Journal
INTERNATIONAL JOURNAL OF ONCOLOGY
Volume 44, Issue 5, Pages 1643-1651Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/ijo.2014.2310
Keywords
TGF-beta; IL-6; Stat3; Smad3; epithelial-mesenchymal transition
Categories
Funding
- National Natural Science Foundation of China [81372277, 81171894, 81201575]
- Program for New Century Excellent Talents in University [NCET-09-0165]
- Jiangsu Province Key Provincial Talents Program [RC2011106]
- '333' Project of Jiangsu Province Government
- Soochow Scholar Project of Soochow University
- Suzhou Key Laboratory for Molecular Cancer Genetics [SZS201209]
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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-beta/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-beta 1 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-beta 1-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-beta 1-induced p-Smad3, Snail, MMP2, and Smad-mediated PAI-1 promoter reporter gene activity in A549 and H1650 cells. Subsequently, AG490 inhibited TGF-beta-induced cell migration and invasion. Moreover, exogenous IL-6 treatment stimulated Stat3 activation, enhanced TGF-beta-induced expression of p-Smad3 and Snail, aggravated the EMT process, and increased lung cancer cell migration and invasion induced by TGF-beta 1. Our findings show that the JAK/STAT3 pathway is required for TGF-beta-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-beta/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-beta/Smad therapeutic strategies.
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