Expression of the matrix Gla protein in urogenital malignancies

Levedakou, Eleni N.; Strohmeyer, T.; Effert, Peter J.; Liu, Edison T.

doi:10.1002/ijc.2910520406

Cited by 61 publications

(45 citation statements)

References 13 publications

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“…49 Moreover, upregulation of MGP has been shown in breast cancer, ovarian cancer, renal cancer and testicular tumors. 48,50,51 MGP is an 84-residue vitamin K-dependent extracellular matrix protein, which is expressed at high levels in heart, kidney and lung and is up-regulated by vitamin D in bone cells. 57 MGP acts as a calcification inhibitor by repressing bone morphogenetic protein 2 (BMP2) in cartilage and vasculature.…”

Section: Discussionmentioning

confidence: 99%

“…MGP has previously been shown to be differentially expressed in carcinomas, including those of the cervix. [48][49][50][51] MGP immunohistochemical analysis was performed on previously established organotypic cultures of primary keratinocytes, FK16A and SiHa cells, 52 3 specimens containing normal cervical epithelium, 22 CIN2/3 lesions and 8 cervical SCCs. In addition to the SCCs, all CIN2/3 biopsies were hrHPV positive.…”

Section: Analysis Of Mgp Protein Levels In Normal Cervical Epitheliummentioning

confidence: 99%

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Gene expression profiling to identify markers associated with deregulated hTERT in HPV‐transformed keratinocytes and cervical cancer

Wilde

Wilting

Meijer

et al. 2007

Intl Journal of Cancer

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Although high-risk human papillomavirus (HPV) infection plays a major role in the development of cervical cancer, additive oncogenic events are involved as well. One key event involves increased activity of telomerase resulting from a deregulated expression of its catalytic subunit hTERT. Our previous microcell-mediated chromosome transfer studies revealed that introduction of human chromosome 6 in the HPV16-immortalized keratinocyte cell line FK16A and in the HPV16-containing cervical cancer cell line SiHa induced growth arrest, resulting from a repression of hTERT mRNA expression and telomerase activity. Here, this model was used to analyze expression profiles associated with hTERT deregulation in HPV-transformed cells. Microarray expression analysis of 12 FK16A/chromosome 6 hybrids, 4 of which were negative for endogenous hTERT and 8 of which were positive for endogenous hTERT, resulted in the identification of 164 differentially expressed genes. Differential expression of a selection of 5 genes was verified by real-time RT-PCR. Of these 164 genes, 32 were also differentially expressed in other HPV transformed cells with deregulated hTERT. For 2 of these genes, encoding AQP3 and MGP, altered expression in hTERT positive cervical carcinomas was confirmed by real-time RT-PCR and immunohistochemistry, respectively. Moreover, increased MGP protein expression was significantly more frequent in high-grade cervical premalignant lesions with elevated hTERT mRNA expression compared to those without. In summary, we identified 32 candidate biomarkers for deregulated hTERT mRNA expression, which may enable the identification of cervical premalignant lesions that are at highest risk to progress to invasive cancer. ' 2007 Wiley-Liss, Inc.Key words: HPV; hTERT; telomerase; cervical carcinogenesis; microarray expression analysis The main risk factor for the development of cervical cancer is infection with high-risk human papillomavirus (hrHPV), 1 which is supported by the detection of hrHPV in virtually all cervical carcinomas. 2 Cervical cancer evolves from preexisting noninvasive premalignant lesions referred to as cervical intraepithelial neoplasia (CIN), graded CIN1 to CIN3. Progression of an hrHPV infected CIN lesion to invasive cancer is a result of further specific (epi)genetic alterations within the host cell genome. 3,4 One of the consequences that is crucial for tumor development is an increased activity of telomerase. 5,6 Telomerase is a ribonucleoprotein that can elongate the chromosomal ends or telomeres, thereby compensating for telomere shortening that is inherent to DNA replication. 7 Whereas most cancer cells display elevated telomerase activity and stabilized telomeres, resulting in an unlimited lifespan, most primary somatic cells exhibit absence of detectable telomerase activity and continuous telomere erosion during cell division. The latter ultimately leads to the induction of senescence. 7 Telomerase consists of several subunits, including a structural RNA component (hTR) that serves as a template dur...

