title: Hepatocyte growth factor activates Wnt pathway by transcriptional activation of LEF1 to facilitate tumor invasion.
abstract: Hepatocyte growth factor (HGF) is a secretory protein that plays important roles in cancer growth and metastasis. Lymphoid-enhancing factor 1 (LEF1) is a transcription factor mediating Wnt/β-catenin signaling. Using microarray analysis, we found HGF induced expression of LEF1 in liver and breast cancer cell lines. HGF induced expression of LEF1 through phosphatidylinositol 3-kinase/Akt and nuclear factor-kappa B (NF-κB) signaling. Multiple NF-κB-binding sites were mapped within 3 kb upstream of LEF1 transcription initiation site. NF-κB binding to a site 2 kb upstream of LEF1 transcription initiation site was confirmed by chromatin immunoprecipitation assay. Knockdown of LEF1 inhibited the expression of Slug and Zinc finger E-box-binding homeobox 2 (ZEB2) and markedly attenuated HGF-induced tumor migration and invasion. Using immunohistochemical staining, we found LEF1 was frequently expressed in multiple types of carcinoma but not in the non-tumorous epithelial cells. Our finding suggest that transcriptional activation of LEF1 is a mechanism of cross talk between HGF/c-Met and Wnt/β-catenin pathways and is essential for HGF-induced tumor invasion.
authors.affiliation: Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan.
authors.forename: Fang-I
authors.initials: FI
authors.lastname: Huang
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Chen
authors.forename: Chih-Ning
authors.initials: CN
authors.lastname: Chang
authors.forename: Ray-Hwang
authors.initials: RH
authors.lastname: Yuan
authors.forename: Yung-Ming
authors.initials: YM
authors.lastname: Jeng
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D005260:Female; D057809:HEK293 Cells; D056945:Hep G2 Cells; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000096:biosynthesis; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000096:biosynthesis / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000096:biosynthesis; D015398:Signal Transduction / Q000235:genetics; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis; D015533:Transcriptional Activation; D060449:Wnt Signaling Pathway; D000074165:Zinc Finger E-box Binding Homeobox 2; D051176:beta Catenin / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D016328:NF-kappa B; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D051176:beta Catenin; D017228:Hepatocyte Growth Factor; D058539:Phosphatidylinositol 3-Kinase; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt