Metastasis Of Ovarian Carcinoma Research Articles

Hematogenous small intestinal metastasis 8 months after removal of epithelial ovarian cancer: a case report

Ovarian cancers usually spread in four different ways: Trans peritoneal spread, direct invasion, lymphatic, and hematogenous. The primary way of metastasis of ovarian carcinoma is considered to be direct peritoneal dissemination in the abdominal cavity and serosa of bowel. Conversely, hematogenous dissemination is rare, and seldom leads to gastrointestinal metastasis. We report a case of a patient who was operated for an epithelial ovarian cancer and presented with small intestinal metastasis 8 months later. Vascular cancer emboli could be detected by microscopy. Immunohistochemistry tests proved the small intestinal metastasis originated from primary ovarian cancer.

989P - Identification research and application for protein phosphorylation modification sites in human ovarian carcinoma

Background: Phosphorylation modification, as one kind of protein post-translational modification (PTM), increases the diverse protein functions, such as cell signaling, protein folding, enzymatic activity, protein degradation, and their subcellular location. However, the subcellular phophoproteomic of ovarian carcinoma mitochondrial proteins has not been elucidated. Methods: Here, an 8-plex isobaric tag for relative and absolute quantification (iTRAQ) proteomics was used to identify mitochondrial expressed proteins (mtEPs) and phosphorylation modification sites of ovarian carcinomas relative to controls, followed by bioinformatics analysis. Results: The iTRAQ-based proteomics identified 5115 proteins and 99 phosphorylated proteins with quantitative information from purified mitochondrial samples, and 262 proteins were significantly related to overall survival in ovarian cancer patients. Interestingly, the results demonstrated that cancer cells exhibit an increased dependence on lipid metabolism, such as biosynthesis of unsaturated fatty acids, butanoate metabolism, fatty acid degradation, fatty acid metabolism, which might play an important role in ovarian carcinoma invasion and metastasis. Moreover 33 proteins related to lipid metabolism as potential markers for the development of ovarian carcinoma were identified.Additionally, 3 drug-associated phosphorylation proteins and 3 phosphorylation proteins as tumor markers in the plasma were obtained. The 99 phosphorylated proteins and TCGA data were integarated, thus obtained 9 important proteins. Among those, HSP60 were highly related with lipid metabolism. In cells with increased Hsp60 levels both the amounts of total mitochondrial short-chain acyl-CoA dehydrogenase (ACADS) proteins and folded ACADS were increased, which may influence mitochondrial protein folding and lipid metabolism. Conclusions: The current study provides a large-scale mitochondrial proteomic profiling and mitochondrion phosphoproteome with quantitative information, a certain number of proteins with the potential biomarkers, drug targets and a novel vision in the lipid metabolism bio-mechanism of human ovarian carcinoma. Legal entity responsible for the study: Hunan Engineering Laboratory for Structural Biology and Drug Design, Xiangya Hospital, Central South University. Funding: Xiangya Hospital Funds for Talent Introduction (to XZ), the grants from China “863” Plan Project (Grant No. 2014AA020610-1 to XZ), the National Natural Science Foundation of China (Grant No. 81272798 and 81572278 to XZ), and the Hunan Provincial Natural Science Foundation of China (Grant No. 14JJ7008 to XZ). Disclosure: All authors have declared no conflicts of interest.

METCAM/MUC18 Decreases the Malignant Propensity of Human Ovarian Carcinoma Cells.

METCAM/MUC18 is an integral membrane cell adhesion molecule (CAM) in the Ig-like gene super-family. It can carry out common functions of CAMs which is to perform intercellular interactions and interaction of cell with extracellular matrix in tumor microenvironment, to interact with various signaling pathways and to regulate general behaviors of cells. We and other two groups previously suggested that METCAM/MUC18 probably be utilized as a biomarker for predicting the malignant tendency of clinical ovarian carcinomas, since METAM/MUC18 expression appears to associate with the carcinoma at advanced stages. It has been further postulated to promote the malignant tendency of the carcinoma. However, our recent research results appear to support the conclusion that the above positive correlation is fortuitous; actually METCAM/MUC18 acts as a tumor and metastasis suppressor for the ovarian carcinoma cells. We also suggest possible mechanisms in the METCAM/MUC18-mediated early tumor development and metastasis of ovarian carcinoma. Moreover, we propose to employ recombinant METCAM/MUC18 proteins and other derived products as therapeutic agents to treat the ovarian cancer patients by decreasing the malignant potential of ovarian carcinoma.

