Inhibition of miR-214-3p Aids in Preventing Epithelial Ovarian Cancer Malignancy by Increasing the Expression of LHX6

In human epithelial ovarian cancer (EOC), various miRNAs can function as either oncogenes or tumor suppressor genes. We investigated miRNAs known to be involved in EOC progression and analyzed their expression in tissues and serum-derived exosomes from benign serous cystadenoma, borderline serous tumor, low-grade serous ovarian cancer, and high-grade serous ovarian cancer patients (HGSO). The HGSO group was divided based on the platinum-free interval, which is defined as the duration from the completion of platinum-based chemotherapy to recurrence. We also analyzed the mRNA levels of target genes that candidate miRNAs might regulate in patient tissues. miR-214-3p was highly expressed in tissues and exosomes derived from EOC with high malignancy and also found to regulate the expression of LIM homeobox domain 6 (LHX6) mRNA. Serum exosomal levels of miR-214-3p were significantly increased in platinum-resistant HGSO (25.2-fold, p < 0.001) compared to the exosomal expression of benign tumor patients. On transfection of miR-214-3p inhibitor in EOC cells, cell proliferation was inhibited while apoptotic cell death was increased. Collectively, we suggest that miR-214-3p in serum exosomes can be a potential biomarker for the diagnosis and prognosis of ovarian tumor, and its inhibition can be a supportive treatment for EOC.

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ZYG11A Is Expressed in Epithelial Ovarian Cancer and Correlates With Low Grade Disease

Frontiers in Endocrinology ◽

10.3389/fendo.2021.688104 ◽

2021 ◽

Vol 12 ◽

Author(s):

Laris Achlaug ◽

Lina Somri-Gannam ◽

Shilhav Meisel-Sharon ◽

Rive Sarfstein ◽

Manisha Dixit ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Growth Hormone Receptor ◽

Histological Grade ◽

Inverse Correlation ◽

Low Grade ◽

Mrna Levels ◽

Knock Out ◽

Coordinated Expression ◽

Candidate Target

The insulin-like growth factors (IGF) are important players in the development of gynecological malignancies, including epithelial ovarian cancer (EOC). The identification of biomarkers that can help in the diagnosis and scoring of EOC patients is of fundamental importance in clinical oncology. We have recently identified the ZYG11A gene as a new candidate target of IGF1 action. The aim of the present study was to evaluate the expression of ZYG11A in EOC patients and to correlate its pattern of expression with histological grade and pathological stage. Furthermore, and in view of previous analyses showing an interplay between ZYG11A, p53 and the IGF1 receptor (IGF1R), we assessed a potential coordinated expression of these proteins in EOC. In addition, zyg11a expression was assessed in ovaries and uteri of growth hormone receptor (GHR) knock-out mice. Tissue microarray analysis was conducted on 36 patients with EOC and expression of ZYG11A, IGF1R and p53 was assessed by immunohistochemistry. Expression levels were correlated with clinical parameters. qPCR was employed to assess zyg11a mRNA levels in mice tissues. Our analyses provide evidence of reduced ZYG11A expression in high grade tumors, consistent with a putative tumor suppressor role. In addition, an inverse correlation between ZYG11A and p53 levels in individual tumors was noticed. Taken together, our data justify further exploration of the role of ZYG11A as a novel biomarker in EOC.

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New therapeutic opportunities for low-grade serous ovarian cancer

Endocrine Related Cancer ◽

10.1530/erc-21-0191 ◽

2021 ◽

Author(s):

Tania Moujaber ◽

Rosemary L Balleine ◽

Bo Gao ◽

Ida Madsen ◽

Paul R Harnett ◽

...

Keyword(s):

