miR-93-5p Suppresses Ovarian Cancer Malignancy and Negatively Regulate CCND2 By Binding To Its 3’UTR Region

Abstract Ovarian cancer is the most lethal gynecological cancer worldwide, but the underlying mechanism of ovarian cancer malignancy acquirement is largely unknown. miRNA is ubiquitously implicated in disease especially in cancer initiation and progression. In current study, we firstly detected the expression level of miR-93-5p in ovarian cancer patient samples and conducted a survival analysis. Our data revealed miR-93-5p is a favorable prognostic factor but is downregulated in ovarian cancer patients. Secondly, CCK8 assay wound healing assay and flow cytometry-based cell cycle analysis and apoptotic cell analysis were performed respectively to study the function of miR-93-5p. Functional analysis show miR-93-5p promotes ovarian cancer malignancy in term of cell proliferation, migration but reduce cell death. Bioinformatic analysis showed Cyclin-D2(CCND2) is a candidate gene of miR-93-5p with the binding site in its 3’UTR region. Furthermore, quantitive-PCR and western blot were utilized to measure miR-93-5p, CCND2 levels in tissues samples and cell lines. Our data suggested miR-93-5p is negatively correlated to the level of CCND2 mRNA and protein. Finally, Luciferase report assay was conducted, and we demonstrated miR-93-5p reduces CCND2 expression by binding to the 3’UTR region. Our study revealed the function of miR-93-5p in ovarian cancer malignancy and declaimed CCND2 as a target of miR-93-5p.

Download Full-text

Prognostic significance of bone marrow FDG uptake in patients with gynecological cancer

Scientific Reports ◽

10.1038/s41598-021-81298-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kotaro Shimura ◽

Seiji Mabuchi ◽

Naoko Komura ◽

Eriko Yokoi ◽

Katsumi Kozasa ◽

...

Keyword(s):

Ovarian Cancer ◽

Bone Marrow ◽

Poor Prognosis ◽

Gynecological Cancer ◽

Prognostic Significance ◽

Standardized Uptake Value ◽

Suppressor Cells ◽

Underlying Mechanism ◽

Fdg Uptake

AbstractWe investigated the prognostic significance and the underlying mechanism of increased bone marrow (BM) 2-(18F) fluoro-2-deoxy-D-glucose as a tracer (FDG)-uptake in patients with gynecological cancer. A list of patients diagnosed with cervical, endometrial, and ovarian cancer from January 2008 to December 2014 were identified. Then, through chart reviews, 559 patients who underwent staging by FDG-positron emission tomography (PET)/computed tomography (CT) and subsequent surgical resection were identified, and their clinical data were reviewed retrospectively. BM FDG-uptake was evaluated using maximum standardized uptake value (SUVmax) and BM-to-aorta uptake ratio (BAR). As a result, we have found that increased BAR was observed in 20 (8.7%), 21 (13.0%), 21 (12.6%) of cervical, endometrial, and ovarian cancer, respectively, and was associated with significantly shorter survival. Increased BAR was also closely associated with increased granulopoiesis. In vitro and in vivo experiments revealed that tumor-derived granulocyte colony-stimulating factor (G-CSF) was involved in the underlying causative mechanism of increased BM FDG-uptake, and that immune suppression mediated by G-CSF-induced myeloid-derived suppressor cells (MDSCs) is responsible for the poor prognosis of this type of cancer. In conclusion, increased BM FDG-uptake, as represented by increased BAR, is an indicator of poor prognosis in patients with gynecological cancer.

Download Full-text

Bioinformatic Analysis: Screening and Identification of Differentially Expressed Genes Modified by m6A in Ovarian Cancer

10.21203/rs.3.rs-111366/v1 ◽

2020 ◽

Author(s):

Huidong Liu ◽

Wen-wen Zhang ◽

Ge Lou

Keyword(s):

