Regulation of Nur77 expression by β-catenin and its mitogenic effect in colon cancer cells.
The orphan nuclear receptor Nur77 is an immediate-early response gene whose expression is rapidly induced by various extracellular stimuli. The aims of this study were to study the role of Nur77 expression in the growth and survival of colon cancer cells and the mechanism by which Nur77 expression was regulated. We showed that levels of Nur77 were elevated in a majority of human colon tumors (9/12) compared to their nontumorous tissues and that Nur77 expression could be strongly induced by different colonic carcinogens including deoxycholic acid (DCA). DCA-induced Nur77 expression resulted in up-regulation of antiapoptotic BRE and angiogenic VEGF, and it enhanced the growth, colony formation, and migration of colon cancer cells. In studying the mechanism by which Nur77 was regulated in colon cancer cells, we found that β-catenin was involved in induction of Nur77 expression through its activation of the transcriptional activity of AP-1 (c-Fos/c-Jun) that bound to and transactivated the Nur77 promoter. Together, our results demonstrate that Nur77 acts to promote the growth and survival of colon cancer cells and serves as an important mediator of the Wnt/β-catenin and AP-1 signaling pathways.
Wu
Hua
H
Institute for Biomedical Research, Xiamen University, Xiamen 361005, China.
Lin
Yayu
Y
Li
Wengang
W
Sun
Zhe
Z
Gao
Weiwei
W
Zhang
Haiping
H
Xie
Lei
L
Jiang
Fuquan
F
Qin
Bin
B
Yan
Tingdong
T
Chen
Liqun
L
Zhao
Yi
Y
Cao
Xihua
X
Wu
Yin
Y
Lin
Bingzhen
B
Zhou
Hu
H
Wong
Alice Sze-Tsai
AS
Zhang
Xiao-Kun
XK
Zeng
Jin-Zhang
JZ
D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D002470:Cell Survival; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003840:Deoxycholic Acid / Q000633:toxicity; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D018808:Transcription Factor AP-1; D051176:beta Catenin; D003840:Deoxycholic Acid; D019869:Phosphatidylinositol 3-Kinases; D048031:JNK Mitogen-Activated Protein Kinases