title: High expression of IGFBP7 in fibroblasts induced by colorectal cancer cells is co-regulated by TGF-β and Wnt signaling in a Smad2/3-Dvl2/3-dependent manner.
abstract: Fibroblasts in the tumor microenvironment are a key determinant in cancer progression and may be a promising target for cancer therapy. Insulin-like growth factor binding protein 7 (IGFBP7) is known as a tumor suppressor in colorectal cancer (CRC). The present study investigated the inductive mechanism of IGFBP7 expression in fibroblasts by supernatant from the CRC cell line, SW620. The results showed that the expression of IGFBP7 was up-regulated in the fibroblasts when treated with SW620 supernatant and exogenous TGF-β1. The IGFBP7 induced by SW620 supernatant or TGF-β1 was partially inhibited by the TGF-β1 specific antibody AF and TGF-β1 receptor antagonist SB431542. The Wnt signaling-targeted genes, c-Myc, CCND1 and the proteins Dvl2/3, were all up-regulated in fibroblasts expressing high levels of IGFBP7, and the up-regulation could be inhibited both by the Wnt signaling antagonist Dickkopf-1 (DKK1) and by the TGF-β1 receptor antagonist SB431542. In conclusion, CRC cells promote the high expression of IGFBP7 in fibroblasts, most likely through the co-regulation of TGF-β and Wnt signaling in a Smad2/3-Dvl2/3 dependent manner. Taken together, these data suggest that the fibroblasts could be a novel therapeutic target in tumor therapy.
authors.affiliation: Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, P. R. China.
authors.forename: Cui
authors.initials: C
authors.lastname: Rao
authors.affiliation: Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, P. R. China.
authors.forename: Shan-Li
authors.initials: SL
authors.lastname: Lin
authors.affiliation: Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, P. R. China.
authors.forename: Wen-Jing
authors.initials: WJ
authors.lastname: Ruan
authors.affiliation: Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, P. R. China.
authors.forename: Huan
authors.initials: H
authors.lastname: Wen
authors.affiliation: Department of Pathology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, P. R. China.
authors.forename: Dan-Ju
authors.initials: DJ
authors.lastname: Wu
authors.affiliation: Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, P. R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Deng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D000072261:Dishevelled Proteins; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation; D060449:Wnt Signaling Pathway
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017077:Culture Media, Conditioned; C000606581:DVL2 protein, human; D000072261:Dishevelled Proteins; D018969:Insulin-Like Growth Factor Binding Proteins; D010750:Phosphoproteins; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C102529:insulin-like growth factor binding protein-related protein 1; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I