Ovarian Cancer ◽

Hormone Receptors ◽

Residual Disease ◽

Objective Response ◽

Response Rates ◽

Steroid Hormone Receptors ◽

Mitogen Activated Protein Kinase ◽

Low Grade ◽

Serous Ovarian Cancer ◽

Platinum Based Chemotherapy

Low-grade serous ovarian cancer (LGSC) is a morphologically and molecularly distinct subtype of ovarian cancer, accounting for ~10% of serous carcinomas. Women typically present at a younger age and have a protracted clinical course compared with the more common, high-grade serous ovarian cancer. Currently, primary treatment of LGSC is the same as other epithelial ovarian cancer subtypes, with treatment for most patients comprised of debulking surgery and platinum/taxane chemotherapy. Primary surgical cytoreduction to no visible residual disease remains a key prognostic factor, however the use of platinum-based chemotherapy in both the upfront and relapsed setting, is being questioned due to low response rates in LGSC. Most LGSC express steroid hormone receptors and selected patients may benefit from endocrine maintenance therapy following chemotherapy, in particular those with evidence of residual disease at completion of surgery. In the recurrent setting, while hormonal therapies may offer disease stabilization with relatively low toxicity, objective response rates remain low. Strategies to increase response rates, including combining with CDK4/6 inhibitors, are being investigated. LGSC have a high prevalence of activating somatic mutations in mitogen-activated protein kinase pathway genes, most commonly in KRAS, BRAF and NRAS. Trametinib, a MEK inhibitor, has shown efficacy over chemotherapy and endocrine therapy. The use of combination targeted therapies, immunotherapy and anti-angiogenic agents, remain active areas of investigation for the treatment of LGSC.

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Effect of estrogen and progesterone receptor expression on progression-free and overall survival outcomes in low-grade serous ovarian cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.5560 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 5560-5560

Author(s):

Marta Llaurado Fernandez ◽

Amy Dawson ◽

Hannah Kim ◽

Nicole Lam ◽

Maegan Bruce ◽

...

Keyword(s):

Ovarian Cancer ◽

Cox Regression ◽

Receptor Expression ◽

Endocrine Treatment ◽

Survival Outcomes ◽

P Value ◽

Low Grade ◽

Serous Ovarian Cancer ◽

Allred Score ◽

Platinum Based Chemotherapy

5560 Background: Research on ER/PR receptor function in low-grade serous ovarian cancer (LGSC) and the determinants of response to treatment are lacking. A recent study (Sehouli et al.,2018) described ER/PR immunohistochemistry (IHC) cut-points that distinguished PFS. Thus, we report on a group of patients with ER/PR expression by IHC in tumor samples of patients with LGSC and used this information to evaluate survival outcomes. Methods: Clinical information and FFPE sections were obtained from the Canadian Ovarian Experimental Unified Resource (COEUR). Tissue microarray (TMA) sections were stained for ER/PR using standard IHC techniques (MK). 50 stage 3 and 5 stage 4 patients were analyzed. ER/PR expression was scored using a simple scoring system ( < 1% cells staining, 1-50%, and ≥ 50%) and Allred scoring. We compared Kaplan-Meier (KM) survival (PFS and OS) curves using Log rank testing and Cox regression was used to model predictive/prognostic factors. A p-value of 0.05 was considered significant. Results: The mean age of the population was 49.5 years (SD;13.7). Ninety percent of patients were treated by surgery followed by platinum-based chemotherapy (PBC). Simple scoring did not discriminate outcomes as well for ER levels. PR Allred score ( < 2, vs 2- < 6 vs ≥6) clearly discriminated KM curves for PFS (p = 0.036) and OS (p = 0.01). For Allred ER score ( < 7 vs.7- < 8 vs 8) did not distinguish PFS (p = 0.4) but notably most patients received PBC after surgery. ER Allred score significantly distinguished OS (p = 0.008). Significant factors on Cox regression for PFS were residuum (p = 0.008;95%CI:1.2-3.1) and PR (p = 0.05;95%CI:0.39-0.99), whereas for OS ER(p = 0.01:95%CI:0.2-0.8) and residuum (p = 0.04;95%CI:1-2.8). Conclusions: ER/PR expression by Allred scoring was associated with PFS and OS. Patients will benefit from much needed research on ER/PR prediction/prognosis in LGSC. This work can inform clinical trials selection/stratification and patient selection for endocrine treatment.

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Faculty Opinions recommendation of Is low-grade serous ovarian cancer part of the tumor spectrum of hereditary breast and ovarian cancer?

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.8266958.8697057 ◽

2011 ◽

Author(s):

Ashley Stuckey

Keyword(s):

Ovarian Cancer ◽

Low Grade ◽

Serous Ovarian Cancer ◽

Breast And Ovarian Cancer ◽

Tumor Spectrum

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Evaluating Targeted Therapies in Ovarian Cancer Metabolism: Novel Role for PCSK9 and Second Generation mTOR Inhibitors

Cancers ◽

10.3390/cancers13153727 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3727

Author(s):

Dafne Jacome Sanz ◽

Juuli Raivola ◽

Hanna Karvonen ◽

Mariliina Arjama ◽

Harlan Barker ◽

...

