Divergent roles of p120-catenin isoforms linked to altered cell viability, proliferation, and invasiveness in carcinogen-induced rat skin tumors.
Divergent roles of p120-catenin isoforms linked to altered cell viability, proliferation, and invasiveness in carcinogen-induced rat skin tumors.
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DOI：
10.1002/mc.22630
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发表时间：
2017-07
影响因子：
4.6
通讯作者：
Dashwood RH
中科院分区：
文献类型：
--
作者：
Wang R;Chen YS;Dashwood WM;Li Q;Löhr CV;Fischer K;Ho E;Williams DE;Dashwood RH
杂环胺 2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶 (PhIP) 靶向大鼠多个器官的肿瘤发生，包括结肠和皮肤。对 PhIP 诱导的皮肤肿瘤进行了突变筛查，结果发现 Hras（7/40，17.5%）和 Tp53（2/40，5%）存在遗传变化，但 Ctnnb1 没有发现遗传变化，Ctnnb1 是 PhIP 诱导的结肠肿瘤中常见的突变基因。尽管不存在 Ctnnb1 突变，β-连环蛋白在 PhIP 诱导的皮肤肿瘤的核和质膜部分中过度表达，这与质膜中 p120-连环蛋白的丢失以及核提取物中出现多个 p120-连环蛋白相关条带一致。实时 RT-PCR 显示，与邻近的正常组织相比，p120-连环蛋白亚型 1 和 4 在 PhIP 诱导的皮肤肿瘤中表达上调，而 p120-连环蛋白亚型 3 表达均匀。在人表皮样癌和结肠癌细胞中，瞬时转染p120-连环蛋白异构体1A增强了细胞活力和细胞侵袭指数，而瞬时转染p120-连环蛋白异构体4A则增加了细胞活力和细胞增殖。 p120-连环蛋白的敲除显示 β-连环蛋白和转录调节靶标 Ccnd1/Cyclin D1 的表达相应减少。免疫共沉淀实验确定了 PhIP 诱导的皮肤肿瘤和人类癌细胞系中 β-连环蛋白与 p120-连环蛋白亚型的关联。研究结果在可能针对不同 p120-连环蛋白亚型的治疗策略的背景下进行了讨论，为规避皮肤癌和结肠癌中通过不同机制产生的组成型活性 β-连环蛋白提供了途径。
The heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) targets multiple organs for tumorigenesis in the rat, including the colon and the skin. PhIP-induced skin tumors were subjected to mutation screening, which identified genetic changes in Hras (7/40, 17.5%) and Tp53 (2/40, 5%), but not in Ctnnb1, a commonly mutated gene in PhIP-induced colon tumors. Despite the absence of Ctnnb1 mutations, β-catenin was overexpressed in nuclear and plasma membrane fractions from PhIP-induced skin tumors, coinciding with loss of p120-catenin from the plasma membrane, and the appearance of multiple p120-catenin-associated bands in the nuclear extracts. Real-time RT-PCR revealed that p120-catenin isoforms 1 and 4 were upregulated in PhIP-induced skin tumors, whereas p120-catenin isoform 3 was expressed uniformly, compared with adjacent normal-looking tissue. In human epidermoid carcinoma and colon cancer cells, transient transfection of p120-catenin isoform 1A enhanced the viability and cell invasion index, whereas transient transfection of p120-catenin isoform 4A increased cell viability and cell proliferation. Knockdown of p120-catenin revealed a corresponding reduction in the expression of β-catenin and a transcriptionally regulated target, Ccnd1/Cyclin D1. Co-immunoprecipitation experiments identified associations of β-catenin with p120-catenin isoforms in PhIP-induced skin tumors and human cancer cell lines. The results are discussed in the context of therapeutic strategies that might target different p120-catenin isoforms, providing an avenue to circumvent constitutively active β-catenin arising via distinct mechanisms in skin and colon cancer.