Microsatellite instability detected in tumor-related genes in C57BL/6J mice with thymic lymphoma induced by N-methyl-N-nitrosourea.
Microsatellite instability (MSI) has been observed within tumors and found to be closely associated with the degree of malignancy and prognosis in tumors. However, whether MSI in tumor-related genes can be induced by a chemical and whether a connection exists between MSI and tumors remain unclear. In the present study, we detected MSI in the tissues of N-methyl-N-nitrosourea (MNU) treated mice by targeting to 5, 29, 30 microsatellite loci in 3 mismatch repair (MMR) genes, 1 DNA repair gene, and 5 tumor suppressor (TS) genes, respectively. Among 26 mice survived in the MNU-group, 18 (69%) mice presented thymic lymphomas. Moreover, 61% (11/18) of the tumors metastasized to the other organs, including the liver, spleen, and kidney. We examined 104 tissues from MNU-treated mice using the 64 loci, and found 8 MSI events involved 4 loci in 4 tissues types. The MSI incidence in MMR, DNA repair, and TS genes was 67% (2/3), 0% (0/1) and 40% (2/5), respectively. MSI occurrence in tumor and non-tumor tissues was 5.6% (1/18) and 0% (0/8) and that in metastasis and non-metastasis tissues was 7.1% (1/14) and 9.4% (6/64), showing no significant difference. MSI loci in intronic regions of Atm, Msh6 and p21 and MSI in the 3'UTR of Pms2 were detected in MNU-treated mice. Specifically, we found a loss of heterozygosity in intron of Atm (ATM-8) in one metastasis mouse. Four similar events occurred in p21 gene intron (P21-1) of another non-metastasis mouse. Another MSI was a heterozygous mutation existed in an Msh6 allele (MSH6-2) in metastasis mouse. We also found a homozygous 2-bp insertion in the 3'UTR of Pms2 in two non-metastasis mice. These results imply that MNU can induce MSI in MMR and TS genes in C57BL/6J mice. MSI frequency does not seem to be associated with tumorigenesis or metastasis.
School of Basic Medical Science, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing 100069, China.
Shuangyue
S
Zhang
School of Basic Medical Science, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing 100069, China.
Xueyun
X
Huo
School of Basic Medical Science, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing 100069, China.
Zhenkun
Z
Li
School of Basic Medical Science, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing 100069, China.
Xiaohong
X
Li
School of Basic Medical Science, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing 100069, China.
Wang
W
Tang
School of Basic Medical Science, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing 100069, China.
Changlong
C
Li
School of Basic Medical Science, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing 100069, China.
Meng
M
Guo
School of Basic Medical Science, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing 100069, China. Electronic address: duduyan@ccmu.edu.cn.
Xiaoyan
X
Du
School of Basic Medical Science, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing 100069, China. Electronic address: czwen@ccmu.edu.cn.
Zhenwen
Z
Chen
D000818:Animals; D053843:DNA Mismatch Repair / Q000187:drug effects / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects* / Q000235:genetics; D016147:Genes, Tumor Suppressor / Q000187:drug effects*; D008223:Lymphoma / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008297:Male; D008770:Methylnitrosourea / Q000633:toxicity*; D008810:Mice, Inbred C57BL; D053842:Microsatellite Instability / Q000187:drug effects*; D013945:Thymoma / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology
D008770:Methylnitrosourea
C57BL/6J mice; Microsatellite instability (MSI); N-methyl-N-nitrosourea (MNU); Thymic lymphoma; Tumor-related genes