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Ovarian tumor AND Ovarian functional and neoplastic tumors [keywords]
- A 9-kg Ovarian Mucinous Cystadenoma in a 14-Year-Old Premenarchal Girl. [Journal Article]
- Am J Case Rep 2014.:326-9.
Background 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. Case Report 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). Conclusions 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.
- Inferring probabilistic miRNA-mRNA interaction signatures in cancers: a role-switch approach. [JOURNAL ARTICLE]
- Nucleic Acids Res 2014 Mar 7.
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]
- Int J Cancer 2014 Mar 4.
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.
- Mirk/dyrk1B kinase is upregulated following inhibition of mTOR. [JOURNAL ARTICLE]
- Carcinogenesis 2014 Mar 28.
The PI3K/PTEN/Akt/mTOR/p70S6K pathway is one of the most frequently deregulated signaling pathways in solid tumors and has a functional role in drug resistance. However, targeting this pathway leads to compensatory activation of several mediators of cell survival. Expression of the reactive oxygen species-controlling kinase Mirk/dyrk1B was increased severalfold by the mammalian target of rapamycin (mTOR) inhibitors RAD001, WYE354 and rapamycin, with less effect by the Akt inhibitors AZD5363 and MK-2206. Upregulation of Mirk messenger RNA (mRNA) expression was mediated by cyclic AMP response element binding protein (CREB) binding to two sites in the Mirk promoter upstream of the transcription start site and one site within exon 4. Depletion of CREB reduced Mirk expression, whereas depletion of mTOR increased it. Moreover, hydroxytamoxifen activation of an Akt-estrogen receptor construct blocked an increase in Mirk mRNA and protein. Addition of a Mirk/dyrk1B kinase inhibitor increased the sensitivity of Panc1 pancreatic cancer cells and three different ovarian cancer cell lines to the mTOR inhibitor RAD001. Targeting Mirk kinase could improve the utility of mTOR inhibitors and so presents an attractive drug target.
- S100A2 is a BRCA1/p63 coregulated tumour suppressor gene with roles in the regulation of mutant p53 stability. [Journal Article]
- Cell Death Dis 2014.:e1070.
Here, we show for the first time that the familial breast/ovarian cancer susceptibility gene, BRCA1, along with interacting ΔNp63 proteins, transcriptionally upregulate the putative tumour suppressor protein, S100A2. Both BRCA1 and ΔNp63 proteins are required for S100A2 expression. BRCA1 requires ΔNp63 proteins for recruitment to the S100A2 proximal promoter region, while exogenous expression of individual ΔNp63 proteins cannot activate S100A2 transcription in the absence of a functional BRCA1. Consequently, mutation of the ΔNp63/p53 response element within the S100A2 promoter completely abrogates the ability of BRCA1 to upregulate S100A2. S100A2 shows growth control features in a range of cell models. Transient or stable exogenous S100A2 expression inhibits the growth of BRCA1 mutant and basal-like breast cancer cell lines, while short interfering RNA (siRNA) knockdown of S100A2 in non-tumorigenic cells results in enhanced proliferation. S100A2 modulates binding of mutant p53 to HSP90, which is required for efficient folding of mutant p53 proteins, by competing for binding to HSP70/HSP90 organising protein (HOP). HOP is a cochaperone that is required for the efficient transfer of proteins from HSP70 to HSP90. Loss of S100A2 leads to an HSP90-dependent stabilisation of mutant p53 with a concomitant loss of p63. Accordingly, S100A2-deficient cells are more sensitive to the HSP-90 inhibitor, 17-N-allylamino-17-demethoxygeldanamycin, potentially representing a novel therapeutic strategy for S100A2- and BRCA1-deficient cancers. Taken together, these data demonstrate the importance of S100A2 downstream of the BRCA1/ΔNp63 signalling axis in modulating transcriptional responses and enforcing growth control mechanisms through destabilisation of mutant p53.
- In vivo multiplexed interrogation of amplified genes identifies GAB2 as an ovarian cancer oncogene. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't]
- Proc Natl Acad Sci U S A 2014 Jan 21; 111(3):1102-7.
High-grade serous ovarian cancers are characterized by widespread recurrent copy number alterations. Although some regions of copy number change harbor known oncogenes and tumor suppressor genes, the genes targeted by the majority of amplified or deleted regions in ovarian cancer remain undefined. Here we systematically tested amplified genes for their ability to promote tumor formation using an in vivo multiplexed transformation assay. We identified the GRB2-associated binding protein 2 (GAB2) as a recurrently amplified gene that potently transforms immortalized ovarian and fallopian tube secretory epithelial cells. Cancer cell lines overexpressing GAB2 require GAB2 for survival and show evidence of phosphatidylinositol 3-kinase (PI3K) pathway activation, which was required for GAB2-induced transformation. Cell lines overexpressing GAB2 were as sensitive to PI3K inhibition as cell lines harboring mutant PIK3CA. Together, these observations nominate GAB2 as an ovarian cancer oncogene, identify an alternative mechanism to activate PI3K signaling, and underscore the importance of PI3K signaling in this cancer.
- Cyclin E1 deregulation occurs early in secretory cell transformation to promote formation of fallopian tube-derived high-grade serous ovarian cancers. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't]
- Cancer Res 2014 Feb 15; 74(4):1141-52.
