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SMAD6 contributes to patient survival in non-small cell lung cancer and its knockdown reestablishes TGF-beta 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-beta (TGF-beta). 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-beta 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.

SUBMITTER: Jeon HS

PROVIDER: S-EPMC3617041 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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

Jeon Hyo-Sung HS Dracheva Tatiana T Yang Sei-Hoon SH Meerzaman Daoud D Fukuoka Junya J Shakoori Abbas A Shilo Konstantin K Travis William D WD Jen Jin J

Cancer research 20081201 23

The malignant transformation in several types of cancer, including lung cancer, results in a loss of growth inhibition by transforming growth factor-beta (TGF-beta). 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, ...[more]

PMID: 19047146

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Project description:BACKGROUND: Transforming growth factor (TGF)-? plays a pivotal role in cancer progression through regulating cancer cell proliferation, invasion, and remodeling of the tumor microenvironment. Cancer-associated fibroblasts (CAFs) are the predominant type of stromal cell, in which TGF-? signaling is activated. Among the strategies for TGF-? signaling inhibition, RNA interference (RNAi) targeting of TGF-? ligands is emerging as a promising tool. Although preclinical studies support the efficacy of this therapeutic strategy, its effect on the tumor microenvironment in vivo remains unknown. In addition, differential effects due to knockdown of various TGF-? ligand isoforms have not been examined. Therefore, an experimental model that recapitulates tumor-stromal interaction is required for validation of therapeutic agents. METHODS: We have previously established a three-dimensional co-culture model of lung cancer, and demonstrated the functional role of co-cultured fibroblasts in enhancing cancer cell invasion and differentiation. Here, we employed this model to examine how knockdown of TGF-? ligands affects the behavior of different cell types. We developed lentivirus vectors carrying artificial microRNAs against human TGF-?1 and TGF-?2, and tested their effects in lung cancer cells and fibroblasts. RESULTS: Lentiviral vectors potently and selectively suppressed the expression of TGF-? ligands, and showed anti-proliferative effects on these cells. Furthermore, knockdown of TGF-? ligands attenuated fibroblast-mediated collagen gel contraction, and diminished lung cancer cell invasion in three-dimensional co-culture. We also observed differential effects by targeting different TGF-? isoforms in lung cancer cells and fibroblasts. CONCLUSIONS: Our findings support the notion that RNAi-mediated targeting of TGF-? ligands may be beneficial for lung cancer treatment via its action on both cancer and stromal cells. This study further demonstrates the usefulness of this three-dimensional co-culture model to examine the effect of therapeutic agents on tumor-stromal interaction.

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

Publications

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

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