SMAD6 contributes to patient survival in non-small cell lung cancer and its knockdown reestablishes TGF-β homeostasis in lung cancer cells Journal Article
| Authors: | Jeon, H. S.; Dracheva, T.; Yang, S. H.; Meerzaman, D.; Fukuoka, J.; Shakoori, A.; Shilo, K.; Travis, W. D.; Jen, J. |
| Article Title: | SMAD6 contributes to patient survival in non-small cell lung cancer and its knockdown reestablishes TGF-β homeostasis in lung cancer cells |
| Abstract: | The malignant transformation in several types of cancer, including lung cancer, results in a loss of growth inhibition by transforming growth factor-β (TGF-β). Here, we show that SMAD6 expression is associated with a reduced survival in lung cancer patients. Short hairpin RNA (shRNA)-mediated knockdown of SMAD6 in lung cancer cell lines resulted in reduced cell viability and increased apoptosis as well as inhibition of cell cycle progression. However, these results were not seen in Beas2B, a normal bronchial epithelial cell line. To better understand the mechanism underlying the association of SMAD6 with poor patient survival, we used a lentivirus construct carrying shRNA for SMAD6 to knock down expression of the targeted gene. Through gene expression analysis, we observed that knockdown of SMAD6 led to the activation of TGF-β signaling through up-regulation of plasminogen activator inhibitor-1 and phosphorylation of SMAD2/3. Furthermore, SMAD6 knockdown activated the c-Jun NH2-terminal kinase pathway and reduced phosphorylation of Rb-1, resulting in increased G0-G1 cell arrest and apoptosis in the lung cancer cell line H1299. These results jointly suggest that SMAD6 plays a critical role in supporting lung cancer cell growth and survival. Targeted inactivation of SMAD6 may provide a novel therapeutic strategy for lung cancers expressing this gene. ©2008 American Association for Cancer Research. |
| Keywords: | immunohistochemistry; signal transduction; cancer survival; controlled study; human tissue; protein phosphorylation; unclassified drug; human cell; cancer growth; cancer patient; cell viability; gene; gene targeting; cell cycle; cell cycle progression; apoptosis; gene expression; smad2 protein; smad3 protein; stress activated protein kinase; transforming growth factor beta; lung non small cell cancer; carcinoma, non-small-cell lung; lung neoplasms; down-regulation; rna, small interfering; cancer cell culture; cell line, tumor; phosphorylation; transduction, genetic; cell growth processes; lentivirus vector; cell cycle arrest; upregulation; homeostasis; malignant transformation; short hairpin rna; cell cycle g1 phase; cell cycle g0 phase; plasminogen activator inhibitor 1; jnk mitogen-activated protein kinases; protein rb 1; smad6 protein; smad6 gene |
| Journal Title: | Cancer Research |
| Volume: | 68 |
| Issue: | 23 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2008-12-01 |
| Start Page: | 9686 |
| End Page: | 9692 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-08-1083 |
| PUBMED: | 19047146 |
| PROVIDER: | scopus |
| PMCID: | PMC3617041 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 3" - "Export Date: 17 November 2011" - "CODEN: CNREA" - "Source: Scopus" |
