Sheng Z, Sun W, Smith E, Cohen C, Sheng Z, Xu X X
Department of Biochemistry and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Oncogene. 2000 Oct 5;19(42):4847-54. doi: 10.1038/sj.onc.1203853.
The physical interaction of epithelial cells with the basement membrane ensures correct positioning and acts as a survival factor for epithelial cells. Cells that detach from the basement membrane often undergo apoptosis; however, in carcinomas, this positional control is absent, permitting disorganized cell proliferation. In the majority of breast and ovarian carcinomas (85-90%), the expression of a candidate tumor suppressor, Disabled-2 (Dab2), is frequently lost. The Dab2-negative tumor cells are no longer in contact with an intact basement membrane, as indicated by the absence of collagen IV (in about 90% of cases). However, in the subset (10-15%) of ovarian tumors in which Dab2 expression is positive, the presence of a basement membrane-like structure around tumor cells was observed. Recombinant adenovirus-mediated expression of Dab2 was used in Dab2-negative ovarian and breast cancer cells, and re-expression of Dab2 was found to lead to cell death or growth arrest. Dab2 expression suppressed MAPK activation and c-fos expression. Plating the infected cells on a basement membrane matrigel rescued the cells from death and growth arrest. Thus, Dab2 exhibits a negative activity for cell growth and survival, which can be countered by attachment of the cells to basement membrane matrix. We conclude that Dab2 functions in cell positioning control and mediates the exigency for basement membrane attachment of epithelial cells. Loss of Dab2 may contribute to the basement membrane-independent, disorganized proliferation of tumor cells in ovarian and breast carcinomas.
上皮细胞与基底膜的物理相互作用确保了细胞的正确定位，并作为上皮细胞的存活因子发挥作用。从基底膜脱离的细胞常常会发生凋亡；然而，在癌症中，这种位置控制缺失，从而导致细胞无序增殖。在大多数乳腺癌和卵巢癌（85 - 90%）中，一种候选肿瘤抑制因子Disabled-2（Dab2）的表达常常缺失。如IV型胶原蛋白的缺失（约90%的病例）所示，Dab2阴性的肿瘤细胞不再与完整的基底膜接触。然而，在Dab2表达呈阳性的卵巢肿瘤亚组（10 - 15%）中，观察到肿瘤细胞周围存在类似基底膜的结构。重组腺病毒介导的Dab2表达被应用于Dab2阴性的卵巢和乳腺癌细胞，结果发现Dab2的重新表达会导致细胞死亡或生长停滞。Dab2的表达抑制了MAPK激活和c-fos表达。将感染的细胞接种在基底膜基质胶上可使细胞免于死亡和生长停滞。因此，Dab2对细胞生长和存活表现出负性活性，而细胞与基底膜基质的附着可抵消这种活性。我们得出结论，Dab2在细胞定位控制中发挥作用，并介导上皮细胞对基底膜附着的迫切需求。Dab2的缺失可能导致卵巢癌和乳腺癌中肿瘤细胞不依赖基底膜的无序增殖。
