Regulation of Nur77 expression by β‐catenin and its mitogenic effect in colon cancer cells

Abstract

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.

Nuclear receptor NR4A1 promotes breast cancer invasion and metastasis by activating TGF-β signalling

“…Nevertheless, NR4A1 was also reported to be highly expressed in colon and pancreatic tumours. Knockdown of NR4A1 in these cancer cells resulted in inhibition of cell growth, induction of apoptosis and decreased angiogenesis 16,17 . These findings suggest that NR4A1 has both a tumour suppressive and pro-oncogenic effect in cancer development.…”

Erratum: The nuclear receptor TR3 regulates mTORC1 signaling in lung cancer cells expressing wild-type p53

“…There is also increasing evidence that TR3 is overexpressed in multiple tumor types and exhibits pro-oncogenic activities (Maruyama et al, 1995;Bras et al, 2000;Kolluri et al, 2003;Ke et al, 2004;Chintharlapalli et al, 2005;Li et al, 2006;Zeng et al, 2006;Zhang, 2007;Cho et al, 2007;Cho et al, 2010;Wu et al, 2010;Azoitei et al, 2010;Lee et al, 2010b) and results summarized in Figure 1 and Supplemental Figure 1 suggest that overexpression of TR3 is a negative prognostic factor for lung cancer patient survival. Thus, drugs that target TR3 may be important for treating cancer and the effective use of TR3 agonists or antagonists will be dependent on understanding the role of these receptors in critical disease-specific pathways.…”

“…Among the earliest studies on the role of TR3 in cancer was the observation that various apoptosis-inducing agents induced nuclear export of TR3 and this resulted in formation of a proapoptotic mitochondrial TR3-bcl-2 complex (Li et al, 2000;Kolluri et al, 2003;Lin et al, 2004;Zhang, 2007;Kolluri et al, 2008;Wu et al, 2010). This pathway is being extensively exploited for drug development.…”

“…With few exceptions, knockdown of TR3 by RNA interference or a related technique in cancer cells resulted in growth inhibition, induction of apoptosis, or decreased angiogenesis indicating that TR3 is a pro-oncogenic factor (Bras et al, 2000;Kolluri et al, 2003;Ke et al, 2004;Zeng et al, 2006;Wu et al, 2010;Azoitei et al, 2010;Lee et al, 2010b). Many different classes of apoptotic agents induce apoptosis in cancer through TR3-dependent pathways (reviewed in Zhang, 2007).…”

Nur77 gene expression levels were involved in different ACTH-secretion autonomy between Cushing’s disease and subclinical Cushing’s disease

“…Choi et al showed that hypoxia-inducible factor (HIF)-1α directly activated Nur77 gene expression in von Hippel-Lindaumutated renal cell carcinomas [13]. In addition to HIF-1α, interleukin-1, β-catenin, and c-fos/c-jun are also upstream stimulatory factors of Nur77 [14,15]. These results suggest the existence of a CRHindependent Nur77 induction pathway, which could play an important role in POMC expression in CD.…”