Differential WNT activity in colorectal cancer confers limited tumorigenic potential and is regulated by MAPK signaling.
Differential WNT activity in colorectal cancer confers limited tumorigenic potential and is regulated by MAPK signaling.
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DOI：
10.1158/0008-5472.can-11-3222
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发表时间：
2012-03-15
期刊：
影响因子：
11.2
通讯作者：
Shivdasani RA
中科院分区：
文献类型：
--
作者：
Horst D;Chen J;Morikawa T;Ogino S;Kirchner T;Shivdasani RA
结直肠癌 (CRC) 以异质亚细胞模式而不是均匀地在细胞核中表达 WNT 效应蛋白 β-连环蛋白。在本研究中，我们通过分析其基础以及与肿瘤起始能力的关系，研究了结直肠癌分子异质性的这一重要方面。表达最高 WNT 表达的 CRC 细胞显示肿瘤起始能力仅略有增加。值得注意的是，高 WNT 活性与强大的 MAPK 信号传导同时激活相关，当 KRAS 表达上调或 EGFR 抑制下调时，会对 WNT 活性产生平行影响。这些发现表明，WNT 本身的高活性可能并不是肿瘤起始潜力或干细胞样潜力的可靠标志。此外，他们认为 MAPK 信号传导是瘤内异质性的关键调节剂，有助于确定 WNT 活性对 CRC 细胞干性表型的影响。
Colorectal cancers (CRCs) express the WNT effector protein β-catenin in a heterogeneous subcellular pattern rather than uniformly in the nucleus. In this study, we investigated this important aspect of molecular heterogeneity in CRCs by analyzing its basis and relationship with tumor initiating capability. CRC cells expressing the highest WNT expression showed only a marginal increase in tumor initiation capacity. Notably, high WNT activity correlated with a coincident activation of robust MAPK signaling, which when upregulated by KRAS expression or downregulated by EGFR inhibition elicited parallel effects on WNT activity. These findings suggested that on its own high WNT activity may not be a reliable signifier of tumor-initiating potential or stem-like potential. Further, they suggest that MAPK signaling is a critical modifier of intratumoral heterogeneity that contributes signiificantly to determining the impact of WNT activity on stemness phenotypes inCRC cells.