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Int J Clin Exp Pathol 2013;6(1):13-23

Original Article
Myenteric denervation in gastric carcinogenesis: differential modulation of nitric oxide
and annexin-A1

Ana Cláudia Polli-Lopes, Cássia F Estofolete, Sonia M Oliani, Sérgio Zucoloto, Fernando Q Cunha, Cristiane D Gil

Department of Anatomy, São José do Rio Preto School of Medicine - FAMERP, São Paulo, SP, Brazil; Department of Biology, Instituto de
Biociências, Letras e Ciências Exatas - IBILCE - UNESP, São José do Rio Preto, SP, Brazil; Department of Pathology and Department of
Pharmacology, Ribeirão Preto School of Medicine - FMRP-USP, Ribeirão Preto, SP, Brazil; Department of Morphology and Genetics, Federal
University of São Paulo - UNIFESP, São Paulo, SP, Brazil

Received September 30, 2012; Accepted October 31, 2012; Epub November 20, 2012; Published January 1, 2013

Abstract: This study evaluated the properties of endogenous nitric oxide synthases (NOS) and annexin-A1 (ANXA1) and determined how they
can be exploited in the N-methyl-N-nitro-N-nitrosoguanidine (MNNG)-induced gastric carcinogenesis and myenteric denervation model. Male
Wistar rats were treated with MNNG and/or aminoguanidine (AG) for 20 weeks. In another set of experiments, rats with nondenervated and
denervated stomachs were treated with MNNG or water for 28 weeks. Fragments of the pyloric region were processed for histopathology, NOS
activity, and immunohistochemistry to explore the activity and expression of constitutive (cNOS) and inducible (iNOS) NO synthase and their
relationship with annexin-A1 (ANXA1) expression. NO inhibition by AG increased the percentage of animals with adenocarcinomas (~29%)
compared with the untreated MNNG group (~4%). Myenteric denervation did not alter NOS activity. cNOS activity was significantly greater in
nondernervated and denervated stomachs with or without lesions (P<0.001) than iNOS activity (P<0.01), as confirmed by
immunohistochemistry. Further, cNOS activity in normal stomachs and outside the lesion area was considerably higher than inside it (P<0.01).
By densitometric analysis of nondenervated and denervated stomachs, ANXA1 expression was modulated in epithelial and inflammatory cells
(mast cells and neutrophils), wherein significant alterations were induced by lesion development and myenteric denervation. In conclusion, NO
protects against the development of gastric adenocarcinomas. The pattern of ANXA1 expression was not associated with NOS activity or
expression, suggesting that NO and ANXA1 act in gastric tumors in disparate pathways. (IJCEP1209032)

Keywords: Benzalkonium chloride, immunohistochemistry, lipocortin-1, N-methyl-N-nitro-N-nitrosoguanidine, nitric oxide synthase,

Address all correspondence to:
Dr. Cristiane D Gil
Department of Morphology and Genetics
Federal University of São Paulo - UNIFESP, Rua Botucatu
740, Ed, Lemos Torres – 3º andar, 04023-900
São Paulo, SP, Brazil.
Phone / Fax: ++55 11 5576-4268
E-mail: cristiane.gil@unifesp.br