Development Of Ovarian Cancer Research Articles

Abstract A015: Age-associated molecular changes may predispose the ovary to malignant transformation leading to ovarian cancer (OVCA)

Abstract Background: Ovarian cancer (OVCA) is a fatal malignancy of women which in most cases is a disease of postmenopausal women. Thus, age-associated changes in women may predispose them to malignancy. Persistent high levels of follicle stimulating hormone (FSH) is a feature of aging and we have shown that aging was associated with increased expression of inflammatory cytokine interleukin 16 (IL-16) and glucose regulatory protein (GRP78), a marker of cellular stress. It is possible that age-associated increased expression of IL-16 and GRP78 might be involved in production of mutagenic 8-OXO-2dG or its cognate enzyme OGG1 and malondialdehyde (MDA) as well as markers of DNA repair mechanisms. The goal of this study was to determine the mechanism of age-associated malignant transformation in the ovary. Materials and Methods: Exploratory study: Archived tissue specimens were selected for immunohistochemical, immunoblotting, genomic studies and immunoassays based on the review of their hematoxylin and eosin staining and final Pathological reports. Specimens were grouped as normal premenopausal women (30-50 years old), normal postmenopausal women (55-85 years old) and ovarian high grade serous carcinoma (HGSC). In vitro study: human ovarian surface epithelium (HOSE) cells were treated with or without FSH for 24 hours, and their cytoplasmic and nuclear fractionations together with that of OVCAR3 (HGSC cell line) cells were extracted. Expression of markers of inflammation (IL-16), oxidative stress (SOD2, GRP78), DNA adducts (8-OXO-2dG/OGG1, MDA) and epigenetics (HDAC1, gH2AX) and were examined. Significant differences in expression of different markers among different age groups and ovarian HGSC, and treated or control OVCAR3 cells were determined by ANOVA and t-tests. Results: Compared with premenopausal women, expression of markers of inflammation and oxidative stress including IL-16, GRP78, SOD2, 8-OXO-2dG/OGG1, MDA as well as markers of epigenetic changes including HDAC1 and gH2AX was significantly higher (<0.0001) in a subset of postmenopausal women. Similar patterns of expression were also observed in patients with ovarian HGSC. Nuclear expression of mutagenic DNA adducts (OGG1, MDA) and inhibitor of DNA damage repair mechanism (GRP78) enhanced during aging. Thus, age-associated inflammation and oxidative stress are predispositions to malignant transformation. This assumption is based on the observation from the treatment of HOSE cells with FSH which showed increased expression of the above markers as also observed in OVCAR3 cells. Conclusion: Expression of IL-16, GRP78, SOD2, 8-OXO-2dG/OGG1, MDA and HDAC1 increased in ovary during aging. These results suggest that aging is associated with persistent inflammation and oxidative stress in ovarian tissues, which predisposes these tissues to malignant transformation leading to OVCA development. Support: NIH/NCI: CA210370 Citation Format: Jessica Ramirez, Elizabeth Paris, Sanjib Basu, Animesh Barua. Age-associated molecular changes may predispose the ovary to malignant transformation leading to ovarian cancer (OVCA) [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A015.

SRC-3/TRAF4 facilitates ovarian cancer development by activating the PI3K/AKT signaling pathway

ObjectiveOvarian cancer is the seventh most common cancer in women, and it causes many deaths in women worldwide. Patients with ovarian cancer have a poor prognosis and low survival rate. This study aimed to explore the role of the SRC-3/TRAF4/PI3K/AKT pathway in ovarian cancer development.MethodsSRC-3 and TRAF4 expression in ovarian cancer cell lines were assessed using qRT-PCR and western-blotting. The expression of SRC-3 and TRAF4 in ovarian cancer cells was downregulated by transient transfection with sh-RNAs. An MTT assay was performed to evaluate cell proliferation. Cell migration and invasion were measured using a Transwell assay. Cell stemness was detected using a cell spheroidization assay and western blotting. The expression levels of stem cell factors and PI3K/AKT pathway proteins were determined by qRT-PCR and western blot analysis.ResultsSRC-3 and TRAF4 were upregulated in ovarian cancer cell lines. TRAF4 is a downstream factor of SRC-3, and the protein level of TRAF4 was regulated by SRC-3. SRC-3 knockdown reduced TRAF4 expression. Silencing SRC-3 or TRAF4 inhibited cell proliferation, migration, and invasion, as well as the expression of stem cell factors. Furthermore, sh-TRAF4 as well as treatment with LY294002, the PI3K/Akt inhibitor, inhibited the phosphorylation of Akt and PI3K, thus repressing the activation of PI3K/AKT signaling pathway in ovarian cancer cell lines. However, TRAF4 overexpression reversed the effect of SRC-3 silencing on cell proliferation, migration, invasion, and stemness.ConclusionOur study demonstrated that SRC-3/TRAF4 promotes ovarian cancer cell growth, migration, invasion, and stemness by activating the PI3K/AKT pathway.

