Ovarian Cancer Migration Research Articles

LINC01320 facilitates cell proliferation and migration of ovarian cancer via regulating PURB/DDB2/NEDD4L/TGF-β axis

Ovarian cancer (OC) is one of the most prevalent and lethal malignancies affecting the female reproductive system, due to its tendency for metastasis and recurrence. This study identified the overexpression of LINC01320 (or long intergenic nonprotein coding RNA 1320) in tissues of ovarian cancer through the analysis of patient samples and online datasets. In vitro and in vivo experiments demonstrate that silencing of LINC01320 expression led to inhibition of proliferation and metastasis of OC cells. RNA pull-down followed by liquid chromatography tandem mass spectrometry (RNA pull-down-LC-MS/MS) revealed that LINC01320 interacted with purine-rich element binding protein B (PURB), a transcriptional repressor. Furthermore, the RNA-seq analysis identified damage-specific DNA binding protein 2 (DDB2) as a major common target of LINC01320 and PURB. Mechanistically, LINC01320 could recruit PURB to the promoter region of DDB2 to repress DDB2 transcription; thus, promoting the expression of NEDD4L and impeding the TGF-β/SMAD signaling pathway, and ultimately facilitating the progression of OC. Finally, rescue experiments confirmed the involvement of the DDB2/NEDD4L/TGF-β axis in LINC01320-mediated OC progression. In conclusion, this study unveils for the first time the pivotal function of the LINC01320/PURB/DDB2/NEDD4L/TGF-β axis and explores its prospective clinical implications in OC.

Pharmacological USP2 targeting suppresses ovarian cancer growth by potentiating apoptosis and ferroptosis

Ovarian cancer is a frequently observed type of gynaecologic malignancy generally associated with poor prognosis around the world. Ubiquitin-specific proteases (USPs) form the largest subfamily of deubiquitylating enzymes and have emerged as potential therapeutic targets against human cancers. Through a systematic analysis of the prognostic significance of USP expression, USP2 was found to be inversely correlated with patient survival in ovarian cancer. Accordingly, we investigated the effects of pharmacological inhibition of USP2 on ovarian cancer by exploiting its small molecule inhibitor ML364. Our findings show that ML364 effectively hindered ovarian cancer growth and migration using a series of in vitro assays. In addition to apoptosis induction, ML364 also sensitized ovarian cancer cells to ferroptosis. Mechanistically, ML364 treatment resulted in cyclin D1 downregulation, increased poly (ADP-ribose) polymerase (PARP) cleavage, and elevated ROS levels in ovarian cancer cells. Collectively, our findings suggest USP2 as a potential therapeutic target in ovarian cancer, and hence, its pharmacological inhibition warrants further investigation.

Exosomal AHSG in ovarian cancer ascites inhibits malignant progression of ovarian cancer by p53/FAK/Src signaling.

The primary cause of mortality in patients with ovarian cancer (OC) is tumor metastasis. A comprehensive understanding of the mechanisms underlying metastasis in OC is essential for accurate prognosis prediction and the development of targeted therapeutic agents. Our findings indicate that alpha-2 Heremans Schmid glycoprotein (AHSG) is downregulated in OC exosomes. Consequently, the objective of this study was to identify novel prognostic markers and potential therapeutic targets for OC. Exosomes derived from OC cells and patient ascites were purified and applied to OC cells to assess their migratory ability using wound-healing and transwell assays. AHSG expression was enhanced by overexpressing lentivirus, and the resulting exosomes were isolated and co-cultured with OC cells to verify their effect on the migration ability of OC. Exosomes in ovarian malignant ascites have been demonstrated to promote OC metastasis. However, our findings indicate that AHSG is down-regulated in OC tissues and ascites exosomes. Furthermore, overexpression of AHSG in OC cells has been shown to markedly decrease their migratory ability, as well as reduce the migratory ability of cancer cells after co-culture of its exosomes with cancer cells. The low expression of AHSG in exosomes derived from OC tissues and ascites is associated with metastatic progression in OC patients. Additionally, cancer-derived AHSG can be transported to OC cells via exosomes, where it inhibits OC migration in vitro and in vivo by regulating the p53/FAK/Src signaling pathway. The present study demonstrated that AHSG, derived from cancer cells, exerts a negative regulatory effect on OC cell motility, migration, and metastasis. These findings suggest that AHSG is a potential candidate for OC treatment.

