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Ovarian tumor AND Ovarian functional and neoplastic tumors [keywords]
- Detection of human papillomavirus-16 e6-oncoprotein in epithelial ovarian tumors samples of iraqi patients. [Journal Article]
- Jundishapur J Microbiol 2014 Sep; 7(9):e11945.
Human papillomavirus (HPV) is the causal factor for cervical cancer. However, the role of HPV infection in ovarian cancer is unclear.This study aimed to determine the presence of human papillomavirus-16 (HPV-16) in ovarian tumor tissues.This was a retrospective study, which included 61 Archived human ovarian tumor tissues embedded in paraffin blocks. The ovarian tumor tissues were divided into four groups. The first group was the malignant ovarian epithelial tumor group; it included 31 cases with invasive surface epithelial ovarian tumors. The second group was the borderline epithelial ovarian tumor group: it included four cases with borderline intermediate malignancy. The third group was the benign epithelial ovarian tumors group: it included 18 cases with benign epithelial ovarian tumors. The fourth group had functional ovarian cystic lesions: it included eight cases with non-neoplastic functional ovarian cysts. Sections were made from each of the paraffin embedded blocks and examined using immunohistochemistry to detect HPV 16-E6-oncoprotein in ovarian tumor tissues.Out of the eight cases with functional cysts only one case (12.5%) expressed HPV. No HPV expression was seen in cases with benign and borderline tumors. Out of the 31 cases with one malignant surface epithelial ovarian tumor only three (9.67%) cases expressed HPV. There was no significant statistical difference in HPV expression among neoplastic and non-neoplastic ovarian tumors included in the present study (P= 0.476).HPV type 16 was detected in only 9.67% of malignant epithelial tumors. It appears that HPV infection plays a relatively minor role in the pathogenesis of ovarian carcinomas.
- A functional genomic approach identifies FAL1 as an oncogenic long noncoding RNA that associates with BMI1 and represses p21 expression in cancer. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.]
- Cancer Cell 2014 Sep 8; 26(3):344-57.
In a genome-wide survey on somatic copy-number alterations (SCNAs) of long noncoding RNA (lncRNA) in 2,394 tumor specimens from 12 cancer types, we found that about 21.8% of lncRNA genes were located in regions with focal SCNAs. By integrating bioinformatics analyses of lncRNA SCNAs and expression with functional screening assays, we identified an oncogene, focally amplified lncRNA on chromosome 1 (FAL1), whose copy number and expression are correlated with outcomes in ovarian cancer. FAL1 associates with the epigenetic repressor BMI1 and regulates its stability in order to modulate the transcription of a number of genes including CDKN1A. The oncogenic activity of FAL1 is partially attributable to its repression of p21. FAL1-specific siRNAs significantly inhibit tumor growth in vivo.
- A 9-kg ovarian mucinous cystadenoma in a 14-year-old premenarchal girl. [Journal Article]
- Am J Case Rep 2014.:326-9.
Female, 14.Ovarian mucinous cystadenoma.Abdominal enlargement • abdominal pain • constipation.-.-.Obstetrics and Gynecology.Rare disease.Although ovarian tumors are most commonly observed in adults, they relatively rarely occur in children. The majority of ovarian masses encountered in the premenarchal or childhood stages are non-neoplastic lesions such as benign functional cysts. Epithelial tumors account for 8-10% of all ovarian tumors and are histologically classified as mucinous or serous. The most common benign epithelial ovarian tumor is cystadenoma.We report the case of a 14-year-old premenarchal girl with chronic abdominal pain, constipation, and abdominal enlargement. A computed tomography detected a huge left ovarian cystic tumor. A 9-kg ovarian tumor was removed surgically. Pathology showed a benign mucinous cystadenoma (MCA).Ovarian neoplasms in children present a diagnostic quandary, and very often the diagnoses are missed or delayed. When the diagnosis is made, a prompt and fertility-preserving surgical treatment must be performed and followed to prevent recurrence.
- Prognostic analysis of invasive circulating tumor cells (iCTCs) in epithelial ovarian cancer. [Comparative Study, Journal Article, Research Support, N.I.H., Extramural]
- Gynecol Oncol 2014 Sep; 134(3):581-90.