Keyword(s):

Ovarian Cancer ◽

Lipid Metabolism ◽

Cell Survival ◽

Drug Testing ◽

Cancer Metabolism ◽

Ex Vivo ◽

Specific Inhibitor ◽

Low Grade ◽

Serous Ovarian Cancer

Background: Dysregulated lipid metabolism is emerging as a hallmark in several malignancies, including ovarian cancer (OC). Specifically, metastatic OC is highly dependent on lipid-rich omentum. We aimed to investigate the therapeutic value of targeting lipid metabolism in OC. For this purpose, we studied the role of PCSK9, a cholesterol-regulating enzyme, in OC cell survival and its downstream signaling. We also investigated the cytotoxic efficacy of a small library of metabolic (n = 11) and mTOR (n = 10) inhibitors using OC cell lines (n = 8) and ex vivo patient-derived cell cultures (PDCs, n = 5) to identify clinically suitable drug vulnerabilities. Targeting PCSK9 expression with siRNA or PCSK9 specific inhibitor (PF-06446846) impaired OC cell survival. In addition, overexpression of PCSK9 induced robust AKT phosphorylation along with increased expression of ERK1/2 and MEK1/2, suggesting a pro-survival role of PCSK9 in OC cells. Moreover, our drug testing revealed marked differences in cytotoxic responses to drugs targeting metabolic pathways of high-grade serous ovarian cancer (HGSOC) and low-grade serous ovarian cancer (LGSOC) PDCs. Our results show that targeting PCSK9 expression could impair OC cell survival, which warrants further investigation to address the dependency of this cancer on lipogenesis and omental metastasis. Moreover, the differences in metabolic gene expression and drug responses of OC PDCs indicate the existence of a metabolic heterogeneity within OC subtypes, which should be further explored for therapeutic improvements.

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Trace Amine-Associated Receptor 1 (TAAR1) Is a Positive Prognosticator for Epithelial Ovarian Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22168479 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8479

Author(s):

Tilman L. R. Vogelsang ◽

Aurelia Vattai ◽

Elisa Schmoeckel ◽

Till Kaltofen ◽

Anca Chelariu-Raicu ◽

...

Keyword(s):

Ovarian Cancer ◽

Overall Survival ◽

Epithelial Ovarian Cancer ◽

Tnm Classification ◽

Rank Correlation ◽

University Hospital ◽

Cancer Tissue ◽

Low Grade ◽

High Grade ◽

Trace Amine

Trace amine-associated receptor 1 (TAAR1) is a Gαs- protein coupled receptor that plays an important role in the regulation of the immune system and neurotransmission in the CNS. In ovarian cancer cell lines, stimulation of TAAR1 via 3-iodothyronamine (T1AM) reduces cell viability and induces cell death and DNA damage. Aim of this study was to evaluate the prognostic value of TAAR1 on overall survival of ovarian carcinoma patients and the correlation of TAAR1 expression with clinical parameters. Ovarian cancer tissue of n = 156 patients who were diagnosed with epithelial ovarian cancer (serous, n = 110 (high-grade, n = 80; low-grade, n = 24; unknown, n = 6); clear cell, n = 12; endometrioid, n = 21; mucinous, n = 13), and who underwent surgery at the Department of Obstetrics and Gynecology, University Hospital of the Ludwig-Maximilians University Munich, Germany between 1990 and 2002, were analyzed. The tissue was stained immunohistochemically with anti-TAAR1 and evaluated with the semiquantitative immunoreactive score (IRS). TAAR1 expression was correlated with grading, FIGO and TNM-classification, and analyzed via the Spearman’s rank correlation coefficient. Further statistical analysis was obtained using nonparametric Kruskal-Wallis rank-sum test and Mann-Whitney-U-test. This study shows that high TAAR1 expression is a positive prognosticator for overall survival in ovarian cancer patients and is significantly enhanced in low-grade serous carcinomas compared to high-grade serous carcinomas. The influence of TAAR1 as a positive prognosticator on overall survival indicates a potential prognostic relevance of signal transduction of thyroid hormone derivatives in epithelial ovarian cancer. Further studies are required to evaluate TAAR1 and its role in the development of ovarian cancer.

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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

Cells ◽

10.3390/cells10030519 ◽

2021 ◽

Vol 10 (3) ◽

pp. 519

Author(s):

Eleni Anastasiadou ◽

Elena Messina ◽

Tiziana Sanavia ◽

Lucia Mundo ◽

Federica Farinella ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Therapeutic Strategy ◽

Target Genes ◽

Ovarian Cancer Cells ◽

Oncogenic Signaling ◽

Experimental Conditions ◽

Skov3 Cells ◽

In Silico Analyses ◽

Post Therapy

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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