PEA3 Is Necessary for Optimal Epidermal Growth Factor Receptor–Stimulated Matrix Metalloproteinase Expression and Invasion of Ovarian Tumor Cells

Dahl, Karen D. Cowden; Zeineldin, Reema; Hudson, Laurie G.

doi:10.1158/1541-7786.mcr-07-0019

Cited by 48 publications

(46 citation statements)

References 44 publications

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“…The Sp1 binding site is essential for basal transcriptional activity of both MMP s as only ∼10% and ∼30% of transcription activity is observed when Sp1 at −102 on MT1-MMP in human fibrosarcoma HT-1080 and at −91 on MMP-2 in astroglioma cells is mutated respectively [38], [39]. The role of PEA3 in regulating MMP-2 and MT1-MMP expression has been demonstrated previously and inhibition of PEA3 expression using siRNA reduced MT1-MMP level by 50% in ovarian cancer cells [37], [40]. Binding of PEA3 to the MT1-MMP promoter in ovarian tumor cells is mediated through epidermal growth factor receptor (EGFR) signaling pathway [37].…”

Section: Discussionmentioning

confidence: 68%

“…The role of PEA3 in regulating MMP-2 and MT1-MMP expression has been demonstrated previously and inhibition of PEA3 expression using siRNA reduced MT1-MMP level by 50% in ovarian cancer cells [37], [40]. Binding of PEA3 to the MT1-MMP promoter in ovarian tumor cells is mediated through epidermal growth factor receptor (EGFR) signaling pathway [37]. However, activation of EGFR signaling pathway downregulated MMP-2 synthesis in SiHa cells [41].…”

Section: Discussionmentioning

confidence: 83%

“…Both MMP-2 and MT1-MMP promoters have no TATA box but contain binding elements for Sp1 family and PEA3, a member of Ets family, located within a 500 bp upstream flanking region of both promoters [37]–[39]. The lack of a TATA box in these two MMP promoters emphasizes the interplay among different combinations of transcription factors in the regulation of their expression.…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

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HPV16 Oncoproteins Promote Cervical Cancer Invasiveness by Upregulating Specific Matrix Metalloproteinases

et al. 2013

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“…Transcription factors specificity protein 1, hypoxia-inducible factor 2 alpha, and Krüppel-like factor 8 have been identified as potent regulators of MMP-14 expression in prostate cancer, renal cell carcinoma, and breast cancer [11–13]. In ovarian cancer cells, polyomavirus enhancer activator 3 (PEA3) is able to induce MMP-14 expression via direct binding to its promoter, and knockdown of PEA3 reduces the MMP-14 levels [14]. In addition, hepatocyte nuclear factor 4 alpha exhibits oncogenic activity through directly binding to the MMP-14 promoter and facilitating its transcription in neuroblastoma [15].…”

Section: Introductionmentioning

confidence: 99%

miRNA-337-3p inhibits gastric cancer progression through repressing myeloid zinc finger 1-facilitated expression of matrix metalloproteinase 14

et al. 2016

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Matrix metalloproteinase 14 (MMP-14), a membrane-anchored MMP that promotes the tumorigenesis and aggressiveness, is highly expressed in gastric cancer. However, the transcriptional regulators of MMP-14 expression in gastric cancer still remain largely unknown. In this study, through mining computational algorithm programs and chromatin immunoprecipitation datasets, we identified adjacent binding sites of myeloid zinc finger 1 (MZF1) and miRNA-337-3p (miR-337-3p) within the MMP-14 promoter. We demonstrated that MZF1 directly bound to the MMP-14 promoter to facilitate its nascent transcription and expression in gastric cancer cell lines. In contrast, endogenous miR-337-3p suppressed the MMP-14 expression through recognizing its binding site within MMP-14 promoter. Mechanistically, miR-337-3p repressed the binding of MZF1 to MMP-14 promoter via recruiting Argonaute 2 and inducing repressive chromatin remodeling. Gain- and loss-of-function studies demonstrated that miR-337-3p suppressed the growth, invasion, metastasis, and angiogenesis of gastric cancer cells in vitro and in vivo through repressing MZF1-facilitated MMP-14 expression. In clinical specimens and cell lines of gastric cancer, MZF1 was highly expressed and positively correlated with MMP-14 expression. Meanwhile, miR-337-3p was under-expressed and inversely correlated with MMP-14 levels. miR-337-3p was an independent prognostic factor for favorable outcome of gastric cancer, and patients with high MZF1 or MMP-14 expression had lower survival probability. Taken together, these data indicate that miR-337-3p directly binds to the MMP-14 promoter to repress MZF1-facilitatd MMP-14 expression, thus suppressing the progression of gastric cancer.

