A clinical prognostic model of oxidative stress-related genes linked to tumor immune cell infiltration and the prognosis of ovarian cancer patients.

Background: According to statistics, ovarian cancer (OV) is the most prevalent type of gynecologic malignancy and has the highest mortality rate of all gynecologic tumors. Although several studies have shown that oxidative stress (OS) contributes significantly to the onset and progression of cancer, the role of OS in OV needs to be investigated further. Thus, it is critical to comprehend the function of OS-related genes in OV. Methods: In this study, all data related to the transcriptome and clinical status of the patients were retrieved from "The Cancer Genome Atlas" (TCGA) and "Gene Expression Omnibus" (GEO) databases. Using the unsupervised cluster analysis technique, all patients with OV were classified into two different subtypes (categories) based on the OS gene. All hub genes were screened using the weighted gene co-expression network analysis (WGCNA). Since the hub genes and the differentially expressed genes (DEGs) in both categories were found to intersect, the univariate Cox regression analysis was implemented. A multivariate Cox analysis was also performed to construct a novel clinical prognosis model, which was validated using data from the GEO cohort. In addition, the relationship between risk score and immune cell infiltration level was evaluated using CIBERSORT. Finally, qRT-PCR was used to confirm the expression of the genes used to construct the model. Results: Two subtypes of OS were obtained. The findings indicated that OS-C1 had a better survival outcome than OS-C2. The results of WGCNA yielded 112 hub genes. For univariate COX regression analyses, 49 OS-related trait genes were obtained. Finally, a clinical prognostic model containing two genes was constructed. This model could differentiate between patients with OV having varying years of survival in the TCGA and GEO cohorts. The model risk score was verified as an independent prognostic indicator. According to the results of CIBERSORT, many tumor-infiltrating immune cells were found to be significantly related to the risk score. Furthermore, the results revealed that patients with low-risk OV in the CTLA4 treatment group had a high likelihood of benefiting from immunotherapy. qRT-PCR results also showed that the expression of MARVELD1 and VSIG4 was high in the OV samples. Conclusions: Analysis of the results suggested that the newly developed model, which contained two characteristic OS-related genes, could successfully predict the survival outcomes of all patients with OV. The findings of this study could offer valuable information and insights into the refinement of personalized therapy and immunotherapy for OV in the future.

Stem Cell-Associated Signatures Help to Predict Diagnosis and Prognosis in Ovarian Serous Cystadenocarcinoma.

Ovarian serous cystadenocarcinoma (OV) is a fatal gynecologic cancer with a five-year survival rate of only 46%. Resistance to platinum-based chemotherapy is a prevalent factor in OV patients, leading to increased mortality. The platinum resistance in OV is driven by transcriptome heterogeneity and tumor heterogeneity. Studies have indicated that ovarian cancer stem cells (OCSCs), which are chemoresistant and help in disease recurrence, are enriched by platinum-based chemotherapy. Stem cells have a significant influence on the OV progression and prognosis of OV patients and are key pathology mediators of OV. However, the molecular mechanisms and targets of OV have not yet been fully understood. In this study, systematic research based on the TCGA-OV dataset was conducted for the identification and construction of key stem cell-related diagnostic and prognostic models for the development of multigene markers of OV. A six-gene diagnostic and prognostic model (C19orf33, CBX2, CSMD1, INSRR, PRLR, and SLC38A4) was developed based on the differentially expressed stem cell-related gene model, which can act as a potent diagnostic biomarker and can characterize the clinicopathological properties of OV. The key genes related to stem cells were identified by screening the genes differentially expressed in OV and control samples. The mRNA-miRNA-TF molecular network for the six-gene model was constructed, and the potential biological significance of this molecular model and its impact on the infiltration of immune cells in the OV tumor microenvironment were elucidated. The differences in immune infiltration and stem cell-related biological processes were determined using gene set variation analysis (GSVA) and single-sample gene set enrichment analysis (ssGSEA) for the selection of molecular treatment options and providing a reference for elucidating the posttranscriptional regulatory mechanisms in OV.

