MSX2 is an oncogenic downstream target of activated WNT signaling in ovarian endometrioid adenocarcinoma.
MSX2 is an oncogenic downstream target of activated WNT signaling in ovarian endometrioid adenocarcinoma.
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DOI：
10.1038/onc.2011.123
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发表时间：
2011-10-06
期刊：
影响因子：
8
通讯作者：
Cho, K. R.
中科院分区：
文献类型：
--
作者：
Zhai, Y.;Iura, A.;Yeasmin, S.;Wiese, A. B.;Wu, R.;Feng, Y.;Fearon, E. R.;Cho, K. R.
卵巢类囊腺癌（OEA）经常表现出典型WNT信号传导的组成性激活，通常是稳定和失调β-连环蛋白的致癌突变的结果。在之前的工作中，我们使用基于微阵列的方法比较了β-catenin失调和未失调的OEAs中的基因表达，作为鉴定在卵巢癌发病机制中具有重要作用的新型β-catenin/TCF靶基因的策略。在微阵列研究中突出显示的基因是MSX 2，它编码一种同源框转录因子。我们发现，与β-catenin调节完整的OEAs相比，MSX 2表达在β-catenin调节异常的原发性人类和小鼠OEAs中显著增加。通过WNT 3a配体或GSK 3 β抑制剂处理的WNT途径激活有效诱导MSX 2，并且TCF 4的显性阴性形式的异位表达抑制卵巢癌细胞中的MSX 2表达。染色质免疫沉淀研究表明，β-catenin/TCF通过与MSX 2基因多个区域的TCF结合元件结合直接调节MSX 2表达。值得注意的是，发现异位MSX 2表达促进啮齿动物RK 3E模型上皮细胞系的肿瘤转化，并增强体外永生化人卵巢上皮细胞和体内卵巢癌细胞的侵袭力。使用shRNA方法抑制携带β-catenin突变的卵巢恶性肿瘤细胞中的内源性MSX 2表达，在体外和体内抑制了细胞的肿瘤性质。MSX 2在选定的卵巢癌细胞中的表达诱导了上皮间质转化（EMT）的变化，但基于对卵巢细胞系和原发性肿瘤组织的分析，MSX 2对EMT的影响似乎是复杂的和依赖于环境的。我们的研究结果表明MSX 2是β-catenin/TCF的直接下游转录靶点，并且在携带WNT/β-catenin通路缺陷的OEAs的癌症表型中具有关键贡献作用。
Ovarian endometrioid adenocarcinomas (OEAs) frequently exhibit constitutive activation of canonical WNT signaling, usually as a result of oncogenic mutations that stabilize and dysregulate the β-catenin protein. In prior work, we used microarray-based methods to compare gene expression in OEAs with and without dysregulated β-catenin as a strategy for identifying novel β-catenin/TCF target genes with important roles in ovarian cancer pathogenesis. Among the genes highlighted by the microarray studies was MSX2, which encodes a homeobox transcription factor. We found MSX2 expression was markedly increased in primary human and murine OEAs with dysregulated β-catenin compared to OEAs with intact β-catenin regulation. WNT pathway activation by WNT3a ligand or GSK3β inhibitor treatment potently induced MSX2, and ectopic expression of a dominant negative form of TCF4 inhibited MSX2 expression in ovarian cancer cells. Chromatin immunoprecipitation studies demonstrated that β-catenin/TCF directly regulates MSX2 expression via binding to TCF binding elements in multiple regions of the MSX2 gene. Notably, ectopic MSX2 expression was found to promote neoplastic transformation of the rodent RK3E model epithelial cell line and to enhance the invasiveness of immortalized human ovarian epithelial cells in vitro and ovarian carcinoma cells in vivo. Inhibition of endogenous MSX2 expression in ovarian endometrioid cancer cells carrying a β-catenin mutation using shRNA approaches inhibited neoplastic properties of the cells in vitro and in vivo. Expression of MSX2 in selected ovarian carcinoma cells induced changes suggestive of epithelial-mesenchymal transition (EMT), but based on analysis of ovarian cell lines and primary tumor tissues, effects of MSX2 on EMT appear to be complex and context-dependent. Our findings indicate MSX2 is a direct downstream transcriptional target of β-catenin/TCF and has a key contributing role in the cancer phenotype of OEAs carrying WNT/β-catenin pathway defects.
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