Institute of Biotechnology, University of Helsinki, Helsinki 00014, Finland and.
Carcinogenesis. 2013 Oct;34(10):2409-14. doi: 10.1093/carcin/bgt188. Epub 2013 May 30.
Peutz-Jeghers patients develop hamartomatous polyps and carcinomas of the gastrointestinal tract. Cyclooxygenase-2 accelerates polyp growth in Lkb1 (+/-) mice modelling Peutz-Jeghers polyposis. In this study, we aimed to evaluate the effect of the mutagenic carcinogen N-methylnitrosourea (MNU) on gastrointestinal tumourigenesis in Lkb1 (+/-) mice and to investigate the role of cyclooxygenase-2 on the tumourigenesis. We treated 40 Lkb1 (+/-) and 51 wild-type mice with MNU, 10 mice from both groups received the cyclooxygenase-2 inhibitor celecoxib. Carcinogen-treated Lkb1 (+/-) mice displayed worse survival (60%) than treated wild-type (100%, P = 0.028) or untreated Lkb1 (+/-) mice (92%, P = 0.045). Also, the gastrointestinal tumour burden was almost 10-fold higher in carcinogen-treated (2181 mm(3)) than in untreated (237 mm(3), P = 0.00045) Lkb1 (+/-) mice. Celecoxib was much less efficient in reducing tumourigenesis in MNU-treated mice (by 23%; 1686 mm(3)) than in untreated mice (76%; 58 mm(3)). Surprisingly, the increase in tumour burden in MNU-treated mice was not accompanied by consistent histological changes, with only a single focus of epithelial dysplasia noted. This study suggests that MNU promotes Peutz-Jeghers polyposis independently from the acceleration by cyclooxygenase-2.
Peutz-Jeghers 患者会出现胃肠道的错构瘤和癌。环氧化酶-2 加速 Lkb1（+/-）小鼠模型中 Peutz-Jeghers 息肉病的息肉生长。在这项研究中，我们旨在评估诱变致癌剂 N-甲基-N-亚硝基脲（MNU）对 Lkb1（+/-）小鼠胃肠道肿瘤发生的影响，并研究环氧化酶-2在肿瘤发生中的作用。我们用 MNU 处理 40 只 Lkb1（+/-）和 51 只野生型小鼠，两组各有 10 只接受环氧化酶-2 抑制剂塞来昔布治疗。致癌剂处理的 Lkb1（+/-）小鼠的存活率（60%）明显低于处理的野生型（100%，P = 0.028）或未处理的 Lkb1（+/-）小鼠（92%，P = 0.045）。此外，致癌剂处理的 Lkb1（+/-）小鼠（2181mm3）的胃肠道肿瘤负担几乎是未处理的 Lkb1（+/-）小鼠（237mm3，P = 0.00045）的 10 倍。与未处理的小鼠（76%，58mm3）相比，塞来昔布在减少 MNU 处理小鼠的肿瘤发生方面的效率要低得多（减少 23%，1686mm3）。令人惊讶的是，MNU 处理的小鼠肿瘤负担的增加并没有伴随一致的组织学变化，仅注意到一个上皮异型增生的焦点。本研究表明，MNU 可促进 Peutz-Jeghers 息肉病的发生，而与环氧化酶-2 的加速无关。
