Changes in matrix metalloproteinases and their endogenous inhibitors during tumor progression in the uterine cervix

Nair, S. Asha; Karunagaran, Devarajan; Nair, M. Balaraman; Sudhakaran, P. R.

doi:10.1007/s00432-002-0411-9

Cited by 42 publications

(16 citation statements)

References 27 publications

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“…Our observation was also supported by the findings of Asha Nair et al . which reported that TIMP-2 levels were increased during tumor progression in the uterine cervix [33]. However our results are in contrast with Branca et al that demonstrated down regulation of TIMP-2 in invasive cervical carcinomas [34].…”

Section: Discussioncontrasting

confidence: 99%

HPV16 Oncoproteins Promote Cervical Cancer Invasiveness by Upregulating Specific Matrix Metalloproteinases

et al. 2013

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Production of matrix metalloproteinases (MMPs) for degradation of extracellular matrix is a vital step in cancer metastasis. We investigated the effects of HPV16 oncoproteins (16E6, 16E6*I and 16E7), either individually or combined, on the transcription of 7 MMPs implicated in cervical cancer invasiveness. The levels of 7 MMPs reported to be increased in cervical cancer were determined in C33A stably expressing different HPV16 oncoproteins using quantitative RT-PCR and compared with invasion ability of cell lines using in vitro invasion and wound healing assays. Overexpression of MMP-2 and MT1-MMP was detected in HPV16E6E7 expressing cells which correlated with increased cell invasion. Combination of HPV oncoproteins always showed greater effects than its individual form. Inhibition of cell invasion using a specific MMP-2 inhibitor, OA-Hy, and anti-MT1-MMP antibody confirmed that invasion in these cells was dependent on both MMP-2 and MT1-MMP expression. Depletion of HPV16E6E7 by shRNA-mediated knock-down experiments resulted in decreased MMP-2 and MT1-MMP expression levels as well as reduced invasion ability which strongly suggested specific effects of HPV oncoproteins on both MMPs and on cell invasion. Immunohistochemistry study in invasive cervical cancers confirmed the enhanced in vivo expression of these two MMPs in HPV16-infected cells. In addition, possible sites required by HPV16E6E7 on the MMP-2 and MT1-MMP promoters were investigated and PEA3 (at −552/−540 for MMP-2, −303 for MT1-MMP) and Sp1 (at −91 for MMP-2, −102 for MT1-MMP) binding sites were shown to be essential for mediating their transactivation activity. In conclusion, our study demonstrated that HPV16E6 and E7 oncoproteins cooperate in promoting cervical cancer invasiveness by specifically upregulating MMP-2 and MT1-MMP transcription in a similar manner.

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Section: Discussioncontrasting

confidence: 99%

HPV16 Oncoproteins Promote Cervical Cancer Invasiveness by Upregulating Specific Matrix Metalloproteinases

et al. 2013

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“…High expression of MMP‐2 in human cervical carcinoma cell lines have also been associated with presence of HPV (13). MMP‐2 expression has been shown to gradually increase according to the degree of cervical intraepithelial neoplasia (CIN) and cervical carcinoma (14–18). Increased MMP‐9 mRNA and protein expression was found in high grade CIN and squamous cell cervical invasive carcinoma suggesting MMP‐9 to be an early marker of tumor progression (19).…”

Section: Discussionmentioning

confidence: 99%

“…Increased MMP‐9 mRNA and protein expression was found in high grade CIN and squamous cell cervical invasive carcinoma suggesting MMP‐9 to be an early marker of tumor progression (19). High grade cervical squamous intraepithelial lesions (SIL) and squamous cell carcinomas showed intense cellular and stromal reactivity for MMP‐9 when compared to low‐grade cervical SILs and normal cervical epithelium (14). Both vulvar and cervical squamous cell carcinoma are known to develop through premalignant lesions.…”

Section: Discussionmentioning

confidence: 99%

Increased matrix metalloproteinases 2 and 9 and tissue inhibitor of matrix metalloproteinase 2 expression is associated with progression from vulvar intraepithelial neoplasia to invasive carcinoma

Määttä

Santala

Soini

et al. 2010

Acta Obstet Gynecol Scand

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“…Many extracellular proteases have been demonstrated to directly activate MMPs including other MMPs (e.g., MMP-3 activation of the MMP-9 [11]) and non-MMP proteins (e.g., plasmin activation of MMP-3 [12]). High levels of metalloproteinases, especially MMP-2 and/or MMP-9 have been demonstrated in many cancers, including pancreatic [13–20], breast [21], cervical [22], and ovarian cancer [23]. Similarly, the human kallikrein-related peptidases constitute an important group of serine proteases that are up-regulated in various cancers (reviewed in [24–25]).…”

Section: Introductionmentioning

confidence: 99%

Proteolytic action of kallikrein-related peptidase 7 produces unique active matrix metalloproteinase-9 lacking the C-terminal hemopexin domains

Ramani

Kaushal

Haun

2011

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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The gelatinases, matrix metalloproteinase (MMP)-9 and -2, are produced as latent, inactive enzymes that can be proteolytically activated by a number of proteases. In many normal and pathological conditions, where the expression of MMPs is deregulated, changes in the expression of other proteases have also been reported. Human kallikrein-related peptidase 7 (KLK7), a chymotryptic-like serine protease, is overexpressed in many different types of neoplastic conditions, which have also been shown to express high levels of both MMP-9 and -2. Since the activation of MMPs by KLK7 has never been examined, we sought to determine whether KLK7 can activate these MMPs. To test this hypothesis KLK7 was incubated with the recombinant MMPs and the products of the reaction were analyzed for their activity. Incubation of proMMP-9 with KLK7 resulted in the production of a novel truncated, active MMP-9 lacking the C-terminal hemopexin domains. In contrast, KLK7 degraded, but did not activate, proMMP-2. The novel activation of proMMP-9 by KLK7 was further confirmed using conditioned medium prepared from an MMP-9-expressing cell line, MDA-MMP-9. Our results clearly establish that KLK7 activates proMMP-9 to produce a novel truncated, active MMP-9 product not generated by other proteases. These findings suggest that KLK7 may play an important role in the activation of MMP-9 in tumors that express high levels of both these proteases and the resulting truncated MMP may possess altered substrate specificities compared with full-length MMP-9 activated by other proteases.

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Changes in matrix metalloproteinases and their endogenous inhibitors during tumor progression in the uterine cervix

Cited by 42 publications

References 27 publications

HPV16 Oncoproteins Promote Cervical Cancer Invasiveness by Upregulating Specific Matrix Metalloproteinases

HPV16 Oncoproteins Promote Cervical Cancer Invasiveness by Upregulating Specific Matrix Metalloproteinases

Increased matrix metalloproteinases 2 and 9 and tissue inhibitor of matrix metalloproteinase 2 expression is associated with progression from vulvar intraepithelial neoplasia to invasive carcinoma

Proteolytic action of kallikrein-related peptidase 7 produces unique active matrix metalloproteinase-9 lacking the C-terminal hemopexin domains

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