Ovarian Cancer ◽

Differentially Expressed Genes ◽

Clinical Sample ◽

Therapeutic Targets ◽

Enrichment Analysis ◽

Underlying Mechanism ◽

Bioinformatic Analysis ◽

Gene Expression Omnibus ◽

Differentially Expressed ◽

Kegg Pathways

Abstract Background: N6-methyladenosine(m6A) is one of the most common RNA modifications that occurs at the nitrogen-6 position of adenine. Emerging evidence has revealed that regulatory functions of m6A play an essential role in the development of cancer. However the study of m6A in ovarian cancer(OC) is still in our infancy. In this work ,we aimed to identify and analysis the differentially expressed genes(DEGs） modified by m6A which can provide new therapeutic targets and key biomarkers in OC.Methods: We downloaded Microarray datasets GSE146553 and GSE124766 from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified by GEO2R analysis tools. Subsequently, The DAVID database was used to construct Enrichment analysis of GO and KEGG pathways. Next, the DEGs modified by m6A were identified by m6AVar database. Finally, the functional analysis and clinical sample validation of these genes were verified by ONCOMINE, GEPIA, cBioPortal online platform and Kaplan-Meier Plotter.Results:152 DEGs were selected ,and the DEGs were mainly enriched in extracellular exosome, spindle microtubule, response to hypoxia and cell cycle .And we identified 15 DEGs which were modified by m6A:MAPK10、MXRA5、CHD7、MECOM、SCN7A、GREB、PRUNE2、MX2、TOP2A、JAM2、DST、LAPTM5、CDKN2A、GATM and ANGPTL1. After statistical analysis, two DEGs (SCN7A and GAMT) were selected for detailed study. We revealed that SCN7A and GAMT were expressed at a low level in OC. Afterwards, Survival analysis showed that SCN7A and GAMT expression were correlated with OC overall survival. And the expression of SCN7A and GAMT mRNA decreasing in different TNM stages. Finally, we presumed that the modification of m6A spongs GAMT via EIF4A3 or FUS to participate in the occcurrence and the development of OC.Conclusion: Altogether, the current study identified and analysised the DEGs modified by m6A in OC. It will help us to investigate the underlying mechanism and progression of OC. In addition, it can provide new diagnostic markers and potential therapeutic targets in OC.

Download Full-text

Overcoming platinum-acquired resistance in ovarian cancer patient-derived xenografts

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835919839543 ◽

2019 ◽

Vol 11 ◽

pp. 175883591983954 ◽

Cited By ~ 4

Author(s):

Francesca Ricci ◽

Laura Brunelli ◽

Roberta Affatato ◽

Rosaria Chilà ◽

Martina Verza ◽

...

Keyword(s):

Gene Expression ◽

Ovarian Cancer ◽

Cancer Patient ◽

Ovarian Cancer Patient ◽

Acute Stress ◽

Tricarboxylic Acid Cycle ◽

Gynecological Cancer ◽

Acquired Resistance ◽

Platinum Resistance

Background: Epithelial ovarian cancer is the most lethal gynecological cancer and the high mortality is due to the frequent presentation at advanced stage, and to primary or acquired resistance to platinum-based therapy. Methods: We developed three new models of ovarian cancer patient-derived xenografts (ovarian PDXs) resistant to cisplatin (cDDP) after multiple in vivo drug treatments. By different and complementary approaches based on integrated metabolomics (both targeted and untargeted mass spectrometry-based techniques), gene expression, and functional assays (Seahorse technology) we analyzed and compared the tumor metabolic profile in each sensitive and their corresponding cDDP-resistant PDXs. Results: We found that cDDP-sensitive and -resistant PDXs have a different metabolic asset. In particular, we found, through metabolomic and gene expression approaches, that glycolysis, tricarboxylic acid cycle and urea cycle pathways were deregulated in resistant versus sensitive PDXs. In addition, we observed that oxygen consumption rate and mitochondrial respiration were higher in resistant PDXs than in sensitive PDXs under acute stress conditions. An increased oxidative phosphorylation in cDDP-resistant sublines led us to hypothesize that its interference could be of therapeutic value. Indeed, in vivo treatment of metformin and cDDP was able to partially reverse platinum resistance. Conclusions: Our data strongly reinforce the idea that the development of acquired cDDP resistance in ovarian cancer can bring about a rewiring of tumor metabolism, and that this might be exploited therapeutically.

Download Full-text

APPROACH TO THE OVARIAN CANCER PATIENT AT THE END OF LIFE: THE EOLO STUDY (END-OF-LIFE OVARIAN CANCER)

10.26226/morressier.59ba7297d462b80296ca20ee ◽

2017 ◽

Author(s):

Pierluigi Benedetti Panici

Keyword(s):

Ovarian Cancer ◽

Cancer Patient ◽

End Of Life ◽

Ovarian Cancer Patient

Download Full-text

Fas gene promoter –670 polymorphism in gynecological cancer

International Journal of Gynecological Cancer ◽

10.1136/ijgc-00009577-200602001-00028 ◽

2006 ◽

Vol 16 (Suppl 1) ◽

pp. 179-182 ◽

Cited By ~ 2

Author(s):

M. Ueda ◽

Y. Terai ◽

K. Kanda ◽

M. Kanemura ◽

M. Takehara ◽

...

Keyword(s):

Ovarian Cancer ◽

Cervical Cancer ◽

Cancer Patients ◽

Germ Line ◽

Gynecological Cancer ◽

Gene Promoter ◽

Single Nucleotide ◽

Increased Risk ◽

Significant Difference ◽

Germ Line Polymorphism

Single-nucleotide polymorphism at −670 of Fas gene promoter (A/G) was examined in a total of 354 blood samples from normal healthy women and gynecological cancer patients. They consisted of 95 normal, 83 cervical, 108 endometrial, and 68 ovarian cancer cases. Eighty-three patients with cervical cancer had statistically higher frequency of GG genotype and G allele than 95 controls (P= 0.0353 and 0.0278, respectively). There was no significant difference in the genotype or allele prevalence between control subjects and endometrial or ovarian cancer patients. The Fas −670 GG genotype was associated with an increased risk for the development of cervical cancer (OR = 2.56, 95% CI = 1.08–6.10) compared with the AA genotype. The G allele also increased the risk of cervical cancer (OR = 1.60, 95% CI = 1.05–2.43) compared with the A allele. Germ-line polymorphism of Fas gene promoter −670 may be associated with the risk of cervical cancer in a Japanese population.

