Janus Nanofibrous Patch with In Situ Grown Superlubricated Skin for Soft Tissue Repair with Inhibited Postoperative Adhesion.

The patch with a superlubricated surface shows great potential for the prevention of postoperative adhesion during soft tissue repair. However, the existing patches suffer from the destruction of topography during superlubrication coating and lack of pro-healing capability. Herein, we demonstrate a facile and versatile strategy to develop a Janus nanofibrous patch (J-NFP) with antiadhesion and reactive oxygen species (ROS) scavenging functions. Specifically, sequential electrospinning is performed with initiators and CeO2 nanoparticles (CeNPs) embedded on the different sides, followed by subsurface-initiated atom transfer radical polymerization for grafting zwitterionic polymer brushes, introducing superlubricated skin on the surface of single nanofibers. The poly(sulfobetaine methacrylate) brush-grafted patch retains fibrous topography and shows a coefficient of friction of around 0.12, which is reduced by 77% compared with the pristine fibrous patch. Additionally, a significant reduction in protein, platelet, bacteria, and cell adhesion is observed. More importantly, the CeNPs-embedded patch enables ROS scavenging as well as inhibits pro-inflammatory cytokine secretion and promotes anti-inflammatory cytokine levels. Furthermore, the J-NFP can inhibit tissue adhesion and promote repair of both rat skin wounds and intrauterine injuries. The present strategy for developing the Janus patch exhibits enormous prospects for facilitating soft tissue repair.

Synthesis and Evaluation of diaryl ether modulators of the leukotriene A4 hydrolase aminopeptidase activity.

Activation of the aminopeptidase (AP) activity of leukotriene A4 hydrolase (LTA4H) presents a potential therapeutic strategy for resolving chronic inflammation. Previously, ARM1 and derivatives were found to activate the AP activity using the alanine-p-nitroanilide (Ala-pNA) as a reporter group in an enzyme kinetics assay. As an extension of this previous work, novel ARM1 derivatives were synthesized using a palladium-catalyzed Ullmann coupling reaction and screened using the same assay. Analogue 5, an aminopyrazole (AMP) analogue of ARM1, was found to be a potent AP activator with an AC50 of 0.12 µM. An X-ray crystal structure of LTA4H in complex with AMP was refined at 2.7 Å. Despite its AP activity with Ala-pNA substrate, AMP did not affect hydrolysis of the previously proposed natural ligand of LTA4H, Pro-Gly-Pro (PGP). This result highlights a discrepancy between the hydrolysis of more conveniently monitored chromogenic synthetic peptides typically employed in assays and endogenous peptides. The epoxide hydrolase (EH) activity of AMP was measured in vivo and the compound significantly reduced leukotriene B4 (LTB4) levels in a murine bacterial pneumonia model. However, AMP did not enhance survival in the murine pneumonia model over a 14-day period. A liver microsome stability assay showed metabolic stability of AMP. The results suggested that accelerated Ala-pNA cleavage is not sufficient for predicting therapeutic potential, even when the full mechanism of activation is known.

Stem cells implanted with nanofibrous mats for injured endometrial regeneration and immune-microenvironment remodeling.

Severe endometrial injury caused by invasive uterine operation and/or endometritis often results in intrauterine adhesions (IUAs), which are named Asherman's syndrome (AS), further leading to menstrual disorders, infertility and severe complications during pregnancy and delivery. IUAs or AS has been a challenging medical problem. Stem cells are a promising therapeutic modality for endometrial regeneration in patients with refractory AS. Here, we developed a new system of adipose-derived mesenchymal stem cells (ADMSCs) implantation on silk fibroin/polycaprolactone (SF/PCL) electrospun nanofibers (ADMSCs-SF/PCL) and used it in the damaged endometrium of a rat model. After SF/PCL enhanced the proliferation of transplanted ADMSCs, the results showed that the ADMSCs-SF/PCL system could recover morphology, promote regeneration of the glands and angiogenesis by increasing CD31 expression, and reverse endometrial fibrosis by decreasing TGF-ß/Smad expression. In addition, the ADMSCs-SF/PCL system also increased the expression of differentiation and decidualization markers, including HOXA11, HAND2 and FOXO1. Most importantly, the ADMSCs-SF/PCL system could remodel the special immune microenvironment, resulting in dominant NK infiltration and a normal Th1/Th2 bias in the endometrium. Moreover, this treatment had a lower but more persistent effect than estrogen. Thus, the ADMSCs-SF/PCL system enhanced endometrial restoration, suggesting a promising strategy for damaged endometrial regeneration and immune microenvironment remodeling.

