lncRNA UCA1 promotes tumor progression by targeting SMARCD3 in cervical cancer.

Long noncoding RNA urothelial carcinoma associated 1 (UCA1) has been identified as a key molecule in human cancers. However, its functional implications remain unspecified in the context of cervical cancer (CC). This research aims to identify the regulatory mechanism of UCA1 in CC. UCA1 was identified through microarray and confirmed through a quantitative real-time polymerase chain reaction. Proteins that bind with UCA1 were recognized using RNA pull-down assays along with RNA immunoprecipitation. Ubiquitination assays and coimmunoprecipitation were performed to explore the molecular mechanisms of the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily d, member 3 (SMARCD3) downregulated in CC. The effects of UCA1 and SMARCD3 on the progression of CC were investigated through gain- and loss-of-function assays and xenograft tumor formation in vivo. In this study, UCA1 was found to be upregulated in CC cells as well as in human plasma exosomes for the first time. Functional studies indicated that UCA1 promotes CC progression. Mechanically, UCA1 downregulated the SMARCD3 protein stabilization by promoting SMARCD3 ubiquitination. Taken together, we revealed that the UCA1/SMARCD3 axis promoted CC progression, which could provide a new therapeutic target for CC.

Methyltransferase-like 3 aggravates endoplasmic reticulum stress in preeclampsia by targeting TMBIM6 in YTHDF2-dependent manner.

BACKGROUND: With the increasing morbidity and mortality of preeclampsia (PE), it has posed a huge challenge to public health. Previous studies have reported endoplasmic reticulum (ER) stress could contribute to trophoblastic dysfunction which was associated with the N6-methyladenosine (m6A) modification by methyltransferase-like 3 (METTL3), resulting in PE. However, little was known about the relationship between METTL3 and ER stress in PE. Thus, in vitro and in vivo studies were performed to clarify the mechanism about how METTL3 affects the trophoblasts under ER stress in PE and to explore a therapeutic approach for PE. METHODS: An ER stress model in HTR-8/SVneo cells and a preeclamptic rat model were used to study the mechanism and explore a therapeutic approach for PE. Western blot, immunohistochemistry, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and methylated RNA immunoprecipitation (MeRIP)-qPCR were performed to detect the protein, RNA, and methylated transmembrane BAX inhibitor motif containing 6 (TMBIM6) expression levels. The m6A colorimetric and mRNA stability assays were used to measure the m6A levels and TMBIM6 stability, respectively. Short hairpin RNAs (shRNAs) were used to knockdown METTL3 and YTH N6-methyladenosine RNA binding protein 2 (YTHDF2). Flow cytometry and Transwell assays were performed to evaluate the apoptosis and invasion abilities of trophoblasts. RESULTS: Upregulated METTL3 and m6A levels and downregulated TMBIM6 levels were observed in preeclamptic placentas under ER stress. The ER stress model was successfully constructed, and knockdown of METTL3 had a beneficial effect on HTR-8/SVneo cells under ER stress as it decreased the levels of methylated TMBIM6 mRNA. Moreover, overexpression of TMBIM6 was beneficial to HTR-8/SVneo cells under ER stress as it could neutralize the harmful effects of METTL3 overexpression. Similar to the knockdown of METTL3, downregulation of YTHDF2 expression resulted in the increased expression and mRNA stability of TMBIM6. Finally, improved systemic symptoms as well as protected placentas and fetuses were demonstrated in vivo. CONCLUSIONS: METTL3/YTHDF2/TMBIM6 axis exerts a significant role in trophoblast dysfunction resulting in PE while inhibiting METTL3 may provide a novel therapeutic approach for PE.

Pregnancy feasibility in women with mild pulmonary arterial hypertension: a systematic review and meta-analysis.