Validation of ESM1 Related to Ovarian Cancer and the Biological Function and Prognostic Significance.

Background: Ovarian cancer (OC), a serious gynecological malignant disease, remains an enormous challenge in early diagnosis and medical treatment. Based on the GEO and TCGA databases in R language, endothelial cell-specific molecule 1 (ESM1) was confirmed separately with the bioinformatic analysis tool. ESM1 has been demonstrated to be upregulated in multiple cancer types, but the oncogenic mechanism by which ESM1 promotes OC is still largely unknown. Methods: In this study, we used WGCNA and random survival forest variable screening to filter out ESM1 in OC differentially expressed genes (DEGs). Next, we confirmed the mRNA and protein levels of ESM1 in OC samples via PCR and IHC. The correlation between the ESM1 level and clinical data of OC patients was further confirmed, including FIGO stage, lymph node metastasis, and recurrence. The role of ESM1 in OC development was explored by several functional experiments in vivo and in vitro. Then, the molecular mechanisms of ESM1 were further elucidated by bioinformatic end experimental analysis. Results: ESM1 was significantly upregulated in OC and was positively correlated with PFS but negatively correlated with OS. ESM1 knockdown inhibited cell proliferation, apoptosis escape, the cell cycle, angiogenesis, migration and invasion in multiple experiments. Moreover, GSVA found that ESM1 was associated with the Akt pathway, and our results supported this prediction. Conclusion: ESM1 was closely correlated with OC development and progression, and it could be considered a novel biomarker and therapeutic target for OC patients.

E2F8 knockdown suppresses cell proliferation and induces cell cycle arrest via Wnt/β-Catenin pathway in ovarian cancer.

Ovarian cancer is one of the leading causes of death in female reproductive system cancers. However, the pathogenesis of ovarian cancer remains elusive. Our aim is to investigate the potential targets for ovarian cancer. Two microarray datasets were obtained from the Gene Expression Omnibus public database. Using R package limma, the differentially expressed genes (DEGs) were identified from the datasets. There were 95 overlapping DEGs in two microarray datasets. GO, KEGG pathway analysis, and protein-protein interaction (PPI) network analysis were carried out based on the DEGs. Wnt signaling pathway and cell cycle were enriched in the KEGG pathway analysis. Moreover, the top 10 hub genes with the most nodes were determined by PPI network analysis. E2F8, one of hub genes was positively linked to a bad outcome in ovarian cancer patients. Furthermore, E2F8 knockdown suppressed cell proliferation and induced cell cycle arrest in ovarian cancer. In addition, we found that silencing E2F8 inhibited the Wnt/β-catenin signaling pathway. In ovarian cancer cells with E2F8 knockdown, overexpressing β-catenin restored both the suppressed capacity of cell proliferation and cell cycle progression. Therefore, our results revealed that E2F8 had an involvement in the development of ovarian cancer which might act as a therapeutic target.

Pan-cancer Analysis Reveals Cancer-dependent Expression of SOX17 and Associated Clinical Outcomes.

SRY-box containing gene 17 (SOX17) plays a pivotal role in cancer onset and progression and is considered a potential target for cancer diagnosis and treatment. However, the expression pattern of SOX17 in cancer and its clinical relevance remains unknown. Here, we explored the relationship between the expression of SOX17 and drug response by examining SOX17 expression patterns across multiple cancer types. Single-cell and bulk RNA-seq analyses were used to explore the expression profile of SOX17. Analysis results were verified with qPCR and immunohistochemistry. Survival, drug response, and co-expression analyses were performed to illustrate its correlation with clinical outcomes. The results revealed that abnormal expression of SOX17 is highly heterogenous across multiple cancer types, indicating that SOX17 manifests as a cancer type-dependent feature. Furthermore, the expression pattern of SOX17 is also associated with cancer prognosis in certain cancer types. Strong SOX17 expression correlates with the potency of small molecule drugs that affect PI3K/mTOR signaling. FGF18, a gene highly relevant to SOX17, is involved in the PI3K-AKT signaling pathway. Single-cell RNA-seq analysis demonstrated that SOX17 is mainly expressed in endothelial cells and barely expressed in other cells but spreads to other cell types during the development of ovarian cancer. Our study revealed the expression pattern of SOX17 in pan-cancer through bulk and single-cell RNA-seq analyses and determined that SOX17 is related to the diagnosis, staging, and prognosis of some tumors. These findings have clinical implications and may help identify mechanistic pathways amenable to pharmacological interventions.