A novel defined risk signature of endoplasmic reticulum stress-related genes for predicting the prognosis and immune infiltration status of ovarian cancer.

Endoplasmic reticulum (ER) stress, as an emerging hallmark feature of cancer, has a considerable impact on cell proliferation, metastasis, invasion, and chemotherapy resistance. Ovarian cancer (OvCa) is one of the leading causes of cancer-related mortality across the world due to the late stage of disease at diagnosis. Studies have explored the influence of ER stress on OvCa in recent years, while the predictive role of ER stress-related genes in OvCa prognosis remains unexplored. Here, we enrolled 552 cases of ER stress-related genes involved in OvCa from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts for the screening of prognosis-related genes. The least absolute shrinkage and selection operator (LASSO) regression was applied to establish an ER stress-related risk signature based on the TCGA cohort. A seven-gene signature revealed a favorable predictive efficacy for the TCGA, International Cancer Genome Consortium (ICGC), and another GEO cohort (P<0.001, P<0.001, and P=0.04, respectively). Moreover, functional annotation indicated that this signature was enriched in cellular response and senescence, cytokines interaction, as well as multiple immune-associated terms. The immune infiltration profiles further delineated an immunologic unresponsive status in the high-risk group. In conclusion, ER stress-related genes are vital factors predicting the prognosis of OvCa, and possess great application potential in the clinic.

Novel DNA Damage-Related Subtypes Characterization Identifies Uterine Corpus Endometrial Carcinoma (UCEC) Based on Machine Learning.

Objective: Accumulating evidence suggests that DNA damage is associated with numerous gynecological illnesses, particularly advanced uterine corpus endometrial carcinoma (UCEC), illustrating the involvement of the DNA damage pathway in the advancement of UCEC. This research aimed to discover a robust subtype with the potential to contribute to the scientific treatment of UCEC. Methods: In this work, the expression patterns of prognostic DNA damage-related genes were curated, and consensus clustering analyses were undertaken to determine DNA damage subtypes in patients with UCEC in the TCGA cohort. Two DNA damage-related subtypes were identified for further investigation. Differentially expressed genes (DEGs) analysis, gene ontology analysis, mutation analysis, and immune cell infraction analysis were performed to find the molecular mechanism behind it. Finally, the polymerase chain reaction (PCR) was conducted to verify the correlation of the hub genes. Results: In total, 545 patients with UCEC were tested for two distinct DNA damage subtypes. The clinical prognosis was poorer among patients with DNA damage subtype 2 than those in subtype 1. The DEGs analysis and PPI analysis showed that ASMP, BUB1, CENPF, MAD2L1, NCAPG, SGO2, and TOP2A were expressed higher in UCEC tissues than in the normal tissues. Immune cell infraction analysis showed that hub genes were associated with the tumor microenvironment (TME). Conclusion: Altogether, our research identified two distinct DNA damage subtypes that are complicated and heterogeneous. A better knowledge of the characteristics of the TME may be gained by quantitative measurement of DNA damage subtypes in individual patients, which can also lead to the development of more successful treatment regimens.

CRMP2 derived from cancer associated fibroblasts facilitates progression of ovarian cancer via HIF-1α-glycolysis signaling pathway.

