Orphan nuclear receptor Nur77 promotes colorectal cancer invasion and metastasis by regulating MMP-9 and E-cadherin.
Orphan nuclear receptor Nur77 promotes colorectal cancer invasion and metastasis by regulating MMP-9 and E-cadherin.
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DOI：
10.1093/carcin/bgu157
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发表时间：
2014-11
期刊：
影响因子：
4.7
通讯作者：
Jing-Ru Wang;W. Gan;Xiu-Ming Li;Yuan-Yuan Zhao-Yuan;Ying Li;Xing-Xing Lu-Xing;Jianming Li;Hua‐Lang Wu
中科院分区：
文献类型：
--
作者：
Jing-Ru Wang;W. Gan;Xiu-Ming Li;Yuan-Yuan Zhao-Yuan;Ying Li;Xing-Xing Lu-Xing;Jianming Li;Hua‐Lang Wu
Nur 77是核受体超家族的孤儿成员，与肿瘤发生有关。然而，其对结直肠癌（CRC）侵袭和转移的作用在很大程度上尚未得到表征。在这里，我们提出的第一个证据表明，大肠癌的侵袭和转移是由Nur 77调节。Nur 77在临床结直肠癌组织中呈高表达，且与肿瘤的进展期、淋巴结转移、远处转移分期（P = 0.003）、淋巴结转移（P = 0.001）及生存期差（P = 0.03）相关。Nur 77在大肠癌细胞中的过表达增强了细胞的体外侵袭，而Nur 77的敲低降低了细胞的体外和体内侵袭和转移。在研究Nur 77过表达促进结直肠癌侵袭和转移的可能机制时，我们观察到核蛋白Nur 77促进Nur 77下游新靶点基质金属蛋白酶（MMP）-9的表达，随后降低E-cadherin的表达。临床标本的检测进一步显示Nur 77的表达与MMP-9呈正相关，而与E-cadherin呈负相关。有趣的是，Nur 77通过MMP-9和E-cadherin介导的CRC侵袭可以被一些转移诱导因子（包括缺氧和前列腺素E2）模拟。综上所述，Nur 77可以通过调节MMP-9/E-cadherin信号通路促进结直肠癌细胞的侵袭和转移。这些观察结果为通过靶向Nur 77潜在地治疗或预防CRC转移提供了可能的新策略。
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.