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-κB

Abstract

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.

Genetic variation in TLR or NFkappaB pathways and the risk of breast cancer: a case-control study

“…MMP9 expression is regulated by NFκB [44], and in one study was shown to be correlated with NFκB activation in patients with squamous cell carcinoma of the uterine cervix [45]. Although no GWAS studies have found SNPs in MMP9 to affect breast cancer risk, many prior studies have published results that support an association between MMP9 and breast cancer risk.…”

Thymoquinone inhibits matrix metalloproteinase expression in rabbit chondrocytes and cartilage in experimental osteoarthritis

“…Thus, we speculated that NF- κ B may be involved in the inhibition of MMPs by TQ in chodrocytes. Since other signaling pathways such as mitogen-activated protein kinase also play an important role in the regulation of MMPs, 39 further studies are needed to reveal the precise mechanisms that underlie the regulation of MMPs by TQ.…”

The Papillomavirus E2 proteins

“…However, there are detailed studies examining the role of E2 in regulating the expression of Matrix Metalloproteinase-9 (MMP-9) (Akgul et al, 2006; Behren et al, 2005; Gasparian et al, 2007; Muhlen et al., 2010), IL-10 (Bermudez-Morales et al, 2011), hTERT (Lee et al, 2002b), beta 4-integrin (Oldak et al., 2010; Oldak et al, 2004) and the splicing factor SF2/ASF (Mole et al, 2009). …”