BACKGROUND: The aim of this study was to evaluate the pregnancy feasibility of women with mild pulmonary hypertension according to pregnancy outcomes. METHODS: This systematic review and meta-analysis compared the differences in maternal and fetal outcomes between mild and moderate-to-severe pulmonary hypertension. Relevant English and Chinese literature were searched in the PubMed, Embase, Cochrane Central Register of Controlled Trials (COCHRANE), CNKI, WanFang Data, and VIP databases between January 1st, 1990 and April 18th, 2023, and the references of the included articles and relevant systematic reviews were reviewed to determine whether studies were missed. The inclusion criteria were randomized controlled and observational studies (including case-control studies and cohort studies) examining maternal and fetal pregnancy outcomes with pulmonary hypertension. Conference abstracts, case reports, case series reports, non-comparative studies, and review articles were excluded. RESULTS: This meta-analysis included 32 studies. In this study, maternal and fetal outcomes were better in the mild pulmonary hypertension group than in the moderate-to-severe group. Regarding maternal mortality, the mild group was much lower than the moderate to severe group. We found a significant decrease in maternal mortality in the mild group after 2010. However, no significant difference in maternal mortality before and after 2010 was observed in the moderate to severe group. Cardiac complications, ICU admission, neonatal preterm birth, small for gestational age infants, low birth weight infants, neonatal asphyxia, and neonatal mortality were significantly lower in the mild pulmonary hypertension group than in the moderate to severe pulmonary hypertension group. The cesarean section rates of the two groups were similar. However, the vaginal delivery rate in the mild pulmonary hypertension group was significantly higher than that in the moderate to severe pulmonary hypertension group. CONCLUSIONS: This meta-analysis confirmed that pregnancies with mild pulmonary hypertension had significantly better maternal and fetal outcomes than those with moderate to severe pulmonary hypertension. For patients with mild pulmonary hypertension and good cardiac function, continued pregnancy or even delivery should be considered under multidisciplinary monitoring. However, maternal and fetal complications with moderate to severe pulmonary hypertension significantly increase. Hence, it is essential to evaluate pregnancy risk and terminate it in time.

Effects of Intrauterine Infusion of Autologous Platelet-Rich Plasma in Women Undergoing Treatment with Assisted Reproductive Technology: a Meta-Analysis of Randomized Controlled Trials.

Purpose This meta-analysis was conducted to systematically retrieve relevant randomized controlled trials (RCTs) and evaluate the effects of intrauterine infusion of autologous platelet-rich plasma (PRP) in women with thin endometrium, implantation or pregnancy failure undergoing treatment with assisted reproductive technology (ART). Methods We conducted a systematic review and meta-analysis of the retrieved RCTs. Studies on the intrauterine infusion of PRP in women undergoing treatment with ART that were published in PubMed, the Cochrane library, Web of Science, and Embase from inception until June 2022 were included. The data were extracted and analyzed independently using the fixed-effects or random-effects model according to heterogeneity. Results Seven RCTs involving 861 patients (435 in the intervention group and 426 in the control group) were included. The rates of clinical pregnancy (risk ratio [RR]: 2.51; 95% confidence interval [CI]: 2.0-3.13; P < 0.00001), chemical pregnancy (RR: 1.96; 95% CI: 1.58-2.45; P < 0.00001), live births (RR: 7.03; 95% CI: 3.91-12.6; P < 0.00001), and implantation (RR: 3.27; 95% CI: 1.42-7.52; P = 0.005) were significantly higher in the women who received PRP infusion than in the control group. No significant differences were noted in the miscarriage rate (RR: 0.98; 95% CI: 0.39-2.42; P = 0.96) between the two groups. Conclusion In summary, intrauterine infusion of PRP may be an effective therapy for women with thin endometrium and recurrent implantation failure (RIF) undergoing treatment with ART. More population-based RCTs are warranted to verify the efficacy of our evidence.

PVT1/miR-145-5p/HK2 modulates vascular smooth muscle cells phenotype switch via glycolysis: The new perspective on the spiral artery remodeling.

