Metastasis Of Ovarian Cancer Cells Research Articles

Senolytic drugs dasatinib and quercetin combined with Carboplatin or Olaparib reduced the peritoneal and adipose tissue metastasis of ovarian cancer

Chemotherapy and targeted drugs-induced senescent ovarian cancer cells that accumulate in peritoneal adipose tissue contribute significantly to chronic inflammation, disrupt homeostasis, and may fuel various aspects of cancer progression. However, the pro-senescence effects of chemotherapy and targeted drugs on adipose derived stem cells (ADSCs) within peritoneal adipose tissue remain poorly understood. In this study, we show that the first-line chemotherapy and targeted drugs can induce the cellular senescence of ADSCs in vitro and increase the aging of peritoneal adipose tissue in vivo. These treatments significantly promoted the dysregulation of glucose and lipid metabolism, including insulin resistance and liver lipid accumulation. Our study shows that dasatinib and quercetin, as senolytics, effectively restore glucose homeostasis in mice with ovarian cancer and significantly reduce adipose tissue aging. Importantly, combining these drugs with Carboplatin or Olaparib results in a marked decrease in both peritoneal and adipose tissue metastasis of ovarian cancer cells. Mechanistically, we revealed that there is crosstalk between ovarian cancer cells and senescent ADSCs. The crosstalk increases inflammatory cytokines and chemokines production in ADSCs and notably upregulates chemokine receptors on cancer cells. Collectively, these data indicate that senescent ADSCs induced by chemotherapy and targeted therapy drugs impair adipose tissue function. However, the senolytic drugs dasatinib and quercetin, can significantly ameliorate organ aging and damage induced by these treatments. Notably, dasatinib and quercetin combined with Carboplatin or Olaparib reduced the peritoneal and adipose tissue metastasis of ovarian cancer, ultimately benefiting the mice undergoing chemotherapy and targeted therapy.

Diosgenin inhibits proliferation and migration of ovarian cancer cells and induce apoptosis via upregulation of PTEN.

Diosgenin, a natural steroidal sapogenin, has recently attracted a high amount of attention, as an effective anticancer agent in ovarian cancer. However, diosgenin mediated anticancer impacts are still not completely understood. Thus, the present study evaluated the effect of diosgenin on the proliferation, apoptosis, and metastasis of ovarian cancer cells. OVCAR-3 and SKOV-3 cells were treated with diosgenin, cellular viability was assessed by MTT assay and apoptosis was measured by ELISA and evaluated the protein expression levels of apoptotic markers through western blotting. Cell migration was examined by measuring the mRNA levels of genes involved in the cell invasion. The protein expression levels of main components of PI3K signaling were evaluated via western blotting. Diosgenin led to significant inhibition of cellular proliferation in a dose-dependent manner. It also induced apoptosis through upregulating pro-apoptotic markers and downregulating antiapoptotic mediators. In addition, OVCAR-3 cells exposure to diosgenin decreased cell migration and invasion. More importantly, diosgenin downregulated the expression levels of main proteins in PI3K signaling including PI3K, Akt, mTOR, and GSK3. Diosgenin inhibited the proliferation and migration of OVCAR-3 ovarian cancer cells and induced apoptosis, which may be mediated by targeting PI3K signaling.

LLGL2 Inhibits Ovarian Cancer Metastasis by Regulating Cytoskeleton Remodeling via ACTN1.

Epithelial ovarian cancer is the most lethal gynecological malignant tumor. Although debulking surgery, chemotherapy, and PARP inhibitors have greatly improved survival, the prognosis for patients with advanced EOC without HRD is still poor. LLGL2, as a cell polarity factor, is involved in maintaining cell polarity and asymmetric cell division. In the study of zebrafish development, LLGL2 regulated the proliferation and migration of epidermal cells and the formation of cortical F-actin. However, the role of LLGL2 in ovarian cancer has not been described. Our study found, through bioinformatics analysis, that low expression of LLGL2 was significantly associated with a more advanced stage and a higher grade of EOC and a poorer survival of patients. Functional experiments that involved LLGL2 overexpression and knockdown showed that LLGL2 inhibited the migration and invasion abilities of ovarian cancer cells in vitro, without affecting their proliferation. LLGL2-overexpressing mice had fewer metastatic implant foci than the controls in vivo. Mechanistically, immunoprecipitation combined with mass spectrometry analysis suggested that LLGL2 regulated cytoskeletal remodeling by interacting with ACTN1. LLGL2 altered the intracellular localization and function of ACTN1 without changing its protein and mRNA levels. Collectively, we uncovered that LLGL2 impaired actin filament aggregation into bundles by interacting with ACTN1, which led to cytoskeleton remodeling and inhibition of the invasion and metastasis of ovarian cancer cells.