RNA 5-Methylcytosine regulators are associated with cell adhesion and predict prognosis of endometrial cancer.

Background: RNA methylation is a significant form of post-transcriptional modification that has been implicated in various diseases, including cancers. One prominent type of RNA methylation is 5-Methylcytosine (m5C), which primarily regulates RNA stability, transcription, and translation. However, the role of m5C-related gene regulation in cell adhesion within uterine corpus endometrial carcinoma (UCEC) remains unexplored. Therefore, the objective of this study was to investigate the association between RNA m5C methylation and UCEC and develop a prognostic predictive model to forecast survival outcomes in UCEC patients. Methods: The RNA datasets were acquired from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The dataset was used to explore the interaction relationships of m5C regulators in UCEC. Unsupervised clustering analysis identified clusters with distinct m5C modification patterns. Different clusters underwent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment level analysis to investigate the effects of pathways related to m5C methylation, which were further validated through in vitro cellular experiments. A prognostic predictive model was developed using the least absolute shrinkage and selection operator (LASSO) and multivariate regression analysis. Results: Two clusters with distinct m5C modification patterns were identified using unsupervised cluster analysis. Furthermore, the prognosis of cluster 2 was found to be worse. Enrichment analysis showed alterations in cell adhesion-related pathways in both clusters, as well as differences between the clusters. Through this analysis, we identified 25 genes with significant prognostic value. Finally, a prognostic predictive model comprising NSUN2 and YBX1 was constructed. Conclusions: In conclusion, diverse m5C modification patterns display distinct cell adhesion properties in UCEC, which are correlated with prognosis and offer significant potential as prognostic markers for UCEC assessment. We developed a prognostic predictive model to accurately predict the prognosis of UCEC.

Function of m5C RNA methyltransferase NOP2 in high-grade serous ovarian cancer.

RNA methyltransferase nucleolar protein p120 (NOP2), commonly referred to as NOP2/Sun RNA methyltransferase family member 1 (NSUN1), is involved in cell proliferation and is highly expressed in various cancers. However, its role in high-grade serous ovarian cancer (HGSOC) remains unclear. Our study investigated the expression of NOP2 in HGSOC tissues and normal fimbria tissues, and found that NOP2 was significantly upregulated in HGSOC tissues. Our experiments showed that NOP2 overexpression promoted cell proliferation in vivo and in vitro and increased the migration and invasion ability of HGSOC cells in vitro. Furthermore, we identified Rap guanine nucleotide exchange factor 4 (RAPGEF4) as a potential downstream target of NOP2 in HGSOC. Finally, our findings suggest that the regulation of NOP2 and RAPGEF4 may depend on m5C methylation levels.

Contrast-Enhanced Ultrasonography for Transabdominal and Transrectal Ultrasound in Staging Cervical Cancer: A Reliability Study.

OBJECTIVE: This retrospective study aimed to evaluate the consistency of transrectal contrast-enhanced ultrasonography (TR-CEUS) with post-operative pathology and the value of contrast-enhanced ultrasonography (CEUS) in staging surgically treated cervical cancer when combined with conventional ultrasonography (US). METHODS: From October 2020 to March 2023, hospitalized patients with stage IB and II cervical cancer confirmed by total hysterectomy were consecutively enrolled. The standard images of US and CEUS by transabdominal (TA-US/CEUS) and transrectal (TR-US/CEUS) approaches and magnetic resonance imaging (MRI) were acquired, on which the size and stage of the tumors were evaluated, and the consistency of results with the pathological specimen was analyzed. RESULTS: Thirty-nine patients with cervical cancer were finally enrolled in this study. The results showed that CEUS significantly improved the reliability of TA-US in evaluating tumor diameter; the intraclass correlation coefficient (ICC) was from 0.672 to 0.735. TR-US indicated good reliability with or without the addition of CEUS (ICC = 0.796 and 0.780). In terms of tumor staging, CEUS improved the consistency of transabdominal (weighted κ values from 0.689 to 0.731) and transrectal staging of tumors (κ from 0.758 to 0.785), and the staging of TR-US combined with TR-CEUS had the highest consistency with post-operative results, similar to MRI (κ, respectively 0.785 and 0.789). CEUS can reflect the heterogeneity of the tumor. Heterogeneous enhancement and perfusion defects were more common in >2 cm cervical cancer (50%, 20/40 and 52.5%, 21/40), respectively, and perfusion defects were more common in moderately to poorly differentiated tumors (66.67%, 20/30). CONCLUSION: For stage IB and IIA cervical cancer, CEUS can aid in assessing the International Federation for Gynecology and Obstetrics staging of tumors alongside TA-US and TR-US. The combination of TR-US and TR-CEUS has shown good consistency with pathology in the staging of cervical cancer, comparable to that of MRI.

