Rhizoctonia bataticola lectin induces apoptosis and inhibits metastasis in ovarian cancer cells by interacting with CA 125 antigen differentially expressed on ovarian cells

AbstractThe lectin, galectin-3 (Gal3), has been implicated in a variety of inflammatory and oncogenic processes, including tumor growth, invasion, and metastasis. The interactions of Gal3 and MUC16 represent a potential targetable pathway for the treatment of MUC16-expressing malignancies. We found that the silencing of Gal3 in MUC16-expressing breast and ovarian cancer cells in vitro inhibited tumor cell invasion and led to attenuated tumor growth in murine models. We therefore developed an inhibitory murine monoclonal anti–Gal3 carbohydrate-binding domain antibody, 14D11, which bound human and mouse Gal3 but did not bind human Galectins-1, -7, -8 or -9. Competition studies and a docking model suggest that the 14D11 antibody competes with lactose for the carbohydrate binding pocket of Gal3. In MUC16-expressing cancer cells, 14D11 treatment blocked AKT and ERK1/2 phosphorylation, and led to inhibition of cancer cell Matrigel invasion. Finally, in experimental animal tumor models, 14D11 treatment led to prolongation of overall survival in animals bearing flank tumors, and retarded lung specific metastatic growth by MUC16 expressing breast cancer cells. Our results provide evidence that antibody based Gal3 blockade may be a viable therapeutic strategy in patients with MUC16-expressing tumors, supporting further development of human blocking antibodies against Gal3 as potential cancer therapeutics.

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Ovarian Cancer Cell Invasiveness Correlates With Increased Cell Deformability

ASME 2012 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2012-80624 ◽

2012 ◽

Author(s):

Wenwei Xu ◽

Roman Mezencev ◽

Byungkyu Kim ◽

Lijuan Wang ◽

John McDonald ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Single Cells ◽

Metastatic Cancer ◽

Ovarian Surface Epithelium ◽

Surface Epithelium ◽

Ovarian Cancer Cells ◽

Cell Deformability ◽

Ovarian Cells ◽

And Migration

Cancer cells undergo a variety of biochemical and biophysical transformations when compared to identical cells displaying a healthy phenotypic state, cancer cells show a drastic reduction of stiffness upon malignancy[1, 2] and change of stiffness of single cells can indicate the presence of disease [3–6]. Besides, metastatic cancer has a higher deformability than their benign counterparts[7, 8]. Using atomic force microscopy, we demonstrated that cancerous ovarian cells (OVCAR3, OVCAR4, HEY and HEYA8) are substantially softer than the healthy immortalized ovarian surface epithelium (IOSE) cells. In addition, within the different types of cancerous ovarian cells, increased invasiveness and migration are directly correlated with increased cell deformability. These results indicate that stiffness of individual cells can distinguish not only ovarian cancer cells from healthy cells types, but also invasive cancer types from less invasive types. Stiffness may provide an alternative and convenient biomarker to grade the metastasis potential of cancer cells.

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CA 125 Production and Release by Ovarian Cancer Cells In Vitro

The International Journal of Biological Markers ◽

10.1177/172460089801300405 ◽

1998 ◽

Vol 13 (4) ◽

pp. 200-206 ◽

Cited By ~ 17

Author(s):

E.P. Beck ◽

A. Moldenhauer ◽

E. Merkle ◽

F. Kiesewetter ◽

W. Jäger ◽

...

Keyword(s):

Cell Cycle ◽

Ovarian Cancer ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Human Tumor ◽

Cellular Growth ◽

Ca 125 ◽

Ovarian Cancer Cells ◽

Cell Cycle Distribution ◽

Cycle Arrest

The antigenic determinant CA 125 is a high molecular weight glycoprotein which is elevated in more than 80% of patients with epithelial ovarian cancer. Despite its good performance as a human tumor marker, only little is known about its physiological function. According to recent publications, CA 125 production and release appear to be related to cellular growth. In order to investigate this putative relationship more closely, we analyzed the pattern of CA 125 production and release by ovarian cancer cells during exponential cell growth, during cell cycle arrest by colchicine and during inhibition of cellular protein synthesis by cycloheximide. The results were correlated with the cell cycle distribution. According to our results, the main determinant of CA 125 release into the culture supernatant is the total cell count. Although cell cycle arrest in the G2 + M phase by means of colchicine treatment resulted in the death of most cells, which was reflected by an increased release of CA 125, no differences in the intracellular production rate between colchicine treated and untreated cells were seen. In contrast, treatment of cells with cycloheximide not only resulted in decreasing cell numbers but also in a complete inhibition of CA 125 production by surviving cells.

