scholarly journals The Role of TRIP6, ABCC3 and CPS1 Expression in Resistance of Ovarian Cancer to Taxanes

2021 ◽  
Vol 23 (1) ◽  
pp. 73
Author(s):  
Karolina Seborova ◽  
Alzbeta Kloudova-Spalenkova ◽  
Kamila Koucka ◽  
Petr Holy ◽  
Marie Ehrlichova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
Ovarian Carcinoma ◽  
De Novo ◽  
Ovarian Cancer Cells ◽  
In Vivo Models ◽  
Resistant Mouse

The main problem precluding successful therapy with conventional taxanes is de novo or acquired resistance to taxanes. Therefore, novel experimental taxane derivatives (Stony Brook taxanes; SB-Ts) are synthesized and tested as potential drugs against resistant solid tumors. Recently, we reported alterations in ABCC3, CPS1, and TRIP6 gene expression in a breast cancer cell line resistant to paclitaxel. The present study aimed to investigate gene expression changes of these three candidate molecules in the highly resistant ovarian carcinoma cells in vitro and corresponding in vivo models treated with paclitaxel and new experimental Stony Brook taxanes of the third generation (SB-T-121605 and SB-T-121606). We also addressed their prognostic meaning in ovarian carcinoma patients treated with taxanes. We estimated and observed changes in mRNA and protein profiles of ABCC3, CPS1, and TRIP6 in resistant and sensitive ovarian cancer cells and after the treatment of resistant ovarian cancer models with paclitaxel and Stony Brook taxanes in vitro and in vivo. Combining Stony Brook taxanes with paclitaxel caused downregulation of CPS1 in the paclitaxel-resistant mouse xenograft tumor model in vivo. Moreover, CPS1 overexpression seems to play a role of a prognostic biomarker of epithelial ovarian carcinoma patients’ poor survival. ABCC3 was overexpressed in EOC tumors, but after the treatment with taxanes, its up-regulation disappeared. Based on our results, we can suggest ABCC3 and CPS1 for further investigations as potential therapeutic targets in human cancers.

scholarly journals Role of microRNAs as Clinical Cancer Biomarkers for Ovarian Cancer: A Short Overview

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 169 ◽  
Author(s):  
Cristina Elena Staicu ◽  
Dragoș-Valentin Predescu ◽  
Călin Mircea Rusu ◽  
Beatrice Mihaela Radu ◽  
Dragos Cretoiu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Simultaneous Detection ◽  
Clinical Signs ◽  
In Vivo Models ◽  
Circulating Micrornas ◽  
Clinical Biomarkers ◽  
Molecular Clustering

Ovarian cancer has the highest mortality rate among gynecological cancers. Early clinical signs are missing and there is an urgent need to establish early diagnosis biomarkers. MicroRNAs are promising biomarkers in this respect. In this paper, we review the most recent advances regarding the alterations of microRNAs in ovarian cancer. We have briefly described the contribution of miRNAs in the mechanisms of ovarian cancer invasion, metastasis, and chemotherapy sensitivity. We have also summarized the alterations underwent by microRNAs in solid ovarian tumors, in animal models for ovarian cancer, and in various ovarian cancer cell lines as compared to previous reviews that were only focused the circulating microRNAs as biomarkers. In this context, we consider that the biomarker screening should not be limited to circulating microRNAs per se, but rather to the simultaneous detection of the same microRNA alteration in solid tumors, in order to understand the differences between the detection of nucleic acids in early vs. late stages of cancer. Moreover, in vitro and in vivo models should also validate these microRNAs, which could be very helpful as preclinical testing platforms for pharmacological and/or molecular genetic approaches targeting microRNAs. The enormous quantity of data produced by preclinical and clinical studies regarding the role of microRNAs that act synergistically in tumorigenesis mechanisms that are associated with ovarian cancer subtypes, should be gathered, integrated, and compared by adequate methods, including molecular clustering. In this respect, molecular clustering analysis should contribute to the discovery of best biomarkers-based microRNAs assays that will enable rapid, efficient, and cost-effective detection of ovarian cancer in early stages. In conclusion, identifying the appropriate microRNAs as clinical biomarkers in ovarian cancer might improve the life quality of patients.

