Organ differences in the impact of p27^kip1 deficiency on carcinogenesis induced by N‐methyl‐N‐nitrosourea

Abstract

To evaluate the impact of p27 on carcinogenesis in various organs, N-methyl-N-nitrosourea (MNU), a direct-acting alkylating agent, was given to p27 knock-out mice. Groups of 20-40 male and female mice with null, hetero- or wild-type p27 alleles were given drinking water containing 240 ppm MNU or distilled water every other week for five cycles. The incidence and multiplicity of the induced proliferative lesions were then histologically evaluated at weeks 14 and 20. MNU treatment induced various lesions including squamous hyperplasia and squamous cell carcinoma in the forestomach, atypical hyperplasia and adenocarcinomas in the fundic and pyloric glands, adenomas and adenocarcinomas in the duodenum, malignant lymphomas in the thymus, liver, kidney and spleen and alveolar hyperplasia, adenomas, adenocarcinomas and malignant lymphomas in the lung. Although the incidences of the lesions in the forestomach, fundic and pyloric glands did not differ among the p27 genotypes, those of alveolar hyperplasia of the lung and malignant lymphoma of the thymus were significantly increased in p27-null males as compared with both wild- and hetero-type animals. Moreover, in both p27(+/+) and p27(+/-) cases, the rates for p27-positive cells were obviously increased in proliferative lesions of the pyloric gland and the lung. However, an increased rate of p27-positive cells was not observed in malignant lymphoma of the thymus. These findings suggest that p27 does not control the cell cycle equally in all organs affected by MNU-induced carcinogenesis.

Successful development of squamous cell carcinoma and hyperplasia in RGEN-mediated p27 KO mice after the treatment of DMBA and TPA

“…Tumor development of the intestine, lung, pituitary and reproductive tract was induced by 4Gy whole-body γ-irradiation in p27 (I/IIΔ) KO mice [ 6 ]. High tumor susceptibility was detected in various tissues of p27 (I/IIΔ) KO mice after ENU and MNU treatment [ 6 9 ]. However, most chemical carcinogens induced the development of only a single tumor type in p27 (I/IIΔ) KO mice; DMH, BBN, MBN and DEN treatment increased the progression of gastrointestinal tumor [ 8 ], urinary bladder tumor [ 10 ], esophageal cancer [ 11 ], and liver tumor [ 12 ], respectively.…”

“…Intestinal and lung adenocarcinoma and pituitary tumors were found in p27 KO mice with exon I and II deletion (I/IIΔ) challenged with γ-irradiation and N-ethyl-N-nitrosourea (ENU) injection [ 6 ], while skin tumor and intestinal adenoma were significantly increased in p27 (I/IIΔ) KO mice after DMBA and TPA treatment [ 7 ]. Also, dimethylhydrazine (DMH)-treated germline deletion p27 (exon I and II) mice presented only gastrointestinal adenocarcinoma malignancies, but N-methyl-N-nitrosourea (MNU) treatment induced hyperplasia and carcinoma in various organs [ 8 9 ]. Carcinoma of the urinary bladder and esophageal cancer were significantly higher in p27 (I/IIΔ) KO mice treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) and methylbenzylnitrosamine (MBN) [ 10 11 ].…”

Protocol for chemically induced murine gastric tumor model

“…i.g 10 weeks 36 weeks 6.3% Masui et al. (1997) Intestine (duodenum) MNU C57BL/6 240 ppm, d.w 5 weeks 20 weeks 0%–6.3% Ogawa et al. (2013) MNU C57BL/6 50 mg/kg, i.p 1 time 20–30 weeks 14% Qin et al.…”

“…(2000) MNU C57BL/6 50 mg/kg, i.p 1 time 30–40 weeks 56% Qin et al. (2000) Colon H. pylori + MNU C57BL/6J 240 ppm, d.w 5 weeks 70 weeks 85% Ogawa et al. (2013) Lung MNU C57BL/6 240 ppm, d.w 5 weeks 20 weeks 11%–25% Ogawa et al.…”

Serum carcinoembryonic antigen (CEA) levels are associated with the decrease/loss of p27 immunohistochemical expression in non-small cell lung cancer

“…Cyclin dependent kinase inhibitor 1B (P27kip1; CDKN1B) regulates cellular proliferation and senescence. The gene encoded protein binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4 complexes, blocking G1/S transition and controlling the cycle cell in all organs [1,2]. In this regard, some group has observed that SIRT1, a class III histone deacetylase, is an important regulator of p27kip1 expression, reducing its expression through the ubiquitin-proteasome pathway [3].…”