title: JAK/STAT3 signaling is required for TGF-β-induced epithelial-mesenchymal transition in lung cancer cells.
abstract: Epithelial-mesenchymal transition (EMT), a key step in the early stages of cancer metastasis, is orchestrated by several signaling pathways, including IL-6/JAK/STAT3 and TGF-β/Smad signaling. However, an association between the two signaling pathways during the EMT process is largely unknown. Here, we focused on lung cancer and demonstrated that TGF-β1 induced the phosphorylation of Smad3 (p-Smad3), upregulation of Snail, a fibroblast-like morphology, and downregulation of E-cadherin as well as upregulation of vimentin in lung cancer cell lines. SIS3 (an inhibitor of Smad3) suppressed TGF-β1-induced activation of Smad3, upregulation of Snail and the EMT process. Importantly, the JAK2/STAT3-specific inhibitor AG490 blocked Stat3 phosphorylation, resulting in attenuated levels of TGF-β1-induced p-Smad3, Snail, MMP2, and Smad-mediated PAI-1 promoter reporter gene activity in A549 and H1650 cells. Subsequently, AG490 inhibited TGF-β-induced cell migration and invasion. Moreover, exogenous IL-6 treatment stimulated Stat3 activation, enhanced TGF-β-induced expression of p-Smad3 and Snail, aggravated the EMT process, and increased lung cancer cell migration and invasion induced by TGF-β1. Our findings show that the JAK/STAT3 pathway is required for TGF-β-induced EMT and cancer cell migration and invasion via upregulation of the expression of p-Smad3 and Snail, and the IL-6/JAK/STAT3 and TGF-β/Smad signaling synergistically enhance EMT in lung carcinomas. The present study suggests a novel rationale for inhibiting cancer metastasis using anti-IL-6/JAK/STAT3 and anti-TGF-β/Smad therapeutic strategies.
authors.affiliation: Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou 215123, P.R. China.
authors.forename: Reng-Yun
authors.initials: RY
authors.lastname: Liu
authors.affiliation: Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou 215123, P.R. China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou 215123, P.R. China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Lei
authors.affiliation: Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou 215123, P.R. China.
authors.forename: Longqiang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou 215123, P.R. China.
authors.forename: Haiping
authors.initials: H
authors.lastname: Yang
authors.affiliation: Suzhou Key Laboratory for Molecular Cancer Genetics, Suzhou 215123, P.R. China.
authors.forename: Zeyi
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou 215123, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou 215123, P.R. China.
authors.forename: Hong-Tao
authors.initials: HT
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D051900:Smad3 Protein; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D053612:Janus Kinases