LncRNA GAS5 suppression of the malignant phenotype of ovarian cancer via the miR-23a-WT1 axis.

Growth arrest-specific 5 (GAS5) is a long noncoding RNA (lncRNA) that regulates cell viability. GAS5 lncRNA has been shown to decrease colorectal and breast cancer carcinogenesis. Although the function and mechanisms related to lncRNA GAS5 in the development of ovarian cancer (OC) remains unclear. The goal of this study was to clarify the essential functions of lncRNA GAS5 in regulating OC progression and its underlying mechanism. Relative levels of lncRNA GAS5 in OC and normal ovarian tissues were identified by quantitative real-time polymerase chain reaction (qRT-PCR). The regulatory effects of lncRNA GAS5 on the proliferation and apoptosis of SK-OV-3 cells were evaluated. Moreover, bioinformatics tools were used to predict a novel target [microRNA (miRNA)] of lncRNA GAS5. To explore the key functions of the lncRNA GAS5/miRNA-23a/WT1 regulatory loop in mediating OC progression, we performed functional experiments and a dual-luciferase reporter (DLR) gene assessment. Downregulation of lncRNA GAS5 was found in tissues of OC, which was positively correlated with a poor prognosis. In addition, SK-OV-3 cells with a lower expression of lncRNA GAS5 and accelerated cancer cell migration demonstrated a lower percentage of apoptosis in in vitro experiments. It was demonstrated that lncRNA GAS5 acts as a molecular sponge for miR-23a in OC cells. Additionally, WT1 was detected as a miR-23atarget genein OC cells, and through sponging miR-23a, lncRNA GAS5 positively regulated WT1 expression. Rescue tests demonstrated that enhancing the outputs of the miR-23a-WT1 axis reversed the impacts of lncRNA GAS5 silencing on cell proliferation and apoptosis in OC. The lncRNA GAS5/miR-23a/WT1 cascade was found participate in the progression of OC. lncRNA GAS5 also decreases OC progression by upregulating WT1 and attenuating miR-23a, suggesting that it could be an advantageous therapeutic target for OC intervention.

MicroRNA-592 Inhibits the Growth of Ovarian Cancer Cells by Targeting ERBB3.

Objectives: Ovarian cancer is the most lethal gynecologic malignancy, and targeted therapy for different pathological types and molecular phenotypes is urgent to be studied. Studies have shown that MicroRNA-592 (miR-592) plays an important negative regulatory role in the occurrence of gastrointestinal malignancies, breast cancer, non-small cell lung cancer, and glioma, but the expression of miR-592 in ovarian cancer and the mechanism of action are still unclear. Methods: The expressions of miR-592 were examined by RT-PCR and Western Blot. Cell viability and migratory capacity were detected by CCK-8 and transwell assay. TargetScan (http://www.targetscan.org) was analyzed to predict potential targets of miR-592. Then Dual-luciferase reporter gene assay was performed to verify the targeting relationship between miR-592 and ERBB3. A mouse xenograft model was applied to confirm the effect of miR-592. Results: In our study, we found that the expression of miR-592 is reduced in epithelial ovarian cancer tissues. The exogenous expression of miR-592 inhibits the proliferation, migration, and invasion in epithelial ovarian cancer tumor cells. Furthermore, the exogenous expression of miR-592 inhibits tumor growth in the nude mouse xenograft model. Therefore, miR-592 may play a role of tumor suppressor miRNA in the occurrence and development of ovarian cancer. Further experiments demonstrated that tumor-related ERBB3 is a target gene mediated by miRNA-592. The dual-luciferase reporter system was used to identify miRNA-592 target genes; qPCR and Western Blot were used to detect the expression of ERBB3. Mechanical experiments confirmed that miRNA-592 negatively regulated ERBB3.Conclusion: Together, these findings identify a heretofore unrecognized link between miR-592 and ERBB3 and suggest that targeting on miR-592 warrants attention as a novel and potential therapeutic strategy for ovarian cancer.

Comprehensively analyzing the genetic alterations, and identifying key genes in ovarian cancer.

