Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
Graduate School of Medicine, Hokkaido University, Sapporo 060-0815, Japan.
Sci Rep. 2017 Mar 10;7:44328. doi: 10.1038/srep44328.
Several lines of evidence have revealed that newly emerging transformed cells are often eliminated from the epithelium, though the underlying molecular mechanisms of this cancer preventive phenomenon still remain elusive. In this study, using mammalian cell culture systems we have identified plectin, a versatile cytoskeletal linker protein, as a novel regulator for apical extrusion of RasV12-transformed cells. Plectin is accumulated in RasV12 cells when they are surrounded by normal epithelial cells. Similarly, cytoskeletal proteins tubulin, keratin, and Epithelial Protein Lost In Neoplasm (EPLIN) are also accumulated in the transformed cells surrounded by normal cells. Knockdown or functional disruption of one of these molecules diminishes the accumulation of the others, indicating that the accumulation process of the individual protein mutually depends on each other. Furthermore, plectin-knockdown attenuates caveolin-1 (Cav-1) enrichment and PKA activity in RasV12 cells and profoundly suppresses the apical extrusion. These results indicate that the plectin-microtubules-EPLIN complex positively regulates apical elimination of RasV12-transformed cells from the epithelium in a coordinated fashion. Further development of this study would open a new avenue for cancer preventive medicine.
有几条线索表明，新出现的转化细胞经常从上皮细胞中被清除，尽管这种癌症预防现象的潜在分子机制仍难以捉摸。在这项研究中，我们使用哺乳动物细胞培养系统，鉴定了中间丝结合蛋白 plectin，一种多功能细胞骨架连接蛋白，作为 RasV12 转化细胞顶端挤出的新型调节剂。当 RasV12 细胞被正常上皮细胞包围时，plectin 会在其中积累。同样，微管蛋白、角蛋白和上皮蛋白丢失在 Neoplasm（EPLIN）等细胞骨架蛋白也在上皮细胞周围的转化细胞中积累。这些分子中的一个的敲低或功能破坏会减少其他分子的积累，表明单个蛋白的积累过程相互依赖。此外，plectin 敲低会减弱 RasV12 细胞中窖蛋白 1（Cav-1）的富集和蛋白激酶 A（PKA）活性，并显著抑制顶端挤出。这些结果表明，plectin-微管-EPLIN 复合物以协调的方式正向调节 RasV12 转化细胞从上皮细胞中的顶端消除。进一步研究这一课题将为癌症预防医学开辟新的途径。