Circulating tumor cells (CTCs) have been introduced as a biomarker in detecting advanced epithelial ovarian cancer (EOC). The goals are to examine the prevalence of the invasive subpopulation of CTCs (iCTCs) in patients at high risk of EOC and to compare this biomarker to serum CA125.We used a unique cell adhesion matrix (CAM)-based, functional cell enrichment and identification platform to isolate iCTCs from 129 preoperative patients. We confirmed the identity of iCTCs using positive epithelial (Epi+) markers and negative hematopoietic lineage (HL-) markers. Sensitivity and specificity of the assays were examined and iCTCs/CA125 were correlated with overall survival (OS), progression-free survival (PFS) and clinical parameters.We found a 41.2% sensitivity, 95.1% specificity and 77.8% positive predictive value (PPV) of the iCTC assay in detecting patients with stage I and II EOC malignancy, and a 83% sensitivity and 97.3% PPV in detecting all stages of EOC malignancy. However, a positive CA125 test provided weak evidence to detect stage I and II malignancy (61.6% PPV) and all EOC (92.1% PPV), because of its 76.2% specificity. A significantly stronger concordance in OS and PFS of clinical factors (tumor stage, debulking and platinum sensitivity) was noted for elevated iCTCs than for serum CA125.The CAM-initiated CTC enrichment/identification method enabled the detection of early stage EOC. iCTCs were better correlated with worse OS and PFS, more specific and better PPV than CA125 in detecting EOC malignancy in patients at high risk of EOC.
- A germline mutation in the BRCA1 3'UTR predicts Stage IV breast cancer. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't]
- BMC Cancer 2014.:421.
A germline, variant in the BRCA1 3'UTR (rs8176318) was previously shown to predict breast and ovarian cancer risk in women from high-risk families, as well as increased risk of triple negative breast cancer. Here, we tested the hypothesis that this variant predicts tumor biology, like other 3'UTR mutations in cancer.The impact of the BRCA1-3'UTR-variant on BRCA1 gene expression, and altered response to external stimuli was tested in vitro using a luciferase reporter assay. Gene expression was further tested in vivo by immunoflourescence staining on breast tumor tissue, comparing triple negative patient samples with the variant (TG or TT) or non-variant (GG) BRCA1 3'UTR. To determine the significance of the variant on clinically relevant endpoints, a comprehensive collection of West-Irish breast cancer patients were tested for the variant. Finally, an association of the variant with breast screening clinical phenotypes was evaluated using a cohort of women from the High Risk Breast Program at the University of Vermont.Luciferase reporters with the BRCA1-3'UTR-variant (T allele) displayed significantly lower gene expression, as well as altered response to external hormonal stimuli, compared to the non-variant 3'UTR (G allele) in breast cancer cell lines. This was confirmed clinically by the finding of reduced BRCA1 gene expression in triple negative samples from patients carrying the homozygous TT variant, compared to non-variant patients. The BRCA1-3'UTR-variant (TG or TT) also associated with a modest increased risk for developing breast cancer in the West-Irish cohort (OR=1.4, 95% CI 1.1-1.8, p=0.033). More importantly, patients with the BRCA1-3'UTR-variant had a 4-fold increased risk of presenting with Stage IV disease (p=0.018, OR=3.37, 95% CI 1.3-11.0). Supporting that this finding is due to tumor biology, and not difficulty screening, obese women with the BRCA1-3'UTR-variant had significantly less dense breasts (p=0.0398) in the Vermont cohort.A variant in the 3'UTR of BRCA1 is functional, leading to decreased BRCA1 expression, modest increased breast cancer risk, and most importantly, presentation with stage IV breast cancer, likely due to aggressive tumor biology.
- Sineoculis homeobox homolog 1 protein as an independent biomarker for gastric adenocarcinoma. [Journal Article, Research Support, Non-U.S. Gov't]
- Exp Mol Pathol 2014 Aug; 97(1):74-80.