CircCDK17 promotes the proliferation and metastasis of ovarian cancer cells by sponging miR-22-3p to regulate CD147 expression.

Ovarian cancer (OC) is a common malignancy in women of reproductive age. Circular RNAs (circRNAs) are emerging players in OC progression. We investigated the function and mechanism of circular RNA hsa_circ_0027803 (circCDK17) in OC pathogenesis. Real‑time PCR (RT-qPCR) and western blot were utilized for gene and protein expression analysis, respectively. Cell counting kit‑8 (CCK-8), EdU and Transwell assays investigated OC cell proliferation, migration and invasion. The associations between circCDK17, miR-22-3p and CD147 were examined by dual-luciferase reporter and RNA-protein immunoprecipitation (RIP) assays. The in vivo model of OC nude mice was constructed to explore the role of circCDK17. CircCDK17 was increased in OC tissue and cells, and patients with higher expression of circCDK17 had a shorter survival. CircCDK17 downregulation inhibited OC cell proliferation, migration and invasion, and reduced epithelial-mesenchymal transition (EMT)-related markers. In vivo experiments showed that circCDK17 silencing inhibited OC tumor growth and metastasis. CircCDK17 depletion reduced CD147 level via sponging miR-22-3p. MiR-22-3p knockdown overturned effect of circCDK17 depletion on OC cell proliferation, migration and invasion. Meanwhile, overexpressed CD147 restored functions of circCDK17 downregulation on OC development. CircCDK17 is an important molecule that regulates OC pathogenic process through miR-22-3p/CD147.

PINK1-PTEN axis promotes metastasis and chemoresistance in ovarian cancer via non-canonical pathway

BackgroundOvarian cancer is commonly associated with a poor prognosis due to metastasis and chemoresistance. PINK1 (PTEN-induced kinase 1) is a serine/threonine kinase that plays a crucial part in regulating various physiological and pathophysiological processes in cancer cells.MethodsThe ATdb database and "CuratedOvarianData" were used to evaluate the effect of kinases on ovarian cancer survival. The gene expression in ovarian cancer cells was detected by Western blot and quantitative real-time PCR. The effects of gene knockdown or overexpression in vitro were evaluated by wound healing assay, cell transwell assay, immunofluorescence staining, immunohistochemistry, and flow cytometry analysis. Mass spectrometry analysis, protein structure analysis, co-immunoprecipitation assay, nuclear-cytoplasmic separation, and in vitro kinase assay were applied to demonstrate the PINK1-PTEN (phosphatase and tensin homolog) interaction and the effect of this interaction. The metastasis experiments for ovarian cancer xenografts were performed in female BALB/c nude mice.ResultsPINK1 was strongly associated with a poor prognosis in ovarian cancer patients and promoted metastasis and chemoresistance in ovarian cancer cells. Although the canonical PINK1/PRKN (parkin RBR E3 ubiquitin protein ligase) pathway showed weak effects in ovarian cancer, PINK1 was identified to interact with PTEN and phosphorylate it at Serine179. Remarkably, the phosphorylation of PTEN resulted in the inactivation of the phosphatase activity, leading to an increase in AKT (AKT serine/threonine kinase) activity. Moreover, PINK1-mediated phosphorylation of PTEN impaired the nuclear import of PTEN, thereby enhancing the cancer cells’ ability to resist chemotherapy and metastasize.ConclusionsPINK1 interacts with and phosphorylates PTEN at Serine179, resulting in the activation of AKT and the inhibition of PTEN nuclear import. PINK1 promotes ovarian cancer metastasis and chemotherapy resistance through the regulation of PTEN. These findings offer new potential therapeutic targets for ovarian cancer management.

Hypoxia promotes the growth and metastasis of ovarian cancer cells by suppressing ferroptosis via upregulating SLC2A12

BackgroundOvarian cancer has been a worldwide health burden for women and its progression is highly hypoxia-independent. Here, we investigated the exact mechanisms by which hypoxia contributes to the malignant progression of ovarian cancer. MethodMTT, transwell, colony formation, and scratch wound healing assays were carried out for cellular functions. The underlying mechanism by which hypoxia functions was explored by RNA-seq, enrichment analysis, western blotting, qRT-PCR, flow cytometry, ChIP, luciferase reporter, and ELISA. Finally, animal experiments including the xenograft model and tumor metastasis model were constructed to validate the role of SLC2A12 in vivo. ResultsHypoxia treatment promoted the cell proliferation, mobility, and colony growth abilities of the two ovarian cancer cell lines HO-8910 and A2780. RNA-seq and enrichment analysis showed that SLC2A12 was hyper-expressed under hypoxia condition and it may be related to glutathione and lipid metabolism. Besides, the expression of SLC2A12 was negatively correlated with overall survival. Hypoxia suppressed ferroptosis by SLC2A12 because silencing SLC2A12 declined the cell viability of HO-8910 and A2780 cells under hypoxia conditions, while the ferroptosis inhibitor ferrostatin-1 (Fer-1) breached that result and upregulated the expression of glutathione peroxidase 4 (GPX4). Moreover, hypoxia increased the expression of hypoxia inducible factor 1 A (HIF-1A), and the accumulated HIF-1A binds to hypoxia inducible factor 1 B (HIF1B) to form HIF-1 complex, then promoted the binding of hypoxic response elements (HRE) to SLC2A12 promoter by HIF-1/HRE signal. Subsequently, SLC2A12 regulated glutathione metabolism and in turn inhibited ferroptosis. The animal experiments indicated that silencing SLC2A12 could significantly inhibit tumor growth and metastasis in vivo. ConclusionHypoxia promoted ovarian cancer progression by upregulating SLC2A12 and then regulating glutathione metabolism to inhibit ferroptosis.

Long non-coding RNA NRSN2-AS1 promotes ovarian cancer progression through targeting PTK2/β-catenin pathway

As a common malignant tumor among women, ovarian cancer poses a serious threat to their health. This study demonstrates that long non-coding RNA NRSN2-AS1 is over-expressed in ovarian cancer tissues using patient sample and tissue microarrays. In addition, NRSN2-AS1 is shown to promote ovarian cancer cell proliferation and metastasis both in vitro and in vivo. Mechanistically, NRSN2-AS1 stabilizes protein tyrosine kinase 2 (PTK2) to activate the β-catenin pathway via repressing MG-53-mediated ubiquitinated degradation of PTK2, thereby facilitating ovarian cancer progression. Rescue experiments verify the function of the NRSN2-AS1/PTK2/β-catenin axis and the effects of MG53 on this axis in ovarian cancer cells. In conclusion, this study demonstrates the key role of the NRSN2-AS1/PTK2/β-catenin axis for the first time and explores its potential clinical applications in ovarian cancer.

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.

Dicalcin suppresses invasion and metastasis of mammalian ovarian cancer cells by regulating the ganglioside-Erk1/2 axis

Metastasis, a multistep process including cancer cell migration and invasion, is the major cause of mortality in patients with cancer. Here, we investigated the effect of dicalcin, a Ca2+-binding protein, on the invasion and metastasis of ovarian cancer (OC) cells. Extracellularly administered dicalcin bound to the membrane of OV2944 cells, mouse OC cells, and suppressed their migration in vitro; however, cell viability or proliferation were unaffected. Repeated intraperitoneal injection of a partial peptide of dicalcin (P6) prolonged the survival, and reduced the number of microcolonies in the livers of cancer-bearing mice. P6 bound to the ganglioside GM1b in a solid-phase assay; treatment with P6 inhibited the constitutive activation of Erk1/2 in OC cells, whereas excess administration of GM1b augmented Erk activity and cancer cell migration in vitro. Thus, dicalcin, a novel suppressor of invasion and metastasis of OC cells, acts via the GM1b-Erk1/2 axis to regulate their migration.

A comparative analysis of 2D and 3D experimental data for the identification of the parameters of computational models

Computational models are becoming an increasingly valuable tool in biomedical research. Their accuracy and effectiveness, however, rely on the identification of suitable parameters and on appropriate validation of the in-silico framework. Both these steps are highly dependent on the experimental model used as a reference to acquire the data. Selecting the most appropriate experimental framework thus becomes key, together with the analysis of the effect of combining results from different experimental models, a common practice often necessary due to limited data availability. In this work, the same in-silico model of ovarian cancer cell growth and metastasis, was calibrated with datasets acquired from traditional 2D monolayers, 3D cell culture models or a combination of the two. The comparison between the parameters sets obtained in the different conditions, together with the corresponding simulated behaviours, is presented. It provides a framework for the study of the effect of the different experimental models on the development of computational systems. This work also provides a set of general guidelines for the comparative testing and selection of experimental models and protocols to be used for parameter optimization in computational models.

LncRNA LINC01123 promotes malignancy of ovarian cancer by targeting hsa-miR-516b-5p/VEGFA.

Long non-coding RNAs (lncRNAs) play a critical role in the development of ovarian cancer (OC). The study aimed to determine the role of LncRNA LINC01123 in OC bio-progression, which is upregulated in OC tissues during OC progression. Bioinformatics methods, GEPIA, and qRT-PCR were used to reveal the level and correlation of LINC01123, hsa-miR-516b-5p, and VEGFA, in OC cell lines. MTT, EdU, TUNEL, and Transwell assays were performed to assess the bioactivity of OC cell. Target sites of LINC01123 and hsa-miR-516b-5p were predicted using Starbase, and the potential linkage points of VEGFA and hsa-miR-516b-5p were predicted using TargetScan. These sites and linkage points were confirmed by double luciferase reporter assay. LINC01123 was upregulated in OC cell lines and LINC01123 silencing suppressed the proliferation and metastasis of OC cells, but promoted cell apoptosis. hsa-miR-516b-5p was linked to LINC01123 and. VEGFA was downstream of hsa-miR-516b-5p. Importantly, silencing of hsa-miR-516b-5p reversed the inhibitory impact of si-LINC01123. The result of hsa-miR-516b-5p inhibitor + si-LINC01123 co-transfection were rescued by si-VEGFA. LINC01123 promotes OC development by dampening miR-516b-5p function, and may be a novel target for treating OC.

Dysregulation of Cholesterol Homeostasis in Ovarian Cancer.

Cholesterol plays an essential role in maintaining the rigidity of cell membranes and signal transduction. Various investigations confirmed empirically that the dysregulation of cholesterol homeostasis positively correlates with tumor progression. More specifically, recent studies suggested the distinct role of cholesterol in ovarian cancer cell proliferation, metastasis and chemoresistance. In this review, we summarize the current findings that suggest the contribution of cholesterol homeostasis dysregulation to ovarian cancer progression and resistance to anti-cancer agents. We also discuss the therapeutic implications of cholesterol-lowering drugs in ovarian cancer.

Targeting PUF60 prevents tumor progression by retarding mRNA decay of oxidative phosphorylation in ovarian cancer.

Ovarian cancer (OC) is the leading cause of death from gynecological malignancies, and its etiology and pathogenesis are currently unclear. Recent studies have found that PUF60 overexpressed in various cancers. However, the exact function of PUF60 in global RNA processing and its role in OC has been unclear. The expression of PUF60 and its relationship with clinical characteristics were analyzed by multiple database analysis and immunohistochemistry. Phenotypic effects of PUF60 on ovarian cancer cell proliferation and metastasis were examined by in vitro cell proliferation assay, migration assay, and in vivo xenograft models and lung metastasis models. RNA immunoprecipitation, seahorse analyses, RNA stability assay were used to study the effect of PUF60 on the stability of oxidative phosphorylation (OXPHOS)-related genes in OC. We report PUF60 is highly expressed in OC with frequent amplification of up to 33.9% and its upregulation predicts a poor prognosis. PUF60 promotes the proliferation and migration of OC cells both in vitro and in vivo. Mechanistically, we demonstrated that silencing of PUF60 enhanced the stability of mRNA transcripts involved in OXPHOS and decreased the formation of processing bodies (P-bodies), ultimately elevating the OXPHOS level. Our study unveils a novel function of PUF60 in OC energy metabolism. Thus, PUF60 may serve as a novel target for the treatment of patients with OC.

Long noncoding RNA LOC646029 functions as a ceRNA to suppress ovarian cancer progression through the miR-627-3p/SPRED1 axis.

Long noncoding RNAs (lncRNAs) play a crucial regulatory role in the development and progression of multiple cancers. However, the potential mechanism by which lncRNAs affect the recurrence and metastasis of ovarian cancer remains unclear. In the current study, the lncRNA LOC646029 was markedly downregulated in metastatic ovarian tumors compared with primary tumors. Gain- and loss-of-function assays demonstrated that LOC646029 inhibits the proliferation, invasiveness, and metastasis of ovarian cancer cells in vivo and in vitro. Moreover, the downregulation of LOC646029 in metastatic ovarian tumors was strongly correlated with poor prognosis. Mechanistically, LOC646029 served as a miR-627-3p sponge to promote the expression of Sprouty-related EVH1 domain-containing protein 1, which is necessary for suppressing tumor metastasis and inhibiting KRAS signaling. Collectively, our results demonstrated that LOC646029 is involved in the progression and metastasis of ovarian cancer, which may be a potential prognostic biomarker.

EFEMP2 upregulates PD-L1 expression via EGFR/ERK1/2/c-Jun signaling to promote the invasion of ovarian cancer cells

BackgroundFibulin-like extracellular matrix protein 2 (EFEMP2) has been reported to be related to the progression of various cancers. We have previously reported that EFEMP2 was highly expressed in ovarian cancer and was strongly associated with poor prognosis in patients. This study intends to further explore its interacting proteins and possible downstream signaling pathways.MethodThe expression of EFEMP2 was detected by RT-qPCR, ICC and western blot in 4 kinds of ovarian cancer cells with different migration and invasion ability. Cell models with strong or weak EFEMP2 expression were constructed by lentivirus transfection. The effects of the down-regulation and up-regulation of EFEMP2 on the biological behavior of ovarian cancer cells were studied through in-vitro and in-vivo functional tests. The phosphorylation pathway profiling array and KEGG database analyses identified the downstream EGFR/ERK1/2/c-Jun signaling pathway and the programmed death-1 (PD-L1) pathway enrichment. Additionally, the protein interaction between EFEMP2 and EGFR was detected by immunoprecipitation.ResultEFEMP2 was positively correlated with the invasion ability of ovarian cancer cells, its down-regulation inhibited the migrative, invasive and cloning capacity of cancer cells in vitro and suppressed the tumor proliferation and intraperitoneal diffusion in vivo, while its up-regulation did the opposite. Moreover, EFEMP2 could bind to EGFR to induce PD-L1 regulation in ovarian cancer, which was caused by the activation of EGFR/ERK1/2/c-Jun signaling. Similar to EFEMP2, PD-L1 was also highly expressed in aggressive cells and had the ability to promote the invasion and metastasis of ovarian cancer cells both in vitro and in vivo, and PD-L1 upregulation was partly caused by EFEMP2 activation. Afatinib combined with trametinib had an obvious effect of inhibiting the intraperitoneal diffusion of ovarian cancer cells, especially in the group with low expression of EFEMP2, while overexpression of PD-L1 could reverse this phenomenon.ConclusionEFEMP2 could bind to EGFR to activate ERK1/2/c-Jun pathway and regulate PD-L1 expression, furthermore PD-L1 was extremely essential for EFEMP2 to promote ovarian cancer cells invasion and dissemination in vitro and in vivo. Targeted therapy against the source gene EFEMP2 is our future research direction, which may better inhibit the invasion and metastasis of ovarian cancer cells.