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Membrane-type I matrix metalloproteinase-dependent ectodomain shedding of mucin16/ CA-125 on ovarian cancer cells modulates adhesion and invasion of peritoneal mesothelium

Biological Chemistry ◽

10.1515/hsz-2014-0155 ◽

2014 ◽

Vol 395 (10) ◽

pp. 1221-1231 ◽

Cited By ~ 18

Author(s):

Lana Bruney ◽

Kaitlynn C. Conley ◽

Natalie M. Moss ◽

Yueying Liu ◽

M. Sharon Stack

Keyword(s):

Ovarian Cancer ◽

Matrix Metalloproteinase ◽

Cancer Cells ◽

Ca 125 ◽

Ovarian Cancer Cells ◽

Type I ◽

Ectodomain Shedding ◽

Peritoneal Tissue ◽

Catalytically Active ◽

Membrane Type

Abstract Mucin16 [MUC16/cancer antigen 125 (CA-125)], a high-molecular-weight glycoprotein expressed on the ovarian tumor cell surface, potentiates metastasis via selective binding to mesothelin on peritoneal mesothelial cells. Shed MUC16/CA-125 is detectable in sera from ovarian cancer patients. We investigated the potential role of membrane type 1 matrix metalloproteinase (MT1-MMP, MMP-14), a transmembrane collagenase highly expressed in ovarian cancer cells, in MUC16/CA-125 ectodomain shedding. An inverse correlation between MT1-MMP and MUC16 immunoreactivity was observed in human ovarian tumors and cells. Further, when MUC16-expressing OVCA433 cells were engineered to overexpress MT1-MMP, surface expression of MUC16/CA-125 was lost, whereas cells expressing the inactive E240A mutant retained surface MUC16/CA-125. As a functional consequence, decreased adhesion of cells expressing catalytically active MT1-MMP to three-dimensional meso-mimetic cultures and intact ex vivo peritoneal tissue explants was observed. Nevertheless, meso-mimetic invasion is enhanced in MT1-MMP-expressing cells. Together, these data support a model wherein acquisition of catalytically active MT1-MMP expression in ovarian cancer cells induces MUC16/CA-125 ectodomain shedding, reducing adhesion to meso-mimetic cultures and to intact peritoneal explants. However, proteolytic clearing of MUC16/CA-125, catalyzed by MT1-MMP, may then expose integrins for high-affinity cell binding to peritoneal tissues, thereby anchoring metastatic lesions for subsequent proliferation within the collagen-rich sub-mesothelial matrix.

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204 ALTERED GENE EXPRESSION FOLLOWING EXPOSURE TO BISPHENOL A IN HUMAN OVARIAN CANCER CELLS EXPRESSING ESTROGEN RECEPTORS BY MICROARRAY

Reproduction Fertility and Development ◽

10.1071/rdv23n1ab204 ◽

2011 ◽

Vol 23 (1) ◽

pp. 201 ◽

Cited By ~ 3

Author(s):

B.-R. Yi ◽

E.-B. Jeung ◽

K.-C. Choi

Keyword(s):

Gene Expression ◽

Ovarian Cancer ◽

Growth Factor ◽

Bisphenol A ◽

Cancer Cells ◽

Ovarian Cancer Cells ◽

Human Ovarian Cancer ◽

Altered Gene Expression ◽

Ovarian Cells ◽

Altered Gene

Although endocrine-disrupting chemicals (EDC) may interfere with the endocrine system(s) of animals and humans and have an estrogenicity or androgenicity, the exact mechanism(s) underlying their detrimental effects is not clearly understood. Among them, bisphenol A (BPA) is widespread in the environment and is commonly ingested by animals because it is used in the manufacture of polycarbonate plastics, food-storage containers, and other plastics. Thus, in this study, we evaluated altered gene expression following exposure to BPA by microarry in human ovarian cancer cells, which highly express oestrogen receptors (ER). Treatment with BPA and endogenous oestrogen (E2) for 24 h resulted in an increase in cell proliferation and enhanced the oestrogen response element (ERE) activity in human BG-1 ovarian cancer cells with ER. Bisphenol A-induced cell growth and the activation of ERE were reversed by an oestrogen receptor antagonist, ICI 182 780, suggesting that ER appear to be involved in BPA-induced cell growth and ERE activation in these ovarian cells. Following BPA treatment, the expression levels of representative genes, namely, apoptosis inhibitor 4 (survivin), RAB31 ras oncogene family, v-myc, v-myb, cyclin A2, cyclin B1, amphiregulin, insulin-like growth factor binding protein 4, chemokine-like factor 3, fibroblast growth factor, and E2F transcription factor 4, were subsequently confirmed in these ovarian cells by real-time PCR. Taken together, these results indicate distinctly altered expression of responsive genes following exposure to BPA, and implicate distinct effects of endogenous E2 and environmental EDC in human ovarian cancer cells expressing ER. This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST; No. 2010-0003093).

