Kang Moon-Il, Baker Alyson R, Dextras Christopher R, Cabarcas Stephanie M, Young Matthew R, Colburn Nancy H
Laboratory of Cancer Prevention, National Cancer Institute, Frederick, MD, USA.
Genes Cancer. 2012 Jan;3(1):37-50. doi: 10.1177/1947601912448820.
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 PKCα and oncogenic transcription factor STAT3 phosphorylation and not through the canonical Wnt/β-catenin pathway. Similar to Wnt5a knockdown, inhibitors of PKCα 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 PKCα-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 PKCα and STAT3 activation. Coordinate overactivation of Wnt5a expression and STAT3 signaling is observed in human skin and colon cancers as well as glioblastoma.
转录因子AP-1（激活蛋白-1）调控许多驱动肿瘤促进和进展的基因。虽然AP-1活性的基础水平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、侵袭以及其他推动致癌作用的事件。我们试图发现致癌作用抑制剂所靶向的基因，这些基因不会同时抑制细胞增殖或存活。转基因TAM67（显性负性c-Jun）可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小鼠表皮的表达谱分析揭示了许多功能上重要的基因，这些基因在野生型小鼠中由肿瘤启动子诱导表达，但在表达AP-1阻断剂的小鼠中则不然。当前研究现已确定，在TAM67抑制二甲基苯并蒽/十四烷酰佛波醇乙酯（DMBA/TPA）诱导的致癌作用时，Wnt5a信号传导是TAM67的一个新靶点。Wnt5a是致瘤性小鼠JB-6细胞和Ras转化的人鳞状细胞癌HaCaT-II4细胞维持肿瘤表型所必需的，因为Wnt5a基因敲低会抑制非锚定依赖性生长和肿瘤异种移植生长。致癌性Wnt5a介导的信号通路通过蛋白激酶PKCα的激活以及致癌性转录因子STAT3的磷酸化来传导，而不是通过经典的Wnt/β-连环蛋白信号通路。与Wnt5a基因敲低类似，PKCα抑制剂可阻断小鼠JB-6和人HaCaT-II4肿瘤细胞中的STAT3激活。此外，Wnt5a基因敲低会抑制STAT3调控基因FAS、MMP3、IRF1和细胞周期蛋白D1的表达。用PKCα特异性激活剂处理小鼠Wnt5a基因敲低细胞可挽救STAT3的磷酸化。因此，Wnt5a信号传导是维持鳞状细胞癌细胞肿瘤表型所必需的，AP-1阻断对Wnt5a的靶向作用有助于抑制皮肤癌发生，并且该信号通路通过PKCα和STAT3激活来传导。在人类皮肤癌、结肠癌以及胶质母细胞瘤中观察到Wnt5a表达和STAT3信号传导的协同过度激活。