As the predominant stroma cells of tumor microenvironment (TME), cancer associated fibroblasts (CAFs) are robust tumor player of different malignancies. However, less is known about the regulatory mechanism of CAFs on promoting progression of ovarian cancer (OvCA). In the present study, the conditioned medium of primary CAFs (CAF-CM) from OvCA was used to culture cell lines of epithelial ovarian cancer (EOC), and showed a potent role in promoting proliferation, migration and invasion of cancer cells. Mass spectrum (MS) analysis identified that Collapsin response mediator protein-2 (CRMP2), a microtubule-associated protein involved in diverse malignancies, derived from CAFs was a key regulator responsible for mediating these cell events of OvCA. In vitro study using recombinant CRMP2 (r-CRMP2) revealed that the protein promoted proliferation, invasion, and migration of OvCA cells through activation of hypoxia-inducible factor (HIF)-1α-glycolysis signaling pathway. The CRMP2 was abundantly expressed in OvCA, with a well correlation with metastasis and poor prognosis, as analyzed from 118 patients' samples. Inhibition of the CRMP2 derived from CAFs by neutralizing antibodies significantly attenuated the tumor size, weights, and metastatic foci numbers of mice in vivo. Our finding has provided a novel therapeutic clue for OvCA based on TME.

The Difference of Gut Microbiota and Their Correlations With Urinary Organic Acids Between Autistic Children With and Without Atopic Dermatitis.

Autism is a kind of biologically based neurodevelopmental condition, and the coexistence of atopic dermatitis (AD) is not uncommon. Given that the gut microbiota plays an important role in the development of both diseases, we aimed to explore the differences of gut microbiota and their correlations with urinary organic acids between autistic children with and without AD. We enrolled 61 autistic children including 36 with AD and 25 without AD. The gut microbiota was sequenced by metagenomic shotgun sequencing, and the diversity, compositions, and functional pathways were analyzed further. Urinary organic acids were assayed by gas chromatography-mass spectrometry, and univariate/multivariate analyses were applied. Spearman correlation analysis was conducted to explore their relationships. In our study, AD individuals had more prominent gastrointestinal disorders. The alpha diversity of the gut microbiota was lower in the AD group. LEfSe analysis showed a higher abundance of Anaerostipes caccae, Eubacterium hallii, and Bifidobacterium bifidum in AD individuals, with Akkermansia muciniphila, Roseburia intestinalis, Haemophilus parainfluenzae, and Rothia mucilaginosa in controls. Meanwhile, functional profiles showed that the pathway of lipid metabolism had a higher proportion in the AD group, and the pathway of xenobiotics biodegradation was abundant in controls. Among urinary organic acids, adipic acid, 3-hydroxyglutaric acid, tartaric acid, homovanillic acid, 2-hydroxyphenylacetic acid, aconitic acid, and 2-hydroxyhippuric acid were richer in the AD group. However, only adipic acid remained significant in the multivariate analysis (OR = 1.513, 95% CI [1.042, 2.198], P = 0.030). In the correlation analysis, Roseburia intestinalis had a negative correlation with aconitic acid (r = -0.14, P = 0.02), and the latter was positively correlated with adipic acid (r = 0.41, P = 0.006). Besides, the pathway of xenobiotics biodegradation seems to inversely correlate with adipic acid (r = -0.42, P = 0.18). The gut microbiota plays an important role in the development of AD in autistic children, and more well-designed studies are warranted to explore the underlying mechanism.

Metformin Facilitates Osteoblastic Differentiation and M2 Macrophage Polarization by PI3K/AKT/mTOR Pathway in Human Umbilical Cord Mesenchymal Stem Cells.

Mesenchymal stem cells (MSCs) are the most promising multipotent stem cells that can differentiate into osteoblasts, chondrocytes, and adipocytes. This cellular flexibility contributes to widespread clinical use of MSCs in tissue repair and regeneration. The immune system is a key player in regulating bone remodeling. In recent years, the association between the immune system and bone metabolism has become an increasing focus of interest. Metformin, a glucose-lowering drug, exerts powerful impact on metabolic signaling. However, whether metformin can modulate bone metabolism or whether metformin can influence immune milieu by regulation of macrophages has not been thoroughly elucidated. Herein, we specifically explored the complex interactions between macrophages and human umbilical cord mesenchymal stem cells (UC-MSCs) in the context of metformin. Our research demonstrated that metformin not only stimulated osteogenesis of UC-MSCs but also influenced the immune system via promoting M2 but reducing M1 macrophages. Mechanically, we found that metformin-treated M2 macrophages possessed more potent osteoinductive capacity in our coculture system. Molecularly, these metformin-stimulated M2 macrophages facilitated osteogenesis via activating the PI3K/AKT/mTOR pathway. As demonstrated by using PI3K-specific inhibitor LY294002, we found that the pathway inhibitor partly reversed osteoinductive activity which was activated by coculture of metformin-treated M2 macrophages. Overall, our novel research illuminated the cooperative and synergistic effects of metformin and M2 macrophages on the dynamic balance of bone metabolism.

