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1197 KiB

Open AccessArticle

Claudin 4 Is Differentially Expressed between Ovarian Cancer Subtypes and Plays a Role in Spheroid Formation

by Kristin L. M. Boylan, Benjamin Misemer, Melissa S. DeRycke, John D. Andersen, Katherine M. Harrington, Steve E. Kalloger, C. Blake Gilks, Stefan E. Pambuccian and Amy P. N. Skubitz

Int. J. Mol. Sci. 2011, 12(2), 1334-1358; https://doi.org/10.3390/ijms12021334 - 22 Feb 2011

Cited by 33 | Viewed by 9779

Abstract

Claudin 4 is a cellular adhesion molecule that is frequently overexpressed in ovarian cancer and other epithelial cancers. In this study, we sought to determine whether the expression of claudin 4 is associated with outcome in ovarian cancer patients and may be involved [...] Read more.

Claudin 4 is a cellular adhesion molecule that is frequently overexpressed in ovarian cancer and other epithelial cancers. In this study, we sought to determine whether the expression of claudin 4 is associated with outcome in ovarian cancer patients and may be involved in tumor progression. We examined claudin 4 expression in ovarian cancer tissues and cell lines, as well as by immunohistochemical staining of tissue microarrays (TMAs; n = 500), spheroids present in patients’ ascites, and spheroids formed in vitro. Claudin 4 was expressed in nearly 70% of the ovarian cancer tissues examined and was differentially expressed across ovarian cancer subtypes, with the lowest expression in clear cell subtype. No association was found between claudin 4 expression and disease-specific survival in any subtype. Claudin 4 expression was also observed in multicellular spheroids obtained from patients’ ascites. Using an in vitro spheroid formation assay, we found that NIH:OVCAR5 cells treated with shRNA against claudin 4 required a longer time to form compact spheroids compared to control NIH:OVCAR5 cells that expressed high levels of claudin 4. The inability of the NIH:OVCAR5 cells treated with claudin 4 shRNA to form compact spheroids was verified by FITC-dextran exclusion. These results demonstrate a role for claudin 4 and tight junctions in spheroid formation and integrity. Full article

(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer)

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462 KiB

Open AccessArticle

Expression and Clinical Role of Protein of Regenerating Liver (PRL) Phosphatases in Ovarian Carcinoma

by Reuven Reich, Shany Hadar and Ben Davidson

Int. J. Mol. Sci. 2011, 12(2), 1133-1145; https://doi.org/10.3390/ijms12021133 - 11 Feb 2011

Cited by 20 | Viewed by 7039

Abstract

The present study analyzed the expression and clinical role of the protein of regenerating liver (PRL) phosphatase family in ovarian carcinoma. PRL1-3 mRNA expression was studied in 184 tumors (100 effusions, 57 primary carcinomas, 27 solid metastases) using RT-PCR. PRL-3 protein expression was [...] Read more.

The present study analyzed the expression and clinical role of the protein of regenerating liver (PRL) phosphatase family in ovarian carcinoma. PRL1-3 mRNA expression was studied in 184 tumors (100 effusions, 57 primary carcinomas, 27 solid metastases) using RT-PCR. PRL-3 protein expression was analyzed in 157 tumors by Western blotting. PRL-1 mRNA levels were significantly higher in effusions compared to solid tumors (p Full article

(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer)

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223 KiB

Open AccessArticle

Identification of Receptor Tyrosine Kinase, Discoidin Domain Receptor 1 (DDR1), as a Potential Biomarker for Serous Ovarian Cancer

by Jinhua Quan, Tetsuro Yahata, Sosuke Adachi, Kosuke Yoshihara and Kenichi Tanaka

Int. J. Mol. Sci. 2011, 12(2), 971-982; https://doi.org/10.3390/ijms12020971 - 31 Jan 2011

Cited by 65 | Viewed by 9805

Abstract

Ovarian cancer, one of the most common gynecological malignancies, has an aggressive phenotype. It is necessary to develop novel and more effective treatment strategies against advanced disease. Protein tyrosine kinases (PTKs) play an important role in the signal transduction pathways involved in tumorigenesis, [...] Read more.

Ovarian cancer, one of the most common gynecological malignancies, has an aggressive phenotype. It is necessary to develop novel and more effective treatment strategies against advanced disease. Protein tyrosine kinases (PTKs) play an important role in the signal transduction pathways involved in tumorigenesis, and represent potential targets for anticancer therapies. In this study, we performed cDNA subtraction following polymerase chain reaction (PCR) using degenerate oligonucleotide primers to identify specifically overexpressed PTKs in ovarian cancer. Three PTKs, janus kinase 1, insulin-like growth factor 1 receptor, and discoidin domain receptor 1 (DDR1), were identified and only DDR1 was overexpressed in all ovarian cancer tissues examined for the validation by quantitative real-time PCR. The DDR1 protein was expressed in 63% (42/67) of serous ovarian cancer tissue, whereas it was undetectable in normal ovarian surface epithelium. DDR1 was expressed significantly more frequently in high-grade (79%) and advanced stage (77%) tumors compared to low-grade (50%) and early stage (43%) tumors. The expression of the DDR1 protein significantly correlated with poor disease-free survival. Although its functional role and clinical utility remain to be examined in future studies, our results suggest that the expression of DDR1 may serve as both a potential biomarker and a molecular target for advanced ovarian cancer. Full article

(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer)

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308 KiB

Open AccessArticle

Combined Effects of Cyclooxygenase-1 and Cyclooxygenase-2 Selective Inhibitors on Ovarian Carcinoma in Vivo

by Wei Li, Jie Wang, Hong-Ru Jiang, Xiao-Li Xu, Jun Zhang, Mei-Lin Liu and Ling-Yun Zhai

Int. J. Mol. Sci. 2011, 12(1), 668-681; https://doi.org/10.3390/ijms12010668 - 18 Jan 2011

Cited by 35 | Viewed by 11126

Abstract

The present study was designed to investigate the combined effects of cyclooxygenase (COX)-1 and COX-2 selective inhibitors on human ovarian SKOV-3 carcinoma cells xenograft-bearing mice. The animals were treated with 3 mg/kg SC-560 (a COX-1 selective inhibitor) alone, 25 mg/kg celecoxib (a COX-2 [...] Read more.

The present study was designed to investigate the combined effects of cyclooxygenase (COX)-1 and COX-2 selective inhibitors on human ovarian SKOV-3 carcinoma cells xenograft-bearing mice. The animals were treated with 3 mg/kg SC-560 (a COX-1 selective inhibitor) alone, 25 mg/kg celecoxib (a COX-2 selective inhibitor) alone, or SC-560/celecoxib by gavage, twice a day for three weeks. To test the mechanism of inhibition of tumor growth by COX selective inhibitors, the index of proliferating cells in tumor tissues was determined by immunostaining and the index of apoptotic cells by the terminal-deoxynucleotidyl-transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) method. The inhibitory rate on tumor growth in the combination group was 35.54% which is significant statistically compared with that of the control group (P < 0.05). In the combination group, the index of cell proliferation and apoptosis were 12.40% and 51.03% respectively, which are significant statistically compared with those of the control group (22.56%, 19.07%, all P < 0.05). These studies indicate that synergism between two COX inhibitors and inhibitor combination treatment has particular potential for chemoprevention of ovarian cancer growth. Full article

(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer)

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237 KiB

Open AccessArticle

Clinicopathological Significance of Loss of ARID1A Immunoreactivity in Ovarian Clear Cell Carcinoma

by Daichi Maeda, Tsui-Lien Mao, Masashi Fukayama, Shunsuke Nakagawa, Tetsu Yano, Yuji Taketani and Ie-Ming Shih

Int. J. Mol. Sci. 2010, 11(12), 5120-5128; https://doi.org/10.3390/ijms11125120 - 13 Dec 2010

Cited by 91 | Viewed by 10075

Abstract

Recent genome-wide analysis has demonstrated that somatic mutations in ARID1A (BAF250) are the most common molecular genetic changes in ovarian clear cell carcinoma (OCCC). ARID1A mutations, which occur in approximately half of OCCC cases, lead to deletion of the encoded protein [...] Read more.

