The promising oncostatic effects of melatonin against ovarian cancer

Melatonin is a pineal hormone, secreted at the subjective night. It is involved in the regulation of many physiological functions, including the sleep-wake cycle, gonadal activity, free radical scavenging, immunomodulation, neuro-protection, and cancer progression. Melatonin acts through cell surface receptors (MT1 and MT2) as well as nuclear receptors. Circadian dysfunction can alter the secretion of melatonin. Inappropriate melatonin level promotes the initiation of many pathologies including cancer. Ovarian cancer is a common form of gynecological disease. Several studies indicate the profound link between impaired melatonin secretion and the progression of ovarian cancer. Melatonin exerts oncostatic effects in multiple ways; it acts as a potent antioxidant, induces apoptosis, and regulates metabolism, and chronic inflammatory response in ovarian cancer cells. Moreover, melatonin improves the efficacy of the current treatment regimen of ovarian cancer and can be used as an adjuvant.

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Effect of the HDAC Inhibitor on Histone Acetylation and Methyltransferases in A2780 Ovarian Cancer Cells

Medicina ◽

10.3390/medicina57050456 ◽

2021 ◽

Vol 57 (5) ◽

pp. 456

Author(s):

Umamaheswari Natarajan ◽

Thiagarajan Venkatesan ◽

Appu Rathinavelu

Keyword(s):

Ovarian Cancer ◽

Histone Acetylation ◽

Cancer Cells ◽

Cancer Progression ◽

Histone Deacetylases ◽

Dna Methyltransferase ◽

Positive Impact ◽

3D Cell Culture ◽

Ovarian Cancer Cells ◽

Histone Hyperacetylation

Background andObjective: Epigenetic modifications are believed to play a significant role in the development of cancer progression, growth, differentiation, and cell death. One of the most popular histone deacetylases inhibitors (HDACIs), suberoylanilide hydroxamic acid (SAHA), also known as Vorinostat, can directly activate p21WAF1/CIP1 gene transcription through hyperacetylation of histones by a p53 independent mechanism. In the present investigation, we evaluated the correlation between histone modifications and DNA methyltransferase enzyme levels following SAHA treatments in A2780 ovarian cancer cells. Materials and Methods: Acetylation of histones and methyltransferases levels were analyzed using RT2 profiler PCR array, immunoblotting, and immunofluorescence methods in 2D and 3D cell culture systems. Results: The inhibition of histone deacetylases (HDAC) activities by SAHA can reduce DNA methyl transferases / histone methyl transferases (DNMTs/HMTs) levels through induction of hyperacetylation of histones. Immunofluorescence analysis of cells growing in monolayers and spheroids revealed significant up-regulation of histone acetylation preceding the above-described changes. Conclusions: Our results depict an interesting interplay between histone hyperacetylation and a decrease in methyltransferase levels in ovarian cancer cells, which may have a positive impact on the overall outcomes of cancer treatment.

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Extracellular Vesicle Transmission of Chemoresistance to Ovarian Cancer Cells Is Associated with Hypoxia-Induced Expression of Glycolytic Pathway Proteins, and Prediction of Epithelial Ovarian Cancer Disease Recurrence

Cancers ◽

10.3390/cancers13143388 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3388

Author(s):

Mona Alharbi ◽

Andrew Lai ◽

Shayna Sharma ◽

Priyakshi Kalita-de Croft ◽

Nihar Godbole ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Progression ◽

Multiple Reaction Monitoring ◽

Metabolic Reprogramming ◽

Ovarian Cancer Cells ◽

Platinum Resistance ◽

Target Cells ◽

Glycolysis Pathway

Hypoxia is a key regulator of cancer progression and chemoresistance. Ambiguity remains about how cancer cells adapt to hypoxic microenvironments and transfer oncogenic factors to surrounding cells. In this study, we determined the effects of hypoxia on the bioactivity of sEVs in a panel of ovarian cancer (OvCar) cell lines. The data obtained demonstrate a varying degree of platinum resistance induced in OvCar cells when exposed to low oxygen tension (1% oxygen). Using quantitative mass spectrometry (Sequential Window Acquisition of All Theoretical Fragment Ion Mass Spectra, SWATH) and targeted multiple reaction monitoring (MRM), we identified a suite of proteins associated with glycolysis that change under hypoxic conditions in cells and sEVs. Interestingly, we identified a differential response to hypoxia in the OvCar cell lines and their secreted sEVs, highlighting the cells’ heterogeneity. Proteins are involved in metabolic reprogramming such as glycolysis, including putative hexokinase (HK), UDP-glucuronosyltransferase 1–6 (UD16), and 6-phosphogluconolactonase (6 PGL), and their presence correlates with the induction of platinum resistance. Furthermore, when normoxic cells were exposed to sEVs from hypoxic cells, platinum-resistance increased significantly (p < 0.05). Altered chemoresistance was associated with changes in glycolysis and fatty acid synthesis. Finally, sEVs isolated from a clinical cohort (n = 31) were also found to be enriched in glycolysis-pathway proteins, especially in patients with recurrent disease. These data support the hypothesis that hypoxia induces changes in sEVs composition and bioactivity that confers carboplatin resistance on target cells. Furthermore, we propose that the expression of sEV-associated glycolysis-pathway proteins is predictive of ovarian cancer recurrence and is of clinical utility in disease management.

