title: Induction of galectin-1 by TGF-β1 accelerates fibrosis through enhancing nuclear retention of Smad2.
abstract: Fibrosis is one of the most serious side effects in cancer patients undergoing radio-/ chemo-therapy, especially of the lung, pancreas or kidney. Based on our previous finding that galectin-1 (Gal-1) was significantly increased during radiation-induced lung fibrosis in areas of pulmonary fibrosis, we herein clarified the roles and action mechanisms of Gal-1 during fibrosis. Our results revealed that treatment with TGF-β1 induced the differentiation of fibroblast cell lines (NIH3T3 and IMR-90) to myofibroblasts, as evidenced by increased expression of the fibrotic markers smooth muscle actin-alpha (α-SMA), fibronectin, and collagen (Col-1). We also observed marked and time-dependent increases in the expression level and nuclear accumulation of Gal-1. The TGF-β1-induced increases in Gal-1, α-SMA and Col-1 were decreased by inhibitors of PI3-kinase and p38 MAPK, but not ERK. Gal-1 knockdown using shRNA decreased the phosphorylation and nuclear retention of Smad2, preventing the differentiation of fibroblasts. Gal-1 interacted with Smad2 and phosphorylated Smad2, which may accelerate fibrotic processes. In addition, up-regulation of Gal-1 expression was demonstrated in a bleomycin (BLM)-induced mouse model of lung fibrosis in vivo. Together, our results indicate that Gal-1 may promote the TGF-β1-induced differentiation of fibroblasts by sustaining nuclear localization of Smad2, and could be a potential target for the treatment of pulmonary fibrotic diseases.
authors.affiliation: Division of Radiation Cancer Sciences, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea.
authors.forename: Min Jin
authors.initials: MJ
authors.lastname: Lim
authors.affiliation: Division of Radiation Cancer Sciences, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Ahn
authors.affiliation: Department of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea.
authors.forename: Jae Youn
authors.initials: JY
authors.lastname: Yi
authors.affiliation: Division of Radiation Cancer Sciences, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea.
authors.forename: Mi-Hyoung
authors.initials: MH
authors.lastname: Kim
authors.affiliation: Division of Radiation Cancer Sciences, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea.
authors.forename: A-Rang
authors.initials: AR
authors.lastname: Son
authors.affiliation: Division of Radiation Cancer Sciences, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea.
authors.forename: Sae-lo-oom
authors.initials: SL
authors.lastname: Lee
authors.affiliation: Department of Applied Bioscience, CHA University, Republic of Korea.
authors.forename: Dae-Seog
authors.initials: DS
authors.lastname: Lim
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Sung Soo
authors.initials: SS
authors.lastname: Kim
authors.affiliation: Department of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea.
authors.forename: Mi Ae
authors.initials: MA
authors.lastname: Kang
authors.affiliation: Division of Biological Science, Sookmyung Women׳s University, Seoul 140-742, Republic of Korea. Electronic address: ysoo@sm.ac.kr.
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Han
authors.affiliation: Division of Radiation Cancer Sciences, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea. Electronic address: immu@kcch.re.kr.
authors.forename: Jie-Young
authors.initials: JY
authors.lastname: Song
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D037483:Galectin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011658:Pulmonary Fibrosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D051899:Smad2 Protein / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: D037483:Galectin 1; D034741:RNA, Small Interfering; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1
keywords: Bleomycin; Fibrosis; Galectin-1; Smad-2; TGF-β