LKB1 modulates lung cancer differentiation and metastasis
| Autor: | Xihong Lin, Takeshi Shimamura, Diego H. Castrillon, Bruce E. Johnson, Danan Li, Matthew R. Ramsey, Lucian R. Chirieac, Jussi Koivunen, Geoffrey I. Shapiro, David J. Kwiatkowski, David C. Christiani, Lei Bao, Pasi A. Jänne, Kate McNamara, Piotr Kozlowski, Mei-Chih Liang, Janakiraman Krishnamurthy, Chad Torrice, Hongbin Ji, Matthew Meyerson, Cristina Contreras, D. Neil Hayes, Roderick T. Bronson, Neal I. Lindeman, George N. Naumov, Samanthi A. Perera, Cheng Fan, Nabeel Bardeesy, Robert F. Padera, Kwok-Kin Wong, Michael C. Wu, Dongpo Cai, Norman E. Sharpless, Liang Chen |
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| Rok vydání: | 2007 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Lung Neoplasms STK11 AMP-Activated Protein Kinases Protein Serine-Threonine Kinases Biology medicine.disease_cause Metastasis Mice Germline mutation AMP-Activated Protein Kinase Kinases CDKN2A Carcinoma Non-Small-Cell Lung Cell Line Tumor Carcinoma medicine Animals Humans Genes Tumor Suppressor Neoplasm Metastasis skin and connective tissue diseases Lung cancer Multidisciplinary Gene Expression Profiling Genes p16 Cancer Cell Differentiation Genes p53 medicine.disease Gene Expression Regulation Neoplastic Disease Models Animal Genes ras Cancer research Carcinogenesis Genes Neoplasm |
| Zdroj: | Nature. 448:807-810 |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | Germline mutation in serine/threonine kinase 11 (STK11, also called LKB1) results in Peutz-Jeghers syndrome, characterized by intestinal hamartomas and increased incidence of epithelial cancers. Although uncommon in most sporadic cancers, inactivating somatic mutations of LKB1 have been reported in primary human lung adenocarcinomas and derivative cell lines. Here we used a somatically activatable mutant Kras-driven model of mouse lung cancer to compare the role of Lkb1 to other tumour suppressors in lung cancer. Although Kras mutation cooperated with loss of p53 or Ink4a/Arf (also known as Cdkn2a) in this system, the strongest cooperation was seen with homozygous inactivation of Lkb1. Lkb1-deficient tumours demonstrated shorter latency, an expanded histological spectrum (adeno-, squamous and large-cell carcinoma) and more frequent metastasis compared to tumours lacking p53 or Ink4a/Arf. Pulmonary tumorigenesis was also accelerated by hemizygous inactivation of Lkb1. Consistent with these findings, inactivation of LKB1 was found in 34% and 19% of 144 analysed human lung adenocarcinomas and squamous cell carcinomas, respectively. Expression profiling in human lung cancer cell lines and mouse lung tumours identified a variety of metastasis-promoting genes, such as NEDD9, VEGFC and CD24, as targets of LKB1 repression in lung cancer. These studies establish LKB1 as a critical barrier to pulmonary tumorigenesis, controlling initiation, differentiation and metastasis. |
| Databáze: | OpenAIRE |
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