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Dynamic changes in the urine proteome in two ovarian cancer rat models

10.1101/604850 ◽

2019 ◽

Author(s):

Yuqiu Li ◽

Linpei Zhang ◽

Wenshu Meng ◽

Youhe Gao

Keyword(s):

Ovarian Cancer ◽

Early Detection ◽

Cancer Progression ◽

The Body ◽

Cancer Development ◽

Ovarian Cancer Cells ◽

Rat Models ◽

Gynecological Malignancy ◽

Injection Model ◽

Differential Proteins

AbstractOvarian cancer is the most lethal gynecological malignancy in women, and it is likely to metastasize and has a poor prognosis. The early and reliable diagnosis and monitoring of ovarian cancer is very important. Without a homeostasis mechanism, urine can reflect early systemic changes in the body and has a great potential to be used for the early detection of cancer. This study tested whether early changes could be detected in two ovarian cancer rat models. Two rat models were established by either intraperitoneal (i.p.) or orthotopic (o.t.) injection of NuTu-19 ovarian cancer cells in female Fischer344 rats. Urine samples from ovarian cancer rats were collected at five time points during cancer development, and urinary proteins from the rats were profiled by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Compared with pre-injection samples, 49 differential proteins that have human orthologues were significantly changed in the orthotopically injected model. Among them, 24 of the differential proteins have previously been reported to be associated with ovarian cancer, six of which were reported to be biomarkers of ovarian cancer. On the 7th day after orthotopic injection, four differential proteins (APOA1, OX2G, CHMP5, HEXB) were identified before obvious metastases appeared. In the intraperitoneal injection model, 76 differential proteins were changed during the course of ovarian cancer development. The results show that urine proteins could enable the early detection and monitoring of ovarian cancer progression and could lay a foundation for further exploration of the biomarkers of ovarian cancer.

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FSCN1 Promotes Epithelial-Mesenchymal Transition Through Increasing Snail1 in Ovarian Cancer Cells

Cellular Physiology and Biochemistry ◽

10.1159/000493622 ◽

2018 ◽

Vol 49 (5) ◽

pp. 1766-1777 ◽

Cited By ~ 8

Author(s):

Jie Li ◽

Songlin Zhang ◽

Meili Pei ◽

Lei Wu ◽

Yanli Liu ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

Ovarian Cancer Cell ◽

Ovarian Cancer Cells ◽

Transwell Assay ◽

Mesenchymal Transition ◽

Novel Target ◽

Snail1 Expression

Background/Aims: Epithelial-mesenchymal transition (EMT) is one of the key mechanisms mediating cancer progression. Snail1 has a pivotal role in the regulation of EMT, involving the loss of E-cadherin and concomitant upregulation of vimentin, among other biomarkers. We have found FSCN1 promoted EMT in ovarian cancer cells, but the precise mechanism of FSCN1 in EMT process has not been clearly elucidated. Methods: The levels of FSCN1 and snail1 were determined in epithelial ovarian cancer(EOC) specimen and in ovarian cancer cells by RT-qPCR. The changes of EMT makers and effects on snail1 by FSCN1 were examined by overexpression or depletion of FSCN1 in EOC cells by RT-qPCR and western blotting. The invasiveness of the FSCN1-modified EOC cells was examined in transwell assay. Co-immunoprecipitation (IP) was performed to detect the interaction between snail1 and FSCN1 in EOC cells. Results: We found FSCN1 and snail1 significantly increased in EOC, and especially in EOC with metastasis. FSCN1 was positively correlated with snail1 expression at the cellular/histological levels. Moreover, we further showed that FSCN1 physiologically interacted with and increased the levels of snail1 to promote ovarian cancer cell EMT. Conclusion: FSCN1 promote EMT through snail1 in ovarian cancer cells. FSCN1 is an attractive novel target for inhibiting invasion and metastasis of EOC cells.