Though significant improvements have been made in the treatment methods for ovarian cancer (OC), the prognosis for OC patients is still poor. Exploring hub genes associated with the development of OC and utilizing them as appropriate potential biomarkers or therapeutic targets is highly valuable. In this study, the differentially expressed genes (DEGs) were identified from an independent GSE69428 Gene Expression Omnibus (GEO) dataset between OC and control samples. The DEGs were processed to construct the protein-protein interaction (PPI) network using STRING. Later, hub genes were identified through Cytohubba analysis of the Cytoscape. Expression and survival profiling of the hub genes were validated using GEPIA, OncoDB, and GENT2. For exploring promoter methylation levels and genetic alterations in hub genes, MEXPRESS and cBioPortal were utilized, respectively. Moreover, DAVID, HPA, TIMER, CancerSEA, ENCORI, DrugBank, and GSCAlite were used for gene enrichment analysis, subcellular localization analysis, immune cell infiltration analysis, exploring correlations between hub genes and different diverse states, lncRNA-miRNA-mRNA co-regulatory network analysis, predicting hub gene-associated drugs, and conducting drug sensitivity analysis, respectively. In total, 8947 DEGs were found between OC and normal samples in GSE69428. After STRING and Cytohubba analysis, 4 hub genes including TTK (TTK Protein Kinase), (BUB1 mitotic checkpoint serine/threonine kinase B) BUB1B, (Nucleolar and spindle-associated protein 1) NUSAP1, and (ZW10 interacting kinetochore protein) ZWINT were selected as the hub genes. Further, it was validated that these 4 hub genes were significantly up-regulated in OC samples compared to normal controls, but overexpression of these genes was not associated with overall survival (OS). However, genetic alterations in those genes were found to be linked with OS and disease-free (DFS) survival. Moreover, this study also revealed some novel links between TTK, BUB1B, NUSAP1, and ZWINT overexpression and promoter methylation status, immune cell infiltration, miRNAs, gene enrichment terms, and various chemotherapeutic drugs. Four hub genes, including TTK, BUB1B, NUSAP1, and ZWINT, were revealed as tumor-promotive factors in OC, having the potential to be utilized as novel biomarkers and therapeutic targets for OC management.

MiR-134-3p driven by anisomycin impairs ovarian cancer stem cell activity through inhibiting GPR137 expression.

Background: Ovarian cancer recurrence and metastasis are predominantly attributed to ovarian cancer stem cells; however, the mechanism by which anisomycin regulates human ovarian cancer stem cells (HuOCSCs) remains unclear. Methods: cDNA microArray was used to screen microRNAs (miRNAs) targeted by anisomycin, and RT-qPCR validated the miRNA targets. TargetScan database, GO enrichment analysis, and RT-qPCR, accompanied by a fluorescent reporter system, were employed to verify the miRNA target genes. In vitro experimental cell proliferation inhibition assay, flow cytometry, Transwell, angiogenesis assay, and in vivo transplantation tumor assay were implemented to assess the ability of the overexpressed miRNAs to hinder HuOCSC activity. Western blot, RT-qPCR, and immunofluorescence were applied to measure the transcriptional and protein-level expression of the miRNA target genes and their related genes. Bioinformatic analysis predicted and deciphered the role of the miRNA target genes and related genes in the development and prognosis of ovarian cancer. Results: The expression levels of multiple DLK1-DIO3 imprinted microRNA cluster members were altered by anisomycin, among which miR-134-3p expression was most significantly elevated. miR-134-3p overexpression significantly suppressed HuOCSC activity. The screening and validation of target genes uncovered that miR-134-3p was able to markedly suppress GPR137 expression. Additionally, miR-134-3p regulated the cytoskeleton, migration-related protein in the NDEL1/DYNEIN/TUBA1A axis through targeting GPR137. Bioinformatics prediction unveiled a close association of GPR137, NDEL1, DYNC1H1, and TUBA1A with ovarian cancer development and prognosis. Conclusions: The activity of HuOCSCs may be compromised by anisomycin through the regulation of miR-134-3p, which inhibits the GPR137/NDEL1/DYNEIN/TUBA1A axis.

Evaluation of estrogen receptor, progesterone receptor, and Ki 67 immunoexpression in epithelial ovarian tumors with histopathological correlation

