The Genomic Effects Of Orphan Nuclear Receptor Nur77 On Tumor Promoting Or Suppression And Its Related Mechanisms

Nur77,a member of nuclear receptor,is implicated in cancer development.However,its contributions to colorectal cancer(CRC)invasion and metastasis are unknown.In this study,we found that Nur77 is overexpressed in clinical CRC tissue,and this elevated expression was significantly associated with advanced tumor,lymph nodes,distant metastasis stage,lymph node metastasis and poor survival.The in vitro and in vivo experiments showed that overexpression of Nur77 in CRC cells significantly promoted CRC cells invasion,while knockdown of Nur77 greatly impaired CRC cells invasion and metastasis.In studying the possible mechanism by which overexpression of Nur77 contributes to CRC invasion and metastasis,we observed that matrix metalloproteinase(MMP)-9 is a novel target gene of Nur77.Nur77 directly binds to the promoter of MMP-9 and regulates its expression in CRC cells,which subsequently decreased the expression of E-cadherin,a critical protein in Epithelial–mesenchymal transition(EMT).Examination of clinical samples showed that Nur77 expression is positively correlated with MMP-9,whereas negatively correlated with E-cadherin.Interestingly,Nur77-mediated CRC invasion via MMP-9 and E-cadherin could be mimicked by some metastasis-inducible factors,including hypoxia and prostaglandin E2.Collectively,we presented the first evidence that Nur77 promotes CRC cells invasion and metastasis through regulating MMP-9/E-cadherin signaling axis,and provided a possible novel strategy for potentially preventing or treating CRC through targeting of Nur77.Nur77,a member of nuclear receptor superfamily,plays critical roles in inflammation and immunity.However,its function in tumor microenvironment remains unclear.In this study,we found that deletion of Nur77 significantly enhanced tumor metastasis compared with wild-type mice.Additionally,compared to the conditioned media derived from the peritoneal macrophages of Nur77+/+ mice(CM1),the conditioned media derived from the peritoneal macrophages of Nur77-/-mice(CM2)significantly promoted the epithelial–mesenchymal transition(EMT)of cancer cells,which further enhanced migratory and invasive abilities of cancer cells.Furthermore,We found that proinflammatory factor TNF-? is required for EMT,invasion and metastasis of tumor cells.In addition,we found that CSF-1R is a novel target gene of Nur77,and the upregulation of CSF-1R induced by Nur77 could significantly enhance the migration of inflammatory and immune cells.Consistent with this results,the number of inflammatory and immune cells infiltrated in tumor metastases of Nur77-/-mice was significantly decreased than that of Nur77+/+ mice.Taken together,these results suggest that host Nur77 expression plays a key role in antitumor immune response and inhibiting tumor metastasis.