Recent genome-wide analysis has demonstrated that somatic mutations in ARID1A (BAF250) are the most common molecular genetic changes in ovarian clear cell carcinoma (OCCC). ARID1A mutations, which occur in approximately half of OCCC cases, lead to deletion of the encoded protein and inactivation of the putative tumor suppressor. In this study, we determined the significance of loss of ARID1A immunoreactivity with respect to several clinicopathological features in a total of 149 OCCCs. First, we demonstrated that ARID1A immunohistochemistry showed concordance with the mutational status in 91% of cases with 100% sensitivity and 66% specificity. Specifically, among 12 OCCC cases for which ARIDA mutational status was known, ARIDIA immunoreactivity was undetectable in all 9 cases harboring ARID1A mutations and was undetectable in one of 3 cases with wild-type ARID1A. With respect to the entire cohort, ARID1A immunoreactivity was undetectable in 88 (59%) of 149 OCCCs. There was no significant difference between ARID1A negative and positive cases in terms of histopathologic features, age, clinical stage, or overall survival. In conclusion, this study provides further evidence that mutations in ARID1A resulted in loss of ARID1A protein expression in OCCC, although no significant differences between ARID1A positive and negative cases were observed with respect to any clinicopathological features examined. Full article

(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer)

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240 KiB

Open AccessArticle

Lewis (y) Antigen Overexpression Increases the Expression of MMP-2 and MMP-9 and Invasion of Human Ovarian Cancer Cells

by Limei Yan, Bei Lin, Lili Gao, Song Gao, Chuan Liu, Changzhi Wang, Yifei Wang, Shulan Zhang and Masao Iwamori

Int. J. Mol. Sci. 2010, 11(11), 4441-4451; https://doi.org/10.3390/ijms11114441 - 8 Nov 2010

Cited by 45 | Viewed by 10726

Abstract

Lewis (y) antigen is a difucosylated oligosaccharide present on the plasma membrane, and its overexpression is frequently found in human cancers and has been shown to be associated with poor prognosis. Our previous studies have shown that Lewis (y) antigen plays a positive [...] Read more.

Lewis (y) antigen is a difucosylated oligosaccharide present on the plasma membrane, and its overexpression is frequently found in human cancers and has been shown to be associated with poor prognosis. Our previous studies have shown that Lewis (y) antigen plays a positive role in the process of invasion and metastasis of ovarian cancer cells. However, the mechanisms by which Lewis (y) antigen enhances the invasion and tumor metastasis are still unknown. In this study, we established a stable cell line constitutively expressing Lewis (y) antigen (RMG-1-hFUT) by transfecting the cDNA encoding part of the human α1,2-fucosyltransferase (α1,2-FUT) gene into the ovarian cancer cell line RMG-1, and investigated whether Lewis (y) antigen regulates the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9, and tissue inhibitors of metalloproteinases (TIMP-1) and TIMP-2. We found that RMG-1-hFUT cells exhibited higher invasive capacities than their control cells. In addition, expression of TIMP-1 and TIMP-2 was down-regulated and expression of MMP-2 and MMP-9 was up-regulated. Anti-Lewis (y) antigen antibody treatment significantly reversed the expression of TIMP-1, TIMP-2, MMP-2 and MMP-9. Taken together, we provide the first evidence that down-regulation of TIMP-1 and TIMP-2 and up-regulation of MMP-2 and MMP-9 represents one of the mechanisms by which Lewis (y) antigen promotes cell invasion. Full article

(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer)

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2471 KiB

Open AccessArticle

Lewis Y Promotes Growth and Adhesion of Ovarian Carcinoma-Derived RMG-I Cells by Upregulating Growth Factors

by Feifei Li, Bei Lin, Yingying Hao, Yan Li, Juanjuan Liu, Jianping Cong, Liancheng Zhu, Qing Liu and Shulan Zhang

Int. J. Mol. Sci. 2010, 11(10), 3748-3759; https://doi.org/10.3390/ijms11103748 - 29 Sep 2010

Cited by 16 | Viewed by 11325

Abstract

Lewis y (LeY) antigen is a difucosylated oligosaccharide carried by glycoconjugates on the cell surface. Overexpression of LeY is frequently observed in epithelial-derived cancers and has been correlated to the pathological staging and prognosis. However, the effects of LeY on ovarian cancer are [...] Read more.