INTRODUCTION: Vascular smooth muscle cells (VSMC) switched from a contractile phenotype to a synthetic phenotype during the decidual spiral artery (SPAs) remodeling process. The lncRNA plasmacytoma variant translocation 1 (PVT1) and glucose metabolism have been found to regulate the VSMC phenotype switch. This study aimed to analyze the dynamic expression of PVT1 and glycolytic key enzymes hexokinase2 (HK2) at different remodeling stages in early human pregnancy and elucidate the underlying mechanism of the PVT1/miR-145-5p/HK2 axis involved in the spiral artery remodeling. METHODS: qRT-PCR, Western blot (WB) analysis, Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) were used to detect the expression and localization of PVT1 and HK2 in decidual tissue. HA-VSMCs were transfected with specific siRNA, shRNA and plasmids to regulate corresponding genes. Extracellular lactate, cellular ATP, ROS, and intracellular NADPH levels were measured using the corresponding assay kits. Migration was measured by wound-healing and Transwell assays. Contractile phenotypic markers α-SMA, MYH11 with calponin and synthetic phenotypic markers OPN and vimentin were detected by WB. The PDC model was used to detect the degree of spiral arterial remodeling. RESULTS: PVT1 and HK2 were upregulated with gestational age (GA) increasing in decidual tissue during the early pregnancy. HK2 regulated the glycolytic activity and VSMC phenotype switch in vitro. PVT1 regulated the glycolytic activity and VSMC phenotype switch through HK2. PVT1 played a ceRNA role in regulating HK2 expression by sponging miR-145-5p. PVT1 and HK2 influenced spiral artery remodeling in the PDC model. DISCUSSION: PVT1 and HK2 were upregulated, and miR-145-5p was downregulated in decidua with the GA increasing. Meanwhile, the PVT1/miR-145-5p/HK2 axis may be involved in regulating the phenotypic switch and migratory capacity of VSMCs by affecting glycolysis in decidual SPAs remodeling.

Correlation of miRNA and VEGF expression with the outcome of early-onset severe preeclampsia in patients receiving expectant treatment.

The present study was planned to explore the relationship between miRNA and VEGF expression in serum as well as placenta tissue with the outcome of early-onset severe preeclampsia (EOSP) in patients receiving expectant treatment. Sixty EOSP patients who had expectant treatment indications were divided into the success group (n = 46) and the failure group (n = 14) according to the pregnancy outcomes. miR-210 and miR-155 expression levels were studied in serum, ante partum, and in placenta tissue. The vascular endothelial growth factor (VEGF) and soluble VEGF receptor 1 (sFlt-1) expression levels were also explored. miR-210 and miR-155 expression levels in serum and placenta tissue before treatment, ante partum, and after accouchement of the success group were significantly lower than those of the failure group. Further, VEGF expression levels in serum and placenta tissue before treatment, ante partum, and after accouchement of the success group were significantly higher than those of the failure group. However, sFlt-1 expression levels in the success group showed a decrease in comparison to the failure group. The increase of miR-210, miR-155 levels, sFlt-1 levels, and the decrease of VEGF levels in EOSP patients might be correlated with the failure of expectant treatment.

Transcriptomic analysis of stromal cells from patients with endometrial carcinoma.

Tumor microenvironment plays a critical role in cancer pathogenesis. In this study, we performed transcriptomic analysis of stromal cells from patients diagnosed with endometrial carcinoma. Endometrial stromal cells from patients and healthy donors were cultured and total RNA was extracted for RNA integrity examination and gene profiling analysis. Gene ontology (GO) and KEGG analysis were also performed. In this study, we found that, in endometrial stromal cells from endometrial cancer patients, a total of 605 genes were changed (fold change ≥2, p-value <0.05). From these, 275 were up-regulated and 330 were down-regulated genes. In addition, GO analysis showed that the differentially expressed genes (DEGs) were involved in various biological processes including cell adhesion, biological adhesion, bone development and extracellular matrix organization. Furthermore, KEGG analysis of the DEGs identified four pathways including Wnt signaling pathway, cadherin signaling pathway, ECM-receptor interaction, and focal adhesion. Our study identified 605 DEGs in stromal cells from endometrial carcinoma which mapped to a variety of biological processes. These results may contribute to understanding the molecular mechanisms o of endometrial carcinoma pathogenesis.

