Carcinogen-induced squamous papillomas and oncogenic progression in the absence of the SSeCKS/AKAP12 metastasis suppressor correlate with FAK upregulation.
Carcinogen-induced squamous papillomas and oncogenic progression in the absence of the SSeCKS/AKAP12 metastasis suppressor correlate with FAK upregulation.
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DOI：
10.1002/ijc.25828
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发表时间：
2011-10-15
影响因子：
6.4
通讯作者：
Gelman, Irwin H.
中科院分区：
文献类型：
--
作者：
Akakura, Shin;Bouchard, Rene;Bshara, Wiam;Morrison, Carl;Gelman, Irwin H.
SSeCKS/Gravin/AKAP12 (SSeCKS) 负向调节细胞周期进展的能力被认为与其对关键信号分子（如蛋白激酶 A 和 C、钙调蛋白和细胞周期蛋白）的时空支架活性有关。在许多癌症类型中，包括黑色素瘤和非黑色素瘤皮肤癌，SSeCKS 在进展为恶性肿瘤时下调。 SSeCKS 的强制重新表达在通过抑制 VEGF 介导的新血管形成来抑制转移方面尤其有效。我们之前已经表明，SSeCKS-null (KO) 小鼠表现出以激活的 Akt 为标志的前列腺增生和局灶性发育不良。为了确定 KO 小鼠是否表现出增加的皮肤癌发生，用 12-O-十四烷酰佛波醇-13-乙酸酯和 7,12-二甲基苯并蒽局部治疗 WT 和 KO C57BL/6 小鼠。与WT小鼠相比，KO小鼠发生鳞状乳头状瘤的速度更快、数量更多，并且还表现出显着增加的鳞状细胞癌进展。未经治疗的 KO 表皮层比年龄匹配的 WT 小鼠的表皮层更厚，并且 FAK 和磷酸化 ERK1/2 水平显着增加，这两种物质是致癌物诱导的鳞状乳头状瘤进展为癌症的已知介质。与WT小鼠胚胎成纤维细胞(MEF)中的蛋白质水平相比，FAK缺失细胞中的SSeCKS水平升高，而SSeCKS缺失细胞中的FAK水平升高。 WT MEF 细胞中的 RNAi 研究表明，SSeCKS 和 FAK 会减弱彼此的表达。我们的研究表明 SSeCKS 可能通过负向调节 FAK 表达来预防皮肤癌进展。
The ability of SSeCKS/Gravin/AKAP12 (SSeCKS) to negatively regulate cell cycle progression is thought to relate to its spatiotemporal scaffolding activity for key signaling molecules such as protein kinase A and C, calmodulin, and cyclins. SSeCKS is downregulated upon progression to malignancy in many cancer types, including melanoma and non-melanoma skin cancer. The forced re-expression of SSeCKS is especially potent in suppressing metastasis through the inhibition of VEGF-mediated neovascularization. We have previously shown that SSeCKS-null (KO) mice exhibit hyperplasia and focal dysplasia in the prostate marked by activated Akt. To address whether KO-mice exhibit increased skin carcinogenesis, WT and KO C57BL/6 mice were treated topically with 12-O-tetradecanoylphorbol-13-acetate and 7,12-dimethylbenzanthracene. Compared to WT mice, KO mice developed squamous papillomas more rapidly and in greater numbers, and also exhibited significantly increased progression to squamous cell carcinoma. Untreated KO epidermal layers were thicker than those in age-matched WT mice, and exhibited significantly increased levels of FAK and phospho-ERK1/2, known mediators of carcinogen-induced squamous papilloma progression to carcinoma. Compared to protein levels in WT mouse embryo fibroblasts (MEF), SSeCKS levels were increased in FAK-null cells whereas FAK levels were increased in SSeCKS-null cells. RNAi studies in WT MEF cells suggest that SSeCKS and FAK attenuate each other’s expression. Our study implicates a role for SSeCKS in preventing of skin cancer progression possibly through negatively regulating FAK expression.
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