Lewis y (LeY) antigen is a difucosylated oligosaccharide carried by glycoconjugates on the cell surface. Overexpression of LeY is frequently observed in epithelial-derived cancers and has been correlated to the pathological staging and prognosis. However, the effects of LeY on ovarian cancer are not yet clear. Previously, we transfected the ovarian cancer cell line RMG-I with the α1,2-fucosyltransferase gene to obtain stable transfectants, RMG-I-H, that highly express LeY. In the present study, we examined the proliferation, tumorigenesis, adhesion and invasion of the cell lines with treatment of LeY monoclonal antibody (mAb). Additionally, we examined the expression of TGF-β1, VEGF and b-FGF in xenograft tumors. The results showed that the proliferation and adhesion in vitro were significantly inhibited by treatment of RMG-I-H cells with LeY mAb. When subcutaneously inoculated in nude mice, RMG-I-H cells produced large tumors, while mock-transfected cells RMG-I-C and the parental cells RMG-I produced small tumors. Moreover, the tumor formation by RMG-I-H cells was inhibited by preincubating the cells with LeY mAb. Notably, the expression of TGF-β1, VEGF and b-FGF all increased in RMG-I-H cells. In conclusion, LeY plays an important role in promoting cell proliferation, tumorigenecity and adhesion, and these effects may be related to increased levels of growth factors. The LeY antibody shows potential application in the treatment of LeY-positive tumors. Full article

(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer)

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Review

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780 KiB

Open AccessReview

Role of Versican, Hyaluronan and CD44 in Ovarian Cancer Metastasis

by Miranda P. Ween, Martin K. Oehler and Carmela Ricciardelli

Int. J. Mol. Sci. 2011, 12(2), 1009-1029; https://doi.org/10.3390/ijms12021009 - 31 Jan 2011

Cited by 106 | Viewed by 13674

Abstract

There is increasing evidence to suggest that extracellular matrix (ECM) components play an active role in tumor progression and are an important determinant for the growth and progression of solid tumors. Tumor cells interfere with the normal programming of ECM biosynthesis and can [...] Read more.

There is increasing evidence to suggest that extracellular matrix (ECM) components play an active role in tumor progression and are an important determinant for the growth and progression of solid tumors. Tumor cells interfere with the normal programming of ECM biosynthesis and can extensively modify the structure and composition of the matrix. In ovarian cancer alterations in the extracellular environment are critical for tumor initiation and progression and intra-peritoneal dissemination. ECM molecules including versican and hyaluronan (HA) which interacts with the HA receptor, CD44, have been shown to play critical roles in ovarian cancer metastasis. This review focuses on versican, HA, and CD44 and their potential as therapeutic targets for ovarian cancer. Full article

(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer)

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Open AccessReview

Epigenetic Regulation of Cancer-Associated Genes in Ovarian Cancer

by Mi Jeong Kwon and Young Kee Shin

Int. J. Mol. Sci. 2011, 12(2), 983-1008; https://doi.org/10.3390/ijms12020983 - 31 Jan 2011

Cited by 54 | Viewed by 17795

Abstract

The involvement of epigenetic aberrations in the development and progression of tumors is now well established. However, most studies have focused on the epigenetic inactivation of tumor suppressor genes during tumorigenesis and little is known about the epigenetic activation of cancer-associated genes, except [...] Read more.