MicroRNA-135a-3p is downregulated and serves as a tumour suppressor in ovarian cancer by targeting CCR2

MicroRNAs have been demonstrated to play a crucial role in the development of ovarian cancer. Many studies prove that forms of miR-135a, including miR-135a-5p and miR-135a-3p, serve as tumour suppressors in multiple cancers. Nevertheless, the precise function of miR-135a-3p and the molecular mechanisms underlying the involvement of miR-135a-3p in ovarian carcinoma cell growth and metastasis remain largely unknown. Herein, we report that miR-135a-3p expression was significantly downregulated in ovarian carcinoma tissues compared with corresponding adjacent non-tumour tissues. Ectopic miR-135a-3p expression inhibited ovarian carcinoma cell proliferation, migration and invasion in vitro. Additionally, the overexpression of miR-135a-3p inhibited epithelial-mesenchymal transition (EMT) in ovarian cancer cells. A luciferase reporter assay confirmed that the C-C chemokine receptor type 2 (CCR2) gene was the target of miR-135a-3p. In addition, CCR2 depletion mimicked the inhibitory effects of miR-135a-3p on ovarian cancer cells in vitro. Rescue experiments using CCR2 overexpression further verified that CCR2 was a functional target of miR-135a-3p. Xenograft model assays demonstrated that miR-135a-3p functions as an anti-oncogene by targeting CCR2 in vivo. Taken together, these data prove that miR-135a-3p serves as a tumour suppressor gene in ovarian cancer by regulating CCR2.

Abstract B57: Adhesion and beyond: CD44 in ovarian cancer spheroids

Abstract Epithelial ovarian carcinoma (EOC) metastasis is characterized by the shedding of malignant cells from the surface of the primary tumor and their implantation onto the peritoneal surface lining the abdominal cavity in addition to more distant sites. This shedding of malignant cells from the primary site results as either single cells or free-floating multicellular aggregates, known as spheroids, in the ascites. Although single cells and spheroids may potentially seed metastases, considerable evidence now suggests that the aggregation of cells is important for anchorage-independent cell survival and growth, and spheroid formation may represent an important intermediate survival mechanism to facilitate EOC dissemination. Recent studies have uncovered human transmembrane cell adhesion molecule CD44 standard (CD44s) isoform expression correlating with high-grade and advanced-stage ovarian carcinoma. Moreover, it has also been suggested that CD44s may be an important mediator of ovarian cancer cell implantation in the peritoneal cavity, enhancing the metastatic potential of ovarian cancer cells. Thus, we investigated the functional significance of CD44 standard by means of in vitro culture experiments with ovarian cancer spheroids. After characterizing 8 EOC cell lines, a spectrum of CD44 expression was observed and two cell lines with high CD44s (ES-2 and SKOV-3) and two cell lines low in CD44s (OVCAR-4 and OVSAHO) were chosen for further testing. Interestingly, the high CD44s-expressing cell lines formed larger spheroids that adhered significantly faster to a monolayer of primary mesothelial cells. Stable knockdown of CD44 using CRISPR/Cas9 in these 2 cell lines reduced spheroid formation, suggesting that differential expression of CD44 standard plays a role in cell-cell adhesion. When ES-2 CD44-/- cells were injected i.p. into athymic nude mice, decreased ascites production and mesentery tumor burden were observed as well as increased overall survival. However, CD44 knockdown also significantly increased metastasis to the lung, suggesting a suppressive role for CD44 in EOC metastasis as well. These in vivo data imply that CD44 enhances the metastatic potential in ovarian cancer spheroids influencing peritoneal tumor growth while suppressing metastasis to lung tissue. Citation Format: Joelle D. Sacks, Hilal Gurler Main, Goda G. Muralidhar, Osama Elfituri, Hao-Liang Xu, Andre A. Kajdacsy-Balla, Maria V. Barbolina. Adhesion and beyond: CD44 in ovarian cancer spheroids. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B57.

