Involvement of the FGF18 gene in colorectal carcinogenesis, as a novel downstream target of the beta-catenin/T-cell factor complex.
To search for potential molecular targets for development of novel anticancer drugs, we have been analyzing expression profiles of clinical samples from cancer patients, using a genome-wide cDNA microarray. In experiments with colon cancer cells, the gene encoding fibroblast growth factor 18 (FGF18) was among those that showed elevated expression. The promoter region of this gene was found to contain putative Tcf4-binding motifs; moreover a reporter-gene assay using luciferase activity as a marker and an electromobility shift assay indicated that FGF18 is a downstream transcription target in the beta-catenin/Tcf4 pathway. We showed that exogenous FGF18 promoted growth of NIH3T3 cells in an autocrine manner and that transfection of FGF18 short interfering RNAs suppressed growth of colon cancer cells in culture. Our results indicate that FGF18 is activated in colon cancers as a direct downstream target of the Wnt signaling pathway and that it might represent a marker for early diagnosis and a molecular target for treatment of this life-threatening tumor.
Shimokawa
Takashi
T
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Furukawa
Yoichi
Y
Sakai
Michihiro
M
Li
Meihua
M
Miwa
Nobutomo
N
Lin
Yu-Min
YM
Nakamura
Yusuke
Y
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000236:Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001665:Binding Sites; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D000073940:Transcription Factor 4; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D051176:beta Catenin
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; C090743:Tcf4 protein, mouse; C544895:Tcf7l2 protein, mouse; D015534:Trans-Activators; D000073940:Transcription Factor 4; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051176:beta Catenin; C113569:fibroblast growth factor 18; D005346:Fibroblast Growth Factors