SNAI2 promotes the development of ovarian cancer through regulating ferroptosis.

This study aims to explore the regulatory mechanism of SNAI2 in ovarian cancer, and to uncover its correlation with ferroptosis. A human normal ovarian cell line IOSE-80 and four ovarian cancer cell lines (SKOV3, A2780 and CAOV3) were applied to detect SNAI2 and ferrptosis level, and an elevated SNAI2 expression and the occurrence of ferroptosis were observed in ovarian cancer cells, especially in SKOV3 cells. Then, results from a series of cellular behaviors experiments revealed that SNAI2 knockdown greatly suppressed cell viability, migration, invasion, and promoted cell apoptosis, as well as promoting the occurrence of ferroptosis in SKOV3 cells. The effects of SNAI2 knockdown on SKOV3 cells were similar to erastin, an inducer of ferroptosis. Subsequently, SNAI2 was verified to directly bind to the promoter of SLC7A11 by luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay. Furthermore, mice were subcutaneously injected with SKOV3 cells to induce tumor formation. Erastin exhibited an anti-tumor effect on mice suffering from ovarian cancer, which was partly weakened by SNAI2 overexpression. In conclusion, this study disclosed that SNAI2 knockdown or erastin exhibited an anti-tumor activity in ovarian cancer by promoting ferroptosis, shedding new insights of the regulatory mechanism of SNAI2-mediated ferroptosis in ovarian cancer.

Comparison of the outcomes between laparoscopic surgery and conventional open surgery in treating patients with stage II endometrial carcinoma: A protocol for systematic review and meta-analysis.

BACKGROUND: Endometrial carcinoma is a prevalent form of cancer. In fact, its incidence ranks fourth among European and North American females. Moreover, it is the most common gynecological malignant disease. Laparotomy, bilateral salpingo-oophorectomy, total abdominal hysterectomy, etc were common methods adopted in conventional open surgery. Recent developments in laparoscopic surgery (LPS) has made it more effective. The present study aims to compare the outcomes between LPS and a conventional open surgical procedure to treat stage II endometrial carcinoma patients. METHODS: A comprehensive search will be conducted on Cochrane library, PubMed, Web of Science, EMBASE, and China National of Knowledge Infrastructure to collect LPS and conventional open surgery in treating stage II endometrial carcinoma. The search will consider all articles published since the inception of the databases till July 2021. A pair of scholars will perform independent screening of the literature and extracted data to evaluate the bias risk in the selected studies. Afterwards, RevMan5.3 software will be used to conduct a meta-analysis. CONCLUSION: This study will conduct a meta-analysis to compare the clinical efficacy of LPS and conventional open surgery in the treatment of stage II endometrial carcinoma.

Nonlinearity-induced nanoparticle circumgyration at sub-diffraction scale.