Abstract Background: Ovarian cancer ranks sixth among women’s cancers globally and seventh among cancer-related deaths. Around 90% of ovarian cancers have an epithelial genesis. Steroid hormones like progesterone and estrogen largely influence the development of ovarian cancers. In ovarian neoplasms, the proliferation marker Ki 67 helps forecast the course of the disease. Objective: To study the immunohistochemical expression pattern of estrogen receptor (ER), progesterone receptor (PR), and Ki 67 in the surface epithelial ovarian tumors (SEOTs) and correlate the findings with the standard histopathological. Materials and Methods: This prospective study was conducted in the Department of Pathology, MKCG Medical College and Hospital, Brahmapur, from November 2020 to October 2022 on 62 surface epithelial ovarian tumor cases. All the patients were evaluated for standard histopathological parameters and immuno-histochemistry (IHC) status using ER, PR, and Ki 67 as primary antibodies. Results: A total of 62 cases of SEOTs constituted the study group, of which 42 (67.74%) were benign, 5 (8.06%) were borderline, and 15 (24.2%) were malignant on histopathological evaluation: serous SEOTs (41, 66.12%), mucinous SEOTs (18, 29.03%), endometrioid SEOTs (2, 3.22%), and clear cell carcinoma (1, 1.61%). ER expression was more in malignant tumors (10/15; 66.66%) than in borderline (3/5; 60%) and benign (11/42; 26.19%), but the expression of PR was more in benign (27/42; 64.28%), followed by borderline (3/5; 60%) and malignant (8/15; 53.33%) SEOTs. Expression of Ki 67 was found to be more malignant (14/15; 93.33%) than borderline (4/5; 80%) and benign (2/42; 4.76%) SEOTs. Conclusion: ER and Ki 67 were expressed more in malignant, followed by borderline and benign, whereas PR expression was more innocent than borderline and malignant.

Abnormal expression of long non-coding RNA FGD5-AS1 affects the development of ovarian cancer through regulating miR-107/RBBP6 axis.

Long non-coding RNAs (lncRNAs) are important players in cancer development. LncRNA FGD5-AS1 has been reported as a potential oncogene in ovarian cancer (OC). The present paper focused on the action mechanism of FGD5-AS1 in OC. Clinical OC samples were collected for expression analyses of FGD5-AS1, RBBP6, and miR-107. The expression of FGD5-AS1, RBBP6, and miR-107 in OC cells was altered by transfection. OC cell proliferation was assessed by MTT and colony formation assays, and angiogenesis of human umbilical vein endothelial cells (HUVECs) cultured with OC cell supernatants by matrigel angiogenesis assay. The interactions among FGD5-AS1, miR-107, and RBBP6 were detected by luciferase reporter assay. FGD5-AS1 and RBBP6 were strongly expressed and miR-107 was poorly expressed in clinical OC samples and OC cell lines. FGD5-AS1 or RBBP6 overexpression in Hey and SKOV3 cells could potentiate OC cell proliferation and HUVEC angiogenesis, while FGD5-AS1 or RBBP6 knockdown in OC cells inhibited the above cellular processes. FGD5-AS1 targeted miR-107 to positively regulate RBBP6 expression. Additionally, miR-107 overexpression or RBBP6 knockdown in SKOV3 cells partially reversed the FGD5-AS1-dependent stimulation of OC cell proliferation and HUVEC angiogenesis. FGD5-AS1 may act as a promoter of OC via miR-107/RBBP6 axis.

Low expression of m6A reader YTHDC1 promotes progression of ovarian cancer via PIK3R1/STAT3/GANAB axis.

Background: N6-Methyladenosine (m6A) is considered to be the most prevalent and abundant internal modification observed in mRNA between viruses and mammals. As a reversible epigenetic modification, m6A controls gene expression in diverse physiological and pathological processes. Accumulating evidence in recent years reveals that aberrant expression of m6A reader proteins may have tumor-suppressing or carcinogenic functions. However, the biological role and mechanism of m6A reader YTH Domain Containing 1 (YTHDC1) in ovarian cancer progression remain inadequately understood. Methods: Quantitative RT-PCR, immunohistochemistry, Western blot, and bioinformatics analyses were undertaken for studying the YTHDC1 expression in ovarian cancer. In vitro and in vivo models were used to examine the role of YTHDC1. RNA sequencing, RNA immunoprecipitation sequencing, m6A-modified RNA immunoprecipitation, actinomycin-D assay, chromatin immunoprecipitation, and Western blot were used in the investigation the regulatory mechanisms among YTHDC1, Signal Transducer and Activator of Transcription 3 (STAT3), Phosphoinositide-3-Kinase Regulatory Subunit 1 (PIK3R1), and Glucosidase II Alpha Subunit (GANAB). Results: Here, we found that YTHDC1 expression is decreased in ovarian cancer. Overexpression of YTHDC1 inhibited ovarian cancer development both in vivo and in vitro. Mechanistically, PIK3R1 was identified to be the direct target for YTHDC1. YTHDC1 enhanced PIK3R1 stability in an m6A-dependent manner, which subsequently inhibited GANAB expression in the N-glycan biosynthesis via the STAT3 signaling. Conclusions: Our findings unveil YTHDC1 as a tumor suppressor in the progression of ovarian cancer and as a potential prognostic biomarker that could serve as a target in ovarian cancer treatment.

