We have continued our efforts to develop in vivo and in vitro models to better understand the mechanistic role of genes that are highly differentially expressed in lung cancers. TGF-beta is a pleiotropic cytokine that plays a central role in maintaining epithelial homeostasis. In early carcinogenesis, TGF-beta acts as a tumor suppressor by inhibiting cell proliferation. However, in the late stage, several studies showed that primary tumor cells could reprogram their response to TGF-beta by dysregulation or mutational inactivation of various components of the TGF-beta signaling pathway and through cross-interaction with other oncogenic pathways. We have shown knockdown of SMAD6 inhibited cell viability and proliferation through cell cycle arrest and induction of apoptosis in lung cancer cells, but not normal bronchial epithelial cells. We examined the gene expression changes and observed that knockdown of SMAD6 led to activation of TGF-beta signaling. Our results show that SMAD6 plays a critical role in supporting cell growth and survival by inhibiting the TGF-beta signaling pathway in lung cancer cells. Targeted inactivation of SMAD6 could provide a novel therapeutic strategy for lung cancers expressing this gene. In our in vivo study, we have generated transgenic mice carrying a gene, PGP9.5, which is frequently overexpressed in lung cancers. We are collaborating with Dr. Ilona Linnoila (Cell and Cancer Biology Branch, CCR) to examine these transgenic animals for transgene expression as well as potential lung carcinogenesis and interactions with other lung tumor animal models. Preliminary findings from Dr. Linnoila's laboratory have shown that transgenic animals with PGP9.5 overexpression in lung epithelium led to EMU-induced lung carcinogenesis.
| Hong, Kyeong-Man; Yang, Sei-Hoon; Chowdhuri, Sinchita Roy et al. (2007) Inactivation of LLC1 gene in nonsmall cell lung cancer. Int J Cancer 120:2353-8 |
| He, Ping; Varticovski, Lyuba; Bowman, Elise D et al. (2004) Identification of carboxypeptidase E and gamma-glutamyl hydrolase as biomarkers for pulmonary neuroendocrine tumors by cDNA microarray. Hum Pathol 35:1196-209 |
| Monitto, Constance L; Dong, Seung-Myung; Jen, Jin et al. (2004) Characterization of a human homologue of proteolysis-inducing factor and its role in cancer cachexia. Clin Cancer Res 10:5862-9 |
| Krop, Ian; Player, Audrey; Tablante, Ana et al. (2004) Frequent HIN-1 promoter methylation and lack of expression in multiple human tumor types. Mol Cancer Res 2:489-94 |
| Player, Audrey; Gillespie, John; Fujii, Takeshi et al. (2003) Identification of TDE2 gene and its expression in non-small cell lung cancer. Int J Cancer 107:238-43 |
