Regulation of norrin receptor frizzled-4 by Wnt2 in colon-derived cells.
Regulation of norrin receptor frizzled-4 by Wnt2 in colon-derived cells.
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DOI：
10.1186/1471-2121-8-12
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发表时间：
2007-03-26
期刊：
影响因子：
--
通讯作者：
Holcombe RF
中科院分区：
文献类型：
--
作者：
Planutis K;Planutiene M;Moyer MP;Nguyen AV;Pérez CA;Holcombe RF
Norrin是一种有效的Wnt途径配体。该信号通路的异常激活可导致结肠癌，但基于Norrin的信号通路在结肠癌发生中的作用及其与传统Wnt配体激活该通路的关系尚不清楚。新鲜的正常人结肠组织和所有研究的细胞系都表达Fz4、LRP5和Norrin的mRNA，但Colo205不表达Fz4。经WNT3a CM处理后，NCM460细胞的典型Wnt途径吞吐量略有增加，但Wnt2和Wnt1对其有抑制作用。结肠癌细胞株RKO对Wnt3a CM、Wnt2和Wnt1的应答是通过增加典型的Wnt途径的吞噬能力来实现的。Wnt5A不影响两种细胞系中Wnt途径的吞噬能力。Wnt2，而不是Wnt3a，抑制了NCM460中Fz4的表达，但在RKO或另一结肠癌细胞株HCT116中不表达。通过RT-PCR和Norrin结合实验在RNA和蛋白质水平上证实了这种对Fz4的影响。WNT2作用于NCM460细胞后，其余9种FZ受体的表达均无明显变化。结果提示，结肠粘膜和结肠肿瘤可能存在两个自身调节的正Wnt反馈环，一个是通过Wnt：Fz相互作用引起的典型信号，另一个是通过Norrin：Fz4相互作用引起的信号。后一种相互作用可能是通过Wnt2对Fz4表达的调节来调节的。与正常粘膜细胞失去Fz4相比，癌细胞保留Fz4可以为肿瘤细胞提供选择性优势。在肿瘤微环境中，FZ4的表达可能在对Wnt信号的应答中起关键作用。
Norrin is a potent Wnt pathway ligand. Aberrant activation of this signaling pathway can result in colon tumors but the role of norrin-based signaling in the genesis of colon cancer, and its relationship to activation of the pathway by traditional Wnt ligands, is not defined. Fresh normal human colon tissue and all the cell lines studied expressed mRNA for Fz4, LRP5 and norrin, except Colo205 which lacked Fz4 expression. Canonical Wnt pathway throughput was increased slightly in NCM460 following treatment with Wnt3a CM but was inhibited by Wnt2 and Wnt1. The colon cancer cell line, RKO, responded to Wnt3a CM, Wnt2 and Wnt1 by increasing canonical Wnt pathway throughput. Wnt5a did not affect Wnt pathway throughput in either cell line. Wnt2, but not Wnt3a, abrogated Fz4 expression in NCM460, but not in RKO or another colon cancer cell line, HCT116. This effect on Fz4 was confirmed at both the RNA and protein levels via RT-PCR and a norrin binding assay. The expression of all others 9 Fz receptors did not change after treatment of NCM460 cells with Wnt2. The data suggests that colonic mucosa and colon tumors may possess two autoregulatory positive Wnt feedback loops, one through canonical signals induced by Wnt:Fz interactions and one through signals resulting from norrin:Fz4 interactions. The latter interactions may be modulated via regulation of Fz4 expression by Wnt2. Retention of Fz4 by cancers, in contrast to the loss of Fz4 by normal mucosal cells, could provide a selective advantage to the tumor cells. Fz4 expression may play a critical role in responses to Wnt signaling in the tumor microenvironment.
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影响因子：
3.4
作者：
Byun, T;Karimi, M;Holcombe, RF
通讯作者：
Holcombe, RF
影响因子：
56.9
作者：
He, TC;Sparks, AB;Kinzler, KW
通讯作者：
Kinzler, KW
影响因子：
4.1
作者：
Kondo, H;Hayashi, H;Hayashi, K
通讯作者：
Hayashi, K
DOI：
10.1136/mp.55.4.220
发表时间：
2002-08-01
期刊：
JOURNAL OF CLINICAL PATHOLOGY-MOLECULAR PATHOLOGY
影响因子：
--
作者：
Holcombe, RF;Marsh, JL;Truong, T
通讯作者：
Truong, T
影响因子：
64.5
作者：
Cadigan, KM;Fish, MP;Nusse, R
通讯作者：
Nusse, R