Exploring tumor microenvironment in molecular subtyping and prognostic signatures in ovarian cancer and identification of SH2D1A as a key regulator of ovarian cancer carcinogenesis

IntroductionA deadly gynecological cancer, ovarian cancer (OV), has a poor prognosis because of late-stage diagnosis and few targeted therapies. Addressing the tumor microenvironment (TME) in solid tumors has shown promise since it is crucial in promoting cancer progression. MethodsWe obtained bulk RNA-seq data from TCGA-OV, GSE26712, GSE102073, and ICGC cohorts, as well as scRNA-seq data from EMTAB8107, GSE118828, GSE130000, and GSE154600 cohorts using the TISCH2 database. The ConsensusClusterPlus package was used to cluster the OV tumor tissues hierarchically to determine two molecularly different groups (C1 and C2). A total of ten different types of machine learning techniques with 101 combinations were used for prognostic model construction. Using eight TME algorithms integrated into the IOBR R package, the bulk RNA-seq dataset was analyzed. For in vitro experiments, OVCAR3 and SKOV3, two OV cell lines, were used. The migratory potential of the ovarian cancer cells was assessed using Transwell assay, while proliferation was assessed using CCK8 assay. ResultsBased on TME-related gene set expression, two distinct molecular subgroups (C1 and C2) were identified through consensus clustering, with C1 showing higher TME activity. Further analysis indicated that C1 had increased cancer-associated fibroblasts (CAFs), M1 macrophages, and CD8+ T cells, suggesting a more activated and pro-inflammatory TME. Drug sensitivity analysis revealed that 5-Fluorouracil might be beneficial to C1 patients. Functional differences between C1 and C2 were identified, including cell adhesion, mononuclear cell differentiation, and leukocyte migration. A machine learning model was developed to create a TME-related prognostic signature, demonstrating strong prognostic capabilities across multiple datasets. High-risk patients showed a more immune-suppressive TME and higher tumor stemness. ScRNA-seq disclosed a highly activated TME-related signature in OV. Cancer cell lines had significantly higher SH2D1A mRNA expression than normal ovarian epithelial cells. We observed that SH2D1A knockdown in 2 ovarian cancer cell lines (OVCAR3 and SKOV3) reduced migration and proliferation through a series of in-vitro experiments. ConclusionTME-associated genes were efficient in ovarian cancer molecular subtyping. A TME-based prognosis model was constructed for vigorous prognostic stratification efficacy across multiple datasets. Moreover, we identified a pivotal role of SH2D1A in promoting proliferation and migration in ovarian cancer.

Comprehensive Analyses and Experiments Confirmed IGFBP5 as a Prognostic Predictor Based on an Aging-genomic Landscape Analysis of Ovarian Cancer.

Ovarian cancer (OC) is one of the malignant diseases of the reproductive system in elderly women. Aging-related genes (ARGs) were involved in tumor malignancy and cellular senescence, but the specifics of these mechanisms in OC remain unknown. ARGs expression and survival data of OC patients were collected from TCGA and CPTAC databases. Subtype classification was used to identify the roles of hub ARGs in OC progression, including function enrichment, immune infiltration, and drug sensitivity. LASSO regression was utilized to confirm the prognosis significance for these hub ARGs. MTT, EdU, Transwell, and wounding healing analysis confirmed the effect of IGFBP5 on the proliferation and migration ability of OC cells. ARGs were ectopically expressed in OC tissues compared to normal ovary tissues. Three molecular subtypes were divided by ARGs for OC patients. There were significant differences in ferroptosis, m6A methylation, prognosis, immune infiltration, angiogenesis, differentiation level, and drug sensitivity among the three groups. LASSO regression indicated that 4 signatures, FOXO4, IGFBP5, OGG1 and TYMS, had important prognosis significance. Moreover, IGFBP5 was significantly correlated with immune infiltration. The hub ARG, IGFBP5, expression was significantly decreased in OC patients compared to normal women. IGFBP5 could also reduce the migration and proliferation ability of OC cells compared to vector and NC groups. IGFBP5 was correlated with OC prognosis and associated with OC migration and proliferation. This gene may serve as potential prognostic biomarkers and therapeutic targets for OC patients.

Ubiquitin Ligase TRIM22 Inhibits Ovarian Cancer Malignancy via TCF4 Degradation.

