International Journal of Radiation Oncology*Biology*Physics
Biology ContributionGenetic Background Modulates Gene Expression Profile Induced by Skin Irradiation in Ptch1 Mice
Introduction
Inherited mutations of the Patched homolog 1 (Drosophila) tumor suppressor gene in human beings predispose to nevoid basal cell carcinoma syndrome (NBCCS), an autosomal dominantly inherited disorder associated with the development of multiple basal cell carcinomas (BCCs) (1), occurring with greater incidence in portals of radiotherapy.
The risk of the sporadic form of this tumor type is modulated by genetic predisposition, as individuals with first-degree relatives affected by BCCs have an increased risk of developing this tumor with respect to the general population (2), although the responsible factors remain unknown. Ionizing radiation is also an important and established risk factor for BCCs in both sporadic cases and in NBCCS patients (3).
Patched (Ptch1) heterozygous mice recapitulate the etiology and the histopathology of human BCC, and offer opportunities to investigate the role of genetic background in radiation-induced BCC susceptibility. Indeed, crosses between the Patched (Ptch1) gene knock-out mouse and outbred mouse lines that are skin carcinogenesis resistant and susceptible (Car-R and Car-S, respectively) (4) show different responses to radiation-induced BCC (5). Ptch1 knock-out mice are also particularly susceptible to radiation-induced medulloblastomas (6). To study the early changes associated with radiation-induced BCC in different genetic backgrounds, we examined the gene expression profile of the normal or irradiated skin of F1S Ptch1neo67/+ and F1R Ptch1neo67/+ mice generated by crossing Ptch1 heterozygous gene knock-out (Ptch1neo67/+) males on a CD1 background with Car-S and Car-R female mice (6). Our results identify several candidate genes and pathways that might be involved in genetic resistance or susceptibility to radiation-induced skin tumorigenesis. Our results point to the potential role of transcriptional changes in conferring resistance to radiation-induced skin tumorigenesis.
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Mice and treatment
Mice lacking one Ptch1 allele (Ptch1neo67/+), derived by gene targeting of 129Sv embryonic stem cells, were maintained on the outbred CD1 strain background (5) and crossed with either Car-R or Car-S mice to obtain F1 progeny lacking one Ptch1 allele (designated F1R and F1S, respectively) (Fig. 1). Groups of 8-10 F1R and F1S mice were whole-body irradiated with a single dose of 3 Gy X-radiation at 2 days of age as described (5). Control groups were left untreated. Mice were sacrificed at 4 weeks
Results
RNAs derived from all the samples were of good quality, since their RNA Integrity Number (RIN) ranged from 7.3 to 9.4. Basal transcript levels in nonirradiated F1R and F1S mice were similar, with only six known genes (H2-D1, LOC56628, Mela, Oasl2, Scd2, Slc13a3) and 3 unknown transcripts (2810417H13Rik, 9230117E20Rik, C430014N20Rik) showing fourfold or greater differences.
In the skin of irradiated F1R mice, 71 transcripts were differentially expressed (fourfold or greater change), 66 of which
Discussion
Fig. 2, Fig. 3 show examples of 10 genes the mRNA levels of which modulated by radiation in a genetic background-dependent way. Indeed, in both F1R and F1S mice, these genes were up- or downregulated in adult skin after neonatal whole-body radiation treatment, although the modulation was more pronounced in F1R (Fig. 2) than in F1S mice (Fig. 3). Some of these genes participated in multiple pathways pointed out by the gene expression profile analysis (Table 3). Desmocollin 2 (Dsc2) gene is
Conclusion
In the present study, we find that radiation induces a persistent change in the gene expression profile in mice genetically resistant to skin carcinogenesis but only a minimal response in the genetically susceptible mice. These results raise the possibility that a transcriptional response to radiation represents a mechanism by which the organism counteracts radiation effects that could lead to BCC tumorigenesis. Thus, genetic susceptibility to radiation-induced BCC may rest in the lack of an
Acknowledgments
We thank the BioGeM Gene Expression Core (Ariano Irpino) for the expression profile analysis. This work was funded in part by grants from Associazione and Fondazione Italiana Ricerca Cancro (AIRC and FIRC) and by a grant (RISC-RAD) from the European Commission.
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Conflict of interest: none.