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Molecular and biological analysis of the mechanisms of impaired wound healing in gastrointestinal tract.-The role of fibroblast growth factor receptor 3-IIIb.

胃肠道伤口愈合受损机制的分子和生物学分析。-成纤维细胞生长因子受体 3-IIIb 的作用。

基本信息

批准号：
13470264
负责人：
KANAI Michiyuki
金额：
$ 9.15万
依托单位：
Tazuke Kofukai Medical Research Institute
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

The initial purpose of the study was to analyze the functional role of Fibroblast Growth Factor Receptor 3-IlIb (FGFR3-IIIb), which has been shown to be expressed specifically by colonic epithelial cells, in the process of normal or impaired wound healing of gastrointestinal tract and found that the contribution of the receptor to epithelial wound healing was not significant. We alternatively investigate whether a change in the gene expression and splice variations of FGFR3 is associated with malignant progression in human gastrointestinal cancers. First, we examined the gene expression of FGFR3 isoforms in human esophageal, gastric, and colorectal cancer patients by RT-PCR. FGFR3 has three alternatively spliced isoforms. FGFR3-IIIb and FGFR3-ILIc are the transmembrane -type isoforms and have different ligand specificities. The third isoform, FGFR3ΔTM, is the soluble isoform lacking the transmembrane domain and secreted extracellularly. The incidence of FGFR3-IIIc in the esophageal carcinoma was significantly higher than in the normal human esophageal biopsies. In contrast, FGFR3-IIIb and FGFR3ΔTM were significantly increased in the colorectal carcinomas compared to the normal tissue from the same patients. Next, we investigated the importance of FGFR3-IIIc in epithelial cancer cells. We showed that the ecdysone-inducible expression of FGFR3-IIIc in human squamous cell carcinoma DJM1 cells greatly enhanced anchorage-dependent and -independent growth, and wound healing in response to FGF2. Thus, FGFR3c has the potential to enhance malignant progression in epithelial cancers. Although the physiological significance of FGFR3ΔΔTM has not yet been defined, our findings suggest that the increased expression of FGFR3-IIIc together with FGFR3-IIIb and FGFR3ΔATM may be important markers for malignancy and potential anti-cancer therapeutic targets in gastrointestinal cancers.

本研究的初步目的是分析结肠上皮细胞特异性表达的成纤维细胞生长因子受体3-IIb(FGFR3-IIIb)在胃肠道正常或受损伤口愈合过程中的功能作用，发现该受体在上皮伤口愈合过程中的作用不明显。此外，我们还研究了FGFR3基因表达和剪接变异的变化是否与人类胃肠癌的恶性进展有关。首先，我们通过RT-PCR检测了FGFR3亚型在食道癌、胃癌和结直肠癌患者中的基因表达。FGFR3有三种选择性剪接的异构体。FGFR3-IIIb和FGFR3-iLIC是跨膜型异构体，具有不同的配体特异性。第三种异构体FGFR3ΔTM是一种不含跨膜结构域的可溶性异构体，在细胞外分泌。食管癌组织中FGFR3-IIIc的表达显著高于正常食管壁组织。相反，结直肠癌组织中FGFR3-IIIb和FGFR3ΔTM的表达均显著高于同一患者的正常组织。接下来，我们研究了FGFR3-IIIc在上皮性癌细胞中的重要性。我们发现，蜕皮激素诱导的FGFR3-IIIc在人鳞状细胞癌DJM1细胞中的表达极大地促进了FGF2对贴壁和非贴壁生长的依赖和伤口愈合。因此，FGFR3c有可能促进上皮癌的恶性进展。尽管FGFR3ΔΔTM的生理意义尚未明确，但我们的研究结果表明，FGFR3-IIIc、FGFR3-IIIb和FGFR3ΔATM的高表达可能是胃肠道肿瘤恶性程度的重要标志和潜在的抗癌治疗靶点。