Cha Jiyoung Y, Lambert Que T, Reuther Gary W, Der Channing J
Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
Mol Cancer Res. 2008 Mar;6(3):435-45. doi: 10.1158/1541-7786.MCR-07-0187.
We identified the IIIb C2 epithelial cell-specific splice variant of fibroblast growth factor receptor 2 (FGFR2 IIIb C2) receptor tyrosine kinase in a screen for activated oncogenes expressed in T-47D human breast carcinoma cells. We found FGFR2 IIIb C2 expression in breast carcinoma cell lines and, additionally, expression of the mesenchymal-specific FGFR2 IIIc splice variant in invasive breast carcinomas. FGFR2 IIIc expression was associated with loss of epithelial markers and gain of mesenchymal markers. Although FGFR2 IIIb is expressed in epithelial cells, previous studies on FGFR2 IIIb transformation have focused on NIH 3T3 fibroblasts. Therefore, we compared the transforming activities of FGFR2 IIIb C2 in RIE-1 intestinal cells and several mammary epithelial cells. FGFR2 IIIb C2 caused growth transformation of epithelial cells but morphologic transformation of only NIH 3T3 cells. FGFR2 IIIb C2-transformed NIH 3T3, but not RIE-1 cells, showed persistent activation of Ras and increased cyclin D1 protein expression. NIH 3T3 but not RIE-1 cells express keratinocyte growth factor, a ligand for FGFR2 IIIb C2. Ectopic treatment with keratinocyte growth factor caused FGFR2 IIIb C2-dependent morphologic transformation of RIE-1 cells, as well as cyclin D1 up-regulation, indicating that both ligand-independent and stromal cell-derived, ligand-dependent mechanisms contribute to RIE-1 cell transformation. Our results support cell context distinct mechanisms of FGFR2 IIIb C2 transformation.
在对T-47D人乳腺癌细胞中表达的活化癌基因进行的筛选中，我们鉴定出了成纤维细胞生长因子受体2（FGFR2 IIIb C2）受体酪氨酸激酶的IIIb C2上皮细胞特异性剪接变体。我们在乳腺癌细胞系中发现了FGFR2 IIIb C2的表达，此外，在浸润性乳腺癌中还发现了间充质特异性FGFR2 IIIc剪接变体的表达。FGFR2 IIIc的表达与上皮标志物的丧失和间充质标志物的增加有关。尽管FGFR2 IIIb在上皮细胞中表达，但先前关于FGFR2 IIIb转化的研究主要集中在NIH 3T3成纤维细胞上。因此，我们比较了FGFR2 IIIb C2在RIE-1肠细胞和几种乳腺上皮细胞中的转化活性。FGFR2 IIIb C2导致上皮细胞的生长转化，但仅导致NIH 3T3细胞的形态转化。FGFR2 IIIb C2转化的NIH 3T3细胞（而非RIE-1细胞）显示出Ras的持续激活和细胞周期蛋白D1蛋白表达的增加。NIH 3T3细胞而非RIE-1细胞表达角质形成细胞生长因子，这是FGFR2 IIIb C2的一种配体。用角质形成细胞生长因子进行异位处理导致RIE-1细胞发生FGFR2 IIIb C2依赖性形态转化，以及细胞周期蛋白D1上调，这表明配体非依赖性和基质细胞衍生的配体依赖性机制均有助于RIE-1细胞转化。我们的结果支持FGFR2 IIIb C2转化的细胞背景特异性机制。
