and miR-125b coordinately repressed five Wnt/beta-catenin negative regulators, resulting in increased Wnt signaling, and Wnt inhibition in cetuximab-resistant cells restored cetuximab responsiveness. Our results describe a double-negative feedback loop between MIR100HG and the transcription factor GATA6, whereby GATA6 represses MIR100HG, but this repression is relieved by miR-125b targeting of GATA6. These findings identify a clinically actionable, epigenetic cause of cetuximab resistance.
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