title: Galectin-3 contributes to melanoma growth and metastasis via regulation of NFAT1 and autotaxin.
abstract: Melanoma is the deadliest form of skin cancer in which patients with metastatic disease have a 5-year survival rate of less than 10%. Recently, the overexpression of a β-galactoside binding protein, galectin-3 (LGALS3), has been correlated with metastatic melanoma in patients. We have previously shown that silencing galectin-3 in metastatic melanoma cells reduces tumor growth and metastasis. Gene expression profiling identified the protumorigenic gene autotaxin (ENPP2) to be downregulated after silencing galectin-3. Here we report that galectin-3 regulates autotaxin expression at the transcriptional level by modulating the expression of the transcription factor NFAT1 (NFATC2). Silencing galectin-3 reduced NFAT1 protein expression, which resulted in decreased autotaxin expression and activity. Reexpression of autotaxin in galectin-3 silenced melanoma cells rescues angiogenesis, tumor growth, and metastasis in vivo. Silencing NFAT1 expression in metastatic melanoma cells inhibited tumor growth and metastatic capabilities in vivo. Our data elucidate a previously unidentified mechanism by which galectin-3 regulates autotaxin and assign a novel role for NFAT1 during melanoma progression.
authors.affiliation: Department of Cancer Biology and Urology, The University of Texas, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Russell R
authors.initials: RR
authors.lastname: Braeuer
authors.forename: Maya
authors.initials: M
authors.lastname: Zigler
authors.forename: Takafumi
authors.initials: T
authors.lastname: Kamiya
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Dobroff
authors.forename: Li
authors.initials: L
authors.lastname: Huang
authors.forename: Woonyoung
authors.initials: W
authors.lastname: Choi
authors.forename: David J
authors.initials: DJ
authors.lastname: McConkey
authors.forename: Einav
authors.initials: E
authors.lastname: Shoshan
authors.forename: Aaron K
authors.initials: AK
authors.lastname: Mobley
authors.forename: Renduo
authors.initials: R
authors.lastname: Song
authors.forename: Avraham
authors.initials: A
authors.lastname: Raz
authors.forename: Menashe
authors.initials: M
authors.lastname: Bar-Eli
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D037502:Galectin 3 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D020868:Gene Silencing; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D008545:Melanoma / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050778:NFATC Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010727:Phosphoric Diester Hydrolases / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D014162:Transfection; D000099189:Lysophospholipase D
chemical_list: D037502:Galectin 3; D050778:NFATC Transcription Factors; D010727:Phosphoric Diester Hydrolases; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000099189:Lysophospholipase D; C494006:NFATC2 protein, human