Oltean Sebastian, Sorg Brian S, Albrecht Todd, Bonano Vivian I, Brazas Robert M, Dewhirst Mark W, Garcia-Blanco Mariano A
Department of Molecular Genetics and Microbiology, Center for RNA Biology, and University Program in Genetics and Genomics, Duke University Medical Center, Durham, NC 27710, USA.
Proc Natl Acad Sci U S A. 2006 Sep 19;103(38):14116-21. doi: 10.1073/pnas.0603090103. Epub 2006 Sep 8.
In epithelial cells, alternative splicing of fibroblast growth factor receptor 2 (FGFR2) transcripts leads to the expression of the FGFR2(IIIb) isoform, whereas in mesenchymal cells, the same process results in the synthesis of FGFR2(IIIc). Expression of the FGFR2(IIIc) isoform during prostate tumor progression suggests a disruption of the epithelial character of these tumors. To visualize the use of FGFR2 exon IIIc in prostate AT3 tumors in syngeneic rats, we constructed minigene constructs that report on alternative splicing. Imaging these alternative splicing decisions revealed unexpected mesenchymal-epithelial transitions in these primary tumors. These transitions were observed more frequently where tumor cells were in contact with stroma. Indeed, these transitions were frequently observed among lung micrometastases in the organ parenchyma and immediately adjacent to blood vessels. Our data suggest an unforeseen relationship between epithelial mesenchymal plasticity and malignant fitness.
在上皮细胞中，成纤维细胞生长因子受体2（FGFR2）转录本的可变剪接导致FGFR2（IIIb）异构体的表达，而在间充质细胞中，相同的过程导致FGFR2（IIIc）的合成。FGFR2（IIIc）异构体在前列腺肿瘤进展过程中的表达表明这些肿瘤的上皮特征受到破坏。为了观察FGFR2外显子IIIc在同基因大鼠前列腺AT3肿瘤中的使用情况，我们构建了报告可变剪接的小基因构建体。对这些可变剪接决定进行成像揭示了这些原发性肿瘤中意外的间充质-上皮转变。在肿瘤细胞与基质接触的部位更频繁地观察到这些转变。实际上，在器官实质中的肺微转移灶以及紧邻血管的部位经常观察到这些转变。我们的数据表明上皮-间充质可塑性与恶性适应性之间存在意想不到的关系。