Identification and validation of m5c-related lncRNA risk model for ovarian cancer.

Ovarian cancer (OC) is one of the common malignant tumors that seriously threaten women's health, and there is a lack of clinical prognostic predictors, while m5c and lncRNA have been shown to be predictive of multiple cancers, including OC. Therefore, our goal was to construct a risk model for OC based on m5c-related lncRNA.340 m5c-related lncRNA were identified and a novel risk model of OC ground on nine m5C-related lncRNA was constructed using LASSO-COX regression analysis. Kaplan-Meier analysis showed there was a significant difference in prognosis between risk groups. We established a nomogram which was a good predictor of overall survival. In addition, GSEA was enriched in multiple pathways and immune function analysis suggested that immune infiltration varies depending on the risk group. In vitro experiments show that AC005562.1, a key lncRNA of the risk model, is highly expressed in OC cells and promotes OC cell proliferation. Finally, we further explored the potential biological markers of m5c-related lncRNA in OC with WGCNA analysis and established a ceRNA network. In conclusion,we have developed a reliable m5c-related prediction model and performed systematic validation and exploration of various aspects. These results can be used for the assessment of OC prognosis and the discovery of novel biomarkers.

Construction of a prognostic signature for serous ovarian cancer based on lactate metabolism-related genes.

Background: The key biochemical feature of malignant tumor is the conversion of energy metabolism from oxidative phosphorylation to glycolysis, which provides sufficient capacity and raw materials for tumor cell rapid growth. Our study aims to construct a prognostic signature for ovarian cancer based on lactate metabolism-related genes (LMRGs). Methods: Data of ovarian cancer and non-diseased ovarian data were downloaded from TCGA and the GTEx database, respectively. LMRGs were obtained from GeneCards and MSigDB databases, and the differentially expressed LMRGs were identified using limma and DESeq2 R packages. Cox regression analysis and LASSO were performed to determine the LMRGs associated with OS and develop the prognostic signature. Then, clinical significance of the prognostic signature in ovarian cancer was assessed. Results: A total of 485 differentially expressed LMRGs in ovarian tissue were selected for subsequent analysis, of which 324 were up-regulated and 161 were down regulated. We found that 22 LMRGs were most significantly associated with OS by using the univariate regression analysis. The prognostic scoring model was consisted of 12 LMRGs (SLCO1B3, ERBB4, SLC28A1, PDSS1, BDH1, AIFM1, TSFM, PPARGC1A, HGF, FGFR1, ABCC8, TH). Kaplan-Meier survival analysis indicated that poorer overall survival (OS) in the high-risk group patients (P<0.0001). This prognostic signature could be an independent prognostic indicator after adjusting to other clinical factors. The calibration curves of nomogram for the signature at 1, 2, and 3 years and the ROC curve demonstrated good agreement between the predicted and observed survival rates of ovarian cancer patients. Furthermore, the high-risk group patients have much lower expression level of immune checkpoint-TDO2 compared with the low-risk group (P=0.024). Conclusions: We established a prognostic signature based on LMRGs for ovarian cancer, and highlighted emerging evidence indicating that this prognostic signature is a promising approach for predicting ovarian cancer prognosis and guiding clinical therapy.

Development and Validation of an Immune-Related Prognostic Signature in Cervical Cancer.