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Circular RNA hsa_circ_0078607 suppresses ovarian cancer progression by regulating miR-518a-5p/Fas signaling pathway

10.21203/rs.3.rs-21388/v1 ◽

2020 ◽

Author(s):

Nan Zhang ◽

Yue Jin ◽

Qiubo Hu ◽

Shanshan Cheng ◽

Chao Wang ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Malignant Tumors ◽

Circular Rna ◽

Luciferase Reporter ◽

Circular Rnas ◽

Ovarian Cancer Cells ◽

Cancer Pathogenesis ◽

Direct Target

Abstract Background: Increasing researches have demonstrated the critical functions of circular RNAs (circRNAs) in the progression of malignant tumors, including ovarian cancer. In this study, we aim to investigate abnormally expression of hsa_circ_0078607 and the role of hsa_circ_0078607 during ovarian cancer pathogenesis.Methods: RT-PCR were used to detect the expression of circ_0078607 in ovarian cancer tissues. To determine the functional roles of circ_0078607 in ovarian cancer, cell proliferation and cell invasion assays were performed. Bioinformatics and luciferase reporter analysis were used to predict the target of circ_0078607.Results: In the present study, we first found that circ_0078607 was downregulated in ovarian cancer. Forced circ_0078607 expression significantly suppressed proliferation and promotes apoptosis of ovarian cancer cells. Mechanically, bioinformatics and luciferase reporter analysis identified that miR-518a-5p as a direct target of circ_0078607, while Fas as a direct target of miR-518a-5p. MiR-518a-5p negatively regulates Fas in ovarian cancer cells, while overexpression of circ_0078607 could increase the expression of Fas inhibited by miR-518a-5p. Furthermore, overexpression of circ_0078607 could inhibit the proliferation and invasion of ovarian cancer cells caused by miR-518a-5p mimic.Conclusion: The results of the present study revealed that circ_0078607 suppresses ovarian cancer progression by sponging oncogenic miR-518a-5p to induce Fas expression, which may provide new therapeutic approach for ovarian cancer.

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TIMP-2 regulates proliferation, invasion and STAT3-mediated cancer stem cell-dependent chemoresistance in ovarian cancer cells

BMC Cancer ◽

10.1186/s12885-020-07274-6 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Ruth M. Escalona ◽

Maree Bilandzic ◽

Patrick Western ◽

Elif Kadife ◽

George Kannourakis ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Lines ◽

Cancer Progression ◽

Mrna Level ◽

Tissue Inhibitors Of Metalloproteinases ◽

Ovarian Cancer Cells ◽

Knock Down ◽

Protein Levels ◽

Response To Chemotherapy

Abstract Background The metzincin family of metalloproteinases and the tissue inhibitors of metalloproteinases (TIMPs) are essential proteins required for biological processes during cancer progression. This study aimed to determine the role of TIMP-2 in ovarian cancer progression and chemoresistance by reducing TIMP-2 expression in vitro in Fallopian tube secretory epithelial (FT282) and ovarian cancer (JHOS2 and OVCAR4) cell lines. Methods FT282, JHOS2 and OVCAR4 cells were transiently transfected with either single or pooled TIMP-2 siRNAs. The expression of different genes after TIMP-2 knock down (T2-KD) or in response to chemotherapy was determined at the mRNA level by quantitative real time PCR (qRT-PCR) and at the protein level by immunofluorescence. Sensitivity of the cell lines in response to chemotherapy after TIMP-2 knock down was investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and 5-Ethynyl-2′-deoxyuridine (EdU) assays. Cell invasion in response to TIMP-2 knockdown was determined by xCELLigence. Results Sixty to 90 % knock down of TIMP-2 expression was confirmed in FT282, OVCAR4 and JHOS2 cell lines at the mRNA and protein levels. TIMP-2 knock down did not change the mRNA expression of TIMP-1 or TIMP-3. However, a significant downregulation of MMP-2 in T2-KD cells occurred at both the protein and activation levels, compared to Control (Cont; scrambled siRNA) and Parental cells (P, transfection reagent only). In contrast, membrane bound MT1-MMP protein levels were significantly upregulated in T2-KD compared to Cont and P cells. T2-KD cells exhibited enhanced proliferation and increased sensitivity to cisplatin and paclitaxel treatments. Enhanced invasion was observed in the T2-KD-JOSH2 and OVCAR4 cells but not in T2-KD-FT282 cells. Treatment with cisplatin or paclitaxel significantly elevated the expression of TIMP-2 in Cont cells but not in T2-KD cells, consistent with significantly elevated expression of chemoresistance and CSC markers and activation of STAT3. Furthermore, a potent inhibitor of STAT3 activation, Momelotinib, suppressed chemotherapy-induced activation of P-STAT3 in OVCAR4 cells with concomitant reductions in the expression of chemoresistance genes and CSC markers. Conclusions The above results suggest that TIMP-2 may have a novel role in ovarian cancer proliferation, invasion and chemoresistance.