The ability of light beams to rotate nano-objects has important applications in optical micromachines and biotechnology. However, due to the diffraction limit, it is challenging to rotate nanoparticles at subwavelength scale. Here, we propose a method to obtain controlled fast orbital rotation (i.e., circumgyration) at deep subwavelength scale, based on the nonlinear optical effect rather than sub-diffraction focusing. We experimentally demonstrate rotation of metallic nanoparticles with orbital radius of 71 nm, to our knowledge, the smallest orbital radius obtained by optical trapping thus far. The circumgyration frequency of particles in water can be more than 1 kHz. In addition, we use a femtosecond pulsed Gaussian beam rather than vortex beams in the experiment. Our study provides paradigms for nanoparticle manipulation beyond the diffraction limit, which will not only push toward possible applications in optically driven nanomachines, but also spur more fascinating research in nano-rheology, micro-fluid mechanics and biological applications at the nanoscale.

Bioinformatics Analysis of Potential Therapeutic Targets and Prognostic Biomarkers amid CXC Chemokines in Ovarian Carcinoma Microenvironment.

BACKGROUND: Ovarian cancer (OC) is one of the leading lethal gynecologic cancers of women around the world. More than 70% of patients are diagnosed with stage III or IV with poor outcome. This is partly because of lacking early effective screening techniques and potential biomarkers of OC. CXC chemokines in tumor microenvironment (TME) and their interaction with relative receptors can excite the downstream signaling pathways to influence tumor progression. However, the role of CXC chemokines in OC has not been identified. METHODS: ONCOMINE, GEPIA, Kaplan-Meier plotter, cBioPortal, TIMER, Metascape, and LinkedOmics were applied in our study. RESULTS: The transcriptional levels of CXCL1/8/9/10/11/12/13/14/16/17 were significantly elevated while CXCL3 was obviously reduced in OC vs normal ovarian tissue. CXCL8/9/11/13 were correlated with clinic pathological stage. Patients with low expression of CXCL8/9/11/13 were associated with better prognosis. We also found that CXCL3 and CXC12 could be used as potential prognostic markers of OC through Kaplan-Meier plotter. Patients with high expression of CXCL3/12 had a significantly better prognosis. Their functions focus on locomotion, signaling, response to stimulus, undergoing the process of multiorganism, immune system, biological regulation, etc. The differentiated CXC chemokines mainly participate in cytokine-cytokine receptor interaction, chemokine signaling pathway, IL-17 signaling pathway, and toll-like receptor signaling pathway. Our results showed that CXC chemokines were highly correlated with infiltration of immune cells. The kinase targets of differentially expressed CXC chemokines are mainly in ATM, LYN, LCK, PLK1, FYN, CDK2, and ATR. CONCLUSIONS: Our results may provide a new insight for selecting precision biomarkers of targeted therapy of OC.

Loss of BMP-10 is correlated with poor survival in ovarian cancer.

INTRODUCTION: The expression of bone morphogenetic protein-10 (BMP-10) is downregulated in some cancer types, but its function and mechanism in ovarian cancer remains unclear. MATERIALS AND METHODS: BMP-10 expression was detected in ovarian cancer tissues and cell lines by using immunochemistry and western blotting. Prognostic value of BMP-10 was evaluated by Kaplan-Meier curve and Cox regression model. Knockdown or overexpression of BMP-10 was conducted by using specific siRNA or pcDNA-BMP-10 in ovarian cancer cell lines. The biological features induced by BMP-10 were observed by MTT assay, wound-healing and transwell assays. RESULTS: BMP-10 expression in ovarian cancer tissues was significantly lower than that in ovarian tissues. Low BMP-10 expression in ovarian cancer tissues was related to advance FIGO stage, higher histologic grade, lymph node metastasis, and peritoneal fluid. Kaplan-Meier analysis revealed that low BMP-10 expression was significantly associated with poor prognosis of patients with ovarian cancer. BMP-10 overexpression or knockdown significantly inhibited or promoted proliferation, migration, and invasion of ovarian cancer cells, respectively. Moreover, administration of neutralizing antibody or human recombinant BMP-10 would reverse these effects on ovarian cancer cells. CONCLUSION: Low BMP-10 expression was associated with poor prognosis and progression of ovarian cancer.