HMGB3 promotes the malignant phenotypes and stemness of epithelial ovarian cancer through the MAPK/ERK signaling pathway

BackgroundOvarian cancer, particularly epithelial ovarian cancer (EOC), is the leading cause of cancer-related mortality among women. Our previous study revealed that high HMGB3 levels are associated with poor prognosis and lymph node metastasis in patients with high-grade serous ovarian carcinoma; however, the role of HMGB3 in EOC proliferation and metastasis remains unknown.MethodsMTT, clonogenic, and EdU assays were used to assess cell proliferation. Transwell assays were performed to detect cell migration and invasion. Signaling pathways involved in HMGB3 function were identified by RNA sequencing (RNA-seq). MAPK/ERK signaling pathway protein levels were evaluated by western blot.ResultsHMGB3 knockdown inhibited ovarian cancer cell proliferation and metastasis, whereas HMGB3 overexpression facilitated these processes. RNA-seq showed that HMGB3 participates in regulating stem cell pluripotency and the MAPK signaling pathway. We further proved that HMGB3 promotes ovarian cancer stemness, proliferation, and metastasis through activating the MAPK/ERK signaling pathway. In addition, we demonstrated that HMGB3 promotes tumor growth in a xenograft model via MAPK/ERK signaling.ConclusionsHMGB3 promotes ovarian cancer malignant phenotypes and stemness through the MAPK/ERK signaling pathway. Targeting HMGB3 is a promising strategy for ovarian cancer treatment that may improve the prognosis of women with this disease.2qup1eeBfJMNesoTGXbg-CVideo

LncRNA gadd7 promotes mitochondrial membrane potential decrease and apoptosis of alveolar type II epithelial cells by positively regulating MFN1 in an in vitro model of hyperoxia-induced acute lung injury.

The mortality and morbidity rates of ovarian cancer (OC) are high, but the underlying mechanisms of OC have not been characterized. In this study, we determined the role of Rho GTPase Activating Protein 30 (ARHGAP30) in OC progression. We measured ARHGAP30 abundance in OC tissue samples and cells using immunohistochemistry (IHC) and RT-qPCR. EdU, transwell, and annexin V/PI apoptosis assays were used to evaluate proliferation, invasiveness, and apoptosis of OC cells, respectively. The results showed that ARHGAP30 was overexpressed in OC tissue samples and cells. Inhibition of ARHGAP30 suppressed growth and metastasis of OC cells, and enhanced apoptosis. Knockdown of ARHGAP30 in OC cells significantly inhibited the PI3K/AKT/mTOR pathway. Treatment with the PI3K/AKT/mTOR pathway inhibitor buparlisib simulated the effects of ARHGAP30 knockdown on growth, invasiveness, and apoptosis of OC cells. Following buparlisib treatment, the expression levels of p-PI3K, p-AKT, and p-mTOR were significantly decreased. Furthermore, buparlisib inhibited the effects of ARHGAP30 upregulation on OC cell growth and invasiveness. In conclusion, ARHGAP30 regulated the PI3K/AKT/mTOR pathway to promote progression of OC.

MiR-2053 inhibits the growth of ovarian cancer cells by downregulating SOX4.

Ovarian cancer is one of the major gynaecological malignancies and a leading cause of cancer-related deaths worldwide. Dysregulation of miR-2053 has been reported in numerous types of cancer; however, its function in ovarian cancer remains largely unknown. In our study, the roles of miR-2053 during the development of ovarian cancer were investigated. miR-2053 expression was examined in ovarian cancer specimens and cells. Furthermore, the detailed functions and downstream targets of miR-2053 were identified. Briefly, the levels of miR-2053 were assessed in ovarian cancer tissues and paired non-cancerous samples, as well as in ovarian cancer cells using reverse transcription-quantitative polymerase chain reaction. The proliferation of cells was determined by cell counting kit-8 kit, and the levels of PCNA were also examined using immunostaining. Cell migration and invasion were evaluated using Transwell assay, and E-cad expression was assessed by immunostaining. In addition, cell apoptosis was determined by flow cytometry, and the expression of cleaved caspase-3 was examined using western blotting. The results revealed the downregulation of miR-2053 in ovarian cancer tissues and cells. Moreover, miR-2053 mimics suppressed the proliferation, migration, and invasion of ovarian cancer cells, while cell apoptosis was promoted. In addition, SOX4 was a putative downstream molecule of miR-2053 in ovarian cancer. Furthermore, SOX4 is involved in miR-2053-regulated growth and metastasis of ovarian cancer cells. In summary, miR-2053 and its novel target SOX4 could serve essential roles during tumour development of ovarian cancer, more importantly, miR-2053/SOX4 axis may be novel candidate for targeted therapy for patients with ovarian cancer.