Sine oculis homeobox homolog 1 (SIX1) protein is a member of the homeobox transcription factor family. Overexpression of SIX1 contributes to cancer progression and is associated with adverse outcomes in various cancer types including breast, ovarian, uterine cervical and liver. To investigate the clinicopathological significance of SIX1 protein expression in gastric adenocarcinomas (GAC), localization of the SIX1 protein was determined in MKN-1, a gastric cancer cell line, using immunofluorescence (IF) staining; SIX1 mRNA level was detected in fresh tissues of GAC and normal gastric mucosa using quantitative real-time polymerase chain reaction (qRT-PCR); and SIX1 protein expression was assessed in 163 GAC, 35 gastric dysplasia and 26 normal gastric mucosa using immunohistochemical (IHC) staining. Correlations between SIX1 protein expression and pathological parameters of GAC were analyzed using Chi-square tests, differences in survival curves were analyzed using log-rank tests, and multivariate survival analysis was performed using the Cox proportional hazards regression model. SIX1 protein showed a mainly cytoplasmic staining pattern in GAC using IF and IHC staining. The positive SIX1 protein expression rate was 80.4% in GAC, which was significantly higher than in either gastric dysplasia (45.7%) or normal gastric mucosa (26.9%) (P<0.01). qRT-PCR data also confirmed increased levels of SIX1 mRNA expression in GAC compared with the normal gastric mucosa in fresh tissues. In addition, the strongly positive SIX1 protein expression rate was significantly correlated with clinical stage, lymph node metastasis and serosal invasion of GAC (P<0.01 or P<0.05), while there was no association with gender, age, tumor size, Lauren classification or histological types of GAC. Notably, strongly positive signals were frequently observed in tumor blood vessels and/or lymphatic vessels. GAC patients with high expression of the SIX1 had shorter overall and disease-free survival rates than those with low SIX1 protein expression (P<0.01). Furthermore, using multivariate analysis, SIX1 protein expression was found to be an independent risk factor for survival in patients with GAC along with clinical stage and serosal invasion (P<0.01). In conclusion, SIX1 protein expression status may be an independent biomarker for prognostic evaluation of GAC.
- CDK2 and CDK4 play important roles in promoting the proliferation of SKOV3 ovarian carcinoma cells induced by tumor-associated macrophages. [Journal Article]
- Oncol Rep 2014 Jun; 31(6):2759-68.
A large quantity of M2-polarized tumor-associated macrophages (TAMs) is present in the tissue, ascitic fluid and peritoneum of ovarian cancer patients. A thorough understanding of the roles of M2-TAM in the development of ovarian cancer may provide new insight into the treatment of this disease. The rapid advancement of omics techniques presents a great challenge to biologists to extract meaningful biological information from vast pools of data. In the present study, using microarray method, we identified 996 genes in SKOV3 ovarian carcinoma cells that underwent expression level changes under the influence of TAMs. Subsequently, based on the protein-protein interactions network and the differentially expressed genes, a network showing the influence of TAMs on SKOV3 cells was constructed. The resulting network was analyzed with CFinder software and four modules were found; these modules were further analyzed using David software to perform functional annotations. It was found that module I was mainly related to tumorigenesis and cell cycle. Hence, 31 genes in module I were analyzed with Cytoscape software to generate a gene-function network, which revealed that four gene proteins (E2F1, RB1, CDK2 and CDK4) were functional. Based on literature review, we postulated that CDK2 and CDK4 were key players in the network. In the subsequent molecular experiments, western blot analysis and kinase activity detection demonstrated that TAMs can significantly boost the expression levels and activities of CDK2 and CDK4 in SKOV3 cells. With 3H-TdR incorporation and flow cytometry assay, the proliferation and cell cycle distribution of SKOV3 cells were detected in the absence or presence of CDK2 and CDK4 inhibitors and the results confirmed that the two kinases played a key role in TAM cells enhancing SKOV3 cell proliferation by promoting G0/G1 to S transition. In the present study, we identified the specific changes in the gene expression profile of SKOV3 cells under the influence of TAMs and explored a method for analyzing the gene expression profile data. The results may aid in the design of subsequent molecular experiments.
- The expression of miR-30a* and miR-30e* is associated with a dualistic model for grading ovarian papillary serious carcinoma. [Journal Article]
- Int J Oncol 2014 Jun; 44(6):1904-14.
