Division of Molecular Medicine and Genetics, Department of Internal Medicine, and the Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Proc Natl Acad Sci U S A. 2012 Jul 10;109(28):11312-7. doi: 10.1073/pnas.1203015109. Epub 2012 Jun 27.
Aberrant activation of canonical Wingless-type MMTV integration site family (Wnt) signaling is pathognomonic of colorectal cancers (CRC) harboring functional mutations in either adenomatous polyposis coli or β-catenin. Coincident with Wnt cascade activation, CRCs also up-regulate the expression of Wnt pathway feedback inhibitors, particularly the putative tumor suppressor, Axin2. Because Axin2 serves as a negative regulator of canonical Wnt signaling in normal cells, recent attention has focused on the utility of increasing Axin2 levels in CRCs as a means to slow tumor progression. However, rather than functioning as a tumor suppressor, we demonstrate that Axin2 acts as a potent promoter of carcinoma behavior by up-regulating the activity of the transcriptional repressor, Snail1, inducing a functional epithelial-mesenchymal transition (EMT) program and driving metastatic activity. Silencing Axin2 expression decreases Snail1 activity, reverses EMT, and inhibits CRC invasive and metastatic activities in concert with global effects on the Wnt-regulated cancer cell transcriptome. The further identification of Axin2 and nuclear Snail1 proteins at the invasive front of human CRCs supports a revised model wherein Axin2 acts as a potent tumor promoter in vivo.
经典 Wnt 信号通路的异常激活是结直肠癌（CRC）的特征，这些 CRC 要么存在腺瘤性息肉病基因（APC）或 β-连环蛋白的功能突变。与 Wnt 级联激活相一致，CRC 还上调 Wnt 通路反馈抑制剂的表达，特别是假定的肿瘤抑制因子 Axin2。由于 Axin2 在正常细胞中作为经典 Wnt 信号的负调节剂，最近的研究重点集中在增加 CRC 中 Axin2 水平作为减缓肿瘤进展的一种手段的效用上。然而，我们证明 Axin2 不是作为肿瘤抑制因子发挥作用，而是通过上调转录抑制因子 Snail1 的活性，诱导功能性上皮-间充质转化（EMT）程序并驱动转移活性，从而成为癌行为的有力促进剂。沉默 Axin2 表达会降低 Snail1 活性，逆转 EMT，并抑制 CRC 的侵袭和转移活性，同时对 Wnt 调节的癌细胞转录组产生全局影响。在人类 CRC 的侵袭前沿进一步鉴定 Axin2 和核 Snail1 蛋白，支持了一种修正模型，即 Axin2 在体内作为一种强有力的肿瘤促进因子发挥作用。