Background: Cervical cancer is the fourth most frequent gynecological malignancy across the world. Immunotherapies have proved to improve prognosis of cervical cancer. However, few studies on immune-related prognostic signature had been reported in cervical cancer. Methods: Raw data and clinical information of cervical cancer samples were downloaded from TCGA and UCSC Xena website. Immunophenoscore of immune infiltration cells in cervical cancer samples was calculated through the ssGSEA method using GSVA package. WGCNA, Cox regression analysis, LASSO analysis, and GSEA analysis were performed to classify cervical cancer prognosis and explore the biological signaling pathway. Results: There were eight immune infiltration cells associated with prognosis of cervical cancer. Through WGCNA, 153 genes from 402 immune-related genes were significantly correlated with prognosis of cervical cancer. A 15-gene signature demonstrated powerful predictive ability in prognosis of cervical cancer. GSEA analysis showed multiple signaling pathways containing Programmed cell death ligand-1 (PD-L1) expression and PD-1 checkpoint pathway differences between high-risk and low-risk groups. Furthermore, the 15-gene signature was associated with multiple immune cells and immune infiltration in tumor microenvironment. Conclusion: The 15-gene signature is an effective potential prognostic classifier in the immunotherapies and surveillance of cervical cancer.

Substrate-dependent modulation of the leukotriene A4 hydrolase aminopeptidase activity and effect in a murine model of acute lung inflammation.

The aminopeptidase activity (AP) of the leukotriene A4 hydrolase (LTA4H) enzyme has emerged as a therapeutic target to modulate host immunity. Initial reports focused on the benefits of augmenting the LTA4H AP activity and clearing its putative pro-inflammatory substrate Pro-Gly-Pro (PGP). However, recent reports have introduced substantial complexity disconnecting the LTA4H modulator 4-methoxydiphenylmethane (4MDM) from PGP as follows: (1) 4MDM inhibits PGP hydrolysis and subsequently inhibition of LTA4H AP activity, and (2) 4MDM activates the same enzyme target in the presence of alternative substrates. Differential modulation of LTA4H by 4MDM was probed in a murine model of acute lung inflammation, which showed that 4MDM modulates the host neutrophilic response independent of clearing PGP. X-ray crystallography showed that 4MDM and PGP bind at the zinc binding pocket and no allosteric binding was observed. We then determined that 4MDM modulation is not dependent on the allosteric binding of the ligand, but on the N-terminal side chain of the peptide. In conclusion, our study revealed that a peptidase therapeutic target can interact with its substrate and ligand in complex biochemical mechanisms. This raises an important consideration when ligands are designed to explain some of the unpredictable outcomes observed in therapeutic discovery targeting LTA4H.

Evaluation of the necessity of laparoscopic repair of a uterine scar defect for cesarean scar pregnancy.

OBJECTIVE: This study aimed to determine the risk factors associated with the necessity of laparoscopic scar defect repair for cesarean scar pregnancy (CSP). METHODS: We retrospectively analyzed 237 patients with CSP who were treated by ultrasound-guided suction curettage and/or laparoscopy in our hospital from April 2012 to November 2019. A total of 199 of these patients underwent ultrasound-guided suction curettage without uterine scar defect repair, while 38 of these patients underwent laparoscopic resection and uterine scar defect repair. We analyzed various clinical variables and compared the efficacy of treatment between the two groups. RESULTS: Gestational age, the maximum transverse diameter (MTD) of the gestational sac, myometrial thickness, the operation time, intraoperative blood loss, and the duration of the hospital stay were significantly different between the two groups. Gestational age, the MTD of the gestational sac, and myometrial thickness were independent risk factors for laparoscopic repair. CONCLUSIONS: Gestational age, the MTD of the gestational sac, and myometrial thickness are important factors associated with the necessity for laparoscopic repair of a uterine scar defect.

LDH-A inhibitors as remedies to enhance the anticancer effects of PARP inhibitors in ovarian cancer cells.

Ovarian cancer is one of the most lethal gynecologic malignancies. It has been shown that PARP inhibitors can selectively target BRCA-mutated ovarian cancer and exert some effects on ovarian cancer without BRCA mutations. However, the mechanism is still unclear. In this study, wild-type BRCA ovarian cancer cells (A2780 and SKOV3) were used. Our results showed that using a PARP inhibitor (olaparib or AG14361) alone significantly inhibited the proliferation of A2780 cells but negligibly inhibited the proliferation of SKOV3 cells. We used RNA sequencing to explore differentially expressed genes and found that PARP inhibitors increased LDH-A in SKOV3 cells, which was confirmed by RT-PCR. Oxamate (a specific inhibitor of LDH-A) was used to investigate whether LDH-A inhibition enhances the suppressive effects of PARP inhibitors on ovarian cancer without BRCA mutations. CCK-8 assays, scratch assays and Transwell assays were used to determine cell proliferation, cell migration ability and invasion ability, respectively. Both olaparib and AG14361 significantly inhibited the proliferation/invasion ability of A2780 cells but not SKOV3 cells. Inhibition of LDH-A can remarkably promote the inhibitory effects of PARP inhibitors on both A2780 and SKOV3 cells. Thus, high expression level of LDH-A influenced the suppressive effects of PARP inhibitors on ovarian cancer with wild-type BRCA, and LDH-A inhibition notably enhanced this effect.

