Hatakeyama M
Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
Oncogene. 2008 Nov 24;27(55):7047-54. doi: 10.1038/onc.2008.353.
Loss of cell polarity and tissue architecture is a hallmark of carcinomas that arise from epithelial cells. Recent studies on Drosophila tumor suppressors have provided evidence that epithelial polarity and cell proliferation are functionally coupled, suggesting a function for polarity defects in the development of carcinomas. This notion is supported by the findings that mammalian orthologs of these Drosophila tumor suppressors are targeted by a number of viral oncoproteins. Chronic infection with Helicobacter pylori is causally associated with gastric carcinoma. H. pylori virulence factor CagA (cytotoxin-associated gene A), which is delivered into gastric epithelial cells through a bacterial type IV secretion system, has an important function in cell transformation through interacting with and deregulating SHP-2 phosphatase, a bona fide oncoprotein that is associated with human malignancies. Recent studies have further revealed that CagA specifically binds and inhibits PAR1/MARK polarity-regulating kinase, thereby causing junctional and polarity defects in epithelial cells. Thus, the bacterial oncoprotein simultaneously targets the polarity-regulating system and growth-regulatory system. These findings indicate that loss of cell polarity underlies the abnormal proliferation of epithelial cells that directs carcinogenesis.
细胞极性和组织结构的丧失是上皮细胞来源的癌症的一个标志。最近对果蝇肿瘤抑制因子的研究提供了证据，表明上皮极性和细胞增殖在功能上是相关联的，这暗示了极性缺陷在癌症发生发展中的作用。这些果蝇肿瘤抑制因子的哺乳动物直系同源物被多种病毒癌蛋白靶向这一发现支持了这一观点。幽门螺杆菌的慢性感染与胃癌有因果关系。幽门螺杆菌毒力因子CagA（细胞毒素相关基因A）通过细菌IV型分泌系统被递送到胃上皮细胞中，它通过与SHP-2磷酸酶相互作用并使其失调，在细胞转化中发挥重要作用，SHP-2磷酸酶是一种与人类恶性肿瘤相关的真正的癌蛋白。最近的研究进一步表明，CagA特异性结合并抑制PAR1/MARK极性调节激酶，从而导致上皮细胞中的连接和极性缺陷。因此，这种细菌癌蛋白同时靶向极性调节系统和生长调节系统。这些发现表明，细胞极性的丧失是上皮细胞异常增殖的基础，而上皮细胞异常增殖会导致癌症发生。