Особенности ранней диагностики новообразований яичников

Aim: to identify clinical and anamnestic risk factors for ovarian masses (OM), as well as to clarify the significance of various diagnostic criteria in the early diagnosis of ovarian cancer (OC). Patients and Methods: a retrospective analysis of 50 cases of patients with OM was conducted. The following groups were formed: the main group (50 patients with OM) and the control group — practically healthy female subjects (32 patients). Retrospectively, depending on the results concerning histology of the removed surgical material, the main group was divided into 2 subgroups: subgroup 1 — 37 patients with benign OM, subgroup 2 — 13 patients with borderline and malignant OM. The patterns of the anamnesis, the level of the Ca-125 tumor marker, the values of the Risk of Malignancy Index (RMI), and the tumor histology structure were assessed. Results: during the study, it was found that in patients with OM, diseases of the gastrointestinal tract (GIT), urinary system (24%), pelvic inflammatory disease (PID), as well as menstrual disorders of various types and uterine fibroids (p<0.05) are more common. The incidence of gynecologic cancer in the family history is also significantly higher in patients with OM vs. the control group (36% and 3%, respectively, p<0.05). Elevated Ca-125 values were noted both in the group with benign ovarian masses and in the group with borderline and malignant ovarian tumors.it has been established that the main risk factors for the OC development are diseases of GIT (Odds Ratio (OR) 2,09) and urinary system (OR 1,53), genetic predisposition to cancer of the reproductive organs (OR 1,86), menstrual disorder (OR 1,86), uterine fibroids (OR 1,74) and a history of PID (OR 1,83). Conclusion: despite a large number of studies devoted to the problem of OC early diagnosis, there is still no reliable criterion with high sensitivity and specificity. Female patients with postmenopause and adverse ultrasound criteria should have high oncological alarm of doctors, even with low values of the Ca-125 oncological marker. KEYWORDS: ovarian tumors, neoplasms, ovarian cancer, risk factors, Ca-125, malignancy index RMI. FOR CITATION: Smirnova A.V., Malyshkina A.I., Khrushkova E.P. Characteristics in early diagnosis of ovarian masses. Russian Journal of Woman and Child Health. 2023;6(2):105–111 (in Russ.). DOI: 10.32364/2618-8430-2023-6-2-105-111.

Age-specific bone turnover prevalence in women with post-menopausal osteoporosis: possibilities of traditional plant therapy during COVID-19 pandemic

Post-menopausal osteoporosis is a chronic age-related illness marked by a decrease of bone density and quality, as well as a higher risk of fragility fractures. Fragility fractures are recognized to have a major impact on individuals and society both personal and financially. In recent years, it has been a hidden epidemic impacting over 200 million people globally. It is claimed that one osteoporosis fracture happens every three seconds throughout the world. The termination of ovarian hormone production, which causes rapid bone loss, puts postmenopausal women at greater risk of developing osteoporosis. The gradual changes in structure, quality and density of the bones lead to the fracture and a rise in morbidity and death among menopausal women. Interventions that enhance a woman’s well-being and quality of life by reducing the intensity and frequency of post-menopausal osteoporosis. Hormone therapy is helpful in managing menopausal symptoms; nevertheless, it has been linked to a number of potentially significant side effects, including the development of ovarian and breast cancer. As a result, there has been an increase in demand for alternative treatment options. Plant species with potential antiosteoporosis characteristics are highlighted and further discussed in order to aid future medication development for treating this illness. Many plants and there components have been demonstrated to have antiosteoporosis action based on a vast number of chemical and pharmacological studies. Plant-derived molecules have lately piqued the curiosity of researchers working on novel medicinal agents. As a result, therapeutic interventions that can delay reduce or prevent bone loss in ageing people, especially postmenopausal women, are essential to a person’s well-being and quality of life. The plants included in this review are those that have been frequently used in traditional medicine and have shown clinical efficacy in the management of post-menopausal osteoporosis. While numerous plants can prevent and treat osteoporosis, only a fraction of plants have been discussed, including their origin, active components, and pharmacological activity, we evaluated the challenges and methods utilized in the therapy of postmenopausal osteoporosis during the COVID-19 pandemic.

GATA3 Encapsulated by Tumor-Associated Macrophage-Derived Extracellular Vesicles Promotes Immune Escape and Chemotherapy Resistance of Ovarian Cancer Cells by Upregulating the CD24/Siglec-10 Axis.