Download Full-text

Quinacrine-Induced Autophagy in Ovarian Cancer Triggers Cathepsin-L Mediated Lysosomal/Mitochondrial Membrane Permeabilization and Cell Death

Cancers ◽

10.3390/cancers13092004 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2004

Author(s):

Prabhu Thirusangu ◽

Christopher L. Pathoulas ◽

Upasana Ray ◽

Yinan Xiao ◽

Julie Staub ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Death ◽

Cytochrome C ◽

Cancer Cells ◽

Apoptotic Cell ◽

Cathepsin L ◽

Membrane Permeabilization ◽

Apoptotic Cell Death ◽

Ovarian Cancer Cells ◽

Autophagic Flux

We previously reported that the antimalarial compound quinacrine (QC) induces autophagy in ovarian cancer cells. In the current study, we uncovered that QC significantly upregulates cathepsin L (CTSL) but not cathepsin B and D levels, implicating the specific role of CTSL in promoting QC-induced autophagic flux and apoptotic cell death in OC cells. Using a Magic Red® cathepsin L activity assay and LysoTracker red, we discerned that QC-induced CTSL activation promotes lysosomal membrane permeability (LMP) resulting in the release of active CTSL into the cytosol to promote apoptotic cell death. We found that QC-induced LMP and CTSL activation promotes Bid cleavage, mitochondrial outer membrane permeabilization (MOMP), and mitochondrial cytochrome-c release. Genetic (shRNA) and pharmacological (Z-FY(tBU)-DMK) inhibition of CTSL markedly reduces QC-induced autophagy, LMP, MOMP, apoptosis, and cell death; whereas induced overexpression of CTSL in ovarian cancer cell lines has an opposite effect. Using recombinant CTSL, we identified p62/SQSTM1 as a novel substrate of CTSL, suggesting that CTSL promotes QC-induced autophagic flux. CTSL activation is specific to QC-induced autophagy since no CTSL activation is seen in ATG5 knockout cells or with the anti-malarial autophagy-inhibiting drug chloroquine. Importantly, we showed that upregulation of CTSL in QC-treated HeyA8MDR xenografts corresponds with attenuation of p62, upregulation of LC3BII, cytochrome-c, tBid, cleaved PARP, and caspase3. Taken together, the data suggest that QC-induced autophagy and CTSL upregulation promote a positive feedback loop leading to excessive autophagic flux, LMP, and MOMP to promote QC-induced cell death in ovarian cancer cells.

Download Full-text

Inhibition of mitochondrial carrier homolog 2 (MTCH2) suppresses tumor invasion and enhances sensitivity to temozolomide in malignant glioma

Molecular Medicine ◽

10.1186/s10020-020-00261-4 ◽

2021 ◽

Vol 27 (1) ◽

Author(s):

Qiuyun Yuan ◽

Wanchun Yang ◽

Shuxin Zhang ◽

Tengfei Li ◽

Mingrong Zuo ◽

...

Keyword(s):

Cell Death ◽

Malignant Glioma ◽

Aerobic Glycolysis ◽

Underlying Mechanism ◽

Bioinformatic Analysis ◽

Mitochondrial Outer Membrane ◽

Invasion Pathways ◽

Western Blots ◽

Mitochondrial Functions ◽

Dependent Cell

Abstract Background Malignant glioma exerts a metabolic shift from oxidative phosphorylation (OXPHOs) to aerobic glycolysis, with suppressed mitochondrial functions. This phenomenon offers a proliferation advantage to tumor cells and decrease mitochondria-dependent cell death. However, the underlying mechanism for mitochondrial dysfunction in glioma is not well elucidated. MTCH2 is a mitochondrial outer membrane protein that regulates mitochondrial metabolism and related cell death. This study aims to clarify the role of MTCH2 in glioma. Methods Bioinformatic analysis from TCGA and CGGA databases were used to investigate the association of MTCH2 with glioma malignancy and clinical significance. The expression of MTCH2 was verified from clinical specimens using real-time PCR and western blots in our cohorts. siRNA-mediated MTCH2 knockdown were used to assess the biological functions of MTCH2 in glioma progression, including cell invasion and temozolomide-induced cell death. Biochemical investigations of mitochondrial and cellular signaling alternations were performed to detect the mechanism by which MTCH2 regulates glioma malignancy. Results Bioinformatic data from public database and our cohort showed that MTCH2 expression was closely associated with glioma malignancy and poor patient survival. Silencing of MTCH2 expression impaired cell migration/invasion and enhanced temozolomide sensitivity of human glioma cells. Mechanistically, MTCH2 knockdown may increase mitochondrial OXPHOs and thus oxidative damage, decreased migration/invasion pathways, and repressed pro-survival AKT signaling. Conclusion Our work establishes the relationship between MTCH2 expression and glioma malignancy, and provides a potential target for future interventions.

Download Full-text