The prospect of molecular targeted therapy for colon cancer applying keratinocyte growth factor receptor (KGFR) gene silencing.

[目的]迄今为止，已报道了22种促进细胞生长和血管生成的成纤维细胞生长因子（fibroblast growth factor，FGF）。FGF组中，FGF-7（Keratinocyte Growth Factor，KGF）和FGF-10（KGF-2）主要由间充质细胞合成，参与上皮细胞的增殖。它们的作用依赖于它们与特定细胞表面KGF受体（KGFR）的结合。本研究旨在探讨角质形成细胞生长因子家族（KGF、KGF-2、KGFR）反义寡核苷酸和小干扰RNA（siRNA）对结肠癌细胞生长的抑制作用。【材料与方法】应用RT-PCR、免疫组化和原位杂交技术检测KGF、KGF-2和KGFR在人结肠癌组织和结肠癌细胞株中的表达和定位。将重组KGF和KGF-2给予结肠癌细胞并评估生长作用。将KGF和KGF-2 mRNA的反义寡核苷酸和KGFR的siRNA转染结肠癌细胞系，并阐明各自的生长抑制作用。[结果与讨论] KGF和KGF-2及其mRNA定位于成纤维细胞和结肠癌细胞中。KGFR及其mRNA定位于结肠癌细胞。这些结果表明，KGF和KGF-2可能有助于结肠癌细胞的生长通过自分泌和旁分泌机制。但在抑制结肠癌细胞生长的研究中，我们未能获得满意的结果。KGF对结肠癌生长的影响是否具有突然性尚不清楚。另一方面，对结肠癌的免疫化学研究表明，在低分化结肠癌中没有发现KGFR，但在许多分化的结肠癌中发现了KGFR。因此，KGF的作用可能与导管结构的形成和维持密切相关。

[Purpose] Twenty-two kinds of fibroblast growth factor (FGF), which contributes the cell growth and the angiogenesis, have been reported to the present. Among FGF group, FGF-7 (Keratinocyte Growth Factor, KGF) and FGF-10 (KGF-2) are mainly synthesized by mesen-chymal cells, and participate in proliferation of the epitherial cells. Their actions are dependent on their binding to a specific cell-surface KGF receptor (KGFR). This study was performed to clarify the growth inhibitory effects of antisense oligonucleotide and short interfering RNA (siRNA) for keratinocyte growth factor family (KGF, KGF-2, KGFR) on colon cancer cells.[Materials and Methods] The expression and localization of KGF, KGF-2 and KGFR in human colon cancer tissue and colon cancer cell lines were examined using RT-PCR, immunohistochemistry and in situ hybridization. The recombinant KGF and KGF-2 were administrated into colon cancer cells and growth effects were estimated. The antisense oligonucleotide for KGF and KGF-2 mRNA and the siRNA for KGFR were transferred into colon cancer cell lines and the each growth inhibitory effects were elucidated.[Results and Discussion] KGF and KGF-2 and their mRNAs were localized in fibroblasts and colon cancer cells. KGFR and its mRNA were localized in colon cancer cells. These findings indicate that KGF and KGF-2 may contribute to colon cancer cell growth via autocrine and paracrine mechanisms. But we failed to obtain a satisfactory result from the study of colon cancer cell growth suppression. It is doubtful that KGF affects the growth of colon cancer precipitately. On the other hand, the study of immunochemistry in colon cancer showed that no KGFR was found in poorly differentiated colon cancer, but it was found in many differentiated colon cancer. Therefore, it is suspected that the affect of KGF is intimately related to the formation of duct structure and its maintenance.