Ovarian cancer is one of the most common malignancies in women. Tripartite motif-containing protein 22 (TRIM22) plays an important role in the initiation and progression of malignant tumors. Similarly, the transcription factor 4 (TCF4) is an essential factor involved in the initiation and progression of many tumors. However, it is still unclear whether TRIM22 can affect TCF4 in ovarian cancer. Therefore, this study aims to investigate the mechanism related to TRIM22 and TCF4 in ovarian cancer. TRIM22 protein and mRNA levels were analyzed in samples from clinical and cell lines. The effects of TRIM22 knockdown and overexpression on cell proliferation, colony formation, migration, invasion, and related biomarkers were evaluated. In addition, the role of ubiquitination-mediated degradation of TCF4 was investigated by qRT-PCR and Western blotting. The association between TRIM22 and TCF4 was evaluated by Western blotting, coimmunoprecipitation, proliferation, colony formation, invasion, migration, and related biomarkers. The results showed that the expression of TRIM22 was minimal in ovarian cancer tissues. Furthermore, upregulation of TRIM22 significantly inhibited ovarian cancer cell proliferation, colony formation, migration, and invasion. In addition, TRIM22 was observed to regulate the degradation of TCF4 through the ubiquitination pathway. TCF4 can reverse the effects of TRIM22 on proliferation, colony formation, migration, and invasion in ovarian cancer cells. TRIM22-mediated ubiquitination of TCF4 at K48 is facilitated by the RING domain. Implications: In conclusion, ubiquitination of TCF4 protein in ovarian cancer is regulated by TRIM22, which has the potential to limit the proliferation, migration, and invasion of ovarian cancer.

TRIM8 promotes ovarian cancer proliferation and migration by targeting VDAC2 for ubiquitination and degradation.

Ovarian cancer is a common gynecological tumor with high malignant potential and poor prognosis. TRIM8, is involved in the development of various tumors, but its precise regulatory role in ovarian cancer is still unknown. The aim of this study was to explore the specific mechanism by which TRIM8 regulates ovarian cancer. We used bioinformatics analysis to screen for high expression of TRIM8 in ovarian cancer. The expression of TRIM8 in healthy and cancerous ovarian tissues was assessed by immunofluorescence. TRIM8 was silenced or overexpressed in ovarian cancer cell lines, with cell proliferation and migration evaluated by CCK8, transwell and clonal formation assays. The effect of TRIM8 on ovarian cancer cells in vivo was assessed by subcutaneous tumor formation experiments in nude mice. The potential interacting protein VDAC2 was identified by mass spectrometry. The mechanism underlying TRIM8 regulation of VDAC2 was evaluated by co-immunoprecipitation and western blotting. TRIM8 was overexpressed in ovarian cancer. TRIM8 promoted the proliferation and migration of ovarian cancer cells in vitro and the growth of subcutaneous tumors in mice in vivo. TRIM8 interacted with VDAC2, weakened the stability of the protein, and promoted its polyubiquitination and subsequent degradation. Knockdown of VDAC2 increased the resistance of ovarian cancer cells to iron death, whereas overexpression of VDAC2 attenuated ovarian cancer progression induced by TRIM8 overexpression. TRIM8 promotes ovarian cancer proliferation and migration by targeting VDAC2 for ubiquitination and degradation, these finding may provide new targets for the treatment of ovarian cancer. TRIM8 degraded VDAC2 through the ubiquitination pathway, increased the resistance of ovarian cancer cells to iron death, and promoted the proliferation and migration of ovarian cancer.

M2 macrophage-derived exosomal circTMCO3 acts through miR-515-5p and ITGA8 to enhance malignancy in ovarian cancer

Tumor-associated macrophages of the M2 phenotype promote cancer initiation and progression. Importantly, M2 macrophage-derived exosomes play key roles in the malignancy of cancer cells. Here, we report that circTMCO3 is upregulated in ovarian cancer patients, and its high expression indicates poor survival. M2-derived exosomes promote proliferation, migration, and invasion in ovarian cancer, but these effects are abolished by knockdown of circTMCO3. Furthermore, circTMCO3 functions as a competing endogenous RNA for miR-515-5p to reduce its abundance, thus upregulating ITGA8 in ovarian cancer. miR-515-5p inhibits ovarian cancer malignancy via directly downregulating ITGA8. The decreased oncogenic activity of circTMCO3-silencing exosomes is reversed by miR-515-5p knockdown or ITGA8 overexpression. Exosomal circTMCO3 promotes ovarian cancer progression in nude mice. Thus, M2 macrophage-derived exosomes promote malignancy by delivering circTMCO3 and targeting the miR-515-5p/ITGA8 axis in ovarian cancer. Our findings not only provide mechanistic insights into ovarian cancer progression, but also suggest potential therapeutic targets.

PITPNA-AS1 Inhibits Cell Proliferation and Migration in Ovarian Cancer by Regulating the MIR-223-3p/RHOB Axis.

Ovarian cancer is a fatal gynecologic malignancy. Long non-coding RNA (lncRNA) has been verified to serve as key regulator in ovarian cancer tumorigenesis. The aim of the study was to study the functions and mechanism of lncRNA PITPNA-AS1 in ovarian cancer cellular process. Clinical ovarian cancer samples were collected and stored at an academic medical center. Cellular fractionation assays and fluorescence in situ hybridization were conducted to locate PITPNA-AS1 in OC cells. TUNEL staining, colony-forming assays, and Transwell assays were performed for evaluating cell apoptosis as well as proliferative and migratory abilities. Western blot was conducted for quantifying protein levels of epithelialmesenchymal transition markers. The binding relation between genes was verified by RNA pulldown, RNA immunoprecipitation, and luciferase reporter assays. Gene expression levels in ovarian cancer tissues and cells were subjected to RT-qPCR. PITPNA-AS1 level was downregulated in ovarian cancer samples and cells. PITPNA-AS1 overexpression contributed to the accelerated ovarian cancer cell apoptosis and inhibited cell migration, proliferation, and epithelial-mesenchymal transition process. In addition, PITPNA-AS1 interacted with miR-223-3p to regulate RHOB. RHOB knockdown partially counteracted the repressive impact of PITPNA-AS1 on ovarian cancer cell activities. PITPNA-AS1 inhibited ovarian cancer cellular behaviors by targeting miR-223-3p and regulating RHOB.

The oncogenic role and regulatory mechanism of ACAA2 in human ovarian cancer.

Acetyl-CoAacyltransferase2 (ACAA2) is a key enzyme in the fatty acid oxidation pathway that catalyzes the final step of mitochondrial β oxidation, which plays an important role in fatty acid metabolism. The expression of ACAA2 is closely related to the occurrence and malignant progression of tumors. However, the function of ACAA2 in ovarian cancer is unclear. The expression level and prognostic value of ACAA2 were analyzed by databases. Gain and loss of function were carried out to explore the function of ACAA2 in ovarian cancer. RNA-seq and bioinformatics methods were applied to illustrate the regulatory mechanism of ACAA2. ACAA2 overexpression promoted the growth, proliferation, migration, and invasion of ovarian cancer, and ACAA2 knockdown inhibited the malignant progression of ovarian cancer as well as the ability of subcutaneous tumor formation in nude mice. At the same time, we found that OGT can induce glycosylation modification of ACAA2 and regulate the karyoplasmic distribution of ACAA2. OGT plays a vital role in ovarian cancer as a function of oncogenes. In addition, through RNA-seq sequencing, we found that ACAA2 regulates the expression of DIXDC1. ACAA2 regulated the malignant progression of ovarian cancer through the WNT/β-Catenin signaling pathway probably. ACAA2 is an oncogene in ovarian cancer and has the potential to be a target for ovarian cancer therapy.

Abstract 3386: Changes in extracellular vesicle miRNAs from three-dimensional ovarian cancer cell models reflect physiological changes and cancer survival

