Fujiwara Kyoko, Inagaki Yoshinori, Soma Masayoshi, Ozaki Toshinori, Nagase Hiroki
Division of General Medicine, Department of Medicine, Nihon University School of Medicine, Tokyo 173-0032, Japan.
Department of Internal Medicine, Sasaki Foundation Kyoundo Hospital, Tokyo 101-0062, Japan.
Oncol Lett. 2018 Nov;16(5):6670-6676. doi: 10.3892/ol.2018.9495. Epub 2018 Sep 24.
As cancer susceptibility varies among mouse strains, mouse models are powerful tools for the identification of genes responsible for cancer development. Several cancer susceptibility loci have been mapped by genetic analysis using cancer-resistant and cancer-susceptible mouse strains. However, only a few corresponding genes for these loci have been identified, because most of the cancer susceptibility loci are low-penetrance alleles. We reported previously that wild-derived PWK mice showed no tumor development on treatment with the two-stage skin carcinogenesis protocol [induced by 7.12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)], and that this phenotype is dominant-resistant when crossed with the highly susceptible strain FVB. From the analysis of the F1 backcross generation between PWK and FVB, we have mapped the new significant locus on chromosome 4. In the present study, congenic strains were generated with the PWK resistance allele in the FVB background using a phenotype-driven approach, and sought to narrow down the candidate loci and find the responsible gene(s). One of the resistant mice in the N generation carried the remaining PWK allele on chromosomes 4, 7 and 11, and an association study using the progeny of this mouse suggested that the locus on chromosome 11 may affect the cancer susceptibility locus on chromosome 7. On the other hand, no skin tumor susceptibility locus was mapped on chromosome 11 as examined in N2 progeny. These findings suggest that there is at least one tumor-resistance gene on chromosome 7, the function of which could be regulated by gene(s) located on chromosome 11.
由于不同小鼠品系的癌症易感性存在差异，小鼠模型是鉴定癌症发生相关基因的有力工具。通过使用抗癌和癌敏感小鼠品系进行遗传分析，已经定位了几个癌症易感位点。然而，这些位点中只有少数相应的基因被鉴定出来，因为大多数癌症易感位点是低 penetrance 等位基因。我们之前报道过，野生来源的 PWK 小鼠在两阶段皮肤致癌方案（由 7,12-二甲基苯并(a)蒽（DMBA）/12-O-十四酰佛波醇-13-乙酸酯（TPA）诱导）处理下未出现肿瘤发生，并且当与高度易感品系 FVB 杂交时，这种表型是显性抗性的。通过对 PWK 和 FVB 之间的 F1 回交一代进行分析，我们在 4 号染色体上定位了新的显著位点。在本研究中，使用表型驱动方法在 FVB 背景下产生了带有 PWK 抗性等位基因的近交系，并试图缩小候选位点范围并找到相关基因。N 代中的一只抗性小鼠在 4 号、7 号和 11 号染色体上携带了剩余的 PWK 等位基因，对这只小鼠后代进行的关联研究表明，11 号染色体上的位点可能影响 7 号染色体上的癌症易感位点。另一方面，在 N2 后代中检测时，11 号染色体上未定位到皮肤肿瘤易感位点。这些发现表明，7 号染色体上至少存在一个肿瘤抗性基因，其功能可能受位于 11 号染色体上的基因调控。