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Modulation of CA-125 tumor marker shedding in ovarian cancer cells by erlotinib or cetuximab

Gynecologic Oncology ◽

10.1016/j.ygyno.2007.02.010 ◽

2007 ◽

Vol 105 (3) ◽

pp. 716-721 ◽

Cited By ~ 9

Author(s):

Christian Marth ◽

Daniel Egle ◽

Doris Auer ◽

Julia Rössler ◽

Alain G. Zeimet ◽

...

Keyword(s):

Ovarian Cancer ◽

Tumor Marker ◽

Cancer Cells ◽

Ca 125 ◽

Ovarian Cancer Cells

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FGF16 Promotes Invasive Behavior of SKOV-3 Ovarian Cancer Cells through Activation of Mitogen-activated Protein Kinase (MAPK) Signaling Pathway

Journal of Biological Chemistry ◽

10.1074/jbc.m113.535427 ◽

2013 ◽

Vol 289 (3) ◽

pp. 1415-1428 ◽

Cited By ~ 30

Author(s):

Moitri Basu ◽

Satinath Mukhopadhyay ◽

Uttara Chatterjee ◽

Sib Sankar Roy

Keyword(s):

Ovarian Cancer ◽

T Cell ◽

Cancer Cells ◽

Wnt Pathway ◽

Mapk Pathway ◽

Ovarian Tumors ◽

Ovarian Cancer Cells ◽

T Cell Factor ◽

Ovarian Cells ◽

Invasive Behavior

Uncontrolled cell growth and tissue invasion define the characteristic features of cancer. Several growth factors regulate these processes by inducing specific signaling pathways. We show that FGF16, a novel factor, is expressed in human ovary, and its expression is markedly increased in ovarian tumors. This finding indicated possible involvement of FGF16 in ovarian cancer progression. We observed that FGF16 stimulates the proliferation of human ovarian adenocarcinoma cells, SKOV-3 and OAW-42. Furthermore, through the activation of FGF receptor-mediated intracellular MAPK pathway, FGF16 regulates the expression of MMP2, MMP9, SNAI1, and CDH1 and thus facilitates cellular invasion. Inhibition of FGFR as well as MAPK pathway reduces the proliferative and invasive behavior of ovarian cancer cells. Moreover, ovarian tumors with up-regulated PITX2 expression also showed activation of Wnt/β-catenin pathway that prompted us to investigate possible interaction among FGF16, PITX2, and Wnt pathway. We identified that PITX2 homeodomain transcription factor interacts with and regulates FGF16 expression. Furthermore, activation of the Wnt/β-catenin pathway induces FGF16 expression. Moreover, FGF16 promoter possesses the binding elements of PITX2 as well as T-cell factor (Wnt-responsive), in close proximity, where PITX2 and β-catenin binds to and synergistically activates the same. A detail study showed that both PITX2 and T-cell factor elements and the interaction with their binding partners are necessary for target gene expression. Taken together, our findings indicate that FGF16 in conjunction with Wnt pathway contributes to the cancer phenotype of ovarian cells and suggests that modulation of its expression in ovarian cells might be a promising therapeutic strategy for the treatment of invasive ovarian cancers.

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Secretome Identifies Tenascin-X as a Potent Marker of Ovarian Cancer

BioMed Research International ◽

10.1155/2015/208017 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 5

Author(s):

Marianne Kramer ◽

Sandra Pierredon ◽

Pascale Ribaux ◽

Jean-Christophe Tille ◽

Patrick Petignat ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Cancer Patients ◽

Ca 125 ◽

Ovarian Cancer Cells ◽

Serous Ovarian Cancer ◽

Protein Biomarkers ◽

Serum Samples ◽

Cancer Tissues

CA-125 has been a valuable marker for the follow-up of ovarian cancer patients but it is not sensitive enough to be used as diagnostic marker. We had already used secretomic methods to identify proteins differentially secreted by serous ovarian cancer cells compared to healthy ovarian cells. Here, we evaluated the secretion of these proteins by ovarian cancer cells during the follow-up of one patient. Proteins that correlated with CA-125 levels were screened using serum samples from ovarian cancer patients as well as benign and healthy controls. Tenascin-X secretion was shown to correlate with CA-125 value in the initial case study. The immunohistochemical detection of increased amount of tenascin-X in ovarian cancer tissues compared to healthy tissues confirms the potent interest in tenascin-X as marker. We then quantified the tenascin-X level in serum of patients and identified tenascin-X as potent marker for ovarian cancer, showing that secretomic analysis is suitable for the identification of protein biomarkers when combined with protein immunoassay. Using this method, we determined tenascin-X as a new potent marker for serous ovarian cancer.

