SMAD6 contributes to patient survival in non-small cell lung cancer and its knockdown reestablishes TGF-β homeostasis in lung cancer cells

Hyo Sung Jeon, Tatiana Dracheva, Sei Hoon Yang, Daoud Meerzaman, Junya Fukuoka, Abbas Shakoori, Konstantin Shilo, William D. Travis, Jin Jen

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)9686-9692
Number of pages7
JournalCancer Research
Volume68
Issue number23
DOIs
StatePublished - Dec 1 2008
Externally publishedYes

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Transforming Growth Factors
Non-Small Cell Lung Carcinoma
Lung Neoplasms
Homeostasis
Survival
Cell Line
Small Interfering RNA
Cell Survival
Phosphorylation
Apoptosis
Gene Expression
Lentivirus
JNK Mitogen-Activated Protein Kinases
Neoplasm Genes
Plasminogen Activator Inhibitor 1
Growth
Cell Cycle
Up-Regulation
Epithelial Cells

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

SMAD6 contributes to patient survival in non-small cell lung cancer and its knockdown reestablishes TGF-β homeostasis in lung cancer cells. / Jeon, Hyo Sung; Dracheva, Tatiana; Yang, Sei Hoon; Meerzaman, Daoud; Fukuoka, Junya; Shakoori, Abbas; Shilo, Konstantin; Travis, William D.; Jen, Jin.

In: Cancer Research, Vol. 68, No. 23, 01.12.2008, p. 9686-9692.

Research output: Contribution to journalArticle

Jeon, HS, Dracheva, T, Yang, SH, Meerzaman, D, Fukuoka, J, Shakoori, A, Shilo, K, Travis, WD & Jen, J 2008, 'SMAD6 contributes to patient survival in non-small cell lung cancer and its knockdown reestablishes TGF-β homeostasis in lung cancer cells', Cancer Research, vol. 68, no. 23, pp. 9686-9692. https://doi.org/10.1158/0008-5472.CAN-08-1083
Jeon, Hyo Sung ; Dracheva, Tatiana ; Yang, Sei Hoon ; Meerzaman, Daoud ; Fukuoka, Junya ; Shakoori, Abbas ; Shilo, Konstantin ; Travis, William D. ; Jen, Jin. / SMAD6 contributes to patient survival in non-small cell lung cancer and its knockdown reestablishes TGF-β homeostasis in lung cancer cells. In: Cancer Research. 2008 ; Vol. 68, No. 23. pp. 9686-9692.
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