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miR-4461 Regulates the Proliferation and Metastasis of Ovarian Cancer Cells and Cisplatin Resistance

Frontiers in Oncology ◽

10.3389/fonc.2021.614035 ◽

2021 ◽

Vol 11 ◽

Author(s):

Lei Dou ◽

Yi Zhang

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Luciferase Reporter ◽

Ovarian Cancer Cells ◽

Obvious Effect ◽

Proliferation And Metastasis ◽

Direct Target ◽

Cancer Tissues ◽

And Control

microRNAs (miRNAs) are of great significance in cancer treatment, which may have a desirable result on the regulation of tumorigenesis, progression, recurrence, and chemo-resistance of ovarian cancer. However, the research on the further potential application of miR-4461 in ovarian cancer is little and limited. Therefore, the study in this paper focus on the investigation of the of miR-4461 in ovarian cancer progression and chemo-resistance. The phenomenon that the proliferation and metastasis of ovarian cancer cells can be promoted by miR4461 is revealed in functional assays. Through the bioinformatics and luciferase reporter analysis, the PTEN is validated to be the direct target of miR-4461 in ovarian. The association between the expression of miR-4461 and PTEN is negative in in human ovarian cancer tissues. The distinction of growth and metastasis capacity between miR-4461 knockdown ovarian cancer cells and control cells is partially abolished by si-PTEN. Moreover, it was found that cisplatin treatment has obvious effect on the miR-4461 knockdown ovarian cancer cells. In summary, the data given in this paper indicate that the miR-4461 can be regarded as a potential onco-miRNA in ovarian cancer by targeting PTEN.

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Identification and Functional Validation of Differentially Expressed Micrornas in Ascites-derived Ovarian Cancer Cells Compared With Primary Tumour Tissue

10.21203/rs.3.rs-51079/v1 ◽

2020 ◽

Author(s):

Yahui Jiang ◽

Tianjiao Lyu ◽

Hua Liu ◽

Lifei Shen ◽

Yiwen Shi ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Progression ◽

Cancer Metastasis ◽

Primary Tumour ◽

Malignant Ascites ◽

Differentially Expressed ◽

Tumour Tissue ◽

Ovarian Cancer Cells ◽

Hub Genes ◽

Mirnas Expression

Abstract Purpose: Ovarian cancer, manifested by malignant ascites, is the most lethal gynaecological cancer. Suspended ascites-derived spheroids may contribute to ovarian cancer metastasis. MicroRNAs (miRNAs) are also associated with ovarian cancer metastasis. Here, we aimed to investigate the differentially expressed miRNAs (DE-miRNAs) in ascites-derived spheroids compared with primary tumour tissue, which may regulate ovarian cancer metastasis.Methods: The DE-miRNAs between ovarian cancer primary tumour tissues and ascites-derived spheroids were identified by GEO2R screening in dataset GSE65819. We used MiRTarBase and STRING to predict the target hub genes of DE-miRNAs and WebGestalt to perform functional analysis of hub genes. ALGGEN PROMO and TransmiR v2.0 were used to predict the common transcription factors (TFs) that potentially regulate DE-miRNAs expression. The observed differences in DE-miRNAs expression were validated with human ovarian cancer samples and ovarian cancer cell lines using PCR. The functions of DE-miRNAs on ovarian cancer progression were verified by transwell and angiogenesis assays.Results: Through bioinformatics screening and experimental validation, miR-199a-3p, miR-199b-3p, miR-199a-5p, miR-126-3p and miR-145-5p were identified as being significantly downregulated in ascites-derived spheroids compared with primary tumour tissues. In addition, TFAP2A was identified as a potentially common upstream TF regulating the expression of the abovementioned DE-miRNAs. The overexpression of miR-199a-3p, miR-199b-3p, miR-199a-5p could inhibit ovarian cancer invasion, and the overexpression of miR-145-5p could inhibit angiogenesis.Conclusion: The downregulated expression of miR-199a-3p, miR-199b-3p, miR-199a-5p, miR-126-3p and miR-145-5p in ascites-derived spheroids plays a key role in promoting ovarian cancer progression, which may represent novel molecules for targeted therapy for ovarian cancer.