Dynamically Accumulating Homologous Recombination Deficiency Score Served as an Important Prognosis Factor in High-Grade Serous Ovarian Cancer.

Background: The homologous recombination (HR) pathway defects in cancers induced abrogation of cell cycle checkpoints, resulting in the accumulation of DNA damage, mitotic catastrophe, and cell death. Cancers with BRCA1/2 loss and other accumulation of similar genomic scars resulting in HRD displayed increased sensitivity to chemotherapy. Our study aimed to explore HRD score genetic mechanisms and subsequent clinical outcomes in human cancers, especially ovarian cancer. Methods: We analyzed TCGA data of HRD score in 33 cancer types and evaluated HRD score distribution and difference among tumor stages and between primary and recurrent tumor tissues. A weighted gene co-expression network analysis (WGCNA) was performed to identify highly correlated genes representing essential modules contributing to the HRD score and distinguish the hub genes and significant pathways. We verified HRD status predicting roles in patients' overall survival (OS) with univariate and multivariate Cox regression analyses and built the predicting model for patient survival. Results: We found that the HRD score increased with the rise in tumor stage, except for stage IV. The HRD score tended to grow up higher in recurrent tumor tissue than in their primary counterparts (p = 0.083). We constructed 15 co-expression modules with WGCNA, identified co-expressed genes and pathways impacting the HRD score, and concluded that the HRD score was tightly associated with tumor cells replication and proliferation. A combined HRD score ≥42 was associated with shorter OS in 33 cancer types (HR = 1.010, 95% CI: 1.008-1.011, p < 0.001). However, in ovarian cancer, which ranked the highest HRD score among other cancers, HRD ≥42 cohort was significantly associated with longer OS (HR = 0.99, 95% CI: 0.98-0.99, p < 0.0001). We also built a predicting model for 3 and 5 years survival in HGSC patients. Conclusion: A quantitative HRD score representing the accumulated genomic scars was dynamically increasing in proliferating tumor cells since the HRD score was tightly correlated to tumor cell division and replication. We highlighted HRD score biomarker role in prognosis prediction of ovarian cancer.

Research progress on the association between environmental pollutants and the resistance mechanism of PARP inhibitors in ovarian cancer.

The occurrence and progression of ovarian cancer are closely related to genetics and environmental pollutants. Poly(ADP-ribose) polymerase (PARP) inhibitors have been a major breakthrough in the history of ovarian cancer treatment. PARP is an enzyme responsible for post-translational modification of proteins and repair of single-stranded DNA damage. PARP inhibitors can selectively inhibit PARP function, resulting in a synthetic lethal effect on tumor cells defective in homologous recombination repair. However, with large-scale application, drug resistance also inevitably appears. For PARP inhibitors, the diversity and complexity of drug resistance mechanisms have always been difficult problems in clinical treatment. Herein, we mainly summarized the research progress of DNA damage repair and drug resistance mechanisms related to PARP inhibitors and the impact of environmental pollutants on DNA damage repair to aid the development prospects and highlight urgent problems to be solved.

Construction of a ceRNA network of hub genes affecting immune infiltration in ovarian cancer identified by WGCNA.

BACKGROUND: Ovarian cancer is the leading cause of death among gynecological malignancies. Immunotherapy has demonstrated potential effects in ovarian cancer. However, few studies on immune-related prognostic signatures in ovarian cancer have been reported. This study aimed to identify hub genes associated with immune infiltrates to provide insight into the immune regulatory mechanisms in ovarian cancer. METHODS: Raw data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) and University of California, Santa Cruz (UCSC) Xena websites. Single-sample gene set enrichment analysis (ssGSEA) and weighted gene co-expression network analysis (WGCNA) were used to identify hub genes. Kaplan-Meier analysis and differential expression analysis were applied to explore the real hub genes. RESULTS: Through ssGSEA and WGCNA, 7 hub genes (LY9, CD5, CXCL9, IL2RG, SLAMF1, SLAMF6, and SLAMF7) were identified. Finally, LY9 and SLAMF1 were recognized as the real hub genes in immune infiltrates of ovarian cancer. LY9 and SLAMF1 are classified as SLAM family receptors involved in the activation of hematopoietic cells and the pathogenesis of multiple malignancies. Furthermore, 12 lncRNAs and 43 miRNAs significantly related to the 2 hub genes were applied to construct a lncRNA-miRNA-mRNA ceRNA network. The lncRNA-miRNA-mRNA ceRNA network shows upstream regulatory sites of the 2 hub genes. CONCLUSIONS: These findings improve our understanding of the regulatory mechanism of and reveal potential immune checkpoints for immunotherapy for ovarian cancer.

Artesunate-induced ATG5-related autophagy enhances the cytotoxicity of NK92 cells on endometrial cancer cells via interactions between CD155 and CD226/TIGIT.

Uterine corpus endometrial carcinoma (UCEC) is the most prevalent gynecologic cancer in developed countries and lacks efficient therapeutic strategies. Artesunate (ART), a well-modified derivate of artemisinin, exerts potent anti-cancer effects apart from its classical anti-malaria feature. Autophagy is a universal double-edged process in cell survival, and CD155 is a novel immune checkpoint highly expressed in numerous cancers. However, the relationships among ART, autophagy, and CD155 remain unclear in UCEC. In this study, we discovered that ART not only inhibited proliferation and migration, promoted apoptosis, but also induced autophagy in UCEC cells. Meanwhile, ART-induced autophagy elevated the level of CD155 in UCEC cells, thereby enhancing the cytotoxicity of natural killer cell line (NK92) by modulating the interactions between CD155 and its receptors in NK92 cells via upregulation of co-stimulator CD226 and downregulation of co-inhibitor TIGIT. Additionally, ART regulated CD155 partially via ATG5, and knockdown of ATG5 dampened the expression of CD155 in UCEC cells, thus decreasing the cytotoxicity of NK92 cells. Therefore, this study demonstrated the dual anti-cancer effects of ART as it could induce cell-killing directly and indirectly, which provides novel insights into the anti-cancer mechanisms of ART on UCEC.

Identification of hub genes in key hallmarks of ovarian cancer via bioinformatics analysis.

BACKGROUND: Ovarian cancer is one of the most lethal malignant gynecologic tumors worldwide. We aimed to identify critical hallmarks of the surface epithelium between normal ovaries and serous ovarian carcinomas and then obtain the hub genes associated with these critical hallmarks. METHODS: We chose GSE36668, GSE54388 and GSE69428 as data sources and then determined the common gene sets through gene set enrichment analysis (GSEA) to explore essential hallmarks and hub genes driving normal ovarian cells to evolve progressively into a neoplastic state. The differentially expressed genes (DEGs) extracted separately in each gene set were analyzed again through the Metascape website. Kaplan-Meier plotter was used to obtain significant prognostic information. The hub genes were obtained through protein-protein interaction (PPI) network by Cytoscape. Hub genes were confirmed to have higher mRNA and protein expression levels in ovarian cancer tissues than in normal tissues through public databases [Gene Expression Profiling Interactive Analysis (GEPIA) and The Human Protein Atlas]. Correlation analysis of six hub genes showed a strong correlation via R. RESULTS: We obtained 11 common hallmarks from GSEA of the three mentioned datasets and 22 hub genes that showed a significant association with poor survival. CONCLUSIONS: Not only the gene sets enriched by GSEA but also the hub genes extracted by the PPI network indicate that the most fundamental trait of ovarian cancer cells involves their ability to sustain chronic proliferation.

[Effect of umbilical cord mesenchymal stem cells on proliferation and apoptosis of ovarian cancer cells].