Abstract Ovarian Cancer (OC) is the most common gynaecological malignancy and the eighth most diagnosed cancer in females worldwide. Currently, it is the fifth leading cause of cancer-related mortality among patients globally, largely due to delayed diagnosis, chemotherapy resistance, high metastasis rates, and subtype heterogeneity. Recent OC research highlights extracellular vesicles (EVs) as pivotal contributors to intercellular communication and disease progression, elucidating the intricacies of OC pathology. EVs, diverse membrane-derived vesicles released by most cells, carry molecular cargoes containing proteins and nucleic acids. Studies indicate that the biogenesis, packaging, and release of EVs are highly dependent and sensitive to the cellular microenvironment and depend on the in-vitro and in-vivo modelling systems. Labs use varied model systems—2D monolayers, animal models, and innovative 3D models—to investigate EVs' ovarian cancer roles. Therefore, in this study we aimed to compare the miRNA profiles associated with EVs in 3D ovarian cancer cell models, and to identify the pathophysiological relevance of the EVs isolated from these models to the patient derived EVs.In this study, two OC epithelial cell lines, SKOV-3 and OVCAR-, were initially cultured as 2D monolayers and embedded within Gelatin Methacryloyl hydrogels. Over nine days, multiple assays observed spheroid formation within the cell-laden hydrogels. EVs isolated from the cell-conditioned media were characterized per MISEV 2018 guidelines. Small RNA sequencing identified statistically significant miRNAs, subject to gene ontology and gene rank analyses. EVs from a cohort of 60 OC patients were used to identify survival-associated miRNA profiles.Our findings in the cell-laden hydrogels demonstrated OC cell growth, proliferation, and aggregation into spheroidal structures, establishing an ideal 3D model. The isolated EVs were characterized for size, concentration, morphology, and surface markers. Small RNA sequencing revealed 18 significantly different EV-associated miRNA species across 3D vs 2D models, influencing apoptosis, angiogenesis, migration, and proliferation in ovarian cancer. Notably, 3D model-derived EV-associated miRNAs mirrored patient-derived EV-associated miRNA profiles, indicating their pathophysiological relevance.This study establishes a robust 3D OC model in hydrogels, showcasing growth, proliferation, and aggregation capabilities. Differential miRNA profiles between 3D and 2D model EVs highlight the critical roles of these miRNAs in essential ovarian cancer processes. Moreover, similarities between 3D model and patient-derived EV-associated miRNA profiles emphasize the clinical relevance of our model. Citation Format: Nihar Godbole, Akhilandeshwari Ravichandran, Dominic Guanzon, Andrew Lai, Flavio Carrion, Priyakshi Kalita de Croft, Lewis Perrin, John Hooper, Laura Bray, Carlos Salomon. Changes in extracellular vesicle miRNAs from three-dimensional ovarian cancer cell models reflect physiological changes and cancer survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3386.

XTP8 Promotes Ovarian Cancer Progression by Activating AKT/AMPK/mTOR Pathway to Regulate EMT

Ovarian cancer (OC) ranks as the fifth leading cause of cancer-related death in women. The main contributors to the poor prognosis of ovarian cancer are the high rates of recurrence and metastasis. Studies have indicated a crucial role for hepatitis B virus X Ag-Transactivated Protein 8 (XTP8), a protein containing the DEP domain, in various cellular processes, including cell growth, movement, and differentiation, across several types of cancers. However, the role of XTP8 in ovarian cancer remains unclear. We observed elevated expression of XTP8 in ovarian cancer. Silencing XTP8 inhibited cell proliferation, promoted apoptosis, and yielded contrasting results in cells overexpressing XTP8. Furthermore, XTP8 facilitated ovarian cancer invasion and migration, triggering epithelial-mesenchymal transition (EMT). Mechanistically, XTP8 silencing led to reduced phosphorylation levels of AKT, increased p-AMPK levels, and decreased p-mTOR levels, while XTP8 overexpression exerted the opposite effects. Additionally, the activation of p-AMPK rescued the promoting effect of XTP8 on EMT in ovarian cancer cell lines, indicating that XTP8 acts as an oncogene by modulating the AKT/AMPK/mTOR pathway. Through transcriptome sequencing to identify downstream targets of XTP8, we found that XTP8 influences the expression of Caldesmon (CALD1) at both transcriptional and translational levels. CALD1 can be considered a downstream target of XTP8. The collaborative action of XTP8 and CALD1 activates the AKT/AMPK/mTOR pathway, regulating EMT to promote ovarian cancer progression. Inhibiting this signaling axis might represent a potential therapeutic target for ovarian cancer.