scholarly journals METTL3 promotes the initiation and metastasis of ovarian cancer by inhibiting CCNG2 expression via promoting the maturation of pri-microRNA-1246

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Xuehan Bi ◽  
Xiao Lv ◽  
Dajiang Liu ◽  
Hongtao Guo ◽  
Guang Yao ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Molecular Mechanisms ◽  
High Expression ◽  
Ovarian Cancer Cells ◽  
Inadequate Knowledge ◽  
And Migration ◽  
Cancer Tissues

AbstractOvarian cancer is a common gynecological malignant tumor with a high mortality rate and poor prognosis. There is inadequate knowledge of the molecular mechanisms underlying ovarian cancer. We examined the expression of methyltransferase-like 3 (METTL3) in tumor specimens using RT-qPCR, immunohistochemistry, and Western blot analysis, and tested the methylation of METTL3 by MSP. Levels of METTL3, miR-1246, pri-miR-1246 and CCNG2 were then analyzed and their effects on cell biological processes were also investigated, using in vivo assay to validate the in vitro findings. METTL3 showed hypomethylation and high expression in ovarian cancer tissues and cells. Hypomethylation of METTL3 was pronounced in ovarian cancer samples, which was negatively associated with patient survival. Decreased METTL3 inhibited the proliferation and migration of ovarian cancer cells and promoted apoptosis, while METTL3 overexpression exerted opposite effects. Mechanistically, METTL3 aggravated ovarian cancer by targeting miR-1246, while miR-1246 targeted and inhibited CCNG2 expression. High expression of METTL3 downregulated CCNG2, promoted the metabolism and growth of transplanted tumors in nude mice, and inhibited apoptosis. The current study highlights the promoting role of METTL3 in the development of ovarian cancer, and presents new targets for its treatment.

scholarly journals Targeting dormant ovarian cancer cells in vitro and in an in vivo model of platinum resistance

2019 ◽  
Author(s):  
Zhiqing Huang ◽  
Eiji Kondoh ◽  
Zachary Visco ◽  
Tsukasa Baba ◽  
Noriomi Matsumura ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Disease Recurrence ◽  
Mitochondrial Pathway ◽  
Ovarian Cancer Cells ◽  
Serum Free

ABSTRACTObjectiveOvarian cancer cells often exist in vivo as multicellular spheroids. Spheroid formation in vitro has been used to enrich for cancer stem cell populations from primary tumors. Such spheroids exhibit drug resistance and slow proliferation, suggesting involvement in disease recurrence. Our objectives were to characterize cancer spheroid phenotypes, determine gene expression profiles associated with spheroid forming capacity and to evaluate the responsiveness of spheroids to commonly used and novel therapeutic agents.MethodsTumorigenic potential was assessed using anchorage independent growth assays in 24 cell lines. Spheroids from cell lines (N=12) and from primary cancers (N=8) were grown on non-adherent tissue culture plates in serum-free media. Cell proliferation was measured using MTT assays and Ki67 immunostaining. Affymetrix HT U133A gene expression data was used to identify differentially expressed genes based on spheroid forming capacity. Matched monolayers and spheroids (N=7 pairs) were tested for response to cisplatin, paclitaxel and 7-hydroxystaurosporine (UCN-01) while mitochondrial inhibition was performed using oligomycin. Xenograft tumors from intraperitoneal injection of CAOV2-GFP/LUC ovarian cancer cells into nude mice were treated with carboplatin to reduce tumor burden followed by secondary treatment with carboplatin, UCN-01, or Oltipraz. Tumor formation and response was monitored using live imaging.ResultsOf 12 cell lines with increased anchorage-independent growth, 8 also formed spheroids under serum-free spheroid culture conditions. Spheroids showed reduced proliferation (p<0.0001) and Ki67 immunostaining (8% versus 87%) relative to monolayer cells. Spheroid forming capacity was associated with increased mitochondrial pathway activity (p ≤ 0.001). The mitochondrial inhibitors, UCN-01 and Oligomycin, demonstrated effectiveness against spheroids, while spheroids were refractory to cisplatin and paclitaxel. By live in vivo imaging, ovarian cancer xenograft tumors were reduced after primary treatment with carboplatin. Continued treatment with carboplatin was accompanied by an increase in tumor signal while there was little or no increase in tumor signal observed with subsequent treatment with UCN-01 or Oltipraz.ConclusionsOur findings suggest that the mitochondrial pathway in spheroids may be an important therapeutic target in preventing disease recurrence.

