1. LATS2 Is a Tumor Suppressor Gene of Malignant Mesothelioma
- Author
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Toyoaki Hida, Shinya Akatsuka, Takayuki Fukui, Futoshi Ishiguro, Hideki Murakami, Yoshitsugu Horio, Tetsuo Taniguchi, Yutaka Kondo, Tetsuya Mizuno, Yoshitaka Sekido, Shinya Toyokuni, Makiko Fujii, and Hirotaka Osada
- Subjects
Mesothelioma ,Cancer Research ,Tumor suppressor gene ,Cell Cycle Proteins ,Cell Growth Processes ,Protein Serine-Threonine Kinases ,Biology ,Transduction, Genetic ,Cell Line, Tumor ,Humans ,Genes, Tumor Suppressor ,Gene Silencing ,Regulation of gene expression ,Comparative Genomic Hybridization ,Neurofibromin 2 ,Hippo signaling pathway ,Chromosomes, Human, Pair 13 ,Kinase ,Cell growth ,Tumor Suppressor Proteins ,Immunohistochemistry ,Gene Expression Regulation, Neoplastic ,Oncology ,Cell culture ,Cancer research ,Phosphorylation ,Signal transduction ,Gene Deletion - Abstract
Malignant mesothelioma (MM) is an aggressive neoplasm associated with asbestos exposure. We carried out genome-wide array-based comparative genomic hybridization analysis with 14 MM cell lines. Three cell lines showed overlapping homozygous deletion at chromosome 13q12, which harbored the LATS2 (large tumor suppressor homolog 2) gene. With 6 other MM cell lines and 25 MM tumors, we found 10 inactivating homozygous deletions or mutations of LATS2 among 45 MMs. LATS2 encodes a serine/threonine kinase, a component of the Hippo tumor-suppressive signaling pathway, and we transduced LATS2 in MM cells with its mutation. Transduction of LATS2 inactivated oncoprotein YAP, a transcriptional coactivator, via phosphorylation, and inhibited MM cell growth. We also analyzed LATS2 immunohistochemically and found that 13 of 45 MM tumors had low expression of LATS2. Because NF2 is genetically mutated in 40% to 50% of MM, our data indicate that Hippo pathway dysregulation is frequent in MM cells with inactivation of LATS2 or an upstream regulator of this pathway, Merlin, which is encoded by NF2. Thus, our results suggest that the inactivation of LATS2 is one of the key mechanisms for constitutive activation of YAP, which induces deregulation of MM cell proliferation. Cancer Res; 71(3); 873–83. ©2011 AACR.
- Published
- 2011