Vascular endothelial growth factor–regulated ovarian cancer invasion and migration involves expression and activation of matrix metalloproteinases

Wang, Feng-Qiang; So, John; Reierstad, Scott; Fishman, David A.

doi:10.1002/ijc.21421

Cited by 65 publications

(53 citation statements)

References 46 publications

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“…We have previously shown that MMP-7 is overexpressed in the invasive front of EOC and promotes invasion. MMP-7 secretion is increased by vascular endothelial growth factor and IL-8, which are mediators of LPA-induced EOC cell motility and invasion (17,44,51), suggesting a role of MMP-7 in the LPA-induced EOC metastasis. In the present study, we clarified the role of MMP-7 in EOC by sense and antisense MMP-7 gene transfection.…”

Section: Discussionmentioning

confidence: 99%

“…Total MMP-7 concentration in DOV13 conditioned medium was determined by Quantikine ELISA kit (R&D Systems, Inc., Minneapolis, MN) as described previously (44). All assays were done in triplicate.…”

Section: Elisa and Gelatin Zymographymentioning

confidence: 99%

“…The ovarian carcinoma cell line DOV13 was provided by Dr. R. Bast, Jr. (M. D. Anderson Cancer Center, Houston, TX), and R182 was provided by Dr. G. Mor (Yale University, New Haven, CT) and cultured as reported previously (5,44). Experiments were done with cells in the logarithmic phase of growth.…”

Section: Cell Culture and Establishment Of Stable Cell Linesmentioning

confidence: 99%

“…Reverse-transcribed products were then amplified using iQ SYBR Green Supermix for real-time PCR. The MMP-7, LPA1, LPA2, LPA3, LPA4, and glyceraldehyde-3-phosphate dehydrogenase primers were as described in previous studies (17,35,44,87). PCR products were analyzed electrophoretically Matrigel invasion assay of MMP-7 siRNA-transfected R182 cells with or without the treatment of 10 Amol/L LPA.…”

Section: Rna Preparation and Quantitative Reverse Transcription-pcrmentioning

confidence: 99%

“…We previously reported that the proangiogenic molecules vascular endothelial growth factor and interleukin (IL)-8 induce the secretion/activation of MMP-7 in EOC (43,44). Other reports also found that LPA could induce the expression of vascular endothelial growth factor and IL-8 (43,45).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Matrilysin Expression by Antisense or RNA Interference Decreases Lysophosphatidic Acid–Induced Epithelial Ovarian Cancer Invasion

Wang

Smicun

Calluzzo

et al. 2006

Molecular Cancer Research

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Our previous reports show that matrilysin [matrix metalloproteinase (MMP)-7] is overexpressed in epithelial ovarian cancer (EOC) and recombinant MMP-7 promotes EOC invasion in vitro. In the present study, we further evaluated the correlation of MMP-7 expression to EOC invasiveness and examined its role in lysophosphatidic acid (LPA)-induced invasion. By sense and antisense gene transfection in vitro, we show that overexpression of MMP-7 in all MMP-7 stably transfected DOV13 clones significantly enhanced their invasiveness, although MMP-7 antisense transfection caused a 91% decrease of MMP-7 expression (P < 0.01) and 87% decrease of invasion (P < 0.05) in geneticin (G418)-selected DOV13 clone P47-M7As-3 compared with vector-transfected control.As assessed by MMP-7 ELISA, LPA treatment at 10 to 80 Mmol/L significantly stimulated the secretion of total MMP-7 in DOV13 conditioned medium (P < 0.01). In addition, LPA apparently induced the activation of MMP-7 in DOV13 cells as detected by gelatin zymography. In the antisense MMP-7-transfected DOV13 clone (P47-M7As-3), LPA-increased invasion was significantly decreased compared with vector control. Moreover, knocking down of MMP-7 by small interfering RNA also suppressed LPA-induced invasion in two EOC cell lines (DOV13 and R182). Altogether, our results show that MMP-7 expression is correlated with EOC invasiveness and LPA-induced MMP-7 secretion/ activation may represent a new mechanism that facilitates ovarian cancer invasion besides the well-known induction of MT1-MMP-mediated proMMP-2 activation by LPA. (Mol Cancer Res 2006;4(11):831 -41)

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Section: Discussionmentioning

confidence: 99%

Section: Elisa and Gelatin Zymographymentioning

confidence: 99%

Section: Cell Culture and Establishment Of Stable Cell Linesmentioning

confidence: 99%

Section: Rna Preparation and Quantitative Reverse Transcription-pcrmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Inhibition of Matrilysin Expression by Antisense or RNA Interference Decreases Lysophosphatidic Acid–Induced Epithelial Ovarian Cancer Invasion