Efficacy of Anti-VEGF/VEGFR Agents on Animal Models of Endometriosis: A Systematic Review and Meta-Analysis.

BACKGROUND/OBJECTIVE: Vascular endothelial growth factor (VEGF) is the most important promotor of angiogenesis. Some studies indicate that anti-angiogenic agents that interfere with VEGF and its receptor (VEGFR), i.e., anti-VEGF/VEGFR agents, may be applied to treat endometriosis. This meta-analysis investigated the efficacy of anti-VEGF/VEGFR agents in animal models of endometriosis. METHODS: A systematic literature search was performed for animal studies published in English or Chinese from January 1995 to June 2016, which evaluated the effect of anti-VEGF/VEGFR agents on endometriosis. The databases were: PubMed, Web of Science, BIOSIS, Embase, and CNKI. The quality of included studies was assessed using the SYRCLE tool. The random-effect models were used to combine the results of selected studies. Heterogeneity was assessed using H2statistic and I2 statistic. Subgroup analyses were performed to determine the source of heterogeneity in endometriosis scores and follicle numbers. RESULTS: We identified 13 studies that used anti-VEGF/VEGFR agents in various animal models. The meta-analysis showed that anti-VEGF/VEGFR agents were associated with smaller size (standardized mean difference (SMD) -0.96, 95% CI -1.31 to -0.62; P < 0.0001) and weight (SMD -1.70, 95% CI -2.75 to -0.65; P = 0.002) of endometriosis lesions, relative to the untreated controls, as well as a lower incidence rate of endometriosis (risk ratio 0.26, 95% CI 0.07 to 0.93; P = 0.038) and endometriosis score (SMD -1.17, 95% CI -1.65 to -0.69; P < 0.0001); the number of follicles were similar (SMD -0.78, 95% CI -1.65 to 0.09; P = 0.08). CONCLUSIONS: Anti-VEGF/VEGFR agents appeared to inhibit the growth of endometriosis, with no effect on ovarian function. Anti-angiogenic therapy may be a novel strategy in treating endometriosis.

Association between glutathione S-transferase M1/T1 gene polymorphisms and susceptibility to endometriosis: A systematic review and meta-analysis.

Endometriosis is a polygenic/multifactorial disease caused by interactions between multiple genes and the environment. Findings from studies evaluating the association between the glutathione S-transferase (GST) M1/T1 null genotype and susceptibility to endometriosis are inconsistent. This meta-analysis updated and reevaluated the possible associations between GSTM1, GSTT1 and combined GSTM1/GSTT1 (null genotype versus wild-type) gene polymorphisms and susceptibility to endometriosis. The PubMed, Embase and Chinese BioMedical Literature databases and Google Scholar were searched for case-control genetic association studies on GSTM1/GSTT1 (null genotype versus wild-type) gene polymorphisms and endometriosis in comparison with non-endometriosis or healthy controls. Fixed-effect and random-effect meta-analytical techniques were conducted for the outcome measure and subgroup analyses. The meta-analysis demonstrated significant associations between the GSTM1 [odds ratio (OR)=1.56; 95% confidence interval (CI): 1.25-1.95; P<0.0001), GSTT1 (OR=1.31; 95% CI: 1.02-1.68; P=0.037) and GSTM1/GSTT1 (OR=1.68; 95% CI: 1.29-2.17; P<0.0001) null genotypes and increased risk for endometriosis. The results suggest that the GSTM1, GSTT1, and combined GSTM1/GSTT1 null genotypes increase susceptibility to endometriosis. Additional well-designed studies and precise analyses are warranted to confirm these findings.

Prognostic significance of L1 cell adhesion molecule in cancer patients: A systematic review and meta-analysis.