Metastatic cardiophrenic lymph node resection following full-thickness resection of right diaphragm for advanced ovarian carcinoma

ObjectiveOvarian carcinomas sometimes metastasize to the cardiophrenic lymph node. We present a surgical technique for metastatic cardiophrenic lymph node resection following full-thickness resection of the right diaphragm. MethodsA 51-year-old woman presented with ovarian carcinoma and cardiophrenic lymph node metastasis with peritoneal dissemination. The surgical procedure for metastatic cardiophrenic lymph node resection following full-thickness resection of the right diaphragm was as follows. (1) Stripping of the right diaphragm peritoneum was started from the ventral side toward the dorsal side. At the area where stripping was ceased due to tendon or muscle invasion, the thoracic cavity was opened. Full-thickness resection of the diaphragm was proceeded in the left-right direction. (2) The bare area was exposed. Full-thickness resection of the diaphragm was continued along the bare area. (3) After the right diaphragm resection was completed, the remaining right diaphragm was cut toward the cranial side. The metastatic cardiophrenic lymph node was grasped and pulled by forceps, and subsequently resected using a vessel-sealing device. (4) After thoracic chest tube placement, the diaphragmatic defect was closed by continuous non-absorbable sutures. ResultsWe successfully achieved metastatic cardiophrenic lymph node resection following full-thickness resection of the right diaphragm without intra- or postoperative complications. ConclusionMetastatic cardiophrenic lymph node resection is a simple procedure for gynecologic surgeons who are able to perform full-thickness resection of the diaphragm.

Tumor-associated macrophages promote the metastasis of ovarian carcinoma cells by enhancing CXCL16/CXCR6 expression

This study investigated the underlying mechanism by which C-X-C motif chemokine ligand 16 (CXCL16)/C-X-C motif chemokine receptor 6 (CXCR6) signaling is activated by tumor-associated macrophages and assists in regulating the metastasis of ovarian carcinoma. Specimens of ovarian carcinoma tissue and adjacent tissue were collected from 20 ovarian carcinoma patients. Human THP-1 cells were induced to differentiate into macrophages, which were then co-cultured with SKOV3 cells and low concentrations of tumor necrosis factor-α (TNF-α) to simulate the inflammatory microenvironment of ovarian carcinoma. Additionally, small interfering RNA (siRNA) targeting CXCR6 was transfected into SKOV3 cells; after which, the levels of nuclear factor kappa B p65 (NF-κB p65) protein and phosphorylated PI3K and Akt were measured. The migration and invasion abilities of the SKOV3 cells were also tested. The levels of TNF-α, interluekin-6 (IL-6), NF-κB p65, CXCL16, and CXCR6 expression in the ovarian carcinoma tissues were higher than those in the precancerous tissues. CXCR6 expression was positively correlated with TNF-α, IL-6, and CXCL16 expression. Co-culture of SKOV3 cells with macrophages significantly promoted CXCL16, CXCR6, NF-κB, and p65 expression by the SKOV3 cells, increased their levels of phosphorylated PI3K and Akt, and increased the migration and invasion abilities of SKOV3 cells. Silencing of CXCR6 or blocking the PI3K/Akt signal pathway markedly attenuated the expression of NF-κB p65 and phosphorylation of PI3K and Akt, as well as the migration and invasion abilities of SKOV3 cells. These findings demonstrate that macrophages can promote the migration and invasion of ovarian carcinoma cells by affecting the CXCL16/CXCR6 pathway.

Sister Mary Joseph Nodule: A Harbinger of Malignancy

Sister Mary Joseph’s nodule is a rare umbilical cutaneous metastasis defined as an irregular lump on the umbilicus, ranging from 0.5 to 2 cm, reaching up to 10 cm as a result of metastasis from visceral malignancies. It can be smooth, non-ulcerated or ulcerated necrotic mass with or without blood, mucinous, serous or purulent discharge [1]. The frequency of abdominopelvic cancers with umbilical metastasis is estimated between 1 and 3% [1, 2]. Here, we report an umbilical metastasis of an advanced ovarian carcinoma in a very young female.

