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1.
bioRxiv ; 2023 May 20.
Article in English | MEDLINE | ID: mdl-37292891

ABSTRACT

The remarkable potential of human endometrium to undergo spontaneous remodeling is shaped by controlled spatiotemporal gene expression patterns. Although hormone-driven transcription shown to govern these patterns, the post-transcriptional processing of these mRNA transcripts, including the mRNA splicing in the endometrium is not studied yet. Here, we report that the splicing factor, SF3B1 is central in driving alternative splicing (AS) events that are vital for physiological responses of the endometrium. We show that loss of SF3B1 splicing activity impairs stromal cell decidualization as well as embryo implantation. Transcriptomic analysis revealed that SF3B1 depletion decidualizing stromal cells led to differential mRNA splicing. Specifically, a significant upregulation in mutually exclusive AS events (MXEs) with SF3B1 loss resulted in the generation of aberrant transcripts. Further, we found that some of these candidate genes phenocopy SF3B1 function in decidualization. Importantly, we identify progesterone as a potential upstream regulator of SF3B1-mediated functions in endometrium possibly via maintaining its persistently high levels, in coordination with deubiquitinating enzymes. Collectively, our data suggest that SF3B1-driven alternative splicing plays a critical role in mediating the endometrial-specific transcriptional paradigms. Thus, the identification of novel mRNA variants associated with successful pregnancy establishment may help to develop new strategies to diagnose or prevent early pregnancy loss.

2.
Ann Palliat Med ; 10(7): 7534-7542, 2021 Jul.
Article in English | MEDLINE | ID: mdl-34353041

ABSTRACT

BACKGROUND: This study sought to compare the efficacy and surgery complications of the modified Broström procedure and the modified Karlsson procedure in treating patients with chronic lateral ankle instability (CLAI). METHODS: Full-text publications on the clinical efficacy of Broström's and Karlsson's procedures were retrieved from multiple databases. Review Manager 5.0 was adopted for the meta-analysis, sensitivity analysis, and bias analysis. RESULTS: Nine studies comprising a total of 643 patients were identified. The meta-analysis suggested that the American Orthopedic Foot and Ankle Society (AOFAS) scores of patients in the Karlsson group were higher than those of patients in the Broström group [mean deviation (MD) =6.31, 95% confidence interval (CI): 2.31-10.30, P=0.002; P for heterogeneity <0.00001, I2=58%]. The Tegner scores of patients in the Karlsson group were higher than those of patients in the Broström group (MD =0.72, 95% CI: 0.48-0.95, P=0.24; P for heterogeneity <0.00001, I2=23%). Operation times in the Broström group were higher than those in the Karlsson group (MD =-15.50, 95% CI: -19.98--11.02, P<0.00001; P for heterogeneity <0.00001, I2=63%). Patients in the Karlsson group had higher levels of satisfaction than those in the Broström group (MD =0.63, 95% CI: 0.47-0.79, P<0.00001; P for heterogeneity =0.91, I2=0%). No significant difference was observed in surgery complications between the Karlsson and Broström groups [odds ratio (OR) =1.71, 95% CI: 0.79-3.71, P=0.18; P for heterogeneity =0.99, I2=0%]. DISCUSSION: Based on the heterogeneity analysis results, this study showed that Karlsson's procedure was more efficient and safer than Broström's treatment in the treatment of CLAI patients.


Subject(s)
Ankle , Joint Instability , Ankle Joint/surgery , Humans , Joint Instability/surgery , Retrospective Studies , Treatment Outcome
3.
Biosci Biotechnol Biochem ; 84(6): 1160-1167, 2020 Jun.
Article in English | MEDLINE | ID: mdl-32125225

ABSTRACT

Endometrial cancer (EC) is generally considered as a disease that affects older women. We attempt to explore the role of actin­like protein 8 (ACTL8) in EC and how it achieves its function. Based on the data from The Cancer Genome Atlas (TCGA), we found that ACTL8 expression was up-regulated in EC tissues and correlated with shorter overall survival of EC patients. ACTL8 expression was significantly associated with age, clinical-stage, or grade. Cox proportional hazards model analysis revealed that ACTL8 expression, grade, and clinical-stage were promising independent prognostic factors of EC. Knockdown of ACTL8 repressed the proliferative, migrating and invading capabilities of human EC cell lines KLE and Ishikawa. Silencing ACTL8 up-regulated the negative cell cycle regulator p21 and epithelial marker E-cadherin, and down-regulated the positive cell cycle regulator Cyclin A, mesenchymal markers MMP-9 and N-cadherin in KLE cells. Collectively, these outcomes illustrated that ACTL8 might act as a tumor facilitator during EC progression.


