Takagi Mikio, Ikegawa Masaya, Shimada Takashi, Ishikawa Susumu, Kajita Mihoko, Maruyama Takeshi, Kamasaki Tomoko, Fujita Yasuyuki
Division of Molecular Oncology, Institute for Genetic Medicine, Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo, Japan.
Genomics, Proteomics and Biomedical Functions, Department of Life and Medical Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyoto, Japan.
Genes Cells. 2018 Nov;23(11):974-981. doi: 10.1111/gtc.12643. Epub 2018 Oct 2.
At the initial stage of carcinogenesis, transformation occurs in single cells within the epithelium. Recent studies have revealed that the newly emerging transformed cells are often apically eliminated from epithelial tissues. However, the underlying molecular mechanisms of this cancer preventive phenomenon still remain elusive. In this study, we first demonstrate that myosin-II accumulates in Src-transformed cells when they are surrounded by normal epithelial cells. Knock-down of the heavy chains of myosin-II substantially diminishes apical extrusion of Src cells, suggesting that accumulated myosin-II positively regulates the apical elimination of transformed cells. Furthermore, we have identified β-spectrin as a myosin-II-binding protein under the coculture of normal and Src-transformed epithelial cells. β-spectrin is also accumulated in Src cells that are surrounded by normal cells, and the β-spectrin accumulation is regulated by myosin-II. Moreover, knock-down of β-spectrin significantly suppresses apical extrusion of Src cells. Collectively, these results indicate that accumulation of the myosin-II-spectrin complex plays a positive role in apical extrusion of Src-transformed epithelial cells. Further elucidation of the molecular mechanisms of apical extrusion would lead to the establishment of a novel type of cancer preventive medicine.
在致癌作用的初始阶段，上皮组织内的单个细胞会发生转化。最近的研究表明，新出现的转化细胞常常从上皮组织的顶端被清除。然而，这种癌症预防现象的潜在分子机制仍然不清楚。在本研究中，我们首先证明，当Src转化细胞被正常上皮细胞包围时，肌球蛋白II会在这些细胞中积累。敲低肌球蛋白II的重链会显著减少Src细胞的顶端挤出，这表明积累的肌球蛋白II正向调节转化细胞的顶端清除。此外，在正常上皮细胞与Src转化上皮细胞共培养的情况下，我们鉴定出β-血影蛋白是一种肌球蛋白II结合蛋白。β-血影蛋白也会在被正常细胞包围的Src细胞中积累，并且β-血影蛋白的积累受肌球蛋白II调节。此外，敲低β-血影蛋白会显著抑制Src细胞的顶端挤出。总体而言，这些结果表明，肌球蛋白II-血影蛋白复合物的积累在Src转化上皮细胞的顶端挤出中起积极作用。进一步阐明顶端挤出的分子机制将有助于建立一种新型的癌症预防药物。