Abstract A102: ROR2/Wnt5a signaling regulates directional cell migration and early tumor cell invasion in ovarian cancer

Abstract Adhesion to and clearance of the mesothelial monolayer are key events in the early metastatic seeding of ovarian cancer. To identify mediators of ovarian cancer cell adhesion and invasion, we developed and conducted a cellular, high-throughput genetic screen using a human kinome siRNA library. Through this screen, we identified ROR2 as a driver of ovarian cancer adhesion and invasion. ROR2 is a receptor tyrosine kinase that interacts with Wnt5a ligand to activate non-canonical Wnt signaling and has been previously shown to be upregulated in ovarian cancer tissue. However, no prior study has evaluated the mechanistic role of ROR2 in ovarian cancer. Using in vitro adhesion and mesothelial clearance assays, we show that ROR2 promotes ovarian cancer cell adhesion and clearance of the mesothelial monolayer, key early steps in ovarian cancer metastasis. Further, we show that depletion of ROR2 reduces metastatic tumor burden in a syngeneic mouse model of ovarian cancer. Additionally, using a microfluidic device capable of producing stable fluid gradients, we demonstrate that ROR2 expression in ovarian cancer cells serves to drive directed cell migration of tumor cells, preferentially to areas of high Wnt5a ligand. As Wnt5a has been previously shown to be produced and upregulated in the mesothelial cells of the ovarian cancer microenvironment, these findings represent a novel role for ROR2 to promote the homing of ovarian tumor cells to the mesothelial lined metastatic niche by using Wnt5a as a chemotactic cue. These findings support the role of ROR2 as a critical factor contributing to the steps of ovarian cancer metastasis. Therapeutic targeting of the ROR2/Wnt5a signaling axis could provide a means of improving treatment for patients with advanced ovarian cancer. Citation Format: Whitney R. Grither, Breanna Baker, Vasilios A. Morikis, Katherine C. Fuh, Gregoery D Longmore. ROR2/Wnt5a signaling regulates directional cell migration and early tumor cell invasion in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A102.

Abstract B063: Vascular senescence associated cell migration inducing hyaluronidase-1 production promotes ovarian cancer migration and tumorigenesis

Abstract B063: Vascular senescence associated cell migration inducing hyaluronidase-1 production promotes ovarian cancer migration and tumorigenesis

ROR2/Wnt5a Signaling Regulates Directional Cell Migration and Early Tumor Cell Invasion in Ovarian Cancer.

This study demonstrates that ROR2 in ovarian cancer cells is important for directed migration to the metastatic niche and provides a potential signaling axis of interest for therapeutic targeting in ovarian cancer.

LINC00963 Promotes Ovarian Cancer Proliferation, Migration and EMT via the miR-378g/CHI3L1 Axis [Retraction

[This retracts the article DOI: 10.2147/CMAR.S229083.].

Retraction Note: H3K27ac-induced lncRNA PAXIP1-AS1 promotes cell proliferation, migration, EMT and apoptosis in ovarian cancer by targeting miR-6744-5p/PCBP2 axis

Retraction Note: H3K27ac-induced lncRNA PAXIP1-AS1 promotes cell proliferation, migration, EMT and apoptosis in ovarian cancer by targeting miR-6744-5p/PCBP2 axis

CSGALNACT2 restricts ovarian cancer migration and invasion by modulating MAPK/ERK pathway through DUSP1.

Ovarian cancer is one of the leading causes of cancer-related death among women. CSGALNACT2 is a vital Golgi transferase and is related to a variety of human diseases. However, its expression pattern and function in ovarian cancer remain uncertain. The Cancer Genome Atlas and GEPIA databases were used to assess the expression of CSGALNACT2 in ovarian cancer patients. RNA-seq, qRT-PCR, and IHC were used to verify the expression of CSGALNACT2 in ovarian cancer tissues. Then, in vivo and in vitro experiments were conducted to evaluate the role of CSGALNACT2 in the progression of ovarian cancer. RNA-seq and GSEA were used to reveal the potential biological function and oncogenic pathways of CSGALNACT2. We demonstrated that the mRNA expression and protein level of CSGALNACT2 were significantly downregulated in ovarian cancer and ovarian cancer metastatic tissues. CSGALNACT2 can significantly inhibit the migration, invasion, and clonogenic growth of ovarian cancer in vitro and is progressively lost during ovarian cancer progression in vivo. CSGALNACT2 suppresses ovarian cancer migration and invasion via DUSP1 modulation of the MAPK/ERK pathway through RNA-seq, KEGG analysis, and Western blotting. Moreover, CSGALNACT2 expression was correlated with immune cell infiltration and had prognostic value in different immune cell-enriched or decreased ovarian cancer. In addition, patients with CSGALNACT2 downregulation are less likely to benefit from immunotherapy. As an ovarian cancer suppressor gene, CSGALNACT2 inhibits the development of ovarian cancer, and it might be used as a prognostic biomarker in patients with ovarian cancer.

