Frequent Nuclear/Cytoplasmic localization of β-catenin without exon 3 mutations in malignant melanoma
Frequent Nuclear/Cytoplasmic localization of β-catenin without exon 3 mutations in malignant melanoma
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DOI：
10.1016/s0002-9440(10)65278-9
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发表时间：
1999-02-01
影响因子：
6
通讯作者：
Fearon, ER
中科院分区：
文献类型：
--
作者：
Rimm, DL;Caca, K;Fearon, ER
β-连环蛋白在E-钙粘蛋白介导的细胞-细胞粘附中具有关键作用，并且其还作为wnt途径中的下游信号分子起作用。在某些癌症和癌细胞系中发现了β-连环蛋白氨基末端附近的假定糖原合成酶激酶3 β磷酸化位点的突变。这些突变使β-连环蛋白对含有糖原合成酶激酶3 β、腺瘤性结肠息肉病和轴蛋白的复合物的调节具有抗性。因此，β-连环蛋白在胞质溶胶和细胞核中积累并激活T细胞因子/淋巴增强因子转录因子。先前，发现27个黑素瘤细胞系中的6个具有影响N-末端磷酸化位点的β-连环蛋白外显子3突变（Rubinfeld B，Robbins P，Elgamil M，Albert I，Porfiri E，Polakis P：Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science 1997，275：1790-1792）。为了评估β-连环蛋白缺陷在原发性黑色素瘤中的作用，我们对65例黑色素瘤标本进行了免疫组化和DNA测序研究。β-连环蛋白的核和/或细胞质定位是wnt通路激活的潜在指标，在大约三分之一的肿瘤中局部可见，尽管仅在一个病例中发现了β-连环蛋白的克隆体细胞突变（密码子45 Ser->Pro）。我们的研究结果表明，β-连环蛋白突变是罕见的原发性黑色素瘤，在黑色素瘤细胞系的情况相反。尽管如此，β-连环蛋白的激活，如其核和/或细胞质定位所示，似乎在黑色素瘤中很常见，在某些情况下，它可能反映了肿瘤内wnt通路的局灶性和短暂性激活。
beta-Catenin has a critical role in E-cadherin-mediated cell-cell adhesion, and it also functions as a downstream signaling molecule in the wnt pathway. Mutations in the putative glycogen synthase kinase 3 beta phosphorylation sites near the beta-catenin amino terminus have been found in some cancers and cancer cell lines, The mutations render beta-catenin resistant to regulation by a complex containing the glycogen synthase kinase 3 beta, adenomatous polyposis coli, and axin proteins. As a result, beta-catenin accumulates in the cytosol and nucleus and activates T-cell factor/lymphoid enhancing factor transcription factors. Previously, 6 of 27 melanoma cell lines were found to have beta-catenin exon 3 mutations affecting the N-terminal phosphorylation sites (Rubinfeld B, Robbins P, Elgamil M, Albert I, Porfiri E, Polakis P: Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science 1997, 275:1790-1792). To assess the role of beta-catenin defects in primary melanomas, we undertook immunohistochemical and DNA sequencing studies in 65 melanoma specimens. Nuclear and/or cytoplasmic localization of beta-catenin, a potential indicator of wnt pathway activation, was seen focally within roughly one third of the tumors, though a clonal somatic mutation in beta-catenin was found in only one case (codon 45 Ser-->Pro). Our findings demonstrate that beta-catenin mutations are rare in primary melanoma, in contrast to the situation in melanoma cell lines. Nonetheless, activation of beta-catenin, as indicated by its nuclear and/or cytoplasmic localization, appears to be frequent in melanoma, and in some cases, it may reflect focal and transient activation of the wnt pathway within the tumor.