HEF1, a novel target of Wnt signaling, promotes colonic cell migration and cancer progression.
HEF1, a novel target of Wnt signaling, promotes colonic cell migration and cancer progression.
复制标题
DOI：
10.1038/onc.2010.632
复制
发表时间：
2011-06-09
期刊：
影响因子：
8
通讯作者：
Liu, W.
中科院分区：
文献类型：
--
作者：
Li, Y.;Bavarva, J. H.;Wang, Z.;Guo, J.;Qian, C.;Thibodeau, S. N.;Golemis, E. A.;Liu, W.
规范的Wnt/β-Catenin通路的调控失调和Wnt信号靶基因的异常激活在结直肠癌中是常见的，并与肿瘤的进展有关。HEF1(人类丝状蛋白增强子1，也被称为NEDD9或Cas-L)的表达变化与黑色素瘤、乳腺癌和结直肠癌的进展有关。然而，对HEF1的调控及其在结直肠癌发生中的作用尚不完全清楚。我们在这里确定HEF1是一个新的Wnt信号靶点。WNT3a、β-catenin和Dvl2呈剂量依赖性上调HEF1的表达，而shRNA下调β-catenin的表达则抑制HEF1的表达。此外，在结直肠癌细胞系和原发肿瘤组织中，以及在Apcmin/+小鼠的结肠和腺瘤息肉中，观察到HEF1的mRNA和蛋白水平升高。此外，结直肠肿瘤组织中的HEF1水平随肿瘤分级的升高而升高。染色质免疫沉淀(ChIP)分析和HEF1启动子分析表明，在HEF1启动子上有三个功能TCF结合位点，负责Wnt信号诱导的HEF1。异位表达HEF1促进细胞增殖和集落形成，而shRNA下调SW480细胞中HEF1的表达则相反，并抑制移植瘤的生长。此外，HEF1在SW480细胞中的过表达促进了细胞的迁移和侵袭。总之，我们的结果确定了HEF1作为典型的Wnt/β-Catenin信号通路在细胞增殖、迁移和肿瘤发生中的一个新的中介作用，以及在结直肠肿瘤发生和发展中的重要角色。HEF1可能是结直肠癌靶向药物的一个有吸引力的候选药物。
Misregulation of the canonical Wnt/β-catenin pathway and aberrant activation of Wnt signaling target genes are common in colorectal cancer and contribute to cancer progression. Altered expression of HEF1 (Human Enhancer of Filamentation 1, also known as NEDD9 or Cas-L) has been implicated in progression of melanoma, breast, and colorectal cancer. However, the regulation of HEF1 and the role of HEF1 in colorectal cancer tumorigenesis are not fully understood. We here identify HEF1 as a novel Wnt signaling target. The expression of HEF1 was up-regulated by Wnt3a, β-catenin, and Dvl2 in a dose-dependent fashion, and was suppressed following β-catenin down-regulation by shRNA. In addition, elevated HEF1 mRNA and protein levels were observed in colorectal cancer cell lines and primary tumor tissues, as well as in the colon and adenoma polyps of Apcmin/+ mice. Moreover, HEF1 levels in human colorectal tumor tissues increased with the tumor grade. Chromatin immunoprecipitation (ChIP) assays and HEF1 promoter analyses revealed three functional TCF-binding sites in the promoter of HEF1 responsible for HEF1 induction by Wnt signaling. Ectopic expression of HEF1 increased cell proliferation and colony formation, while down-regulation of HEF1 in SW480 cells by shRNA had the opposite effects and inhibited the xenograft tumor growth. Furthermore, overexpression of HEF1 in SW480 cells promoted cell migration and invasion. Together, our results determined a novel role of HEF1 as a mediator of the canonical Wnt/β-catenin signaling pathway for cell proliferation, migration, and tumorigenesis, as well as an important player in colorectal tumorigenesis and progression. HEF1 may represent an attractive candidate for drug targeting in colorectal cancer.
登录
查看更多内容
影响因子：
8
作者：
Donninger, H;Bonome, T;Birrer, MJ
通讯作者：
Birrer, MJ
影响因子：
6
作者：
Li, YC;Park, MJ;Kim, YN
通讯作者：
Kim, YN
影响因子：
4.8
作者：
Fujino, H;West, KA;Regan, JW
通讯作者：
Regan, JW
影响因子：
5.3
作者：
Law, SF;O'Neill, GM;Golemis, EA
通讯作者：
Golemis, EA
影响因子：
64.8
作者：
Ji, Hongbin;Ramsey, Matthew R.;Wong, Kwok-Kin
通讯作者：
Wong, Kwok-Kin