Targeting of Noncanonical Wnt5a Signaling by AP-1 Blocker Dominant-Negative Jun When It Inhibits Skin Carcinogenesis.
Targeting of Noncanonical Wnt5a Signaling by AP-1 Blocker Dominant-Negative Jun When It Inhibits Skin Carcinogenesis.
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DOI：
10.1177/1947601912448820
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发表时间：
2012-01-01
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影响因子：
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通讯作者：
Colburn, Nancy H
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作者：
Kang, Moon-Il;Baker, Alyson R;Colburn, Nancy H
转录因子AP-1（激活蛋白-1）调节许多驱动肿瘤促进和进展的基因。虽然基础水平的AP-1活性对正常细胞增殖和细胞存活很重要，但过度激活的AP-1依赖性基因表达会刺激炎症、血管生成、侵袭和其他促进癌变的事件。我们试图发现致癌抑制剂靶向的基因，这些基因也不会抑制细胞增殖或存活。转基因TAM67（显性阴性c-Jun）抑制小鼠皮肤肿瘤发生和肿瘤进展，而不抑制细胞增殖或诱导过度增殖。野生型和K14-TAM67小鼠表皮的表达谱揭示了一些功能显著的基因，这些基因在野生型小鼠中由肿瘤启动子诱导，而在表达AP-1阻滞剂的小鼠中则没有。目前的研究发现，当Wnt5a信号抑制DMBA/ tpa诱导的癌变时，它是TAM67的新靶点。在致瘤小鼠JB6细胞和ras转化的人鳞状癌HaCaT-II4细胞中，Wnt5a是维持肿瘤表型所必需的，因为Wnt5a敲低抑制锚定非依赖性和肿瘤异种移植物的生长。wnt5a介导的致癌途径通过激活蛋白激酶PKCalpha和致癌转录因子STAT3磷酸化而不是通过典型的Wnt/ β -catenin途径发出信号。与Wnt5a敲低类似，PKCalpha抑制剂阻断了小鼠JB6和人HaCaT-II4肿瘤细胞中STAT3的激活。此外，stat3调控基因FAS、MMP3、IRF1和cyclin D1的表达被Wnt5a敲低抑制。用pkcalpha特异性激活剂处理小鼠Wnt5a敲低细胞可挽救STAT3的磷酸化。因此，在鳞状癌细胞中，Wnt5a信号通路是维持肿瘤表型所必需的，通过AP-1阻断靶向Wnt5a有助于抑制皮肤癌变，该信号通路穿越PKCalpha和STAT3激活。在人类皮肤和结肠癌以及胶质母细胞瘤中观察到Wnt5a表达和STAT3信号的协调过激活。
The transcription factor AP-1 (activator protein-1) regulates a number of genes that drive tumor promotion and progression. While basal levels of AP-1 activity are important for normal cell proliferation and cell survival, overactivated AP-1-dependent gene expression stimulates inflammation, angiogenesis, invasion, and other events that propel carcinogenesis. We seek to discover genes targeted by carcinogenesis inhibitors that do not also inhibit cell proliferation or survival. Transgenic TAM67 (dominant-negative c-Jun) inhibits mouse skin tumorigenesis and tumor progression without inhibiting cell proliferation or induced hyperproliferation. Expression profiling of wild-type and K14-TAM67 mouse epidermis has revealed a number of functionally significant genes that are induced by tumor promoters in wild-type mice but not in those expressing the AP-1 blocker. The current study now identifies Wnt5a signaling as a new target of TAM67 when it inhibits DMBA/TPA-induced carcinogenesis. Wnt5a is required to maintain the tumor phenotype in tumorigenic mouse JB6 cells and Ras-transformed human squamous carcinoma HaCaT-II4 cells, as Wnt5a knockdown suppresses anchorage-independent and tumor xenograft growth. The oncogenic Wnt5a-mediated pathway signals through activation of the protein kinase PKCalpha and oncogenic transcription factor STAT3 phosphorylation and not through the canonical Wnt/beta-catenin pathway. Similar to Wnt5a knockdown, inhibitors of PKCalpha blocked STAT3 activation in both mouse JB6 and human HaCaT-II4 tumor cells. Moreover, expression of STAT3-regulated genes FAS, MMP3, IRF1, and cyclin D1 was suppressed with Wnt5a knockdown. Treatment of mouse Wnt5a knockdown cells with a PKCalpha-specific activator rescued phosphorylation of STAT3. Thus, Wnt5a signaling is required for maintaining the tumor phenotype in squamous carcinoma cells, Wnt5a targeting by the AP-1 blockade contributes to inhibition of skin carcinogenesis, and the signaling pathway traverses PKCalpha and STAT3 activation. Coordinate overactivation of Wnt5a expression and STAT3 signaling is observed in human skin and colon cancers as well as glioblastoma.