scholarly journals Knockdown of TRIM44 inhibits the progression of human epithelial ovarian cancer via the FOXM1-EZH2 signaling pathway

2021 ◽  
Author(s):  
Fanling Meng ◽  
Jing Ding ◽  
Xihai Chen ◽  
Lin Sui ◽  
Yuanlong Hu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Tumor Model ◽  
Ovarian Cancer Cells ◽  
In Vitro Proliferation

Abstract Background. Tripartite motif‑containing protein 44 (TRIM44) was recently identified as a novel oncogene that is overexpressed in several types of human cancers. However, the biological functions of TRIM44 in epithelial ovarian cancer (EOC) remain unclear. Here, we aimed to investigate the role of TRIM44 in EOC and its clinical implications.Methods. The expression of TRIM44 in different ovarian cancer cell lines were detected by western blot. TRIM44 was knocked down by shRNA transfection. The in vitro proliferation, invasion, migration and apoptosis of ovarian cancer cells were detected by CCK8, colony formation assay, transwell filters, tube formation assay and flow cytometry analysis, respectively. The growth ability of xenograft tumors in vivo was examined by a nude mouse metastatic tumor model. Finally, we carried out gene chip analysis and IPA to analyze the potential gene network.Results. High expression of TRIM44 was observed in EOC tissues and cell lines. Knockdown of TRIM44 expression substantially suppressed the proliferation, migration, invasion and colony-forming ability of EOC cells in vitro and attenuated tumor growth in vivo. Mechanistic studies showed that silencing TRIM44 dramatically down regulated the expression of FOXM1, EZH2, CCNE2, CCND3 and BIRC5 in EOC cells, at least in part through inactivation of the FOXM1-EZH2 signaling pathway.Conclusion. Collectively, these data suggest that TRIM44 downregulation inhibits the progression of EOC cells through the suppression of the FOXM1-EZH2 signaling pathway. These results provide novel insight into the role of TRIM44 in tumorigenesis and suggest it could be a potential therapeutic target of ovarian carcinoma.

scholarly journals RAC1/miR-3613/RAC1 feedback loop contributes to ovarian cancer progression

2021 ◽  
Author(s):  
Changzhong Li ◽  
Ruobing Leng ◽  
Yunfang Meng ◽  
Na Li ◽  
Feifei Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Progression ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Inhibitory Effect ◽  
Ovarian Cancer Cells ◽  
Negative Feedback Loop

Abstract The RAC1 signal pathway is involved in various tumor cell biological processes. Here, the role of RAC1-miR-3613-RAC1 negative feedback loop in ovarian cancer was explored. Results showed that RAC1 knockdown up-regulated miR-3613, which in turn inhibited RAC1 expression. RAC1 counteracted the inhibitory effect of miR-3613 on the proliferation and invasion of ovarian cancer cells in vitro and on the tumor growth in vivo. In ovarian cancer, miR-3613 expression was negatively correlated with RAC1, and patients with low miR-3613 expression had poor prognosis. These findings indicate the role of RAC1-miR-3613-RAC1 negative feedback loop in the malignant progression of ovarian cancer and its possible therapeutic values.

scholarly journals Estrogen receptor-α mediates gene expression changes and growth response in ovarian cancer cells exposed to estrogen

2005 ◽  
Vol 12 (4) ◽  
pp. 851-866 ◽  
Author(s):  
Amanda J M O’Donnell ◽  
Kenneth G Macleod ◽  
David J Burns ◽  
John F Smyth ◽  
Simon P Langdon
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
Estrogen Receptor ◽  
Ovarian Carcinoma ◽  
Significant Role ◽  
Target Genes ◽  
De Novo ◽  
Estrogen Receptor Α ◽  
Ovarian Cancer Cells ◽  
Real Time Quantitative Pcr

Estrogens play a significant role in the development, growth, invasion and metastasis of ovarian tumors. The transcriptional program regulated by 17β-estradiol (E2) in human ovarian cancer cell lines was analyzed using cDNA microarrays containing 1200 cancer-related genes. Twenty-eight transcripts had at least a threefold change in expression in E2-treated PEO1 ovarian carcinoma cells compared with controls. These differences were confirmed by real-time quantitative PCR and shown to be dependent upon the expression of functional estrogen receptor-α (ERα). Consistent with this, these gene expression changes were blocked by the anti-estrogen tamoxifen. The use of ERα- and ERβ-specific ligands allowed molecular dissection of the E2 response and showed that ERα activation was responsible for the observed changes in gene expression, whereas ERβ played no significant role. Inhibition of de novo protein synthesis by cycloheximide was used to distinguish between primary and secondary target genes regulated by E2. Actinomycin D was used to show that changes in gene expression levels induced by E2 were a result of changes in transcription and not due to changes in mRNA stability. The results presented here demonstrate that estrogen-driven growth of epithelial ovarian carcinoma is mediated by activation of ERα-mediated, and not ERβ-mediated, transcription.

scholarly journals PAX2 Induces Tubular-Like Structures in Normal and Ovarian Cancer Cells

2020 ◽  
Author(s):  
Kholoud Alwosaibai ◽  
Ensaf Munawer Al-Hujaily ◽  
Salmah Alamri ◽  
Kenneth Garson ◽  
Barbara C. Vanderhyden
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Cells ◽  
Cancer Progression ◽  
Ovarian Cancer Cells ◽  
Ovarian Surface Epithelial ◽  
Vascular Channels ◽  
Ovarian Epithelial Cells

AbstractIn adult tissues, PAX2 protein is expressed in normal oviductal epithelial cells but not in normal ovarian surface epithelial cells. Studies have reported that PAX2 is expressed in a subset of serous ovarian carcinoma cases but the role of PAX2 in the initiation and progression of ovarian cancer remains unknown. The aim of this study was to understand the biological consequences of Pax2 expression in normal and cancerous mouse epithelial (MOSE) cells. We found that Pax2 overexpression in both normal and cancerous ovarian epithelial cells induced the formation of vascular channels both in vitro and in vivo. The results indicate a possible contribution of PAX2 to ovarian cancer progression by increasing the vascular channels to supply nutrients to the tumor cells.

scholarly journals Role of the Exosome Secretion Machinery in Ovarian Carcinoma: In Vitro and In Vivo Models

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Esther Channah Broner ◽  
Hadil Onallah ◽  
Tali Tavor Re’em ◽  
Ben Davidson ◽  
Reuven Reich
Keyword(s):  
Ovarian Carcinoma ◽  
Mrna Expression ◽  
Carcinoma Cells ◽  
Serous Carcinoma ◽  
Clinical Role ◽  
In Vivo Models ◽  
Ovarian Carcinoma Cells

Objective. We recently reported on the expression and clinical role of molecules that mediate exosome secretion in high-grade serous carcinoma. In the present study, the biological role of these molecules was analyzed. Methods. OVCAR8 and ES-2 ovarian carcinoma cells were studied using a combination of CRISPR/Cas9 technology and two 3D in vitro models—spheroids emulating effusions and alginate scaffolds representing solid lesions. Isolation of exosomes was validated by electron microscopy. TSAP6, NSMASE2, RAB27A, and RAB27B mRNA and protein levels were analyzed using qRT-PCR and Western blotting, respectively. Tumor aggressiveness was studied in vitro using scratch assay, invasion assay, and matrix metalloproteinase (MMP) activity assay and in vivo using a mouse model. Results. In OVCAR8 cells, mRNA expression of TSAP6 and RAB27A was significantly higher in spheroids compared to scaffolds, whereas the opposite was true for NSMASE2 mRNA. In ES-2 cells, TSAP6 and RAB27B mRNA expression was significantly higher in spheroids versus scaffolds. In addition, nSMase2 and TSAP6 protein expression was significantly higher in scaffolds compared to spheroids. CRISPR-edited cells with silencing of NSMASE2, TSAP6, and RAB27A/B had reduced migration, invasion, and MMP activity. Additionally, knockout (KO) of these molecules resulted in significantly diminished exosome secretion. In vivo assay showed that when injected to mice, OVCAR8 RAB27A/B KO cells, as opposed to control OVCAR8 cells, did not form ascites or visible tumor lesions and had reduced MMP expression. Conclusion. The present study provides evidence that different models for culturing ovarian carcinoma cells affect the expression of molecules mediating exosome secretion and that these molecules have a tumor-promoting role. Silencing these molecules may consequently have therapeutic relevance in this cancer.

scholarly journals FBW7 suppresses ovarian cancer development by targeting the N6-methyladenosine binding protein YTHDF2

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Fei Xu ◽  
Jiajia Li ◽  
Mengdong Ni ◽  
Jingyi Cheng ◽  
Haiyun Zhao ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Progression ◽  
Biological Effects ◽  
Ovarian Cancer Cells ◽  
Promoting Effect ◽  
In Vivo Models ◽  
Cancer Cell Survival ◽  
Cancer Tissues

Abstract Background The tumor suppressor FBW7 is the substrate recognition component of the SCF E3-ubiquitin ligase complex that mediates proteolytic degradation of various oncogenic proteins. However, the role of FBW7 in ovarian cancer progression remains inadequately understood. Methods IP-MASS, co-IP, immunohistochemistry, and western blotting were used to identify the potential substrate of FBW7 in ovarian cancer. The biological effects of FBW7 were investigated using in vitro and in vivo models. LC/MS was used to detect the m6A levels in ovarian cancer tissues. MeRIP-Seq and RNA-Seq were used to assess the downstream targets of YTHDF2. Results We unveil that FBW7 is markedly down-regulated in ovarian cancer tissues and its high expression is associated with favorable prognosis and elevated m6A modification levels. Consistently, ectopic FBW7 inhibits ovarian cancer cell survival and proliferation in vitro and in vivo, while ablation of FBW7 empowers propagation of ovarian cancer cells. In addition, the m6A reader protein, YTHDF2, is identified as a novel substrate for FBW7. FBW7 counteracts the tumor-promoting effect of YTHDF2 by inducing proteasomal degradation of the latter in ovarian cancer. Furthermore, YTHDF2 globally regulates the turnover of m6A-modified mRNAs, including the pro-apoptotic gene BMF. Conclusions Our study has demonstrated that FBW7 suppresses tumor growth and progression via antagonizing YTHDF2-mediated BMF mRNA decay in ovarian cancer.

scholarly journals Plasma cells shape the mesenchymal identity of ovarian cancers through transfer of exosome-derived microRNAs

2021 ◽  
Vol 7 (9) ◽  
pp. eabb0737
Author(s):  
Zhengnan Yang ◽  
Wei Wang ◽  
Linjie Zhao ◽  
Xin Wang ◽  
Ryan C. Gimple ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Ovarian Cancer Cells ◽  
Mesenchymal Phenotype ◽  
Ovarian Cancers ◽  
Novel Approach

Ovarian cancer represents a highly lethal disease that poses a substantial burden for females, with four main molecular subtypes carrying distinct clinical outcomes. Here, we demonstrated that plasma cells, a subset of antibody-producing B cells, were enriched in the mesenchymal subtype of high-grade serous ovarian cancers (HGSCs). Plasma cell abundance correlated with the density of mesenchymal cells in clinical specimens of HGSCs. Coculture of nonmesenchymal ovarian cancer cells and plasma cells induced a mesenchymal phenotype of tumor cells in vitro and in vivo. Phenotypic switch was mediated by the transfer of plasma cell–derived exosomes containing miR-330-3p into nonmesenchymal ovarian cancer cells. Exosome-derived miR-330-3p increased expression of junctional adhesion molecule B in a noncanonical fashion. Depletion of plasma cells by bortezomib reversed the mesenchymal characteristics of ovarian cancer and inhibited in vivo tumor growth. Collectively, our work suggests targeting plasma cells may be a novel approach for ovarian cancer therapy.

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