Histological grade has already been recognized as a very important prognostic factor for ovarian papillary serous carcinoma (OPSC). On the basis of pathogenetic mechanisms, recent findings suggest a dualistic model of OPSC consisting of types I (low-grade) and II (high-grade) cancers. High-grade OPSC is responsible for most ovarian cancer deaths. The goal of our investigation was to identify the differences in key miRNAs and possible regulators through miRNA microarray chip analysis, as well as functional target prediction and clinical outcome between the low and high-grade OPSC patients. The pathogenic basis in differentiation of ovarian cancer subtypes was studied to provide insight into diagnosis and therapy for high-grade cases. Through microarray analysis, we found that miR-30a* and miR-30e* were the top 2 significantly different miRNAs between type I and type II OPSC patients, and both were remarkably downregulated in the latter type. ATF3 and MYC were indicated as potential co-targets of miR-30a* and miR-30e*, and showed a significant upregulation in type II patients. As ATF3 and MYC are often associated with aggressive behavior and poor differentiation, especially in human cancers, these results are in good agreement with our findings and point toward a regulating differentiation function of the miR-30a* and miR-30e* genes. Further analysis using leave‑one-out cross predictions and Kaplan-Meier survival analysis strongly suggested that miR-30a* and miR-30e* can be used as biomarkers to tailor histological grade before starting the regimen, and they showed important roles in ovarian cancer differentiation resulting in poorer prognosis. In general, miR-30a* and miR-30e* coupled with expression data that reveal pathogenic regulation to predict histological differentiation, may operate to direct the formation of early detection and therapeutic approaches to individual OPSC patients, especially differentiation therapy to high-grade cases.
- Inferring probabilistic miRNA-mRNA interaction signatures in cancers: a role-switch approach. [Journal Article, Research Support, Non-U.S. Gov't]
- Nucleic Acids Res 2014; 42(9):e76.
Aberrant microRNA (miRNA) expression is implicated in tumorigenesis. The underlying mechanisms are unclear because the regulations of each miRNA on potentially hundreds of mRNAs are sample specific. We describe a novel approach to infer Probabilistic MiRNA-mRNA Interaction Signature ('ProMISe') from a single pair of miRNA-mRNA expression profile. Our model considers mRNA and miRNA competition as a probabilistic function of the expressed seeds (matches). To demonstrate ProMISe, we extensively exploited The Cancer Genome Atlas data. As a target predictor, ProMISe identifies more confidence/validated targets than other methods. Importantly, ProMISe confers higher cancer diagnostic power than using expression profiles alone. Gene set enrichment analysis on averaged ProMISe uniquely revealed respective target enrichments of oncomirs miR-21 and 145 in glioblastoma and ovarian cancers. Moreover, comparing matched breast (BRCA) and thyroid (THCA) tumor/normal samples uncovered thousands of tumor-related interactions. For example, ProMISe-BRCA network involves miR-155/183/21, which exhibits higher ProMISe coupled with coherently higher miRNA expression and lower target expression; oncomirs miR-221/222 in the ProMISe-THCA network engage with many downregulated target genes. Together, our probabilistic approach of integrating expression and sequence scores establishes a functional link between the aberrant miRNA and mRNA expression, which was previously under-appreciated due to the methodological differences.
- Loss of HSulf-1 expression enhances tumorigenicity by inhibiting Bim expression in ovarian cancer. [Journal Article, Research Support, N.I.H., Extramural]
- Int J Cancer 2014 Oct 15; 135(8):1783-9.
The expression of human Sulfatase1 (HSulf-1) is downregulated in the majority of primary ovarian cancer tumors, but the functional consequence of this downregulation remains unclear. Using two different shRNAs (Sh1 and Sh2), HSulf-1 expression was stably downregulated in ovarian cancer OV202 cells. We found that HSulf-1-deficient OV202 Sh1 and Sh2 cells formed colonies in soft agar. In contrast, nontargeting control (NTC) shRNA-transduced OV202 cells did not form any colonies. Moreover, subcutaneous injection of OV202 HSulf-1-deficient cells resulted in tumor formation in nude mice, whereas OV202 NTC cells did not. Also, ectopic expression of HSulf-1 in ovarian cancer SKOV3 cells significantly suppressed tumor growth in nude mice. Here, we show that HSulf-1-deficient OV202 cells have markedly decreased expression of proapoptotic Bim protein, which can be rescued by restoring HSulf-1 expression in OV202 Sh1 cells. Enhanced expression of HSulf-1 in HSulf-1-deficient SKOV3 cells resulted in increased Bim expression. Decreased Bim levels after loss of HSulf-1 were due to increased p-ERK, because inhibition of ERK activity with PD98059 resulted in increased Bim expression. However, treatment with a PI3 kinase/AKT inhibitor, LY294002, failed to show any change in Bim protein level. Importantly, rescuing Bim expression in HSulf-1 knockdown cells significantly retarded tumor growth in nude mice. Collectively, these results suggest that loss of HSulf-1 expression promotes tumorigenicity in ovarian cancer through regulating Bim expression.