c-Cbl mediates the degradation of tumorigenic nuclear β-catenin contributing to the heterogeneity in Wnt activity in colorectal tumors.
c-Cbl mediates the degradation of tumorigenic nuclear β-catenin contributing to the heterogeneity in Wnt activity in colorectal tumors.
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DOI：
10.18632/oncotarget.12107
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发表时间：
2016-11-01
期刊：
影响因子：
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通讯作者：
Chitalia V
中科院分区：
文献类型：
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作者：
Shashar M;Siwak J;Tapan U;Lee SY;Meyer RD;Parrack P;Tan J;Khatami F;Francis J;Zhao Q;Hartshorn K;Kolachalama VB;Rahimi N;Chitalia V
尽管在大多数结肠直肠癌（CRC）中结肠腺瘤性息肉病（APC）的丢失，但并非所有CRC都具有Wnt活化的标志，例如核β-连环蛋白。考虑到核β-连环蛋白在人CRC中的致病和预后作用，这强调了其他Wnt调节因子的存在，这些调节因子的定义是重要的。在此，我们研究了Casitas B系淋巴瘤（c-Cbl）对细胞核β-连环蛋白的影响，β-连环蛋白是一种由于APC功能丧失或CTNNB 1功能获得突变而在CRC中上调的癌蛋白。尽管c-Cbl在实体瘤中的突变的机制原理和最近的发现，但关于其在CRC中的功能重要性知之甚少。我们在人类CRC患者队列中的研究表明，核β-连环蛋白和c-Cbl之间存在负相关。进一步的研究表明，c-Cbl活性的丧失显著增强了细胞培养物和小鼠异种移植模型中的细胞核β-连环蛋白和CRC肿瘤生长。c-Cbl与β-catenin相互作用并以独立于CTNNB 1或APC突变状态的方式下调β-catenin。这项研究证明了c-Cbl作为CRC的负调节因子的先前未被认识的功能。
Despite the loss of Adenomatous Polyposis Coli (APC) in a majority of colorectal cancers (CRC), not all CRCs bear hallmarks of Wnt activation, such as nuclear β-catenin. This underscores the presence of other Wnt regulators that are important to define, given the pathogenic and prognostic roles of nuclear β-catenin in human CRC. Herein, we investigated the effect of Casitas B-lineage lymphoma (c-Cbl) on nuclear β-catenin, which is an oncoprotein upregulated in CRC due to loss-of-function APC or gain-of-function CTNNB1 mutations. Despite mechanistic rationale and recent discoveries of c-Cbl's mutations in solid tumors, little is known about its functional importance in CRC. Our study in a cohort of human CRC patients demonstrated an inverse correlation between nuclear β-catenin and c-Cbl. Further investigation showed that the loss of c-Cbl activity significantly enhanced nuclear β-catenin and CRC tumor growth in cell culture and a mouse xenograft model. c-Cbl interacted with and downregulated β-catenin in a manner that was independent of CTNNB1 or APC mutation status. This study demonstrates a previously unrecognized function of c-Cbl as a negative regulator of CRC.