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Targeting CA-125 Transcription by Development of a Conditionally Replicative Adenovirus for Ovarian Cancer Treatment

Cancers ◽

10.3390/cancers13174265 ◽

2021 ◽

Vol 13 (17) ◽

pp. 4265

Author(s):

Er Yue ◽

Guangchao Yang ◽

Yuanfei Yao ◽

Guangyu Wang ◽

Atish Mohanty ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Treatment ◽

Cancer Cells ◽

Cancer Patients ◽

Essential Gene ◽

In Vivo Studies ◽

Ca 125 ◽

Ovarian Cancer Cells ◽

Specific Expression ◽

Dna Fragment

CA-125, encoded by the MUC16 gene, is highly expressed in most ovarian cancer cells and thus serves as a tumor marker for monitoring disease progression or treatment response in ovarian cancer patients. However, targeting MUC16/CA-125 for ovarian cancer treatment has not been successful to date. In the current study, we performed multiple steps of high-fidelity PCR and obtained a 5 kb DNA fragment upstream of the human MUC16 gene. Reporter assays indicate that this DNA fragment possesses transactivation activity in CA-125-high cancer cells, but not in CA-125-low cancer cells, indicating that the DNA fragment contains the transactivation region that controls specific expression of the MUC16 gene in ovarian cancer cells. We further refined the promoter and found a 1040 bp fragment with similar transcriptional activity and specificity. We used this refined MUC16 promoter to replace the E1A promoter in the adenovirus type 5 genome DNA, where E1A is an essential gene for adenovirus replication. We then generated a conditionally replicative oncolytic adenovirus (CRAd) that replicates in and lyses CA-125-high cancer cells, but not CA-125-low or -negative cancer cells. In vivo studies showed that intraperitoneal virus injection prolonged the survival of NSG mice inoculated intraperitoneally (ip) with selected ovarian cancer cell lines. Furthermore, the CRAd replicates in and lyses primary ovarian cancer cells, but not normal cells, collected from ovarian cancer patients. Collectively, these data indicate that targeting MUC16 transactivation utilizing CRAd is a feasible approach for ovarian cancer treatment that warrants further investigation.

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Knockdown CD44 Promotes Amyloid-Beta Degradation in Ovarian Cancer Cells By Regulating CD36 Expression

10.21203/rs.3.rs-946298/v1 ◽

2021 ◽

Author(s):

Ying Xu ◽

Yunge Gao ◽

Luomeng Qian ◽

Wangyou Feng ◽

Tingting Song ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

Amyloid Beta ◽

Functional Enrichment ◽

Differentially Expressed ◽

Receptor Interaction ◽

Ovarian Cancer Cells ◽

Cd36 Expression ◽

Skov3 Cells

Abstract Background: CD44 is highly expressed in many cancers, including ovarian cancer. Its interactions with ligands are involved in tumor progression, prognosis, and metastasis. However, the function of CD44 in the advancement of ovarian cancer remains unclear. Methods and Results: RNA sequencing was used to investigate the possible molecules and pathways regulated by CD44 in ovarian cancer to compare gene expression in CD44-knockdown SKOV3 cells and control cells. Identify the differentially expressed genes and then proceed to functional enrichment analysis. The results showed that genes differentially expressed were enriched in ECM-receptor interaction, Protein digestion and absorption, Focal adhesion, Notch signaling pathway, microRNA in cancer, and TGF-beta signaling pathway. Furthermore, the analysis of the proteins interaction network revealed the interaction between CD44 and CD36 in SKOV3 cells. Further analysis showed that CD36, a molecule that may be involved in ECM-receptor interaction, was low expressed in CD44-knockdown SKOV3 cells. And the results showed that knockdown CD44 induces amyloid-beta degradation in ovarian cancer cells by regulating CD36 expression. The analyses of the public database demonstrated that the CD36 expression was related to the clinical survival of ovarian cancer. Conclusions: Our study showed that CD44 might up-regulate the CD36 expression in ovarian cancer, thereby exerting a cancer-promoting effect.

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