Low‐grade ovarian serous carcinoma metastasis to the maxilla

AbstractThe maxillofacial region is an uncommon site for metastases from distant primary tumours, representing only 1–2% of malignancies at this site. Such metastases usually present in the mandible rather than the maxilla. The most common sites of primary tumour are the breast, lung and kidney. We describe the clinical, radiological and histologic features of the first‐known case of a low‐grade serous carcinoma of the ovary metastasising to the posterior maxilla. Low‐grade serous carcinoma of the ovary is an uncommon entity and is biologically distinct from high‐grade serous carcinoma. Extra‐abdominal spread is uncommon and bony metastases are rare. Intraosseous metastases are often associated with disseminated disease and confer a poor prognosis.

Identification of core aberrantly expressed microRNAs in serous ovarian carcinoma

MicroRNAs (miRNAs) have recently demonstrated great potential and enormous promise in the diagnosis, prognosis and therapy of various types of cancer. In this study, we performed a comprehensive miRNA expression analysis in the omental metastasis of serous ovarian carcinoma (SOC) using small RNA sequencing. Two hundred and fifty-one aberrantly expressed miRNAs were identified, which clearly separated malignant omentum from normal omentum. Furthermore, miRNA profiles in primary chemo-sensitive and chemo-resistant/refractory SOC were determined using publicly available data. Comparing miRNA expression profiles in omental metastases and primary chemo-sensitive and chemo-resistant/refractory tumors, a set of 70 miRNAs that were aberrantly expressed in both primary and metastatic SOC has been identified for the first time. These core aberrantly expressed miRNAs may play crucial roles in the tumorigenesis, growth, and metastasis of SOC. Therefore, they can serve as potential diagnostic biomarkers and as therapeutic targets for miRNA-mediated therapy. Kaplan–Meier overall survival analysis using The Cancer Genome Atlas data demonstrated that 10 miRNAs (hsa-miR-135, 150, -340, 625, 1908, 3187, -96, -196b, -449c, and -1275) were associated with survival of patients with SOC, which may serve as potential prognostic biomarkers.

Cross-linked hyaluronan gel inhibits the growth and metastasis of ovarian carcinoma

BackgroundThe recurrence, metastasis and poor prognosis are important characteristics of ovarian carcinoma (OC), which are associated with exfoliation of cells from the primary tumor and colonization of the cells in pelvic cavity. On the other hand, the life quality of the patients undergoing surgical resection of OC was influenced by postoperative adhesions. Therefore, preventing postoperative implant tumor and adhesion may be effective methods to improve OC treatment. HyaRegen Gel, a cross-linked hyaluronan gel (CHAG), has been widely used as an anti-adhesive agent following pelvic operation in clinic. However, whether it can affect the implantation and growth of OC cells or not is still not clear.MethodsMigration and invasion assays were applied to detect the effect of CHAG on migration and invasion of OC cells. Western blotting was performed to detect the phosphorylation/activation of EGFR and ERK, and the expression of PCNA and MMP7. Pull down assay was used to analyze the effect of CHAG on the activation of small G protein Rac1. Nude mice implantation tumor model was applied to observe the effect of CHAG on implantation tumor of OC cells.ResultsThe results of in vitro experiments showed that CHAG suppressed both basic and EGF-induced migration and invasion of OC cells, blocked the activation of EGF-initiated EGFR activation, inhibited downstream signal transduction of EGFR, and decreased expression of proliferation and migration/invasion related proteins. Meanwhile, results of in vivo experiments showed that CHAG not only inhibited the formation of implantation tumor of OC cells but also delayed the of the growth of the tumors.ConclusionsCHAG inhibited migration, invasion and proliferation of OC cells in vitro, and suppressed development of implantation tumor of OC in vivo. This made it as both anti-tumor and anti-adhesion agents.

Comparison between multi-slice spiral CT and magnetic resonance imaging in the diagnosis of peritoneal metastasis in primary ovarian carcinoma.

The advent of disease evaluation by means of multi-slice spiral computed tomography (MSCT) and magnetic resonance imaging (MRI) represents a continually emerging role in the evaluation of various diseases; however, its role is yet to be adequately defined. Thus, the aim of the study was to compare the diagnostic value of MSCT and MRI in the diagnosis of peritoneal metastasis in primary ovarian carcinoma. Between January 2013 and December 2015, MSCT or MRI data were collected from 42 patients who had been previously diagnosed with peritoneal metastasis of ovarian carcinoma at the First Affiliated Hospital of Kunming Medical University. The tumor location, size, edge, and shape were all evaluated independently by three qualified imaging physicians using a double-blind method to confirm whether the patients were indeed suffering from peritoneal metastasis, as well as to rank the metastatic lesions recorded on a five-point scale. It was hypothesized that MRI and MSCT were comparable in the evaluation of ovarian carcinoma. Therefore, a receiver operating characteristics (ROC) curve was used to analyze the results and also to directly compare the respective diagnostic values of MSCT and MRI. In total, 165 metastatic lesions were confirmed by means of surgical operation. MSCT revealed 131 metastatic lesions, while MRI confirmed 154 metastatic lesions. The metastatic sites were primarily located on the subphrenic, epiploon, and gastrocolic ligaments and were further confirmed by either MRI or CT. In regard to MSCT, the most common site of underdiagnoses was in the vicinity of the uterus–rectum–fossa. MRI displayed a high detection rate in every site. The omission diagnostic rate of MSCT and MRI were 20.61% and 6.67%, respectively, while the accuracy rates were 79.39% and 93.33%, respectively. The obtained results revealed that the MSCT value of area under the ROC curve was smaller than that for MRI. Our findings provided evidence asserting that MRI, in comparison to MSCT, was more accurate in diagnosing peritoneal metastasis in patients with ovarian carcinoma.

Inhibition of ZEB1 leads to inversion of metastatic characteristics and restoration of paclitaxel sensitivity of chronic chemoresistant ovarian carcinoma cells

ZEB1, a member of the zinc-finger E-box binding homeobox family, is considered to play a crucial role in cancer progression and metastasis. In the current study, we investigated the role of ZEB1 in metastasis and chronic chemoresistance of epithelial ovarian carcinoma (EOC) cells. Using several EOC and acquired paclitaxel (PTX)-resistant EOC cell lines, we investigated whether silencing ZEB1 led to a reversal of the chemoresistance and metastatic potential in vitro and in vivo. Subsequently, the expression of ZEB1 in EOC tissues and its association with the oncologic outcome were investigated. According to the immunohistochemical staining of EOC tissues, as the positivity of ZEB1 expression was increased, the overall survival of EOC patients became poorer (P = 0.0022 for trend). Additionally, cell migration and invasion were significantly decreased by ZEB1 silencing in both PTX-sensitive and PTX- resistant cells. Although PTX-sensitivity was not changed by silencing ZEB1 in parental EOC cells, the depletion of ZEB1 made the PTX-resistant EOC cells more sensitive to PTX treatment. In an animal model, mice injected with ZEB1-silencing PTX-resistant cells survived for longer than the control cell-injected mice. Although the intravenous injection of PTX did not affect the tumor weight of shCtrl cells, the tumor weight of shZEB1 cells was significantly reduced by PTX treatment. The current data indicate the possible involvement of ZEB1 in the metastasis and paclitaxel resistance of EOC, and suggest that targeting this molecule may reverse the malignant potential and improve the oncologic outcome for EOC patients.

Ovarian Cancer with Leptomeningeal Involvement

Ovarian carcinoma ranks fifth in cancer deaths among women and is the most common cause of deaths due to gynecological cancers. Central nerve system metastasis is rare; also leptomeningeal metastasis is very rare. There are a limited number of cases with isolated leptomeningeal metastasis due to ovarian carcinoma in the literature. We aimed to present two cases with ovarian carcinoma and leptomeningeal metastasis.

Molecular Mechanisms of Ovarian Carcinoma Metastasis: Key Genes and Regulatory MicroRNAs.

Metastasis of primary tumors progresses stepwise- from change in biochemistry, morphology, and migratory patterns of tumor cells to the emergence of receptors on their surface that facilitate directional migration to target organs followed by the formation of a specific microenvironment in a target organ that helps attachment and survival of metastatic cells. A set of specific genes and signaling pathways mediate this process under control of microRNA. The molecular mechanisms underlying biological processes associated with tumor metastasis are reviewed in this publication using ovarian cancer, which exhibits high metastatic potential, as an example. Information and data on the genes and regulatory microRNAs involved in the formation of cancer stem cells, epithelial-mesenchymal transition, reducing focal adhesion, degradation of extracellular matrix, increasing migration activity of cancer cells, formation of spheroids, apoptosis, autophagy, angiogenesis, formation of metastases, and development of ascites are presented. Clusters of microRNAs (miR-145, miR-31, miR-506, miR-101) most essential for metastasis of ovarian cancer including the families of microRNAs (miR-200, miR-214, miR-25) with dual role, which is different in different histological types of ovarian cancer, are discussed in detail in a section of the review.

Prostate-specific Membrane Antigen (PSMA) Expression in the Neovasculature of Gynecologic Malignancies: Implications for PSMA-targeted Therapy.

The goal of the study was to examine expression of prostate-specific membrane antigen (PSMA) in neovasculature of gynecologic cancers, as PSMA-targeted therapy has showed a promise in treatment of advanced carcinomas. The study included cervical carcinoma (n=28), vulvar carcinoma (n=20), endometrial carcinoma (n=23), primary ovarian carcinoma (n=21), metastatic ovarian carcinoma (n=25), and normal cervix (n=12) as negative control. All cases were immunostained using anti-CD31 antibody to delineate capillary endothelial cells. In parallel, all cases were immunostained using anti-PSMA antibody. The PSMA staining was assessed in tumor capillaries and in normal tissues and scored as a percentage of CD31 staining. PSMA expression was found in the tumor neovasculature, and no significant expression was identified in vasculature of normal tissues. The extent of PSMA staining in tumor capillaries varied from high expression in ovarian and endometrial cancers, to medium expression in cervical squamous cell carcinomas, and low expression in cervical adenocarcinomas and vulvar cancers. All (100%) cases of primary ovarian carcinoma, ovarian carcinoma metastases, and primary endometrial carcinoma showed PSMA expression in tumor vasculature, which was diffuse in majority of cases. The expression of PSMA in ovarian cancer metastases was similar among different metastatic foci of the same tumor. Fifteen percent of cervical squamous cell carcinoma, 50% of cervical adenocarcinoma, and 75% of vulvar carcinomas showed no capillary expression of PSMA. In conclusion, PSMA is highly and specifically expressed in the neovasculature of ovarian, endometrial, and cervical squamous carcinoma, rendering it a potential therapeutic vascular target.

Evaluation of the correlation of vasculogenic mimicry, ALDH1, KiSS-1, and MACC1 in the prediction of metastasis and prognosis in ovarian carcinoma

BackgroundRecurrence and metastasis are the usual manifestations of treatment failure of epithelial ovarian carcinoma (EOC). Vasculogenic mimicry (VM; blood supply development often seen in highly aggressive cancers), aldehyde dehydrogenase 1 (ALDH1, cancer stem cell biomarker), KiSS-1 (suppressor of tumor metastasis), and metastasis associated in colon cancer-1 (MACC1) are all useful predictive factors for metastasis and prognosis in various cancers. In this study, we analyzed associations among VM, ALDH1, KiSS-1, and MACC1 in EOC, and their respective correlations with clinicopathological characteristics and survival in EOC.MethodsPositive rates of VM, ALDH1, KiSS-1, and MACC1 in 207 whole EOC tissue samples were detected by immunohistochemistry. Patients’ clinical data were also collected.ResultsLevels of VM, ALDH1, and MACC1 were significantly higher, and levels of KiSS-1 significantly lower, in EOC tissues than in benign ovary tumors. Levels of VM, ALDH1, KiSS-1, and MACC1 were associated significantly with tumor/lymph node/metastasis (LNM) grade, implantation, and International Federation of Gynecology and Obstetrics (FIGO) stage, and with patients’ overall survival (OS); whereas the KiSS-1+ subgroup had significantly longer OS than did the KiSS-1− subgroup. In multivariate analysis, high VM, ALDH1 or MACC1 levels, FIGO stage, implantation and low KiSS-1 levels were independently associated with shorter OS in patients with EOC.ConclusionsVM and expressions of ALDH1, KiSS-1, and MACC1 represent promising markers for metastasis and prognosis, and potential therapeutic targets for EOC.

Dangerous Liaisons: Deviant Endothelium NOTCHes toward Tumor Metastasis

In this issue of Cancer Cell, Wieland etal. uncover a feedback loop in which tumor cells, by augmenting Notch signaling, provoke a senescent and pro-inflammatory state in endothelial cells, promoting neutrophil infiltration, tumor cell adhesion, and metastasis. Interfering with this Notch-dependent crosstalk may be a therapeutic approach to block metastasis.

Knockdown of Tripartite Motif Containing 28 suppresses the migration, invasion and epithelial-mesenchymal transition in ovarian carcinoma cells through down-regulation of Wnt/β-catenin signaling pathway.

Tripartite motif containing 28 (TRIM28) is a transcriptional corepressor of Kruppel-associated box zinc finger protein, which has been reported to participate in carcinogenesis. Nonetheless, whether TRIM28 plays a role in the metastasis of ovarian carcinoma (OC) is unclear and requires further investigation. In this study, two OC cell lines (A2780 and OVCAR-3) with stable low expression of TRIM28 were established via RNA interference. We found that the migratory and invasive ability of TRIM28-silenced OC cells significantly decreased. The expression and activity of matrix metallopeptidase (MMP)-2 and MMP-9 in these OC cells were inhibited. The TRIM28 shRNA also suppressed the epithelial-mesenchymal transition (EMT) of OC cells as evidenced by the up-regulated E-cadherin and the downregulated Vimentin and N-cadherin. Additionally, the Wnt/β-catenin signaling pathway was suppressed in TRIM28-silenced OC cells: the activity of β-catenin was inhibited, the expression of total and nuclear β-catenin, Axin 2, T-cell factor 1 (TCF1) and lymphoid enhancer binding factor 1 (LEF1) were decreased, whereas the phosphorylation of β-catenin at Ser33/37 was enhanced. Further, re-expression of active β-catenin in TRIM28-silenced OC cells partly restored their metastasis in vitro. Taken together, our study demonstrates a contributory role of TRIM28 in OC metastasis in vitro, suggesting TRIM28 as a novel therapeutic target for this malignant tumor.

Clinical Impact of microRNAs Associated With Cancer Stem Cells as a Prognostic Factor in Ovarian Carcinoma.

Background: Ovarian carcinoma is a highly lethal gynecological malignancy due to its frequent relapses and adoption of chemoresistance. To develop new biomarkers for disease progression in ovarian carcinoma, CSCs, which are considered to contribute to disease relapse and metastasis, were isolated from human ovarian carcinoma tissues, and differentially expressed microRNAs (miRNAs) in CSCs were identified and assessed the clinical implication of expression of these miRNAs.Methods: Primary cancer cells derived from human ovarian carcinomas were cultured and spheroid-forming cells (SFCs) were isolated. Profiles of miRNA expression in CSC-like SFCs were identified by miRNA microarray and the results were validated by quantitative real-time RT-PCR (qRT-PCR). We also assessed the correlations between miRNA expression levels and clinicopathological parameters in ovarian carcinomas.Results: Five miRNAs (miR-5703, miR-630, miR-1246, miR-424-5p, and miR-320b) were significantly dysregulated in CSC-like SFCs compared with primary cancer cells. The qRT-PCR showed that miR-5703 and miR-1246 expression was significantly higher in ovarian cancer cells than in normal control cells, whereas the miR-424-5p level was significantly lower. Decreased expression of miR-424-5p was significantly associated with distant metastasis in high stage (stage IIII & IV) carcinomas (35.5% vs. 72.2%, respectively, p=0.013)Conclusion: Taken together, miR-5703, miR-630, miR-1246, miR-424-5p, and miR-320b are useful markers for enriching ovarian CSCs. Decreased expression of miR-424-5p in ovarian carcinoma might be a putative biomarker for distant metastasis in ovarian carcinoma.