OBJECTIVE: To observe the effects of human umbilical cord mesenchymal stem cells (UC-MSCs) on the proliferation and apoptosis of human ovarian cancer cell SKOV3.
 Methods: Transwell co-culture was used to observe the targeted homing effect of UC-MSCs on ovarian cancer cells. MTT assay was used to detect the inhibitory effect of UC-MSCs conditioned medium on SKOV3 proliferation, and Annexin V-FITC/PI double staining was used to detect the apoptotic rate. Real-time PCR was used to detect the expression levels of Ki-67, Bcl-2 and Bax genes-relevant to proliferation and apoptosis of SKOV3 cells.
 Results: UC-MSCs targeted SKOV3 cells in vitro. MTT assay showed that UC-MSCs conditioned medium significantly inhibited the proliferation of SKOV3 cells (P<0.01). Annexin V-FITC/PI double staining showed that the apoptotic rate in the 75% conditioned medium group was significantly higher than that in the control group (P<0.05). Real-time PCR showed that the expression of proliferation-related gene Ki-67 decreased significantly (P<0.01). The apoptosis-related gene Bcl-2 expression was decreased dramatically (P<0.01), and Bax expression was increased significantly (P<0.01).
 Conclusion: UC-MSCs can target ovarian cancer cells in vitro, inhibit the proliferation of SKOV3 cells by regulating the expression of Ki-67, and promote the apoptosis of SKOV3 cells by regulating the expression of Bcl-2 and Bax.

Estrogen inhibits autophagy and promotes growth of endometrial cancer by promoting glutamine metabolism.

BACKGROUND: Excessive estrogen exposure is an important pathogenic factor in uterine endometrial cancer (UEC). Recent studies have reported the metabolic properties can influence the progression of UEC. However, the underlying mechanisms have not been fully elucidated. METHODS: Glutaminase (GLS), MYC and autophagy levels were detected. The biological functions of estrogen-MYC-GLS in UEC cells (UECC) were investigated both in vivo and in vitro. RESULTS: Our study showed that estrogen remarkably increased GLS level through up-regulating c-Myc, and enhanced glutamine (Gln) metabolism in estrogen-sensitive UEC cell (UECC), whereas fulvestrant (an ER inhibitor antagonist) could reverse these effects. Estrogen remarkably promoted cell viability and inhibited autophagy of estrogen sensitive UECC. However, CB-839, a potent selective oral bioavailable inhibitor of both splice variants of GLS, negatively regulated Gln metabolism, and inhibited the effects of Gln and estrogen on UECC's growth and autophagy in vitro and / or in vivo. CONCLUSIONS: CB-839 triggers autophagy and restricts growth of UEC by suppressing ER/Gln metabolism, which provides new insights into the potential value of CB-839 in clinical treatment of estrogen-related UEC.

Lactate dehydrogenase is correlated with clinical stage and grade and is downregulated by si­SAΤB1 in ovarian cancer.

Lactate, which is regulated by gene expression, is largely believed to favor tumor growth and survival. Elevated lactate dehydrogenase (LDH) is a negative prognostic biomarker because it is a key enzyme involved in cancer metabolism. Our previous study revealed that special AT­rich­binding protein 1 (SATB1), a genome­organizing protein, was strongly associated with high metastasis rates in ovarian cancer. However, its underlying molecular mechanisms in ovarian cancer are unclear. In the present study, we investigated whether SATB1 modulated LDH expression and examined the relationship between SATB1 and LDH in ovarian cancer. We employed transient siRNA­mediated knockdown of SATB1 in ovarian cancer and explored the effects of this knockdown on the expression levels of key glucose metabolism­related enzyme genes (G6PD, LDH, MDH1, PFK1 and TGM1) and the glucose metabolism­related protein monocarboxylate transporter 1 (MCT1). We comprehensively analyzed the cellular and molecular role of LDH in ovarian cancer to determine whether it could be a conventional clinicopathological parameter. SATB1 knockdown significantly downregulated both LDH and MCT1 levels and markedly upregulated BRCA1 and BRCA2 levels in ovarian cancer cells (P<0.05). Serum LDH levels in ovarian cancer patients were significantly higher than those in patients with benign ovarian tumors (P<0.05). LDH levels at different stages and grades differed significantly in ovarian cancer. Survival curves revealed that higher LDH expression was correlated with shorter survival (P<0.05). SATB1 may reprogram energy metabolism in ovarian cancer by regulating LDH and MCT1 levels to promote metastasis. Serum LDH levels presented diagnostic accuracy with high specificity and may have potential as a conventional clinicopathological parameter for ovarian cancer.