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. 2012 Sep;2(9):1041-6.
doi: 10.1534/g3.112.003525. Epub 2012 Sep 1.

The Lsktm1 Locus Modulates Lung and Skin Tumorigenesis in the Mouse

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Free PMC article

The Lsktm1 Locus Modulates Lung and Skin Tumorigenesis in the Mouse

Antonella Galvan et al. G3 (Bethesda). .
Free PMC article

Abstract

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.

Keywords: cancer modifier genes; disease models; lung cancer; quantitative trait loci (QTLs); single-nucleotide polymorphisms; skin cancer.

Figures

Figure 1
Figure 1
Interval mapping analysis of chromosome 1 region for skin and lung tumor susceptibility in SWR/J x (SWR/J x Car-R) mice. LOD curves for lung tumor multiplicity and skin tumor multiplicity are shown, with 1.5-LOD support intervals at the bottom. Map positions of SNP markers along the chromosome are indicated by small vertical lines.
Figure 2
Figure 2
Interval mapping analysis of chromosome 6 region for skin and lung tumor susceptibility in SWR/J x (SWR/J x Car-R) mice. LOD curve for total lung tumor phenotype, with 1.5-LOD support interval indicated at the bottom. Map positions of SNP markers along the chromosome are indicated by small vertical lines.
Figure 3
Figure 3
Differentially expressed genes in the Lsktm1 locus. (A) Position of the Lsktm1 interval on chromosome 1. The two markers delimiting the 1.5-LOD support interval of the locus, as well as the marker at the LOD score peak for lung tumor multiplicity (rs6312657, in red), are indicated. (B) Bar chart of expression differences (Car-R vs. SWR/J) for genes in proximity of the LOD peak expressed in lung with a significance of P < 0.001 and ordered by their physical position. Expression difference is represented as log2-transformed fold change between the mean expression scores of the two strains. The dashed lines across the bars identify genes with >1.5-fold different mRNA levels between the two mice strains.
Figure 4
Figure 4
Expression analyses of Igfbp2 and Igfbp5 genes in normal lung tissue by qPCR. Transcript levels of SWR/J (n = 13) were compared with those of Car-R (n = 15). Relative quantification represents normalized expression units assessed using the comparative cycle threshold method and a pool of tissues RNA as calibrator. Error bars represent SEM. **P < 0.001, ANOVA.
Figure 5
Figure 5
Clonogenic assay of Igfbp2 and Igfbp5 genes in two lung cancer cell lines. (A) Inhibition of in vitro colony formation of human lung carcinoma NCI-H520 cells by transfection with vectors encoding Igfbp2 (left) and Igfbp5 (right) compared with empty vectors. (B) Inhibition of in vitro colony of mouse lung adenoma LA-4 cells by transfection with vectors encoding Igfbp2 (left) and Igfbp5 (right) compared with empty vectors. Data are mean and SE of 6 independent replicas. *P < 0.0001, ANOVA.

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