Exosome-transmitted miR-30a-5p enhances cell proliferation, migration, and invasion in ovarian cancer

BackgroundOvarian cancer (OC) causes the highest rates of mortality among women’s genital tract malignancies. Micro-ribonucleic acid (miRNA), the most abundant long noncoding RNAs transmitted by exosomes, has been revealed to be a potential marker for OC since 2008. In this study, we aimed to determine the possible roles of miRNAs derived from exosomes in the early diagnosis of OC through miRNA microarray, besides, exploring the underlying mechanisms of miRNAs in the OC progression.MethodsWe isolated exosomes from high invasive OC cell line HO8910PM and its parent cell line HO8910 using transmission electron microscopy and western blot, and performed miRNA microarray to identify the exosome-transmitted miRNA from the two cell lines, respectively. The expression profile was obtained by quantitative analysis, and then the differentially expressed individuals were screened. miRNA-30a-5p, a stable miRNA in both cells of our sequencing data was set for further study. MiR-30a-5p mimics, inhibitor and their corresponding negative controls were applied in OC cells. Then the cell proliferation, migration, and invasion of different groups were analyzed via cell counting-kit 8 (CCK8), wound healing, and Transwell analyses. Besides, ZBE2 and LDH2 expressions were detected by qRT-PCR.ResultsCombined with the data report of miRNA microarray technology, we set miR-30a-5p as our target miRNA to analyze its molecular function in regulating proliferation, migration, and invasion in OC cells. Our results showed that the miR-30a-5p overexpression could significantly enhance the capability of proliferation, migration, and invasion of HO8910 and HO8910PM cells, whereas the miR-30a-5p inhibition showed the opposite tendency (all P < 0.05). Besides, miR-30a-5p may be involved in these oncogenic processes through the upregulation of ZEB2 and LDH2.ConclusionOur results demonstrate that exosome-transmitted miRNA-30a-5p promotes the malignant behavior of OC cells, which may be served as a promising diagnostic and prognostic marker for patients with OC.

Effect of alpha lipoic acid on epithelial mesenchymal transition in SKOV-3 cells

BackgroundOvarian cancer is the fifth leading cause of cancer-related death in women. Patients are usually diagnosed with advanced tumor metastass. Epithelial over cancer cells spread from primary tumor by undergoing epithelial mesenchymal transition (EMT). It has been suggested that alpha lipoic acid (ALA), a natural antioxidant lipophilic compound, reduces the oxidative stress by causing apoptosis and inhibition of proliferation of cell in cancer cells. The aim of our study was to establish a transforming growth factor β1 (TGF β1) dependent epithelial mesenchymal transition model in the SKOV-3 ovarian adenocarcinoma cell line which is an epithelial subtype of ovarian cancer and to investigate the effects of alpha lipoic acid on EMT and ovarian cancer migration. MethodsFor establish an EMT model, SKOV-3 cells were treated with different dose of TGF β1 and XTT cell viability kit was used to find IC 50 dose of ALA. Four different groups that are control, TGF β1, ALA and ALA + TGF β1 were created. Changes in the expression of genes related to EMT markers that are E-cadherin, vimentin, Snail, Slug, Twist and Zeb were analyzed with quantitative real-time PCR. These proteins were determined with the immunocytochemistry method. The migration capacity was analyzed with wound healing assay. Matrigel invasion capacity test was used to show invasion and colonization test to show colonization. ResultsThe dose of TGF β1 was determined 100 ng/ml at 72 h, the IC50 dose of ALA 219.033 µM at 48 h was determined. EMT markers in the TGF β1 group were compatible with EMT and it was shown to inhibit EMT in the groups given ALA. According to wound healing, colonization and invasion experiments, proliferation and invasion increased in TGF β1 group, but decreased in ALA and combined groups (p < 0.05). ConclusionThese results indicate that ALA suppresses the metastasis of ovarian cancer cells by regulating EMT, implying that ALA might be a potential therapeutic agent for the treatment of ovarian cancer.