The fallopian tube is now generally considered the dominant site of origin for high-grade serous ovarian carcinoma. However, the molecular pathogenesis of fallopian tube-derived serous carcinomas is poorly understood and there are few experimental studies examining the transformation of human fallopian tube cells. Prompted by recent genomic analyses that identified cyclin E1 (CCNE1) gene amplification as a candidate oncogenic driver in high-grade serous ovarian carcinoma, we evaluated the functional role of cyclin E1 in serous carcinogenesis. Cyclin E1 was expressed in early- and late-stage human tumor samples. In primary human fallopian tube secretory epithelial cells, cyclin E1 expression imparted malignant characteristics to untransformed cells if p53 was compromised, promoting an accumulation of DNA damage and altered transcription of DNA damage response genes related to DNA replication stress. Together, our findings corroborate the hypothesis that cyclin E1 dysregulation acts to drive malignant transformation in fallopian tube secretory cells that are the site of origin of high-grade serous ovarian carcinomas.
- Microtissue density prognostic factor evaluation based on antigens CD34 and CD 105 in ovarian cancer patients. [Journal Article]
- Ann Agric Environ Med 2013; 20(4):838-42.
Uncontrollable cell division and disorders of the apoptotic processes constitute the key phenomena in cancer transformation. The theory that the tumour growth above critical density is possible due to creation of the new blood vessels during angiogenesis process was put forward in 1971 by Folkman. The panendotelial antibodies targeted against such markers as CD34 are used most frequently in cancer vessel evaluation. The anti-CD34 reacts with the largest number of endoepithelial cells. The second group constitutes the antibodies that agglomerate with the antigens characteristic for proliferous endoepithelial cells. The most popular marker used for functional endothelial tissues is endoglin called CD105. The subject of this publication is to find the answer to a question whether the practical usage of the CD34 and CD 105 as a prognostic factor in predicting failure of a planned treatment, determining expected remission and the total survival rate is possible. 74 patients with the diagnosed ovarian cancer, treated in the I Clinic of Gynecology Oncology and Gynecology, Medical University in Lublin, between years 1999-2004 were included into the analysis. Representative paraffin blocks with the embedded ovarian cancer fragments were used for immunohistochemical research. Density of the microvessels was being evaluated basing on the expression of the antigen CD34 and CD105. Evaluation of the microvessel density with CD34 and CD105 markers is not useful in forecasting survival rate and disease recurrence in patients with ovary cancer.
- Niche-dependent gene expression profile of intratumoral heterogeneous ovarian cancer stem cell populations. [Journal Article, Research Support, Non-U.S. Gov't]
- PLoS One 2013; 8(12):e83651.
Intratumoral heterogeneity challenges existing paradigms for anti-cancer therapy. We have previously demonstrated that the human embryonic stem cells (hESC)-derived cellular microenvironment in immunocompromised mice, enables functional distinction of heterogeneous tumor cells, including cells which do not grow into a tumor in a conventional direct tumor xenograft platform. We have identified and characterized six cancer cell subpopulations each clonally expanded from a single cell, derived from human ovarian clear cell carcinoma of a single tumor, to demonstrate striking intratumoral phenotypic heterogeneity that is dynamically dependent on the tumor growth microenvironment. These cancer cell subpopulations, characterized as cancer stem cell subpopulations, faithfully recapitulate the full spectrum of histological phenotypic heterogeneity known for human ovarian clear cell carcinoma. Each of the six subpopulations displays a different level of morphologic and tumorigenic differentiation wherein growth in the hESC-derived microenvironment favors growth of CD44+/aldehyde dehydrogenase positive pockets of self-renewing cells that sustain tumor growth through a process of tumorigenic differentiation into CD44-/aldehyde dehydrogenase negative derivatives. Strikingly, these derivative cells display microenvironment-dependent plasticity with the capacity to restore self-renewal markers and CD44 expression. In the current study, we delineate the distinct gene expression and epigenetic profiles of two such subpopulations, representing extremes of phenotypic heterogeneity in terms of niche-dependent self-renewal and tumorigenic differentiation. By combining Gene Set Enrichment, Gene Ontology and Pathway-focused array analyses with methylation status, we propose a suite of robust differences in tumor self-renewal and differentiation pathways that underlie the striking intratumoral phenotypic heterogeneity which characterize this and other solid tumor malignancies.
- c-FOS suppresses ovarian cancer progression by changing adhesion. [Journal Article, Research Support, Non-U.S. Gov't]
- Br J Cancer 2014 Feb 4; 110(3):753-63.
C-Fos was initially described as oncogene, but was associated with favourable prognosis in ovarian cancer (OvCa) patients. The molecular and functional aspects underlying this effect are still unknown.Using stable transfectants of SKOV3 and OVCAR8 cells, proliferation, migration, invasion and apoptotic potential of c-FOS-overexpressing clones and controls were compared. Adherence to components of the extracellular matrix was analysed in static assays, and adhesion to E-selectin, endothelial and mesothelial cells in dynamic flow assays. The effect of c-FOS in vivo was studied after intraperitoneal injection of SKOV3 clones into SCID mice, and changes in gene expression were determined by microarray analysis.Tumour growth after injection into SCID mice was strongly delayed by c-FOS overexpression, with reduction of lung metastases and circulating tumour cells. In vitro, c-FOS had only weak influence on proliferation and migration, but was strongly pro-apoptotic. Adhesion to components of the extracellular matrix (collagen I, IV) and to E-selectin, endothelial and mesothelial cells was significantly reduced in c-FOS-overexpressing OvCa cells. This corresponds to deregulation of adhesion proteins and glycosylation enzymes in microarray analysis.In addition to its known pro-apoptotic effect, c-FOS might influence OvCa progression by changing the adhesion of OvCa cells to peritoneal surfaces.