Wang

Smicun

Calluzzo

et al. 2006

Molecular Cancer Research

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Autocrine VEGF‐A/KDR loop protects epithelial ovarian carcinoma cells from anoikis

Sher

Adham

Petrik

et al. 2008

Intl Journal of Cancer

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Epithelial ovarian carcinoma (EOC) patients are usually diagnosed at an advanced stage, characterized by interperitoneal carcinomatosis and production of large volumes of ascites. Vascular endothelial growth factor‐A (VEGF‐A) and its main signaling receptor VEGFR2 (KDR) are coexpressed in primary ovarian tumors, ascitic cells and metastases, suggesting the existence of an autocrine VEGF‐A/KDR loop in EOC cells. In the present study, we examined this possibility and explored the role of this autocrine loop in protecting EOC cells from apoptosis under anchorage free growth conditions (anoikis). We found that 3 different EOC cell lines (Caov3, OVCAR3, SKOV3) express both VEGF‐A and its receptors, including KDR. In these cells, KDR is constitutively phosphorylated and is detected both in the cell plasma membrane and in the nucleus. Treating EOC cells with specific internal inhibitors of KDR kinase activity or a VEGF‐A neutralizing antibody abolished KDR autophosphorylation and resulted in significant increase in apoptosis when cells were grown in single‐cell, anchorage‐free conditions. By contrast, these blocking reagents had no effect on cell viability when EOC cells were grown in adhesive monolayers. In summary, our results indicate that an autocrine VEGF‐A/KDR loop exists in EOC cells and that it plays a role in protecting the cells from anoikis. Our results imply that treating EOC patients with VEGF blocking agents may potentially reduce peritoneal dissemination by decreasing vascular permeability as well as inducing apoptosis of shed ovarian cancer cells in ascites. © 2008 Wiley‐Liss, Inc.

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Differential expression and phosphorylation of Pak1 and Pak2 in ovarian cancer: effects on prognosis and cell invasion

Siu

Wong

Chan

et al. 2010

Intl Journal of Cancer

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Ovarian cancer is a gynecological malignancy with high mortality. Therefore, the identification of novel prognostic and therapeutic targets is important. p21‐activated kinases (Paks) are involved in cytoskeleton reorganization. This study investigated the clinical significance of total and phosphorylated (p) Pak1 and Pak2 as well as their functional roles in ovarian cancer. Expressions of Pak1, p‐Pak1 Thr212, Pak2 and p‐Pak2 Ser20 in ovarian normal and cancerous cell lines as well as in clinical samples of ovarian tumors were evaluated. The effects of Pak1 and Pak2 on ovarian cancer cell functions were determined. Pak1, p‐Pak1 and p‐Pak2 were overexpressed in ovarian cancer cell lines, and clinical samples of ovarian cancers were compared with benign ovarian lesions/inclusion cysts. Similar Pak2 expression levels were observed among normal and cancerous cell lines and clinical samples. After multiple testing correction, high Pak1 and nuclear p‐Pak1 expression in ovarian cancers was significantly associated with histological type and tumor grade, respectively. Pak1 and p‐Pak1 expression was associated with poor overall and disease‐free survival. Pak1 was an independent prognostic factor. Knockdown of Pak1 and Pak2 in ovarian cancer cell lines reduced cell migration and invasion but did not affect cell proliferation and apoptosis. Knockdown of Pak1 also reduced p38 activation and downregulated vascular endothelial growth factor. Conversely, ectopic Pak1 overexpression enhanced ovarian cancer cell migration and invasion in a kinase‐dependent manner, along with increased p38 activation. Our findings suggest that Pak1, p‐Pak1 and p‐Pak2 play important roles in ovarian carcinogenesis. Pak1 and p‐Pak1 may be potential prognostic markers and therapeutic molecular targets in ovarian cancer.

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Vascular endothelial growth factor–regulated ovarian cancer invasion and migration involves expression and activation of matrix metalloproteinases

Cited by 65 publications

References 46 publications

Inhibition of Matrilysin Expression by Antisense or RNA Interference Decreases Lysophosphatidic Acid–Induced Epithelial Ovarian Cancer Invasion

Inhibition of Matrilysin Expression by Antisense or RNA Interference Decreases Lysophosphatidic Acid–Induced Epithelial Ovarian Cancer Invasion

Autocrine VEGF‐A/KDR loop protects epithelial ovarian carcinoma cells from anoikis

Differential expression and phosphorylation of Pak1 and Pak2 in ovarian cancer: effects on prognosis and cell invasion

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