JAK/STAT3 signaling is required for TGF-β-induced epithelial-mesenchymal transition in lung cancer cells

Int J Oncol. 2014 May;44(5):1643-51. doi: 10.3892/ijo.2014.2310. Epub 2014 Feb 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Epithelial-Mesenchymal Transition*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Interleukin-6 / metabolism
  • Janus Kinases / genetics
  • Janus Kinases / metabolism
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology*
  • Neoplasm Invasiveness / genetics
  • Neoplasm Invasiveness / pathology
  • Phosphorylation
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction*
  • Smad3 Protein / metabolism
  • Snail Family Transcription Factors
  • Transcription Factors / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • Tyrphostins / pharmacology


  • Antineoplastic Agents
  • Interleukin-6
  • STAT3 Transcription Factor
  • Smad3 Protein
  • Snail Family Transcription Factors
  • Transcription Factors
  • Transforming Growth Factor beta
  • Tyrphostins
  • alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
  • Janus Kinases