Tumor-associated macrophages (TAMs) possess great potential in the development of ovarian cancer (OC). Aberrant GATA-binding protein-3 (GATA3) expression has been found in TAM-derived extracellular vesicles (EVs). This study is intended to investigate the regulatory mechanism of TAM-derived EVs, expressing GATA3 in immune escape and chemotherapy resistance of OC cells. In silico analysis was employed to identify differentially expressed genes. The expression of GATA3, CD24, and sialic acid-binding igg-like lectin 10 (Siglec-10) in OC tissues and cells was characterized, with their correlation verified. OC cells were co-cultured with TAM-derived EVs and CD8+T cells. The functional significance of GATA3/CD24/Siglec-10 in immune escape and chemotherapy resistance of OC cells was assayed by the gain and loss of function experiments. In vivo experiments were also performed for further validation. High expressions of GATA3, CD24, and Siglec-10 were observed in OC tissues and cells. GATA3 could be transferred by TAM-derived EVs into OC cells, which facilitated immune escape and resistance to cisplatin of OC cells. GATA3 up-regulated CD24 to increase Siglec-10 expression. The in vivo assay confirmed the promoting effect of GATA3 delivered by TAM-derived EVs on OC through activation of the CD24/Siglec-10 axis. Collectively, TAM-derived EVs harboring GATA3 played a tumor-promoting role in immune escape and chemotherapy resistance of OC cells via the CD24/Siglec-10 axis.

HERPUD1 promotes ovarian cancer cell survival by sustaining autophagy and inhibit apoptosis via PI3K/AKT/mTOR and p38 MAPK signaling pathways

HERPUD1 is an important early marker of endoplasmic reticulum stress (ERS) and is involved in the ubiquitination and degradation of several unfolded proteins. However, its role in tumorigenesis is seldom studied, and its role in ovarian cancer is unclear. Lewis y antigen is a tumor-associated sugar antigen that acts as an ‘antenna’ on the cell surface to receive signals from both inside and outside the cell. We previously reported that Lewis y can promote ovarian cancer by promoting autophagy and inhibiting apoptosis. In this study, we detect the expression of HERPUD1 and Lewis y antigens in 119 different ovarian cancer tissues, determine their relationship with clinicopathological parameters, analyze the correlation between these two proteins, and explore the related cancer-promoting mechanisms through MTT, flow cytometry, western blotting, and bioinformatics. HERPUD1 is highly expressed in ovarian cancer, especially in the early stage, and the expression of HERPUD1 and Lewis y antigen was positively correlated. After overexpression of Lewis y antigen, the expression level of HERPUD1 increased. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathways (KEGG) analysis showed that HERPUD1 and its related genes are enriched in regulating immunity, endoplasmic reticulum stress, ubiquitin-dependent degradation, ERS-induced apoptosis, and other key signaling pathways. We also clarified the HERPUD1 network of kinases, microRNA and transcription factor targets, and the impact of HERPUD1 mutations on prognosis. In addition, HERPUD1 promotes the proliferation of ovarian cancer cells, inhibits apoptosis, affects the cell cycle, promotes the occurrence of autophagy, and inhibits EMT and PI3K/AKT/mTOR and p38MAPK pathways. Overall, HERPUD1, regulated by the expression of tumor-associated protein Lewis y, promotes cell survival in the early stages of tumors, suggesting that HERPUD1 may play an important role in the development of ovarian cancer.

Distribution of tumor-associated macrophages and M1/M2 polarization in different types and grades of ovarian tumors

Ovarian cancer represents one of the major causes of gynaecologic cancer mortality worldwide. Tumor-associated macrophages (TAM) are associated with the development and progression of ovarian cancer. TAMs are mainly represented by two types M1 and M2. We investigated the distribution of total, M1, M2 macrophages, tumor cell/macrophage ratio and M1/M2 ratio in mucinous and serous ovarian tumors. The study results showed that total TAM count is significantly higher in serous ovarian tumors, compared to mucinous tumors and the highest infiltration rate is detected in high-grade serous ovarian carcinomas. In addition, the number of M2 macrophages is significantly increased in higher-grade serous ovarian carcinomas. The evaluation of tumor/cell macrophage ratio could be used as an objective measure of macrophage infiltration in ovarian tumors.

Chlorogenic acid regulates the proliferation and migration of high-grade serous ovarian cancer cells through modulating the miR199a5p/DDR1 axis

This study aimed to demonstrate that chlorogenic acid (CGA) has anticancer effects against ovarian cancer. The MTT assay was used to assess the optimum concentrations of CGA on the ovarian cancer cell lines OVCA433 and SKOV3, followed by the rate of apoptosis using Annexin V-FITC/PI. The mitochondrial membrane potential of ovarian tumour cells treated with CGA was evaluated using mitochondrial staining kits followed by Western blot analysis, immunofluorescence, and RT-PCR assays. The Trans-well migration assay conducted the percentage of cell migration, followed by wound healing and colony formation assays. CGA induces activation of mitochondria-mediated intrinsic apoptotic pathways in ovarian cancer cells. The discovery that miR-199a-5p is inversely correlated to DDR1, a receptor tyrosine kinase involved in collagen synthesis, was the major consequence of examining the various mechanisms involved in the development of ovarian cancer. After treatment with CGA, cells derived from ovarian cancer cells were deregulated partially via the miR199a5p/DDR1 axis, significantly affecting tumour suppression. DDR1 has been identified as a direct target of miR199a5p in these ovarian cancer cells. We found that CGA-induced loss of DDR1 caused the inactivation of NF-κB signalling downstream in the MMP, migration, and EMT pathways. The study results showed that CGA is a promising drug candidate for treating ovarian cancer, particularly because it exhibits anti-invasive and migrastatic properties.