Nonlinearity-Induced Multiplexed Optical Trapping and Manipulation with Femtosecond Vector Beams.

Optical trapping and manipulation of atoms, nanoparticles, and biological entities are widely employed in quantum technology, biophysics, and sensing. Single traps are typically achieved with linearly polarized light, while vortex beams form rotationally unstable symmetric traps. Here we demonstrate multiplexed optical traps reconfigurable with intensity and polarization of the trapping beam using intensity-dependent polarizability of nanoparticles. Nonlinearity combined with a longitudinal field of focused femtosecond vortex beams results in a stable optical force potential with multiple traps, in striking contrast to a linear trapping regime. The number of traps and their orientation can be controlled by the cylindrical vector beam order, polarization, and intensity. The nonlinear trapping demonstrated here on the example of plasmonic nanoparticles opens up opportunities for deterministic trapping and polarization-controlled manipulation of multiple dielectric and semiconductor particles, atoms, and biological objects since most of them exhibit a required intensity-dependent refractive index.

Decreased Eph receptor­A1 expression is related to grade in ovarian serous carcinoma.

Eph receptor­A1 (EphA1) was the first member of the erythropoietin producing hepatocellular carcinoma (Eph) family of receptor tyrosine kinases. Although the roles of EphA1 in the tumorigenesis of various human cancers have been investigated, few studies have focused on ovarian carcinoma. The present study aimed to explore the profile of EphA1 expression in ovarian carcinomas, to analyzed the association between EphA1 expression and clinicopathologic parameters, and to investigate the roles of overexpressed EphA1 in ovarian cancer cells. EphA1 protein was detected in ovarian cancer cell lines and in a set of formalin­fixed tissues, including normal fallopian tube, ovarian benign serous cystadenoma, borderline serous tumors and serous carcinoma. Ovarian cancer cell lines HO8910 and A2780 were transiently transfected with EphA1­pCMV6­GFP plasmid, and the proliferation and apoptosis of cells were measured. The association between EphA1 expression and clinicopathological parameters was statistically analyzed. EphA1 expression was negative in HO8910 and weakly positive in A2780 cells. The proliferation rate was significantly reduced in ovarian cancer cells after transfection with EphA1 plasmid compared with cells transfected with mock plasmid or untreated cells, but no obvious alteration in apoptosis was detected among these groups. EphA1 expression was positively detected in all normal fallopian tubes (10/10, 100%) and ovarian benign serous cystadenomas (12/12, 100%) as well as in some borderline serous tumors (9/15, 60%) and ovarian serous carcinomas (33/76, 43.42%). EphA1 expression was associated with grade of ovarian serous carcinomas, with loss of EphA1 more often observed in high­grade tumors (P=0.016) and high Ki67 index tumors (P=0.007). These data suggest that EphA1 might be a useful marker for distinguishing low grade from high­grade ovarian serous carcinoma.

Upregulation of SENP3/SMT3IP1 promotes epithelial ovarian cancer progression and forecasts poor prognosis.

As a crucial member of the small ubiquitin-like modifier system, SUMO-specific protease 3, was identified to be essential for cell proliferation and ribosomal RNA processing. Recent studies showed that SUMO-specific protease 3 was elevated in ovarian cancer compared to normal tissue samples. However, the connection between SUMO-specific protease 3-specific expression and clinicopathological parameters of epithelial ovarian cancer, as well as the physiologically potential role of SUMO-specific protease 3 in epithelial ovarian cancer remained unclear. In this study, an analysis of 124 paraffin-embedded slices by immunohistochemistry indicated that SUMO-specific protease 3 expression was positively correlated with the International Federation of Gynecology and Obstetrics stages (p = 0.025), tumor grade (p = 0.004), and lymph node metastasis (p = 0.001) and was also a critical prognostic factor for the overall survival of epithelial ovarian cancer patients, as revealed by Kaplan-Meier curve analysis. Knockdown of SUMO-specific protease 3 weakened the proliferation, migration, and invasion capability of ovarian cancer cells, down-regulated the expression of Proliferating Cell Nuclear Antigen, Forkhead Box C2, and N-cadherin, and resulted in upregulation of p21 and E-cadherin. Consistent with our results, SUMO-specific protease 3 had been verified to promote cell proliferation, metastasis, and tumorigenesis in multiple malignant cancers, which was a redox-sensitive molecule mediating the epithelial-mesenchymal transition. Collectively, our findings for the first time specifically supported that SUMO-specific protease 3 might play an important role in the regulation of epithelial ovarian cancer progression and could serve as a potential biomarker for prognosis as well as provide a promising therapeutic target against epithelial ovarian cancer.

