Enhancive effect of N,N'-dinitrosopiperazine on inducing precancerous lesion on nasal and/or nasopharyngeal epithelia of TgN(p53mt-LMP1)/HT mice.
OBJECTIVE
To investigate the enhancive effect of N,N'-dinitrosopiperazine (DNP) on induced carcinogenesis in nasal and/or nasopharyngeal epithelia among TgN(p53mt-LMP1)/HT transgenic mice to examine the underlying mechanism for the development of nasopharyngeal carcinoma (NPC).


METHODS
TgN(p53mt-LMP1)/HT transgenic mice and the same strain of C(57)BL/6J wild-type mice both at the age of 5 months were randomly divided into 2 groups in parallel, respectively, i.e., TgN(p53mt-LMP1)/HT cancerous lesion-inducing group (TI), TgN(p53mt-LMP1)/HT control group (TC), C57BL/6J cancerous lesion-inducing group (CI), and C57BL/6J control group (CC). TI and CI mice were treated only with DNP for 16 weeks, twice each week, while TC and CC mice were given the same volume of saline as controls. At the end of treatment, animals were sacrificed to collect epithelial tissue samples from nasal cavity and nasopharynx for pathohistological evaluation by haematoxylin and eosin (HE) staining and for determination on the expression of TRAF2, c-Jun, and p16 by immunohistochemistry.


RESULTS
Atypical hyperplasia was more significant in the samples of TI than in those of TC, CI, and CC, with the rates of lesions being 90%, 10%, 0, and 0 (P<0.01) respectively, though DNP was used alone in a much shortened inducing period at less dosage and without the use of carcinogenic promoter 12-O-tetradecanoylphorbol-13-acetate as usual. The expressions of tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) and c-Jun in these samples were significantly up-regulated in TI (P<0.01), while the expression of p16 was significantly lower in TI than in the other groups (P<0.01).


CONCLUSIONS
TgN(p53mt-LMP1)/HT mice hold inherited constitutional defect in immune surveillance function, which can be aggravated by environmental carcinogens, such as DNP used even though in a much less strength. The enhanced carcinogenesis-inducing effect of DNP on TgN(p53mt-LMP1)/HT mice should be closely associated with abnormal signaling of activator protein-1 (AP-1) pathway, especially up-regulated expressions of TRAF2 and c-Jun, and down-regulated expression of p16.
Tian
Dao-fa
DF
Faculty of Integrative Medicine, Chinese Medicine University of Hunan, and Department of Clinical Laboratory, the First Xiangya Hospital, Changsha 410007, China.
He
Ying-chun
YC
Lu
Fang-guo
FG
Tang
Fa-qing
FQ
D000818:Animals; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009303:Nasopharyngeal Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009602:Nitrosamines / Q000494:pharmacology*; D009669:Nose Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology*; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D009602:Nitrosamines; D047992:TNF Receptor-Associated Factor 2; D016159:Tumor Suppressor Protein p53; D014763:Viral Matrix Proteins; D048031:JNK Mitogen-Activated Protein Kinases; C026156:N,N'-dinitrosopiperazine