MMP-9/RECK Imbalance: A Mechanism Associated with High-Grade Cervical Lesions and Genital Infection by Human Papillomavirus and Chlamydia trachomatis.
BACKGROUND
Matrix metalloproteinases (MMP) are important enzymes in the tumor microenvironment associated with progression of cervical intraepithelial neoplasia (CIN) toward squamous cell carcinoma (SCC) of the cervix. However, the role of MMPs in the inflammatory process associated with Chlamydia trachomatis infection concomitant with the carcinogenic process driven by HPV has not yet been addressed. In the present study, we analyzed the state of the MMP-9-RECK axis in cervical carcinogenesis.


METHODS
The levels of MMP-9 and RECK expression were analyzed by immunocytochemistry in liquid-based cytology samples from 136 women with high-grade cervical lesions (CIN2/CIN3) and cervical SCC diagnosed by LLETZ, and in 196 women without cervical neoplasia or CIN1. Real-time qPCR was performed to analyze expression of MMP-9 and RECK in 15 cervical samples. The presence of HPV-DNA and other genital pathogens was evaluated by PCR.


RESULTS
We found a higher expression of MMP-9 [OR, 4.2; 95% confidence interval (CI), 2.2-7.8] and lower expression of RECK (OR, 0.4; 95% CI, 0.2-0.7) in women with CIN2/CIN3/SCC when compared with women from the control group (no neoplasia/CIN1). A statistically significant association was also found between MMP-9/RECK imbalance and infection by alpha-9 HPV and C. trachomatis. The prevalence of C. trachomatis infection was significantly higher in women with high-grade cervical disease (OR, 3.7; 95% CI, 1.3-11.3).


CONCLUSIONS
MMP-9/RECK imbalance in cervical smears is significantly associated with high-grade cervical diseases and infection by alpha-9 HPV and C. trachomatis.


CONCLUSIONS
MMP-9/RECK imbalance during cervical inflammation induced by C. trachomatis might play a role in HPV-mediated cervical carcinogenesis.
Laboratory of Clinical Cytopathology, School of Pharmaceutical Sciences, University of São Paulo (USP), São Paulo, Brazil.
Michelle G
MG
Discacciati
Clinical Cytology Laboratory, State University of Maringá (UEM), Maringá, Paraná, Brazil.
Fabrícia
F
Gimenes
Laboratory of Clinical Cytopathology, School of Pharmaceutical Sciences, University of São Paulo (USP), São Paulo, Brazil.
Paula C
PC
Pennacchi
Laboratory of Clinical Cytopathology, School of Pharmaceutical Sciences, University of São Paulo (USP), São Paulo, Brazil.
Fernanda
F
Faião-Flores
Department of Obstetrics and Gynecology, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
Luiz C
LC
Zeferino
Department of Obstetrics and Gynecology, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
Sophie M
SM
Derchain
Department of Obstetrics and Gynecology, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
Júlio C
JC
Teixeira
School of Medicine, Santa Casa de São Paulo, INCT-HPV at Santa Casa Research Institute, São Paulo, Brazil.
Maria C
MC
Costa
LEMC Laboratory, Discipline of Infectology, UNIFESP; and Department of Pathology, Santo Amaro University, São Paulo, Brazil.
Marco
M
Zonta
School of Medicine, Santa Casa de São Paulo, INCT-HPV at Santa Casa Research Institute, São Paulo, Brazil.
Lara
L
Termini
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Enrique
E
Boccardo
Laboratory of Medical Investigation (LIM), Department of Pathology, School of Medicine, University of São Paulo, São Paulo, Brazil. Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal. ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal. Molecular Oncology Research Center, Barretos Cancer Hospital, Pio XII Foundation, Barretos, Brazil.
Adhemar
A
Longatto-Filho
Clinical Cytology Laboratory, State University of Maringá (UEM), Maringá, Paraná, Brazil.
Marcia E L
ME
Consolaro
School of Medicine, Santa Casa de São Paulo, INCT-HPV at Santa Casa Research Institute, São Paulo, Brazil. Department of Radiology and Oncology, School of Medicine, University of São Paulo, São Paulo, Brazil.
Luisa L
LL
Villa
Laboratory of Clinical Cytopathology, School of Pharmaceutical Sciences, University of São Paulo (USP), São Paulo, Brazil. silvya@usp.br.
Silvya S
SS
Maria-Engler
D000328:Adult; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000821:virology; D002584:Cervix Uteri / Q000378:metabolism / Q000473:pathology; D002690:Chlamydia Infections / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002692:Chlamydia trachomatis / Q000235:genetics; D003430:Cross-Sectional Studies; D004269:DNA, Bacterial / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D058851:GPI-Linked Proteins / Q000096:biosynthesis / Q000235:genetics*; D015964:Gene Expression Regulation, Bacterial; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D052162:Human papillomavirus 16 / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics*; D065006:Papanicolaou Test; D030361:Papillomavirus Infections / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D002575:Uterine Cervicitis / Q000235:genetics* / Q000378:metabolism / Q000382:microbiology; D014626:Vaginal Smears
D004269:DNA, Bacterial; D004273:DNA, Neoplasm; D004279:DNA, Viral; D058851:GPI-Linked Proteins; C115460:RECK protein, human; D020780:Matrix Metalloproteinase 9