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Section: Discussionmentioning

confidence: 99%

Section: Analysis Of Mgp Protein Levels In Normal Cervical Epitheliummentioning

confidence: 99%

Gene expression profiling to identify markers associated with deregulated hTERT in HPV‐transformed keratinocytes and cervical cancer

Wilde

Wilting

Meijer

et al. 2007

Intl Journal of Cancer

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“…To explore ID4-promoted growth and vascularization of GBM xenografts, we used microarray analysis to examine differential gene expression in U251 cell cultures engineered to express varying levels of ID4, and identified MGP as an ID4 target gene whose expression and associated biologies were consistent with promoting tumor angiogenesis (Chen et al, 1990;Levedakou et al, 1992). MGP is a member of the vitamin K-dependent family of proteins, which includes prothrombin (Proudfoot and Shanahan, 2006).…”

Section: Id4 Elevates Mgp Promoting Gbm Growthmentioning

confidence: 99%

Inhibitor of DNA binding-4 promotes angiogenesis and growth of glioblastoma multiforme by elevating matrix GLA levels

et al. 2010

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Inhibitor of differentiation-4 is highly expressed in glioblastoma multiforme (GBM). We report a novel proangiogenic function for inhibitor of differentiation-4 in the growth of glioblastoma xenografts. Tumor-derived cell cultures expressing elevated levels of ID4 produced enlarged xenografts in immunosuppressed mice that were better vascularized than corresponding control tumors and expressed elevated matrix GLA protein (MGP) that mediated enhanced tumor angiogenesis. Inhibition of MGP resulted in smaller and less vascularized xenografts. Our finding shows a novel function for ID4 in tumor angiogenesis, and identifies ID4 and MGP as possible therapeutic targets for GBM.

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“…Conversely, MGP, PRSS8 and NME2 were downregulated in nodepositive tumours. MGP encodes the matrix G1a protein, the loss of expression of which has been associated with lymph node metastasis in urogenital tumours (Levedakou et al, 1992). The prostasin serine protease, encoded by PRSS8, is a potential invasion suppressor the downregulation of which may contribute to invasiveness and metastatic potential (Chen and Chai, 2002).…”

Section: Expression Profiles and Lymph Node Metastasismentioning

confidence: 99%

Gene expression profiling of colon cancer by DNA microarrays and correlation with histoclinical parameters

et al. 2004

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Different diagnostic and prognostic groups of colorectal carcinoma (CRC) have been defined. However, accurate diagnosis and prediction of survival are sometimes difficult. Gene expression profiling might improve these classifications and bring new insights into underlying molecular mechanisms. We profiled 50 cancerous and noncancerous colon tissues using DNA microarrrays consisting of B8000 spotted human cDNA. Global hierarchical clustering was to some extent able to distinguish clinically relevant subgroups, normal versus cancer tissues and metastatic versus nonmetastatic tumours. Supervised analyses improved these segregations by identifying sets of genes that discriminated between normal and tumour tissues, tumours associated or not with lymph node invasion or genetic instability, and tumours from the right or left colon. A similar approach identified a gene set that divided patients with significantly different 5-year survival (100% in one group and 40% in the other group; P ¼ 0.005). Discriminator genes were associated with various cellular processes. An immunohistochemical study on 382 tumour and normal samples deposited onto a tissue microarray subsequently validated the upregulation of NM23 in CRC and a downregulation in poor prognosis tumours. These results suggest that microarrays may provide means to improve the classification of CRC, provide new potential targets against carcinogenesis and new diagnostic and/or prognostic markers and therapeutic targets.

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Expression of the matrix Gla protein in urogenital malignancies

Cited by 61 publications

References 13 publications

Gene expression profiling to identify markers associated with deregulated hTERT in HPV‐transformed keratinocytes and cervical cancer

Gene expression profiling to identify markers associated with deregulated hTERT in HPV‐transformed keratinocytes and cervical cancer

Inhibitor of DNA binding-4 promotes angiogenesis and growth of glioblastoma multiforme by elevating matrix GLA levels

Gene expression profiling of colon cancer by DNA microarrays and correlation with histoclinical parameters

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