title: Signal transducers and activators of transcription 3-induced metastatic potential in gastric cancer cells is enhanced by glycogen synthase kinase-3β.
abstract: The transcription factor signal transducers and activators of transcription 3 (STAT3) can promote cancer metastasis, but its underlying regulatory mechanisms in gastric cancer cell invasiveness still remain obscure. We investigated the relationship between STAT3 and glycogen synthase kinase-3β (GSK-3β) and its significance in metastatic potential in gastric cancer cells. Immunohistochemical tissue array analysis of 267 human gastric carcinoma specimens showed that the expressions of active forms of STAT3 (pSTAT3) and GSK-3β (pGSK-3β) were found in 68 (25%) and 124 (46%) of 267 gastric cancer cases, respectively, showing a positive correlation (p < 0.001). Cell culture experiments using gastric cancer cell lines SNU-638 and SNU-668 revealed that STAT3 suppression did not affect pGSK-3β expression, whereas GSK-3β inhibition reduced pSTAT3 expression. With respect to metastatic potential in gastric cancer cells, both STAT3 suppression and GSK-3β inhibition decreased cell migration, invasion, and mesenchymal marker (Snail, Vimentin, and MMP9) expression. Moreover, the inhibitory effects of STAT3 and GSK-3β on cell migration were synergistic. These results demonstrated that STAT3 and GSK-3β are positively associated and synergistically contribute to metastatic potential in gastric cancer cells. Thus, dual use of STAT3 and GSK-3β inhibitors may enhance the efficacy of the anti-metastatic treatment of gastric cancer.
authors.affiliation: Department of Anatomy, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Yoon
authors.forename: Young San
authors.initials: YS
authors.lastname: Ko
authors.forename: Sung Jin
authors.initials: SJ
authors.lastname: Cho
authors.forename: Jinju
authors.initials: J
authors.lastname: Park
authors.forename: Young Sun
authors.initials: YS
authors.lastname: Choi
authors.forename: Yiseul
authors.initials: Y
authors.lastname: Choi
authors.forename: Jung-Soo
authors.initials: JS
authors.lastname: Pyo
authors.forename: Sang-Kyu
authors.initials: SK
authors.lastname: Ye
authors.forename: Hong-Duk
authors.initials: HD
authors.lastname: Youn
authors.forename: Jae-Seon
authors.initials: JS
authors.lastname: Lee
authors.forename: Mee Soo
authors.initials: MS
authors.lastname: Chang
authors.forename: Min A
authors.initials: MA
authors.lastname: Kim
authors.forename: Byung Lan
authors.initials: BL
authors.lastname: Lee
mesh_terms: D019943:Amino Acid Substitution; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007150:Immunohistochemistry; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D034741:RNA, Small Interfering / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D013844:Thiazoles / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D014408:Biomarkers, Tumor; D050505:Mutant Proteins; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013844:Thiazoles; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D014508:Urea; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3
keywords: GSK-3β; STAT3; gastric cancer; invasion; migration