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“…Interestingly, factors in the ovarian tumor microenvironment such as lysophosphatidic acid and ligands for the epidermal growth factor receptor down-regulate E-cadherin and modulate cell adhesion [99][100][101][102]. This is due, in part, to production of matrix metalloproteinases (MMPs) that cleave E-cadherin [82,[103][104][105][106], and we and others have reported that MMPs are abundant in the ascities of ovarian cancer patients [9,[107][108]. Another novel mechanism for down-regulation of E-cadherin occurs upon integrin engagement leading to MMP-9 production and E-cadherin ectodomain generation [82].…”

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confidence: 99%

Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression

Hudson

Zeineldin

Stack

2008

Clin Exp Metastasis

Self Cite

165

172

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The mesodermally derived normal ovarian surface epithelium (OSE) displays both epithelial and mesenchymal characteristics and exhibits remarkable phenotypic plasticity during post-ovulatory repair. The majority of epithelial ovarian carcinomas (EOC) are derived from the OSE and represent the most lethal of all gynecological malignancies, as most patients (~70%) present at diagnosis with disseminated intra-abdominal metastasis. The predominant pattern of EOC metastasis involves pelvic dissemination rather than lymphatic or hematologic spread, distinguishing EOC from other solid tumors. Acquisition of the metastatic phenotype involves a complex series of interrelated cellular events leading to dissociation (shedding) and dispersal of malignant cells. A key event in this process is disruption of cell-cell contacts via modulation of intercellular junctional components. In contrast to most carcinomas that downregulate E-cadherin expression during tumor progression, an unique feature of primary well-differentiated ovarian cancers is a gain of epithelial features, characterized by an increase in expression of E-cadherin. Subsequent reacquisition of mesenchymal features is observed in more advanced tumors with concomitant loss of E-cadherin expression and/ or function during progression to metastasis. The functional consequences of this remarkable phenotypic plasticity are not fully understood, but may play a role in modulation of cell survival in suspension (ascites), chemoresistance, and intraperitoneal anchoring of metastatic lesions. Keywords ovarian cancer; epithelium; cadherin; keratin; vimentin; epithelial-mesenchymal transition; plasticity Ovarian Cancer-OverviewTumors arising from the ovarian epithelium account for ~90% of ovarian malignancies and epithelial ovarian carcinoma (EOC) is the leading cause of death from gynecologic malignancy, resulting in approximately 15,280 deaths in the United States alone in 2006 [1]. These distressing statistics are largely due to the low detection rate of disease confined to the ovary (stage 1) when 5-year survival is >90%. Approximately 75% of women are initially diagnosed with disseminated intra-abdominal disease (stage III-IV) and have a 5-year survival of <20%.Ovarian tumors are pathologically heterogeneous with four major histotypes: serous, endometroid, clear cell and mucinous. These classifications are histogenetically based on The early steps of EOC metastasis involve shedding of the cells from the primary tumor to form free floating cells or multi-cellular aggregates (MCAs) in ascites [ Fig. 1]. Cell-cell and cell-matrix adhesion molecules mediate interaction of metastasizing tumor cells with mesothelial cells lining the inner surface of the peritoneal cavity and the sub-mesothelial extracellular matrix (ECM). Localized proteolytic degradation of sub-mesothelial ECM components facilitates migration of tumor cells and anchoring of secondary lesions on adjacent pelvic organs, and at later stages, metastasis to distant organs [9,10]. However, the majority of wo...

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PEA3 Is Necessary for Optimal Epidermal Growth Factor Receptor–Stimulated Matrix Metalloproteinase Expression and Invasion of Ovarian Tumor Cells

Cited by 48 publications

References 44 publications

HPV16 Oncoproteins Promote Cervical Cancer Invasiveness by Upregulating Specific Matrix Metalloproteinases

HPV16 Oncoproteins Promote Cervical Cancer Invasiveness by Upregulating Specific Matrix Metalloproteinases

miRNA-337-3p inhibits gastric cancer progression through repressing myeloid zinc finger 1-facilitated expression of matrix metalloproteinase 14

Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression

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