Kho D H, Bae J A, Lee J H, Cho H J, Cho S H, Lee J H, Seo Y-W, Ahn K Y, Chung I J, Kim K K
Medical Research Center for Gene Regulation, Chonnam National University Medical School, Kwangju, South Korea.
Gut. 2009 Apr;58(4):509-19. doi: 10.1136/gut.2008.150938. Epub 2008 Jul 24.
KITENIN was previously reported to promote metastasis in mouse colon tumour models; however, the signalling mechanism of KITENIN at the cellular level was unknown. Here the functional role of KITENIN with respect to colorectal cancer (CRC) cell invasion and its expression in CRC tissues were investigated.
The effect of KITENIN on cell motility was analysed in a migration and invasion assay upon its overexpression and knockdown. Immunoprecipitation was used to elucidate binding partners, and immunohistochemistry was used to study expression levels.
KITENIN overexpression enhanced the migration of rat intestinal epithelial cells, whereas a loss of invasiveness was observed in CRC cells after KITENIN knockdown. Mechanically, KITENIN served as a scaffolding molecule that simultaneously recruited both Dishevelled (Dvl) and protein kinase C delta (PKC delta) through the membrane-spanning C-terminal region to form a complex that stimulated extracellular signal-regulated kinase (ERK)/activating protein-1 (AP-1) via a PKC delta component but also organised the actin filament via a Dvl component. The KITENIN complex controlled the invasiveness of CRC cells aetiologically harbouring various mutations in APC, beta-catenin or K-ras, in which AP-1 activation is redundant but the organisation of the actin filament is indispensable for cell motility. Clinically, KITENIN expression was significantly higher in colon cancer tissues from advanced stage (III, IV) than that of stage I CRC and also in corresponding metastatic tissues.
The functional KITENIN complex acts as an executor with regard to cell motility and thereby controls CRC cell invasion, which may contribute to promoting metastasis.
此前有报道称KITENIN可促进小鼠结肠肿瘤模型中的转移；然而，KITENIN在细胞水平的信号传导机制尚不清楚。本文研究了KITENIN在结直肠癌（CRC）细胞侵袭方面的功能作用及其在CRC组织中的表达。
通过过表达和敲低KITENIN，在迁移和侵袭试验中分析其对细胞运动性的影响。采用免疫沉淀法阐明结合伴侣，采用免疫组织化学法研究表达水平。
KITENIN过表达增强了大鼠肠上皮细胞的迁移，而敲低KITENIN后，CRC细胞的侵袭性降低。从机制上讲，KITENIN作为一种支架分子，通过跨膜C末端区域同时募集Dishevelled（Dvl）和蛋白激酶Cδ（PKCδ），形成一个复合物，该复合物通过PKCδ组分刺激细胞外信号调节激酶（ERK）/激活蛋白-1（AP-1），但也通过Dvl组分组织肌动蛋白丝。KITENIN复合物在病因上控制了APC、β-连环蛋白或K-ras中存在各种突变的CRC细胞的侵袭性，其中AP-1激活是多余的，但肌动蛋白丝的组织对于细胞运动是必不可少的。临床上，晚期（III、IV期）结肠癌组织中KITENIN的表达明显高于I期CRC，在相应的转移组织中也是如此。
功能性KITENIN复合物在细胞运动方面起执行者的作用，从而控制CRC细胞的侵袭，这可能有助于促进转移。