The L1 cell adhesion molecule (L1CAM) extensively participates in nervous system development and the malignant progression of human tumours. The prognostic value of L1CAM for the survival of patients with solid tumours remains controversial. The present meta-analysis was thus performed to highlight the relationship between L1CAM expression and prognosis in cancer patients. Relevant publications were identified after searching several widely used databases, including PubMed, EMBASE and the ISI Web of Science. A fixed-effect or random-effect meta-analytical model was employed to correlate L1CAM expression with different outcome measures in both entire tumours and stratified subgroups. 37 studies in total with 8552 patients were eligible for the final analysis. Combined hazard ratios (HRs) and 95% confidence intervals (CIs) suggested that high L1CAM expression had an unfavourable impact on overall survival (HR=2.06, 95%CI 1.65-2.57, P<0.001), disease-specific survival (HR=2.45, 95%CI 1.48-4.05, P<0.001), disease-free survival (HR=2.42, 95%CI 1.4-4.19, P=0.002) and progression-free survival/recurrence-free survival (HR=2.07, 95%CI 1.41-3.05, P<0.001). Subgroup analysis revealed a similar correlation in most tumour types. Overall, L1CAM might be an effective poor prognostic factor for patients with various tumour types.

CD147/EMMPRIN overexpression and prognosis in cancer: A systematic review and meta-analysis.

CD147/EMMPRIN (extracellular matrix metalloproteinase inducer) plays an important role in tumor progression and a number of studies have suggested that it is an indicator of tumor prognosis. This current meta-analysis systematically reevaluated the predictive potential of CD147/EMMPRIN in various cancers. We searched PubMed and Embase databases to screen the literature. Fixed-effect and random-effect meta-analytical techniques were used to correlate CD147 expression with outcome measures. A total of 53 studies that included 68 datasets were eligible for inclusion in the final analysis. We found a significant association between CD147/EMMPRIN overexpression and adverse tumor outcomes, such as overall survival, disease-specific survival, progression-free survival, metastasis-free survival or recurrence-free survival, irrespective of the model analysis. In addition, CD147/EMMPRIN overexpression predicted a high risk for chemotherapy drugs resistance. CD147/EMMPRIN is a central player in tumor progression and predicts a poor prognosis, including in patients who have received chemo-radiotherapy. Our results provide the evidence that CD147/EMMPRIN could be a potential therapeutic target for cancers.

Upregulation of forkhead box O3 transcription is involved in C2-ceramide induced apoptosis and autophagy in ovarian cancer cells in vitro.

Ceramide is a bioactive lipid which functions as a tumor suppressor, mediating processes such as apoptosis, growth arrest, senescence and differentiation. The effects of ceramide in ovarian cancers have not been well established. The objective of the present study was to investigate the effects of C2­ceramide treatment in A2780 ovarian cancer cells and its possible molecular mechanism. C2­ceramide-induced proliferation inhibition was analyzed using an MTT assay and Trypan blue test. Flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling were used to identify the induction of apoptosis. Transmission electron microscopy was used to confirm the formation of autophagosomes. Quantitative polymerase chain reaction was performed to analyze the messenger RNA expression of the autophagy and cell death associated genes and western blotting was used to analyze the protein expression of beclin 1, LC3, Akt, forkhead box O3 (FOXO3) and adenosine monophosphate-activated protein kinase in ovarian cancer cells. It was found that C2­ceramide inhibited A2780 cell proliferation in a time­ and dose­dependent manner and C2­ceremide induced A2780 cell apoptosis and autophagy. However, C2­ceramide­induced autophagy did not result in cell death, but instead protected ovarian cancer cells from apoptosis. Akt inhibition and FOXO3 activation were implicated in C2­ceramide­treated ovarian cancer cells. Furthermore, FOXO3 target genes, which were associated with autophagy (MAP1LC3, GABARAP and GABARAPL1) and cell death (BNIP3, BNIP3L, BIM and PUMA), were upregulated. The present study has shown that C2­ceramide induced apoptosis and autophagy in ovarian cancer cells. FOXO3 transcription was upregulated, which may contribute to C2­ceramide­induced apoptosis and autophagy.