Overexpression of ARF1 is associated with cell proliferation and migration through PI3K signal pathway in ovarian cancer.

ADP-ribosylation factor 1 (ARF1) is a small G protein that regulates many cellular processes such as reorganization of the actin cytoskeleton and is highly expressed in various tumor cells and tissues. However, the role of ARF1 in ovarian cancer progression remains unknown. In the present study, we explored the expression patterns of ARF1 in clinical ovarian cancer samples and adjacent noncancerous tissues. The results revealed that ARF1 overexpressed in EOC tissues and cell lines, compared with the adjacent non-tumorous tissues and normal ovarian cells. In addition, the immunoreactivity of ARF1 was positively correlated with EOC grade and Ki-67 expression. Knockdown of ARF1 expression notably inhibited cell proliferation and migration rate of EOC cells by the auxiliary of PI3K. Taken together, our findings provide new insights into the functional role of ARF1 on EOC cell growth and migration and it may serve as a diagnostic and therapeutic target.

Loss of TAB3 expression by shRNA exhibits suppressive bioactivity and increased chemical sensitivity of ovarian cancer cell lines via the NF-κB pathway.

Ovarian cancer is a leading cause of death among gynaecologic malignancies. Despite many years of research, it still remains sparing in reliable diagnostic markers and methods for early detection and screening. Transforming growth factor ß-activated protein kinase 1 (TAK1)-binding protein 3 (TAB3) was initially characterized as an adapter protein essential for TAK1 activation in response to IL-1ß or TNFα, however, the physiological role of TAB3 in ovarian cancer tumorigenesis is still not fully understood. In this study, we evaluated the effects of TAB3 on ovarian cancer cell lines. Expressions of TAB3 and PCNA (proliferating cell nuclear antigen) were found to be gradually increased in EOC tissues and cell lines, by western blot analysis and qRT-PCR. Distribution of TAB3 was further analysed by immunohistochemistry. In vitro, knockdown of TAB3 expression in HO8910 or SKOV3 ovarian cancer cells significantly inhibited bioactivity of ovarian cancer cells, including proliferation and cell-cycle distribution, and promoted chemical sensitivity to cisplatin and paclitaxel treatment via inhibiting NF-κB pathways. In conclusion, our study strongly suggests a novel function of TAB3 as an oncogene that could be used as a biomarker for ovarian cancer. It provides a new insight into the potential mechanism for therapeutic targeting, in chemotherapy resistance, common in ovarian cancer.

c-Yes enhances tumor migration and invasion via PI3K/AKT pathway in epithelial ovarian cancer.

Overexpression of c-Yes has been noted to correlation with several human cancers. However, the effects of c-Yes on epithelial ovarian cancer (EOC) development remain unclear. The aim of this study is going to prove the effects of c-Yes and related mechanisms in proliferation, metastasis and invasion of EOC. Immunohistochemical analysis was performed in 119 human EOC samples, and the data was correlated with clinic pathologic features. Furthermore, western blot analysis is performed for c-Yes in EOC samples and cell lines to evaluate their protein levels and molecular interaction. Kaplan-Meier survival analysis shows that the strong expression of c-Yes exhibited a significant correlation with poor prognosis in human EOC (P<0.01(⁎)). Meanwhile, we found that knockdown of c-Yes by shRNA inhibited the ability of migration and invasion in EOC cells via the PI3K/AKT pathway. In a word, these results suggested that c-Yes plays an important role in migration and invasion of EOC.

