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Background:
 The phosphatidylinositol 3 kinase (PI3K) /AKT signaling pathway is important for cell survival and proliferation, and it has a significant role in carcinogenesis. Deregulated activation of this pathway has been found in many human common malignancies, either by loss of PTEN phosphatase, a negative regulator of PI3K pathway, or by constitutive activation of PI3K or downstream elements including AKT by genetic mutation.
 Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm associated with asbestos exposure. Previous reports showed that the PI3K/AKT pathway was also frequently activated in MPM, but the molecular mechanisms of its pathway activation in MPM cells remain unclear. In the present study, to determine the frequency and key genetic mutations for the PI3K/AKT activation in MPM, we performed expression and/or mutation analyses of the molecules associated with this pathway including PIK3CA, PTEN, and LKB1, using MPM cell lines.
 Methods:
 Twenty MPM cell lines were investigated, 13 cell lines we established from Japanese patients and 7 cell lines from Caucasians. The expressions of AKT and PTEN in MPM cell lines were detected with Western blot analysis. Activated AKT was also analyzed with an anti-phospho-AKT antibody. Mutation analyses of PIK3CA, PTEN, and LKB1 were carried out by genomic PCR and direct sequencing.
 Results:
 Western blot analysis revealed that AKT was prominently activated in 10 (56%) of 18 cell lines studied compared to a normal mesothelial cell line, MeT-5A, under serum-starved condition. The loss of PTEN expression was observed in one cell line, and the following analysis using PTEN complementary DNA synthesized from this cell line showed the existence of an aberrant splicing transcript which lacked exon 2 of the PTEN gene. We demonstrated that this cell line had a homozygous deletion of approximately 40 kb, which encompassed exon 2 of PTEN, while no other mutation was detected in the remaining 19 cell lines. Moreover, no somatic mutation of PIK3CA and LKB1 was detected in the 20 cell lines.
 Conclusion: 
 AKT activation was shown in more than half of the MPM cell lines investigated. Homozygous deletion of PTEN was detected in one cell line with elevated AKT activation. Somatic mutations of PIK3CA, LKB1, and PTEN appear to be infrequent in mesothelioma, suggesting that alterations of other upstream molecules of the PI3K/AKT pathway may be responsible for this signaling pathway activation. Thus, although the activation mechanism of the PI3K/AKT pathway in mesothelioma was not fully elucidated, this pathway may be a potential therapeutic target for mesothelioma due to its frequent activation in MPM cells.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA