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Growth and Molecular Profile of Lung Cancer Cells Expressing Ectopic LKB1

Down-Regulation of the Phosphatidylinositol 3'-Phosphate Kinase/PTEN Pathway¹

Molecular Pathology Program [A. I. J., P. F., M. S-C.], Genomics Unit [O. D.], and Microarray Analysis Unit [A. D.], Spanish National Cancer Center, 28029 Madrid, Spain

Germ-line mutations in LKB1 gene cause the Peutz-Jeghers syndrome (PJS), a genetic disease with increased risk of malignancies. Recently, LKB1-inactivating mutations have been identified in one-third of sporadic lung adenocarcinomas, indicating that LKB1 gene inactivation is critical in tumors other than those of the PJS syndrome. However, the in vivo substrates of LKB1 and its role in cancer development have not been completely elucidated. Here we show that overexpression of wild-type LKB1 protein in A549 lung adenocarcinomas cells leads to cell-growth suppression. To examine changes in gene expression profiles subsequent to exogenous wild-type LKB1 in A549 cells, we used cDNA microarrays. We detected deregulation of 100 genes involved in cell proliferation, apoptosis, and cell adhesion. Strikingly, modification of the expression of well-known p53-responsive genes such as GADD45, TOP2A, and p21 suggests that growth suppression in A549 cells overexpressing LKB1 may be mediated by p53. In addition, PTEN up-regulation indicates that LKB1 could be involved in the PTEN/phosphatidylinositol-3'-kinase(PI3K)/AKT molecular pathway. Thus, our results give some insights into the understanding of how LKB1 inactivation contributes to lung carcinogenesis.

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