Identifying the Role of Oxidative Stress-Related Genes as Prognostic Biomarkers and Predicting the Response of Immunotherapy and Chemotherapy in Ovarian Cancer.

Ovarian cancer (OC) is one of the most frequently seen and fatal gynecological malignancies, and oxidative stress (OS) plays a critical role in the development and chemoresistance of OC. OS-related genes (OSRGs) were obtained from the Molecular Signatures Database. Besides, gene expression profiles and clinical information from The Cancer Genome Atlas (TCGA) were selected to identify the prognostic OSRGs. Moreover, univariate Cox regression, LASSO, and multivariate Cox regression analyses were conducted sequentially to establish a prognostic signature, which was later validated in three independent Gene Expression Omnibus (GEO) datasets. Next, gene set enrichment analysis (GSEA) and tumor mutation burden (TMB) analysis were performed. Afterwards, immune checkpoint genes (ICGs) and the tumor immune dysfunction and exclusion (TIDE) algorithm, together with IMvigor210 and GSE78220 cohorts, were applied to comprehensively explore the role of OSRG signature in immunotherapy. Further, the CellMiner and Genomics of Drug Sensitivity in Cancer (GDSC) databases were also applied in investigating the significance of OSRG signature in chemotherapy. Altogether, 34 prognostic OSRGs were identified, among which 14 were chosen to establish the most valuable prognostic signature. The Kaplan-Meier (KM) analysis suggested that patients with lower OS-related risk score had better prognosis. The area under the curve (AUC) values were 0.71, 0.76, and 0.85 in 3, 5, and 7 years separately, and the stability of this prognostic signature was confirmed in three GEO datasets. As revealed by GSEA and TMB analysis results, OC patients in low-risk group might have better immunotherapeutic response, which was consistent with ICG expression and TIDE analyses. Moreover, both IMvigor210 and GSE78220 cohorts demonstrated that patients with lower OS-related risk score were more likely to benefit from anti-PD-1/L1 immunotherapy. In addition, the association between prognostic signature and drug sensitivity was explored. According to our results in this work, OSRG signature can act as a powerful prognostic predictor for OC, which contributes to generating more individualized therapeutic strategies for OC patients.

Hsa_circ_0000119 promoted ovarian cancer development via enhancing the methylation of CDH13 by sponging miR-142-5p.

Ovarian cancer is the leading cause of gynecological cancer-related death in women, and is difficult to treat. The aim of our study is to explore the role and action mechanism of hsa_circ_0000119 in ovarian cancer, thus to analyze whether the circular RNA is a potential target for the treatment of the disease. In this present study, our data shows that hsa_circ_0000119 and DNA methyltransferase 1 (DNMT1) was increased, while miR-142-5p was decreased in ovarian cancer. Overexpression of hsa_circ_0000119 promoted tumor growth, while silencing of hsa_circ_0000119 resulted in an opposite effects. Decreasing of hsa_circ_0000119 also notably inhibited the proliferation, migration, and invasion of the ovarian cancer cells. Moreover, the data proves that hsa_circ_0000119 negatively regulated miR-142-5p and cadherin 13 (CDH13) expression, but positively regulated DNMT1 expression. miR-142-5p could interact with hsa_circ_0000119 and DNMT1 3'-UTR. Silencing of DNMT1 could reverse the inhibition of hsa_circ_0000119 to miR-142-5p and CDH13 expression. Importantly, higher level of CDH13 promoter methylation existed in the ovarian tumors than that in matched normal tissues. DNA methyltransferase inhibitor could increase the expression of CDH13 in ovarian cancer cells. In addition, our results also prove that increasing of CDH13 or miR-142-5p effectively reversed the inhibition of hsa _circ_0000119 to the cell malignant phenotypes. Overall, our data demonstrate that hsa_circ_0000119 facilitated ovarian cancer development through increasing CDH13 expression via promoting DNMT1 expression by sponging miR-142-5p. Our data demonstrate the potential role of hsa_circ_0000119 in the treatment of ovarian cancer.