Subject(s)
Actins/metabolism , Biomarkers, Tumor/metabolism , Cytoskeletal Proteins/metabolism , Disease Progression , Endometrial Neoplasms/metabolism , Actins/genetics , Antigens, CD/metabolism , Biomarkers, Tumor/genetics , Cadherins/metabolism , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Cell Survival/genetics , Cyclin A/metabolism , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Cytoskeletal Proteins/genetics , Down-Regulation/genetics , Endometrial Neoplasms/pathology , Female , Gene Knockdown Techniques , Humans , Matrix Metalloproteinase 9/metabolism , Middle Aged , Prognosis , Signal Transduction/genetics , Transfection , Up-Regulation/genetics
4.
Oncol Rep ; 39(2): 795-801, 2018 Feb.
Article in English | MEDLINE | ID: mdl-29207149

ABSTRACT

Triple functional domain protein (Trio) is an evolutionarily conserved protein with guanine nucleotide exchange factors that regulate different physiological processes in some types of cancer. However, the expression and function of Trio in cervical cancer are still unknown. The purpose of this study was to detect the expression of Trio in cervical cancer tissues and to evaluate its clinical value. Furthermore, the effects of the Trio on the migration and invasion of cervical cancer cells and its mechanism were investigated in vitro. The results of the present study revealed that Trio expression levels were significantly higher in most of the clinical cervical cancer samples than in adjacent tissues. The clinicopathological significance of Trio expression was also analyzed, and the results revealed that high expression levels in cervical cancer were correlated with lymph node metastasis (P=0.005). The CRISPR/Cas9 system was used to knockdown the endogenous Trio. The inhibition of Trio significantly decreased the migration and invasion abilities of cervical cancer cells. Meanwhile, levels of RhoA/ROCK signaling factors (RhoA, Rock, and p-LIMK), which contributed to cell migration and invasion, were decreased along with the inhibition of Trio. Therefore, Trio may regulate the migration and invasion of cervical cancer through the RhoA/ROCK signaling pathway.


Subject(s)
Gene Knockdown Techniques/methods , Guanine Nucleotide Exchange Factors/genetics , Guanine Nucleotide Exchange Factors/metabolism , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Uterine Cervical Neoplasms/genetics , CRISPR-Cas Systems , Cell Line, Tumor , Cell Movement , Female , Gene Expression Regulation, Neoplastic , HeLa Cells , Humans , Lymphatic Metastasis , Neoplasm Invasiveness , Signal Transduction , Uterine Cervical Neoplasms/metabolism , rho-Associated Kinases/genetics , rho-Associated Kinases/metabolism , rhoA GTP-Binding Protein/genetics , rhoA GTP-Binding Protein/metabolism
6.
Mol Med Rep ; 16(5): 7497-7503, 2017 Nov.
Article in English | MEDLINE | ID: mdl-28944908

ABSTRACT

Endometrial carcinoma is the most common malignancy of the female genital tract and is the fourth most common malignancy among women worldwide. Endometrial adenocarcinoma (EAC) accounts for ~80% of endometrial carcinoma cases. Numerous critical genetic events have been determined to serve an essential role in EAC progression; however, the precise molecular mechanisms underlying EAC progression remain unclear. Pyrosequencing and methylation­specific PCR were used to detect the methylation status of Wnt inhibitory factor 1 (WIF1). Immunohistochemistry and western blot were used to detect the expression of WIF1, Wnt family member 1 and other related pathways. The anticancer role of WIF1 in EAC was investigated in vitro and in vivo. Two of the three EAC cases exhibited significantly high methylation in five CpG sites, and the WIF1 methylation rate in EAC and endometrial tissues was 43.4 and 8%, respectively (P<0.05). The kappa consistency coefficient was ­0.369 between methylation and mRNA expression (P<0.05) and WIF1 expression levels were significantly downregulated in EAC tissues compared with non­tumorous tissues (P<0.01). The 5­year overall survival rates were significantly lower for patients with tumors that negatively expressed WIF1 when compared with the 77.9% exhibited by those with positive WIF1 expression. Furthermore, the proliferation rate of KLE cells was significantly reduced following 5­aza­20­deoxycytidine treatment or WIF1 overexpression in vitro and in vivo, which may be associated with downregulated c­Myc and phosphorylated­extracellular signal­regulated kinase expression. These results demonstrated the important role of WIF1 in EAC tumorigenesis, and suggested that WIF1 may be a potential drug target in EAC treatment.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Adenocarcinoma/pathology , Endometrial Neoplasms/pathology , Repressor Proteins/metabolism , Adaptor Proteins, Signal Transducing/genetics , Adenocarcinoma/mortality , Adult , Aged , Animals , Azacitidine/analogs & derivatives , Azacitidine/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , CpG Islands , DNA Methylation , DNA, Neoplasm/chemistry , DNA, Neoplasm/isolation & purification , DNA, Neoplasm/metabolism , Decitabine , Down-Regulation/drug effects , Endometrial Neoplasms/mortality , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Humans , Mice , Mice, Nude , Middle Aged , Prognosis , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , Repressor Proteins/genetics
7.
Dis Markers ; 2017: 2827435, 2017.
Article in English | MEDLINE | ID: mdl-28827892

ABSTRACT

BACKGROUND: MicroRNA-202 (miR-202) has been reported to be aberrantly regulated in several cancers. The aim of this study is to explore the functional role of miR-202 in EAC tumor growth. MATERIAL AND METHODS: miR-202 expression was detected by qRT-PCR. TargetScan and luciferase reporter assay were used to elucidate the candidate target gene of miR-202. The FOXR2 protein level was assessed by Western blot and immunohistochemistry. Survival analysis was explored for FOXR2 expression in EAC patients. RESULTS: miR-202 expression was significantly decreased in EAC tissues (P < 0.01) compared with that in control tissues. And the downregulate miR-202 was significantly associated with poor prognosis (P < 0.01). Re-expression of miR-202 dramatically suppressed cell proliferation in vitro and tumor growth in vivo. FOXR2 was identified as a direct target of miR-202. In EAC tissues, FOXR2 was upregulated and the increased FOXR2 was significantly associated with poor prognosis. In miR-202-transfected cells, the FOXR2 expression was inversely changed. The analysis of FOXR2 protein expression and miR-202 transcription in EAC tissues showed negative correlation (R = -0.429). CONCLUSION: miR-202 may function as a tumor suppressor in EAC tumor growth by targeting FOXR2 oncogene, which may provide new insights into the molecular mechanism and new targets for treatment of EAC.


Subject(s)
Adenocarcinoma/metabolism , Biomarkers, Tumor/genetics , Cell Proliferation , Endometrial Neoplasms/metabolism , Forkhead Transcription Factors/genetics , MicroRNAs/genetics , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Biomarkers, Tumor/metabolism , Cell Line, Tumor , Endometrial Neoplasms/genetics , Endometrial Neoplasms/pathology , Female , Forkhead Transcription Factors/metabolism , Gene Expression Regulation, Neoplastic , Humans , MicroRNAs/metabolism , Up-Regulation
8.
Oncol Lett ; 13(5): 2949-2956, 2017 May.
Article in English | MEDLINE | ID: mdl-28529556

ABSTRACT

Although microRNAs (miRNAs or miRs) are able to function as oncogenes or tumor suppressors, the role of miR-326 in regulating human cervical cancer cells remains unclear. In the present study, the expression of miR-326 was identified to be downregulated in cervical cancer cell lines and primary tumor samples, and the overexpression of miR-326 decreased cell proliferation, migration and invasion in cervical cell lines. Bioinformatics prediction and experimental validation results revealed that the function of miR-326 was achieved by targeting and repressing ETS domain-containing protein Elk-1 (ELK1) expression. ELK1 was targeted directly by miR-326, which was downregulated in human cervical cancer tissues compared with that in adjacent normal tissues. The results of the present study suggest that miR-326, a potential tumor suppressor, may be used in the treatment of cervical cancer.

9.
Int J Mol Med ; 36(2): 449-54, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26035689

ABSTRACT

Increasing evidence suggests an association between cancer stem cells and the tumor microenvironment. Ovarian cancer stem cell (OCSC) factors can influence the tumor microenvironment and prognosis. However, the effects of OCSCs on macrophage M1/M2 polarization are not yet completely understood. In the present study, we evaluated the effects of OCSCs on macrophage M1/M2 polarization. In addition, we investigated whether the activation of the peroxisome proliferator-activated receptor γ (PPARγ)/nuclear factor-κB (NF-κB) pathway is involved in these effects, thus modulating the M1/M2 differentiation of monocytes into macrophages. The expression levels of markers of the M1 state, such as tumor necrosis factor (TNF)-α, inducible nitric oxide synthase (iNOS) and CD86, as well as those of markers of M2 activation, such as mannose receptor (MR), interleukin (IL)-10 and arginase-1 (Arg-1), were measured by RT-qPCR. We found that the OCSCs promoted the M2 polarization of Raw264.7 macrophages by upregulating the expression of MR, IL-10 and Arg-1, while the expression levels of M1 macrophages markers, including TNF-α, iNOS and CD86 were suppressed. In addition, treatment with OCSCs activated PPARγ and suppressed NF-κB in the Raw264.7 cells. Furthermore, the PPARγ, antagonist GW9662, attenuated the promoting effects of OCSCs on the M2 polarization of macrophages. To the best of our knowledge, the findings of the present study, provide the first evidence that OCSCs promote the M2 polarization of macrophages through the PPARγ/NF-κB pathway.


Subject(s)
Macrophages/immunology , NF-kappa B/immunology , Neoplastic Stem Cells/immunology , Ovarian Neoplasms/immunology , Ovary/immunology , PPAR gamma/immunology , Animals , Cell Line , Cell Line, Tumor , Coculture Techniques , Female , Macrophages/pathology , Mice , Neoplastic Stem Cells/pathology , Ovarian Neoplasms/pathology , Ovary/cytology , Ovary/pathology , Signal Transduction
10.
Zhonghua Fu Chan Ke Za Zhi ; 47(4): 263-7, 2012 Apr.
Article in Chinese | MEDLINE | ID: mdl-22781112

ABSTRACT

OBJECTIVE: To analyze the status of DACH1 gene promoter methylation and explore its association with the expression of DACH1 gene promoter methylation and clinical significance of endometrium carcinoma (EC). METHODS: From February 2004 to August 2008, a total of 80 EC tissue samples with comprehensive surgical pathology staging were collected and used for this study. Twenty normal endometrium tissues in 2008 were abstained from the fractional curettage because of dysfunctional uterine bleeding as control. All samples were confirmed pathologically. Methylation specific PCR (MSP) was performed to detect the promoter methylation of DACH1 gene, and analyze its influence on the expression of DACH1 and the relationship between DACH1 promoter methylation and clinicopathological factors in EC. DACH1 protein expression was detected by western blot. Chi-square test and Pearson test were used for statistical analysis. RESULTS: The rate of promoter methylation of DACH1 gene in the EC tissues was significantly higher than that in the normal endometrium issues (30% vs. 5%, P < 0.05). There was an association between the expression of DACH1 and DACH1 gene promoter methylation (r = -0.30, P < 0.01). There was statistical difference between the methylation of DACH1 and the pathological grade (P < 0.05) or histological type (P < 0.05). But DACH1 gene methylation was not related with the age, stage, myometrial invasion depth and lymphnode metastasis (P > 0.05). CONCLUSIONS: DACH1 gene promoter methylaion could lead to a decrease or absence in the DACH1 expression in EC. The promoter methylation of DACH1 gene may induce the inhibition of DACH1 expression, which might be one of the mechanisms of DACH1 gene inactivation in human EC.


Subject(s)
Adenocarcinoma/genetics , DNA Methylation , Endometrial Neoplasms/genetics , Eye Proteins/genetics , Promoter Regions, Genetic , Transcription Factors/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Adult , Aged , DNA, Neoplasm/genetics , Endometrial Neoplasms/metabolism , Endometrial Neoplasms/pathology , Endometrium/metabolism , Eye Proteins/metabolism , Female , Humans , Middle Aged , Neoplasm Staging , Polymerase Chain Reaction/methods , Transcription Factors/metabolism
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