Polymorphism in apoptotic BAX (-248G>A) gene but not in anti-apoptotic BCL2 (-938C>A) gene and its protein and mRNA expression are associated with cervical intraepithelial neoplasia.
HPV is associated with cervical cancer and plays a crucial role in tumor formation. Apoptosis is regulated by different pathways involving genes that either promote (BCL2 gene) or inhibit (BAX gene) cell death. Our goal was to determine whether the BCL2-938C>A (rs2279115) and BAX-248G>A (rs4645878) single nucleotide polymorphisms (SNPs) are associated with squamous intraepithelial neoplasia (SIL) risk, and whether their phenotypic expression was impaired in these lesions. Two hundred and thirty-one cases showing SIL were classified as low SIL (LSIL, n = 101) or high SIL (HSIL, n = 130), and control subjects (n = 266) with no gynecologically proven SIL were recruited. No statistical difference in the genotype and allelic frequency of the BCL-2-938C>A polymorphism was observed among the groups. BCL2-938C/A and A/A homozygotes carriers had higher distribution of BCL-2-expressing cells in stroma in the SIL group. BCL2 mRNA-expression was not correlated with BCL2-938C>A SNPs in both groups. We did find a strong association of the BAX GG genotype and risk for SIL. No difference was observed between LSIL and HSIL groups. In BAX-248G/A and A/A homozygote carriers, the number of BAX-expressing cells was lower the epithelium area in SIL. However, mRNA expression was higher in SIL patients than in the control group. In conclusion, our data provide evidence that allele G carriers in the BAX-248G>A promoter SNP may influence the development of SIL. However, this genotype does not influence the SIL outcome. Additionally, we suggest a possible role of HPV infection in the inhibition of the expression of BAX protein, decreasing cell death, and favoring cervical carcinogenesis.
Laboratory of Immunology and Immunogenetics in Infectious Diseases, Evandro Chagas National Institute of Infectious Diseases, Oswaldo Cruz Foundation, Avenida Brasil 4365, Rio de Janeiro, 21040-900, Brazil.
Ana Teresa G
AT
Fernandes
Natália P
NP
Rocha
Elena
E
Vendrame
Fabio
F
Russomano
Beatriz J
BJ
Grinsztejn
Ruth K
RK
Friedman
Amanda C
AC
Pinto
Evandro M
EM
Klumb
Elyzabeth
E
Avvad
Jacyara
J
Macedo
Otoniel
O
Martínez-Maza
Maria da Gloria
Mda G
Bonecini-Almeida
D000328:Adult; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D027383:Papillomaviridae / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics* / Q000378:metabolism; D002578:Uterine Cervical Dysplasia / Q000235:genetics* / Q000378:metabolism
D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein