MiR-200c-3p Contrasts PD-L1 Induction by Combinatorial Therapies and Slows Proliferation of Epithelial Ovarian Cancer through Downregulation of β-Catenin and c-Myc

Conventional/targeted chemotherapies and ionizing radiation (IR) are being used both as monotherapies and in combination for the treatment of epithelial ovarian cancer (EOC). Several studies show that these therapies might favor oncogenic signaling and impede anti-tumor responses. MiR-200c is considered a master regulator of EOC-related oncogenes. In this study, we sought to investigate if chemotherapy and IR could influence the expression of miR-200c-3p and its target genes, like the immune checkpoint PD-L1 and other oncogenes in a cohort of EOC patients’ biopsies. Indeed, PD-L1 expression was induced, while miR-200c-3p was significantly reduced in these biopsies post-therapy. The effect of miR-200c-3p target genes was assessed in miR-200c transfected SKOV3 cells untreated and treated with olaparib and IR alone. Under all experimental conditions, miR-200c-3p concomitantly reduced PD-L1, c-Myc and β-catenin expression and sensitized ovarian cancer cells to olaparib and irradiation. In silico analyses further confirmed the anti-correlation between miR-200c-3p with c-Myc and β-catenin in 46 OC cell lines and showed that a higher miR-200c-3p expression associates with a less tumorigenic microenvironment. These findings provide new insights into how miR-200c-3p could be used to hold in check the adverse effects of conventional chemotherapy, targeted therapy and radiation therapy, and offer a novel therapeutic strategy for EOC.

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MiRNA-802 suppresses proliferation and migration of epithelial ovarian cancer cells by targeting YWHAZ

Journal of Ovarian Research ◽

10.1186/s13048-019-0576-3 ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 8

Author(s):

Bo Yang ◽

Li Sun ◽

Lei Liang

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Target Genes ◽

Gene Prediction ◽

Biological Effects ◽

Expression Level ◽

Ovarian Cancer Cells ◽

And Migration

Abstract Background The imbalance of expression of microRNA-802 may have a significant place in tumor progression. However, the bio-function of epithelial ovarian cancer cells remains unclear. Therefore, we setup this study to explore the pathogenesis of epithelial ovarian cancer based on microRNA-802. Methods RT-qPCR analysis was used to measure the expression level of microRNA802 and YWHAZ in epithelial ovarian cancer. CCK-8, colony formation, flow cytometry and transwell assay were used to detect the effects of microRNA-802 on cell proliferation, apoptosis, invasion and migration. Target gene prediction and screening, luciferase reporting experiments were applied to validate the downstream target genes of microRNA-802. The effects of microRNA-802 on the expression of YWHAZ and its biological effects were measured by Western blotting and RT-qPCR. Results Compared with normal cell lines and tissues, the expression level of microRNA-802 was obviously down-regulated in cancer related cell lines and tissues. Overexpression of microRNA-802 could obviously inhibit the invasion and proliferation and induce apoptosis. In addition, YWHAZ was the binding target protein of miR-802 for epithelial ovarian cancer cells. YWHAZ was obviously up-regulated in human epithelial ovarian cancer cells, and YWHAZ was negatively correlated with the expression of miR-802. YWHAZ can partly eliminate the inhibitory effect caused by overexpression of miR-802 on growth and metastasis of epithelial ovarian cancer cells. Conclusion miR-802 can regulate the occurrence and development of epithelial ovarian cancer by targeting YWHAZ.

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MiR-200c sensitizes Olaparib-resistant ovarian cancer cells by targeting Neuropilin 1

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-019-1490-7 ◽

2020 ◽

Vol 39 (1) ◽

Cited By ~ 5

Author(s):

Enrica Vescarelli ◽

Giulia Gerini ◽

Francesca Megiorni ◽

Eleni Anastasiadou ◽

Paola Pontecorvi ◽

...

Keyword(s):

Ovarian Cancer ◽

Western Blot ◽

Cell Lines ◽

Target Genes ◽

Model Systems ◽

Ovarian Cancer Cells ◽

Drug Resistant ◽

Neuropilin 1 ◽

Skov3 Cells ◽

Resistant Cells

Abstract Background Ovarian cancer (OC) is the most lethal gynecological malignancy and the second leading cause of cancer-related death in women. Treatment with PARP inhibitors (PARPi), such as Olaparib, has been recently introduced for OC patients, but resistance may occur and underlying mechanisms are still poorly understood. The aim of this study is to identify target genes within the tumor cells that might cause resistance to Olaparib. We focused on Neuropilin 1 (NRP1), a transmembrane receptor expressed in OC and correlated with poor survival, which has been also proposed as a key molecule in OC multidrug resistance. Methods Using three OC cell lines (UWB, UWB-BRCA and SKOV3) as model systems, we evaluated the biological and molecular effects of Olaparib on OC cell growth, cell cycle, DNA damage and apoptosis/autophagy induction, through MTT and colony forming assays, flow cytometry, immunofluorescence and Western blot analyses. We evaluated NRP1 expression in OC specimens and cell lines by Western blot and qRT-PCR, and used RNA interference to selectively inhibit NRP1. To identify miR-200c as a regulator of NRP1, we used miRNA target prediction algorithms and Pearsons’ correlation analysis in biopsies from OC patients. Then, we used a stable transfection approach to overexpress miR-200c in Olaparib-resistant cells. Results We observed that NRP1 is expressed at high levels in resistant cells (SKOV3) and is upmodulated in partially sensitive cells (UWB-BRCA) upon prolonged Olaparib treatment, leading to poor drug response. Our results show that the selective inhibition of NRP1 is able to overcome Olaparib resistance in SKOV3 cells. Moreover, we demonstrated that miR-200c can target NRP1 in OC cells, causing its downmodulation, and that miR-200c overexpression is a valid approach to restore Olaparib sensitivity in OC resistant cells. Conclusions These data demonstrate that miR-200c significantly enhanced the anti-cancer efficacy of Olaparib in drug-resistant OC cells. Thus, the combination of Olaparib with miRNA-based therapy may represent a promising treatment for drug resistant OC, and our data may help in designing novel precision medicine trials for optimizing the clinical use of PARPi.

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Deregulation of miR-128 in Ovarian Cancer Promotes Cisplatin Resistance

International Journal of Gynecological Cancer ◽

10.1097/igc.0000000000000252 ◽

2014 ◽

Vol 24 (8) ◽

pp. 1381-1388 ◽

Cited By ~ 23

Author(s):

Bing Li ◽

Hong Chen ◽

Nan Wu ◽

Wen-Jing Zhang ◽

Li-Xin Shang

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Cisplatin Resistance ◽

Ovarian Cancer Cell Line ◽

Advanced Ovarian Cancer ◽

Ovarian Cancer Cells ◽

Dependent Manner ◽

Ovarian Carcinomas ◽

Platinum Based Chemotherapy ◽

Skov3 Cells

ObjectivePlatinum-based chemotherapy is the standard treatment in advanced ovarian cancer, but most patients will relapse with drug-resistant disease. MicroRNAs have been demonstrated to function in chemoresistance in cancers. In this study, we focused on the role of miR-128 in cisplatin-resistant ovarian cancer.Materials and MethodsThe expression of miR-128 RNA and its targeted genes, the polycomb ring finger oncogene Bmi-1 and ATP-binding cassette subfamily C member 5 (ABCC5), were investigated in the epithelial ovarian cancer cells and ovarian carcinomas.ResultsmiR-128 expression was significantly reduced in the cisplatin-resistant human epithelial ovarian cancer cell line SKOV3/CP compared with parental SKOV3 cells and decreased upon treatment with cisplatin in a concentration-dependent manner in SKOV3, OVCAR3, and PEO14 cells. Overexpression of miR-128 resensitized SKOV3/CP cells to cisplatin and reduced the expression of cisplatin-resistant–related proteins ABCC5 and Bmi-1, whereas miR-128 inhibitors increased cisplatin resistance in SKOV3 cells. Cisplatin combined with miR-128 agomirs inhibited the growth of SKOV3/CP xenograft tumors more effectively than cisplatin alone. Diminished expression of ABCC5 and Bmi-1 and higher cisplatin concentrations were observed in tumor tissue of mice treated with miR-128 agomirs in addition to cisplatin.ConclusionsTaken together, our findings suggest that miR-128 may act as a promising therapeutic target for improvement of tumor sensitivity to cisplatin.

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NTNG1 Modulates Cisplatin Resistance in Epithelial Ovarian Cancer Cells via the GAS6/AXL/Akt Pathway

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.652325 ◽

2021 ◽

Vol 9 ◽

Author(s):

Shanyu Fang ◽

Yuanyuan Luo ◽

Ying Zhang ◽

Houmei Wang ◽

Qianfen Liu ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Cancer Cells ◽

Cisplatin Resistance ◽

Progression Free Survival ◽

Akt Pathway ◽

Ovarian Cancer Cells ◽

Skov3 Cells ◽

Cancer Tissues

Cisplatin resistance is a challenge in the treatment of epithelial ovarian cancer. Here, clinical data showed that the level of netrin-G1 (NTNG1) in cisplatin-resistant cancer was higher than that in cisplatin-sensitive cancer (2.2-fold, p = 0.005); patients with a high NTNG1 level in cancer tissues had shorter progression-free survival (11.0 vs. 25.0 months, p = 0.010) and platinum-free interval (5.0 vs. 20.0 months, p = 0.021) compared with patients with a low level. Category- or stage-adjusted analyses demonstrated that the association between the NTNG1 level and prognosis occurred in type II or FIGO III/IV cancer. The basal level of NTNG1 in SKOV3/DDP cells (a cisplatin-resistant subline) was higher than that in SKOV3 cells; therefore, NTNG1 was overexpressed in SKOV3 cells, or silenced in SKOV3/DDP cells. Knocking in NTNG1 reduced the action of cisplatin to decrease cell death and apoptosis of SKOV3 cells, accompanied by upregulation of p-AXL, p-Akt and RAD51; however, opposite effects were observed in SKOV3/DDP cells after knocking down NTNG1. Co-immunoprecipitation demonstrated that NTNG1 bound GAS6/AXL. Silencing NTNG1 enhanced cisplatin effects in vivo, decreasing tumor volume/mass. These data suggested that a high NTNG1 level can result in cisplatin resistance in ovarian cancer cells via the GAS6/AXL/Akt pathway and that NTNG1 may be a useful target to overcome resistance.

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Metformin Reduces NGF-Induced Tumour Promoter Effects in Epithelial Ovarian Cancer Cells

Pharmaceuticals ◽

10.3390/ph13100315 ◽

2020 ◽

Vol 13 (10) ◽

pp. 315

Author(s):

Maritza P. Garrido ◽

Renato Salvatierra ◽

Manuel Valenzuela-Valderrama ◽

Christopher Vallejos ◽

Nicole Bruneau ◽

...

Keyword(s):

Ovarian Cancer ◽

Growth Factor ◽

Epithelial Ovarian Cancer ◽

Complementary Therapy ◽

Ovarian Cancer Cells ◽

Angiogenic Potential ◽

Skov3 Cells ◽

High Affinity Receptor ◽

Ovarian Surface Epithelial

Epithelial ovarian cancer (EOC) is a lethal gynaecological neoplasm characterized by rapid growth and angiogenesis. Nerve growth factor (NGF) and its high affinity receptor tropomyosin receptor kinase A (TRKA) contribute to EOC progression by increasing the expression of c-MYC, survivin and vascular endothelial growth factor (VEGF) along with a decrease in microRNAs (miR) 23b and 145. We previously reported that metformin prevents NGF-induced proliferation and angiogenic potential of EOC cells. In this study, we sought to obtain a better understanding of the mechanism(s) by which metformin blocks these NGF-induced effects in EOC cells. Human ovarian surface epithelial (HOSE) and EOC (A2780/SKOV3) cells were stimulated with NGF and/or metformin to assess the expression of c-MYC, β-catenin, survivin and VEGF and the abundance of the tumor suppressor miRs 23b and 145. Metformin decreased the NGF-induced transcriptional activity of MYC and β-catenin/T-cell factor/lymphoid enhancer-binding factor (TCF-Lef), as well as the expression of c-MYC, survivin and VEGF in EOC cells, while it increased miR-23b and miR-145 levels. The preliminary analysis of ovarian biopsies from women users or non-users of metformin was consistent with these in vitro results. Our observations shed light on the mechanisms by which metformin may suppress tumour growth in EOC and suggest that metformin should be considered as a possible complementary therapy in EOC treatment.

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ROS production is required for follicle-stimulating hormone-induced Nrf2 activation in human epithelial ovarian cancer cells

Academic Journal of Second Military Medical University ◽

10.3724/sp.j.1008.2012.00935 ◽

2013 ◽

Vol 32 (9) ◽

pp. 935-939

Author(s):

Jie MA ◽

Qian-qian WANG ◽

Hong LIAO ◽

Yong-bin YANG ◽

Zhi-jun JIN ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Cancer Cells ◽

Follicle Stimulating Hormone ◽

Ovarian Cancer Cells ◽

Ros Production ◽

Nrf2 Activation ◽

Stimulating Hormone

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Combined chemotherapy and allogeneic human Vγ9Vδ2 T lymphocyte-immunotherapies efficiently control the development of human epithelial ovarian cancer cells in vivo

OncoImmunology ◽

10.1080/2162402x.2019.1649971 ◽

2019 ◽

Vol 8 (11) ◽

pp. e1649971 ◽

Cited By ~ 2

Author(s):

Noémie Joalland ◽

Laura Lafrance ◽

Thibauld Oullier ◽

Séverine Marionneau-Lambot ◽

Delphine Loussouarn ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Cancer Cells ◽

T Lymphocyte ◽

Ovarian Cancer Cells ◽

Combined Chemotherapy

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Dasatinib (BMS-35482) Interacts Synergistically With Docetaxel, Gemcitabine, Topotecan, and Doxorubicin in Ovarian Cancer Cells With High SRC Pathway Activation and Protein Expression

International Journal of Gynecological Cancer ◽

10.1097/igc.0000000000000056 ◽

2014 ◽

Vol 24 (2) ◽

pp. 218-225 ◽

Cited By ~ 5

Author(s):

Angeles Alvarez Secord ◽

Deanna Teoh ◽

Jingquan Jia ◽

Andrew B. Nixon ◽

Lisa Grace ◽

...

Keyword(s):

Ovarian Cancer ◽

Protein Expression ◽

Cancer Cells ◽

Combination Index ◽

Chemotherapeutic Agents ◽

Cytotoxic Agents ◽

Ovarian Cancer Cells ◽

Response Curves ◽

Pathway Activation ◽

Skov3 Cells

PurposeThis study aimed to explore the activity of dasatinib in combination with docetaxel, gemcitabine, topotecan, and doxorubicin in ovarian cancer cells.MethodsCells with previously determined SRC pathway and protein expression (SRC pathway/SRC protein IGROV1, both high; SKOV3, both low) were treated with dasatinib in combination with the cytotoxic agents. SRC and paxillin protein expression were determined pretreatment and posttreatment. Dose-response curves were constructed, and the combination index (CI) for drug interaction was calculated.ResultsIn the IGROV1 cells, dasatinib alone reduced phospho-SRC/total SRC 71% and p-paxillin/t-paxillin ratios 77%. Phospho-SRC (3%–33%; P = 0.002 to 0.04) and p-paxicillin (6%–19%; P = 0.01 to 0.05) levels were significantly reduced with dasatinib in combination with each cytotoxic agent. The combination of dasatinib and docetaxel, gemcitabine, or topotecan had a synergistic antiproliferative effect (CI, 0.49–0.68), whereas dasatinib combined with doxorubicin had an additive effect (CI, 1.08).In SKOV3 cells, dasatinib resulted in less pronounced reductions of phospho-SRC/total SRC (49%) and p-paxillin/t-paxillin (62%). Phospho-SRC (18%; P < 0.001) and p-paxillin levels (18%; P = 0.001; 9%; P = 0.007) were significantly decreased when dasatinib was combined with docetaxel and topotecan (p-paxillin only). Furthermore, dasatinib combined with the cytotoxics in the SKOV3 cells produced an antagonistic interaction on the proliferation of these cells (CI, 1.49–2.27).ConclusionsDasatinib in combination with relapse chemotherapeutic agents seems to interact in a synergistic or additive manner in cells with high SRC pathway activation and protein expression. Further evaluation of dasatinib in combination with chemotherapy in ovarian cancer animal models and exploration of the use of biomarkers to direct therapy are warranted.

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