Plakophilin3 downregulation leads to a decrease in cell adhesion and promotes metastasis
Plakophilin3 downregulation leads to a decrease in cell adhesion and promotes metastasis
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DOI：
10.1002/ijc.23797
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发表时间：
2008-11-15
影响因子：
6.4
通讯作者：
Dalal, Sorab N.
中科院分区：
文献类型：
--
作者：
Kundu, Samrat T.;Gosavi, Prajakta;Dalal, Sorab N.
Plakophilin 3是桥粒斑块蛋白，其水平在口咽腔的低分化肿瘤和侵袭性结肠癌中降低。为了检验plakophilin 3缺失刺激肿瘤进展的假设，在3种上皮细胞系HCT 116、HaCaT和胎儿颊粘膜中通过DNA载体驱动的RNA干扰抑制plakophilin 3表达。如悬滴测定中所评估的，斑嗜蛋白3敲低克隆显示细胞-细胞粘附减少，这伴随着细胞迁移增加。HCT 116 plakophilin 3敲低克隆显示桥粒大小减少，如电子显微镜所示。这些改变的桥粒特性伴随着软琼脂中的菌落形成和培养中的高密度生长。HCT 116衍生的克隆在裸鼠中显示出加速的肿瘤形成和增加的肺转移，这一表型与体外观察到的增加的迁移一致，并且与来自人类肿瘤的数据一致，该数据表明plakophiln 3在侵袭性和转移性肿瘤中丢失。这些数据表明，plakophilin 3损失导致细胞-细胞粘附减少，从而刺激肿瘤进展和转移。(C)2008 Wiley-Liss，Inc.
Plakophilin3 is a desmosomal plaque protein whose levels are reduced in poorly differentiated tumors of the oropharyngeal cavity and in invasive colon carcinomas. To test the hypothesis that plakophilin3 loss stimulates neoplastic progression, plakophilin3 expression was inhibited by DNA vector driven RNA interference in 3 epithelial cell lines, HCT116, HaCaT and fetal buccal mucosa. The plakophilin3-knockdown clones showed a decrease in cell-cell adhesion as assessed in a hanging drop assay, which was accompanied by an increase in cell migration. The HCT116 plakophilin3-knockdown clones showed a decrease in desmosome size as revealed by electron microscopy. These altered desmosomal properties were accompanied by colony formation in soft agar and growth to high density in culture. The HCT116-derived clones showed accelerated tumor formation in nude mice and increased metastasis to the lung, a phenotype consistent with the increased migration observed in vitro and is consistent with data from human tumors that suggests that plakophililn3 is lost in invasive and metastatic tumors. These data indicate that plakophilin3 loss leads to a decrease in cell-cell adhesion leading to the stimulation of neoplastic progression and metastasis. (C) 2008 Wiley-Liss, Inc.