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Transcriptome Profiling Reveals Matrisome Alteration as a Key Feature of Ovarian Cancer Progression

Cancers ◽

10.3390/cancers11101513 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1513 ◽

Cited By ~ 4

Author(s):

Sumegha Mitra ◽

Kartikeya Tiwari ◽

Ram Podicheti ◽

Taruni Pandhiri ◽

Douglas B. Rusch ◽

...

Keyword(s):

Gene Expression ◽

Ovarian Cancer ◽

Cancer Progression ◽

3D Culture ◽

Ovarian Cancer Cells ◽

Fallopian Tubes ◽

Rna Seq ◽

Primary Tumors ◽

Metastatic Colonization ◽

Culture Model

Background: Ovarian cancer is the most lethal gynecologic malignancy. There is a lack of comprehensive investigation of disease initiation and progression, including gene expression changes during early metastatic colonization. Methods: RNA-sequencing (RNA-seq) was done with matched primary tumors and fallopian tubes (n = 8 pairs) as well as matched metastatic and primary tumors (n = 11 pairs) from ovarian cancer patients. Since these are end point analyses, it was combined with RNA-seq using high-grade serous ovarian cancer cells seeded on an organotypic three-dimensional (3D) culture model of the omentum, mimicking early metastasis. This comprehensive approach revealed key changes in gene expression occurring in ovarian cancer initiation and metastasis, including early metastatic colonization. Results: 2987 genes were significantly deregulated in primary tumors compared to fallopian tubes, 845 genes were differentially expressed in metastasis compared to primary tumors and 304 genes were common to both. An assessment of patient metastasis and 3D omental culture model of early metastatic colonization revealed 144 common genes that were altered during early colonization and remain deregulated even in the fully developed metastasis. Deregulation of the matrisome was a key process in early and late metastasis. Conclusion: These findings will help in understanding the key pathways involved in ovarian cancer progression and eventually targeting those pathways for therapeutic interventions.

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Paclitaxel-Induced Src Activation Is Inhibited by Dasatinib Treatment, Independently of Cancer Stem Cell Properties, in a Mouse Model of Ovarian Cancer

Cancers ◽

10.3390/cancers11020243 ◽

2019 ◽

Vol 11 (2) ◽

pp. 243 ◽

Cited By ~ 3

Author(s):

Elif Kadife ◽

Emily Chan ◽

Rodney Luwor ◽

George Kannourakis ◽

Jock Findlay ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Progression ◽

Mononuclear Cells ◽

Ovarian Cancer Cells ◽

Small Subset ◽

Ovarian Carcinomas ◽

Ovarian Cancer Cell Lines ◽

Benign Ovarian Tumours ◽

Src Activation

Approximately seventy percent of ovarian cancer patients succumb to the disease within the first 5 years of diagnosis, even after successful surgery and effective chemotherapy treatment. A small subset of chemotherapy resistant cancer stem cells (CSCs) cause relapse of ovarian cancers. This study investigated the association between paclitaxel-mediated Src activation (p-Src) and CSC populations in driving ovarian cancer progression. We demonstrate that patients with high-stage serous ovarian carcinomas have significantly elevated levels of p-Src, compared to patient with low-stage and benign ovarian tumours. Additionally, p-Src was significantly enhanced in ascites-derived tumour cells obtained from recurrent patients, compared to chemonaïve patients. Paclitaxel treatment increased Src activation in ovarian cancer cells, causing enrichment of CSC marker expression in the surviving cells in vitro and in xenografts of nude mice. Dasatinib in combination with paclitaxel significantly suppressed p-Src in ovarian cancer cell lines and xenografts but had no effect on the expression of CSC markers. However, combination of paclitaxel and Dasatinib showed lower trend in invasion in liver and pancreas, compared to paclitaxel-only treatment. The tumours treated with combination therapy also had significantly lower infiltration of mononuclear cells. Robust recurrent tumour growth was observed in all mice groups after termination of treatments. The above results suggest that Dasatinib-mediated inhibition of p-Src may not be crucial for paclitaxel-induced CSC-mediated recurrence in ovarian cancer.

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