Overexpression of cathepsin F, matrix metalloproteinases 11 and 12 in cervical cancer.
BACKGROUND
Cervical carcinoma (CC) is one of the most common cancers among women worldwide and the first cause of death among the Mexican female population. CC progression shows a continuum of neoplastic transitions until invasion. Matrix metalloproteinases (MMPs) and cathepsins play a central role on the enhancement of tumor-induced angiogenesis, cell migration, proliferation, apoptosis and connective tissue degradation. MMPs -2 and -9 expression has been widely studied in cervical cancer. Nevertheless, no other metalloproteinases or cathepsins have been yet related with the progression and/or invasion of this type of cancer.


METHODS
Three HPV18 CC cell lines, two HPV16 CC cell lines and three HPV16 tumor CC tissues were compared with three morphologically normal, HPV negative, cervical specimens by cDNA arrays. Overexpression of selected genes was confirmed by end point semiquantitative reverse transcription-PCR with densitometry. In situ hybridization and protein expression of selected genes was further studied by means of two tissue microarrays, one consisting of 10 HSIL and 15 CC and the other one of 15 normal cervical and 10 LSIL tissues.


RESULTS
TIMP1, Integrins alpha 1 and 4, cadherin 2 and 11, Cathepsins F, B L2, MMP 9, 10 11 and 12 were upregulated and Cathepsin S, L, H and C, Cadherins 3 and 4, TIMP3, MMP 13, Elastase 2 and Integrin beta 8 were found to be downregulated by cDNA arrays. Endpoint RT-PCR with densitometry gave consistent results with the cDNA array findings for all three genes selected for study (CTSF, MMP11 and MMP12). In situ hybridization of all three genes confirmed overexpression in all the HSIL and CC. Two of the selected proteins were detected in LSIL, HSIL and CC by immunohistochemistry.


CONCLUSIONS
Novel undetected CC promoting genes have been identified. Increased transcription of these genes may result in overexpression of proteins, such as CTSF, MMP11 and MMP12 which could contribute to the pathogenesis of CC.
Vazquez-Ortiz
Guelaguetza
G
Oncogenomics Laboratory, Oncology Hospital, National Medical Center SXXI-IMSS, Mexico. guelav@yahoo.com
Pina-Sanchez
Patricia
P
Vazquez
Karla
K
Duenas
Alfonso
A
Taja
Lucia
L
Mendoza
Patricia
P
Garcia
José A
JA
Salcedo
Mauricio
M
D002277:Carcinoma / Q000378:metabolism*; D056646:Cathepsin F; D002403:Cathepsins / Q000096:biosynthesis*; D018076:DNA, Complementary / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D053507:Matrix Metalloproteinase 11; D053508:Matrix Metalloproteinase 12; D008666:Metalloendopeptidases / Q000096:biosynthesis*; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D015345:Oligonucleotide Probes / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D002583:Uterine Cervical Neoplasms / Q000201:enzymology*
D018076:DNA, Complementary; D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D002403:Cathepsins; C534090:CTSF protein, human; D056646:Cathepsin F; D053507:Matrix Metalloproteinase 11; D008666:Metalloendopeptidases; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12