|Title||The Lsktm1 locus modulates lung and skin tumorigenesis in the mouse.|
|Publication Type||Articolo su Rivista peer-reviewed|
|Year of Publication||2012|
|Authors||Galvan, A., Colombo F., Noci S., Pazzaglia Simonetta, Mancuso Mariateresa, Manenti G., Broman K.W., Saran Anna, and Dragani T.A.|
|Journal||G3 (Bethesda, Md.)|
|Keywords||animal, Animals, article, Cell Line, Cell Transformation, chromosome, chromosome map, Chromosome Mapping, Chromosomes, drug screening, Female, Gene expression, gene locus, genetic association, Genetic Loci, genetics, Genome-Wide Association Study, human, Humans, Insulin-Like Growth Factor Binding Protein 2, Insulin-Like Growth Factor Binding Protein 5, Lung Neoplasms, lung tumor, male, Mammalian, Mice, mouse, Neoplastic, Polymorphism, protease-activated receptor 4, proteinase activated receptor 4, Receptors, Single Nucleotide, single nucleotide polymorphism, Skin Neoplasms, skin tumor, somatomedin binding protein 2, somatomedin binding protein 5, Thrombin, thrombin receptor, Tumor, tumor cell line, Tumor Stem Cell Assay|
Alleles derived from skin tumor-resistant Car-R mice provide resistance to both skin and lung tumorigenesis over the susceptibility of the SWR/J strain. In an effort to map tumor modifier loci affecting both tumor types, we carried out a genetic linkage analysis in backcross SWR/J x (SWR/J x Car-R) mice and identified a locus (Lsktm1) on chromosome 1 linked to both skin (LOD score = 3.93) and lung (LOD score = 8.74) tumorigenesis. Two genes, Igfbp5 and Igfbp2, residing in this locus and belonging to the insulin-like growth factor binding protein family were expressed at significantly greater levels in normal lung tissue from cancer-resistant Car-R mice than in cancer-susceptible SWR/J mice. Overexpression of the recombinant Igfbp5 and Igfbp2 genes in two lung cancer cell lines significantly inhibited clonogenicity (P < 0.0001). Collectively, we have identified a single polymorphic locus that affects skin and lung tumorigenesis and identify Igfbp5 and Igfbp2 as candidate modifier genes of lung tumorigenesis.
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