Alternative splicing of fibroblast growth factor receptor 3 produces a secreted isoform that inhibits fibroblast growth factor-induced proliferation and is repressed in urothelial carcinoma cell lines
Alternative splicing of fibroblast growth factor receptor 3 produces a secreted isoform that inhibits fibroblast growth factor-induced proliferation and is repressed in urothelial carcinoma cell lines
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DOI：
10.1158/0008-5472.can-05-1718
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发表时间：
2005-11-15
期刊：
影响因子：
11.2
通讯作者：
Knowles, MA
中科院分区：
文献类型：
--
作者：
Tomlinson, DC;L'Hôte, CG;Knowles, MA
成纤维细胞生长因子受体 (FGFR) 是受体酪氨酸激酶家族，在增殖、分化和肿瘤发生中发挥关键作用。 FGFR3 被确定为在正常人尿路上皮和培养的正常人尿路上皮 (NHU) 细胞中表达的主要家族成员，并表达为 IIIb 亚型。我们还鉴定了一个剪接变体，FGFR3 Delta 8-10，缺乏编码免疫球蛋白样结构域 III 的 COOH 末端一半和跨膜结构域的外显子。之前的报告假设这是一种癌症特异性剪接变体。我们发现 FGFR3 Delta 8-10 是 NHU 细胞中的正常转录物，并被翻译、N-糖基化和分泌。原发性尿路上皮表达高水平的 FGFR3 转录本。在培养中，活跃增殖细胞中的水平降低，但在汇合时和细胞接近衰老时水平升高。过表达 FGFR3 IIIb 的细胞表现出 FGF1 诱导的增殖，但添加 FGFR3 Delta 8-10 会抑制增殖。在源自侵袭性癌的膀胱肿瘤细胞系中，亚型的相对表达存在显着变化，包括 FGFR3 Delta 8-10 比例总体下降，以及在某些情况下 FGFR3 IIIc 的主要表达。总之，NHU 细胞中 FGFR3 IIIb 的选择性剪接代表了生成调节增殖的转录物的正常机制，而在膀胱癌中，FGFR3 亚型的比例显着改变。
Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that play key roles in proliferation, differentiation, and tumorigenesis. FGFR3 was identified as the major family member expressed in both normal human urothelium and cultured normal human urothelial (NHU) cells and was expressed as the IIIb isoform. We also identified a splice variant, FGFR3 Delta 8-10, lacking exons encoding the COOH-terminal half of immunoglobulin-like domain III and the transmembrane domain. Previous reports have assumed that this is a cancer-specific splice variant. We showed that FGFR3 Delta 8-10 is a normal transcript in NHU cells and is translated, N-glycosylated, and secreted. Primary urothelium expressed high levels of FGFR3 transcripts. In culture, levels were reduced in actively proliferating cells but increased at confluence and as cells approached senescence. Cells overexpressing FGFR3 IIIb showed FGF1-induced proliferation, which was inhibited by the addition of FGFR3 Delta 8-10. In bladder tumor cell lines derived from aggressive carcinomas, there were significant alterations in the relative expression of isoforms including an overall decrease in the proportion of FGFR3 Delta 8-10 and predominant expression of FGFR3 IIIc in some cases. In summary, alternative splicing of FGFR3 IIIb in NHU cells represents a normal mechanism to generate a transcript that regulates proliferation and in bladder cancer, the ratio of FGFR3 isoforms is significantly altered.