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Pregnancy and the apoptotic pathway in experimental melanoma

Facina, Anamaria S.a; Facina, Gilb; Guerreiro da Silva, Ismael D.C.b; Corrêa, Silvana A.A.e; Alexandre, Sandra M.c; Logullo, Ângela F.d; Hosomi, Jorge K.c; Nakamura, Mary U.c

doi: 10.1097/CMR.0000000000000452
ORIGINAL ARTICLES: Basic research
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Pregnancy-associated melanoma is defined as melanoma diagnosed during pregnancy or within 1 year of delivery. The association of pregnancy with melanoma is well known, but its underlying molecular mechanisms of association are poorly understood. The aim was to assess the expression of apoptosis-related genes in melanoma tumors during pregnancy in an attempt to elucidate the molecular mechanisms underlying apoptosis-driven activation of melanoma cells in this period. Mice were allocated across two experimental groups (nonpregnant and pregnant) and implanted with the melanoma cell line BF16-F10. Tumor tissue was collected for RNA extraction and purification, and gene expression was quantified using the mouse apoptosis RT2ProfilerTM PCR array. Different intracellular apoptotic pathways were activated (positively or negatively) by pregnancy in tumor cells: intrinsic (21.5%), extrinsic (32%), caspase (14%), apoptosis (21.5%), and caspase-activated DNase (11%). The proportion of upregulated genes for each of these pathways was 100, 30, 50, 17, and 0%, respectively. MetaCore software was then used to analyze gene ontology processes and pathways by building networks. Among the gene ontology processes, the majority of differentiated genes were related to the apoptotic process. The main pathway activated by pregnancy was the intrinsic one (genes Api-5, Bcl2-L1, Birc-2, Birc-3, Bok, and Trp53bp2). Pregnancy activates the intrinsic apoptosis pathway to stimulate caspases 7 and 9, but the final balance is inhibition of apoptosis mechanisms. In mice, pregnancy cannot promote or worsen melanoma.

Departments of aDermatology

bGynecology, Molecular Gynecology Laboratory

cObstetrics

dAnatomic Pathology, Federal University of São Paulo (UNIFESP), São Paulo

eGraduate Program in Public Health, Facvest University Center (UNIFACVEST), Lages, Santa Catarina, Brazil

Correspondence to Anamaria S. Facina, MD, PhD, Department of Dermatology, Federal University of Sao Paulo (UNIFESP), Rua Borges Lagoa 508, São Paulo, SP 04038-001, Brazil Tel/fax: +55 115 575 7200; e-mail: anamaria.facina@unifesp.br

Received October 1, 2017

Accepted March 19, 2018

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.