The involvement of epigenetic aberrations in the development and progression of tumors is now well established. However, most studies have focused on the epigenetic inactivation of tumor suppressor genes during tumorigenesis and little is known about the epigenetic activation of cancer-associated genes, except for the DNA hypomethylation of some genes. Recently, we reported that the overexpression of cancer-promoting genes in ovarian cancer is associated with the loss of repressive histone modifications. This discovery suggested that epigenetic derepression may contribute to ovarian tumorigenesis by constituting a possible mechanism for the overexpression of oncogenes or cancer-promoting genes in tumors. The emerging importance of epigenetic aberrations in tumor initiation and in the regulation of cancer-initiating cells, suggests that epigenetically regulated genes may be promising therapeutic targets and biomarkers. Given that the current challenges in ovarian cancer include the identification of biomarkers for early cancer detection and the discovery of novel therapeutic targets for patients with recurrent malignancies undergoing chemotherapy, understanding the epigenetic changes that occur in ovarian cancer is crucial. This review looks at epigenetic mechanisms involved in the regulation of cancer-associated genes, including the contribution of epigenetic derepression to the activation of cancer-associated genes in ovarian cancer. In addition, possible epigenetic therapies targeting epigenetically dysregulated genes are discussed. A better understanding of the epigenetic changes in ovarian cancer will contribute to the improvement of patient outcomes. Full article

(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer)

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616 KiB

Open AccessReview

MALDI Imaging Mass Spectrometry (MALDI-IMS)―Application of Spatial Proteomics for Ovarian Cancer Classification and Diagnosis

by Johan O. R. Gustafsson, Martin K. Oehler, Andrew Ruszkiewicz, Shaun R. McColl and Peter Hoffmann

Int. J. Mol. Sci. 2011, 12(1), 773-794; https://doi.org/10.3390/ijms12010773 - 21 Jan 2011

Cited by 84 | Viewed by 19701

Abstract

MALDI imaging mass spectrometry (MALDI-IMS) allows acquisition of mass data for metabolites, lipids, peptides and proteins directly from tissue sections. IMS is typically performed either as a multiple spot profiling experiment to generate tissue specific mass profiles, or a high resolution imaging experiment [...] Read more.

MALDI imaging mass spectrometry (MALDI-IMS) allows acquisition of mass data for metabolites, lipids, peptides and proteins directly from tissue sections. IMS is typically performed either as a multiple spot profiling experiment to generate tissue specific mass profiles, or a high resolution imaging experiment where relative spatial abundance for potentially hundreds of analytes across virtually any tissue section can be measured. Crucially, imaging can be achieved without prior knowledge of tissue composition and without the use of antibodies. In effect MALDI-IMS allows generation of molecular data which complement and expand upon the information provided by histology including immuno-histochemistry, making its application valuable to both cancer biomarker research and diagnostics. The current state of MALDI-IMS, key biological applications to ovarian cancer research and practical considerations for analysis of peptides and proteins on ovarian tissue are presented in this review. Full article

(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer)

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1380 KiB

Open AccessReview

Exploring the Immunoproteome for Ovarian Cancer Biomarker Discovery

by Karina Martin, Carmela Ricciardelli, Peter Hoffmann and Martin K. Oehler

Int. J. Mol. Sci. 2011, 12(1), 410-428; https://doi.org/10.3390/ijms12010410 - 14 Jan 2011

Cited by 7 | Viewed by 11440

Abstract

Most scientific efforts towards early detection of ovarian cancer are commonly focused on the discovery of tumour-associated antigens (TAA). Autologous antibodies against TAA, however, may serve as more sensitive diagnostic markers. They circulate in the blood before TAA and are usually more abundant [...] Read more.

Most scientific efforts towards early detection of ovarian cancer are commonly focused on the discovery of tumour-associated antigens (TAA). Autologous antibodies against TAA, however, may serve as more sensitive diagnostic markers. They circulate in the blood before TAA and are usually more abundant than the TAAs themselves as a result of amplification through the humoral immune response. Accumulating evidence also suggests that a humoral response already exists during malignant transformation when aberrant gene expression is translated into premalignant cellular changes. This article reviews the current knowledge about autoantibodies against TAA in ovarian cancer and presents current immunoproteomic approaches for their detection. Full article

(This article belongs to the Special Issue Cancer Molecules in Ovarian Cancer)

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