期刊
CANCER RESEARCH
卷 81, 期 2, 页码 464-475出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-20-2129
关键词
-
类别
资金
- National Research Foundation Singapore
- Singapore Ministry of Health's National Medical Research Council under the STAR Award Program [NMRC/STAR/0017/2013]
- Singapore Ministry of Health's National Medical Research Council Open Fund-Independent Research grant [NMRC/OFIRG/0055/2017]
- MOE
- Yale-NUS college
- Duke-NUS Medical School start-up grants
Aberrant Wnt signaling in cancer drives both widespread gene repression and activation, promoting cancer cell proliferation. Inhibiting Wnt signaling leads to increased gene expression through activation of the ERK and JNK pathways.
Aberrant Wnt signaling drives a number of cancers through regulation of diverse downstream pathways. Wnt/beta-catenin signaling achieves this in part by increasing the expression of protooncogenes such as MYC and cyclins. However, global assessment of the Wnt-regulated transcriptome in vivo in genetically distinct cancers demonstrates that Wnt signaling suppresses the expression of as many genes as it activates. In this study, we examined the set of genes that are upregulated upon inhibition of Wnt signaling in Wnt-addicted pancreatic and colorectal cancer models. Decreasing Wnt signaling led to a marked increase in gene expression by activating ERK and JNK; these changes in gene expression could be mitigated in part by concurrent inhibition of MEK. These findings demonstrate that increased Wnt signaling in cancer represses MAPK activity, preventing RAS-mediated senescence while allowing cancer cells to proliferate. These results shift the paradigm from Wnt/beta-catenin primarily as an activator of transcription to a more nuanced view where Wnt/beta-catenin signaling drives both widespread gene repression and activation. Significance: These findings show that Wnt/beta-catenin signaling causes widespread gene repression via inhibition of MAPK signaling, thus fine tuning the RAS-MAPK pathway to optimize proliferation in cancer.
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