The abnormal expressions of tristetraprolin and the VEGF family in uraemic rats with peritoneal dialysis.

The effect of peritoneal dialysis (PD) with high-glucose dialysis fluid on the VEGF family, tristetraprolin (TTP), angiogenesis and lymphangiogenesis was investigated. Forty male SD rats were randomised into five groups: normal group, sham operation group, uraemia group, PD 2-week group and PD4-week group. After 4 weeks of PD, microvessel density (MVD) and lymphatic vessel density (LVD) were measured. The expressions of both the VEGF family and TTP were detected. Compared with the normal group, the mRNA expression levels of the VEGF family were significantly increased in the uraemia group (P < 0.05), and also in the PD 2-week group and PD4-week group (P < 0.05) compared with uraemia group. The mRNAs of VEGF-A and VEGF-C in 4-week PD group likewise were significantly increased compared with the 2-week PD group. However, the mRNA expression of TTP was significantly decreased in the uraemia group compared with the normal group (P < 0.05), and also in the PD group compared with the uraemia group (P < 0.05). Compared with the normal group, the protein expressions of TTP were significantly decreased in the uraemia group (P < 0.05), and also in the PD group compared with the uraemia group (P < 0.05). Compared with the normal group, the MVD and LVD counts were gradually increased in the PD group, which was associated with PD time. In addition, the expression of TTP gradually decreased over PD time. High-glucose PD fluid and uraemic circumstance resulted in the abnormal expression of TTP and the VEGF family in a PD time-dependent manner; this may lead to UFF through angiogenesis and lymphangiogenesis.

Cyclooxygenase-2 and vascular endothelial growth factor expressions are involved in ultrafiltration failure.

BACKGROUND: Long-term peritoneal dialysis (PD) is associated with ultrafiltration failure (UFF). The aim of the study was to investigate changes in cyclooxygenase-2 (COX-2), vascular endothelial growth factor A (VEGF-A), and vascular endothelial growth factor C (VEGF-C) expressions in a rat model of UFF induced by PD solution. METHODS: Sprague-Dawley rats were divided into six groups (n = 8/group): normal untreated control group, sham operation group, uremic group (nephrectomy without PD), uremic 2-wk PD group (PD solution for 2 wk), uremic 4-wk PD group (PD solution for 4 wk), and uremic 4-wk PD + celecoxib group (PD solution plus COX-2 inhibitor celecoxib 20 mg/kg for 4 wk). Peritoneal function was determined by peritoneal equilibration test. Peritoneal morphology was determined by hematoxylin and eosin and Masson staining. Microvessel and lymphatic microvessel formation was determined by immunohistochemistry. COX-2, VEGF-A, and VEGF-C expressions were determined by real-time polymerase chain reaction and immunohistochemistry. RESULTS: Uremic rat model was successfully established. PD-induced peritoneal morphologic changes associated with UFF, characterized by inflammation, edema, and collagen accumulation. PD solution increased the density of microvessels marked by CD31 (microvessel density) and lymphatic microvessels marked by LYVE-1 (lymphatic vessel density) in peritoneum. COX-2, VEGF-A, and VEGF-C expression levels in the uremic 4-wk PD group were higher than those in the uremic group (all P < 0.05). All these changes were partially reversed by celecoxib. VEGF-A and VEGF-C protein expressions were positively correlated with microvessel density and lymphatic vessel density formation. CONCLUSIONS: COX-2 could increase VEGF-A and VEGF-C expressions in peritoneal tissue, resulting in increased formation of peritoneal microvessels and lymphatic microvessels, playing pivotal roles in the development of UFF.