Pharmacological inhibition of EZH2 using a covalent inhibitor suppresses human ovarian cancer cell migration and invasion.

Metastasis is the cause of poor prognosis in ovarian cancer (OC). Enhancer of Zeste homolog 2 (EZH2), a histone-lysine N-methyltransferase enzyme, promotes OC cell migration and invasion by regulating the expression of tissue inhibitor of metalloproteinase-2 (TIMP2) and matrix metalloproteinases-9 (MMP9). Hence, we speculated that EZH2-targeting therapy might suppress OC migration and invasion. In this study, the expression of EZH2, TIMP2, and MMP9 in OC tissues and cell lines was analyzed using The Cancer Genome Atlas (TCGA) database and western blotting, respectively. The effects of SKLB-03220, an EZH2 covalent inhibitor, on OC cell migration and invasion were investigated using wound-healing assays, Transwell assays, and immunohistochemistry. TCGA database analysis confirmed that the EZH2 and MMP9 mRNA expression was significantly higher in OC tissues, whereas TIMP2 expression was significantly lower than that in normal ovarian tissues. Moreover, EZH2 negatively correlated with TIMP2 and positively correlated with MMP9 expression. In addition to the anti-tumor activity of SKLB-03220 in a PA-1 xenograft model, immunohistochemistry results showed that SKLB-03220 markedly increased the expression of TIMP2 and decreased the expression of MMP9. Additionally, wound-healing and Transwell assays showed that SKLB-03220 significantly inhibited the migration and invasion of both A2780 and PA-1 cells in a concentration-dependent manner. SKLB-03220 inhibited H3K27me3 and MMP9 expression and increased TIMP2 expression in PA-1 cells. Taken together, these results indicate that the EZH2 covalent inhibitor SKLB-03220 inhibits metastasis of OC cells by upregulating TIMP2 and downregulating MMP9, and could thus serve as a therapeutic agent for OC.

Knockdown of ARHGAP30 inhibits ovarian cancer cell proliferation, migration, and invasiveness by suppressing the PI3K/AKT/mTOR signaling pathway

The mortality and morbidity rates of ovarian cancer (OC) are high, but the underlying mechanisms of OC have not been characterized. In this study, we determined the role of Rho GTPase Activating Protein 30 (ARHGAP30) in OC progression. We measured ARHGAP30 abundance in OC tissue samples and cells using immunohistochemistry (IHC) and RT-qPCR. EdU, transwell, and annexin V/PI apoptosis assays were used to evaluate proliferation, invasiveness, and apoptosis of OC cells, respectively. The results showed that ARHGAP30 was overexpressed in OC tissue samples and cells. Inhibition of ARHGAP30 suppressed growth and metastasis of OC cells, and enhanced apoptosis. Knockdown of ARHGAP30 in OC cells significantly inhibited the PI3K/AKT/mTOR pathway. Treatment with the PI3K/AKT/mTOR pathway inhibitor buparlisib simulated the effects of ARHGAP30 knockdown on growth, invasiveness, and apoptosis of OC cells. Following buparlisib treatment, the expression levels of p-PI3K, p-AKT, and p-mTOR were significantly decreased. Furthermore, buparlisib inhibited the effects of ARHGAP30 upregulation on OC cell growth and invasiveness. In conclusion, ARHGAP30 regulated the PI3K/AKT/mTOR pathway to promote progression of OC.