Regulation of Matrix Metalloproteinase-9 Transcription in Squamous Cell Carcinoma of Uterine Cervix: the Role of Human Papillomavirus Gene E2 Expression and Activation of Transcription Factor NF-kappaB

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A. V. Gasparian, M. D. Fedorova, and F. L. Kisseljov^*

Institute of Carcinogenesis, Blokhin Cancer Research Center, Russian Academy of Medical Sciences, Kashirskoe Shosse 24, 115478 Moscow, Russia; fax: (495) 324-1205; E-mail: f_kiss@crc.umos.ru

^* To whom correspondence should be addressed.

Received March 19, 2007; Revision received May 8, 2007

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Matrix metalloproteinase-9 (MMP-9) plays an important role in initiation and progression of squamous cell carcinoma (SCC) of human uterine cervix. Regulation of MMP-9 expression in such tumors is insufficiently studied. Involvement of the human papillomavirus (HPV) gene E2 and transcription factor NF-kappaB in the regulation of MMP-9 transcription has been shown in some model systems and types of malignant tumors. The present work was mainly designed to reveal a possible role of the HPV gene E2 and transcription factor NF-kappaB in the induction of MMP-9 expression in SCC. Specimens of tumor and corresponding adjacent normal tissue from 26 patients with SCC of the uterine cervix were studied. The intact E2 frame was observed in 19 of 26 (73.1%), the E2 gene mRNA was expressed in 10 of 15 (66.7%), NF-kappaB was activated in 17 of 23 (73.9%), and the expression of MMP-9 mRNA was recorded in 10 of 20 (50%) of the informative cases. The MMP-9 transcription did not correlate with gene E2 status, but in all cases correlated with the activation of NF-kappaB transcription factor (10 of 10 vs. 5 of 10 MMP-9-negative cases, p = 0.016). Thus, the NF-kappaB role has been proved in the regulation of MMP-9 transcription in SCC. There was no correlation of the E2 status and MMP-9 expression with clinical/morphological characteristics of the tumors: size, local invasiveness, metastasizing into regional lymph nodes, and level of differentiation. The high intensity of NF-kappaB activation correlated with low degree of differentiation of the tumors studied (p = 0.044). These findings suggested that NF-kappaB should be a molecular factor of the poor prognosis of human SCC.

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KEY WORDS: cervical cancer, E2 gene, papillomavirus, MMP-9, NF-kappaB

DOI: 10.1134/S0006297907080068

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