Orphan nuclear receptor Nur77 promotes colorectal cancer invasion and metastasis by regulating MMP-9 and E-cadherin

Abstract

Nur77, an orphan member of the nuclear receptor superfamily, has been implicated in tumorigenesis. However, its contributions to colorectal cancer (CRC) invasion and metastasis are largely under characterized. Here, we present the first evidence that the invasion and metastasis of CRC is regulated by Nur77. High expression of Nur77 was observed in clinical CRC tissues, and this elevated expression was significantly associated with advanced tumor, lymph nodes, distant metastasis stage (P = 0.003), lymph node metastasis (P = 0.001) and poor survival (P = 0.03). Overexpression of Nur77 in CRC cells enhanced cell invasion in vitro, whereas knockdown of Nur77 diminished cell invasion and metastasis both in vitro and in vivo. In studying the possible mechanism by which overexpression of Nur77 contributes to CRC invasion and metastasis, we observed that the nuclear protein Nur77 promoted the expression of matrix metalloproteinase (MMP)-9, a novel downstream target of Nur77, and subsequently decreased the expression of E-cadherin. Examination of clinical samples further 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, our study demonstrated that Nur77 could promote the invasion and metastasis of CRC cells through regulation of MMP-9/E-cadherin signaling. These observations provide a possible new strategy for potentially treating or preventing the metastasis of CRC through targeting of Nur77.

Ubiquitin-Specific Protease 4-Mediated Deubiquitination and Stabilization of PRL-3 Is Required for Potentiating Colorectal Oncogenesis

“…As shown in Fig. 4C, USP4 knockdown significantly increased E-cadherin expression, an epithelial marker implicated in metastasis of colorectal cancer (31). Overexpression of PRL-3 profoundly impaired E-cadherin expression induced by USP4 knockdown (Fig.…”

“…These cells were cultured as previously described (31). NCM460, a normal human colon mucosal epithelial cell line, was maintained in 50% DMEM and 50% RPMI-1640 medium containing 20% fetal bovine serum in a humidified atmosphere containing 5% CO 2 at 37 C. All cell lines were passaged for fewer than 4 months after resuscitation and were used at the fifth through tenth passage in culture for this study.…”

RARγ Downregulation Contributes to Colorectal Tumorigenesis and Metastasis by Derepressing the Hippo–Yap Pathway

“…These cells were cultured as described previously (34,35). All cell lines were passaged in the laboratory for fewer than 4 months after resuscitation and were used at the fifth through tenth passage in culture for this study.…”

“…SW480 and HT-29 cell lines stably expressing RARg-specific shRNA (shRNA/RARg) or scrambled shRNA control (shRNA/ Control) were constructed using a lentiviral shRNA technique (GeneChem), as described previously by our laboratory (34). The human RARg shRNA target sequences are listed in Supplementary Table S2.…”

“…The experiments were performed as described previously (34). Representative blots are shown from several experiments, and the images were taken and analyzed by an image-forming system with Chemiscope analysis V1.01 software.…”