IRX2 regulates endometrial carcinoma oncogenesis by transcriptional repressing RUVBL1.

Endometrial carcinoma (EC) is a rising concern among gynecological malignancies. Iroquois Homeobox 2 (IRX2), a member of the Iroquois homeobox gene family, demonstrates variable effects in different cancer types, emphasizing the need for extensive exploration of its involvement in EC progression. Utilizing TCGA and GEO databases, as well as performing immunohistochemistry (IHC) analysis on clinical samples, we assessed the expression levels of IRX2 and its promoter methylation in EC. To understand the functional roles of IRX2, we conducted various assays including in vitro CCK-8 assays, colony formation assays, cell invasion assays, and cell apoptosis assays. Moreover, we utilized in vivo subcutaneous xenograft mouse models. Additionally, we performed KEGG pathway and gene set enrichment analyses to gain insights into the underlying mechanisms. To validate the regulatory relationship between IRX2 and RUVBL1, we employed chromatin immunoprecipitation and luciferase reporter assays. Our results indicate significantly reduced levels of IRX2 expression in EC, correlating with higher histological grades, advanced clinical stages, and diminished overall survival. We observed that DNA methylation of the IRX2 promoter suppresses its expression in EC, with cg26333652 and cg11793269 playing critical roles as methylated sites. In contrast, ectopic overexpression of IRX2 substantially inhibits cell proliferation and invasion, and promotes cell apoptosis. Additionally, we discovered that IRX2 exerts negative regulation on the expression of RUVBL1, which is upregulated in EC and associated with a poorer prognosis. In conclusion, our findings indicate that decreased expression of IRX2 facilitates EC cell growth through the regulation of RUVBL1 expression, thereby contributing to the development of EC. Hence, targeting the IRX2-RUVBL1 axis holds promise as a potential therapeutic strategy for EC treatment.

Association of sleep traits with male fertility: a two-sample Mendelian randomization study.

Background: Previous observational studies have investigated the association between sleep-related traits and male fertility; however, conclusive evidence of a causal connection is lacking. This study aimed to explore the causal relationship between sleep and male fertility using Mendelian randomisation. Methods: Eight sleep-related traits (chronotype, sleep duration, insomnia, snoring, dozing, daytime nap, oversleeping, and undersleeping) and three descriptors representing male fertility (male infertility, abnormal sperm, and bioavailable testosterone levels) were selected from published Genome-Wide Association Studies. The causal relationship between sleep-related traits and male fertility was evaluated using multiple methods, including inverse variance weighting (IVW), weighted median, Mendelian randomisation-Egger, weighted model, and simple model through two-sample Mendelian randomisation analysis. Mendelian randomisation-Egger regression was used to assess pleiotropy, Cochrane's Q test was employed to detect heterogeneity, and a leave-one-out sensitivity analysis was conducted. Results: Genetically-predicted chronotype (IVW,OR = 1.07; 95%CL = 1.04-1.12; p = 0.0002) was suggestively associated with bioavailable testosterone levels. However, using the IVW method, we found no evidence of a causal association between other sleep traits and male fertility. Conclusion: This study found that chronotype affects testosterone secretion levels. However, further studies are needed to explain this mechanism.

HOXB2 promotes cisplatin resistance by upregulating lncRNA DANCR in ovarian cancer.

Ovarian cancer (OV) is a highly fatal malignant disease that commonly manifests at an advanced stage. Drug resistance, particularly platinum resistance, is a leading cause of treatment failure because first-line systemic chemotherapy primarily relies on platinum-based regimens. By analyzing the gene expression levels in the Cancer Genome Atlas database, Genotype-Tissue Expression database, and Gene Expression Omnibus datasets, we discerned that HOXB2 was highly expressed in OV and was associated with poor prognosis and cisplatin resistance. Immunohistochemistry and loss-of-function experiments on HOXB2 were conducted to explore its role in OV. We observed that suppressing HOXB2 could impair the growth and cisplatin resistance of OV in vivo and in vitro. Mechanical investigation and experimental validation based on RNA-Seq revealed that HOXB2 regulated ATP-binding cassette transporter members and the ERK signaling pathway. We further demonstrated that HOXB2 modulated the expression of long non-coding RNA DANCR, a differentiation antagonizing non-protein coding RNA, and thus influenced its downstream effectors ABCA1, ABCG1, and ERK signaling to boost drug resistance and cancer proliferation. These results verified that high expression of HOXB2 correlated with platinum resistance and poor prognosis of OV. Therefore, targeting HOXB2 may be a promising strategy for OV therapy.

The SLITRK4-CNPY3 axis promotes liver metastasis of gastric cancer by enhancing the endocytosis and recycling of TrkB in tumour cells.

PURPOSE: Gastric cancer (GC) is a malignant tumour with high mortality, and liver metastasis is one of the main causes of poor prognosis. SLIT- and NTRK-like family member 4 (SLITRK4) plays an important role in the nervous system, such as synapse formation. Our study aimed to explore the functional role of SLITRK4 in GC and liver metastasis. METHODS: The mRNA level of SLITRK4 was evaluated using publicly available transcriptome GEO datasets and Renji cohort. The protein level of SLITRK4 in the tissue microarray of GC was observed using immunohistochemistry. Cell Counting Kit-8, colony formation, transwell migration assays in vitro and mouse model of liver metastasis in vivo was performed to investigate the functional roles of SLITRK4 in GC. Bioinformatics predictions and Co-IP experiments were applied to screen and identify SLITRK4-binding proteins. Western blot was performed to detect Tyrosine Kinase receptor B (TrkB)-related signaling molecules. RESULTS: By comparing primary and liver metastases from GC, SLITRK4 was found to be upregulated in tissues of GC with liver metastasis and to be closely related to poor clinical prognosis. SLITRK4 knockdown significantly abrogated the growth, invasion, and metastasis of GC in vitro and in vivo. Further study revealed that SLITRK4 could interact with Canopy FGF Signalling Regulator 3 (CNPY3), thus enhancing TrkB- related signaling by promoting the endocytosis and recycling of the TrkB receptor. CONCLUSION: In conclusion, the CNPY3-SLITRK4 axis contributes to liver metastasis of GC according to the TrkB-related signaling pathway. which may be a therapeutic target for the treatment of GC with liver metastasis.

Systematic review and meta-analysis: α-adrenergic receptor blockers in chronic prostatitis.

BACKGROUND: Prostatitis seriously endangers the health of men. While they have been widely used in recent years, there remains a lack of systematic evaluation of the clinical efficacy of α-receptor blockers (α-RBs)/α-adrenergic receptor blockers (α-ARBs) in its treatment. Based on this, this study was developed to systematically evaluate the clinical effect of α-ARB in the treatment of prostatitis. METHODS: Randomized controlled trials (RCTs) studying α-RBs or α-ARBs, placebos, or other measures to treat prostatitis were searched in Cochrane Library, PubMed, Embase, and CBM databases from establishment to December 2020. The quality of included articles was evaluated using the Cochrane System Review Manual and Jadad tools, and a meta-analysis was performed using Review Manager 5.3 software. RESULTS: A total of six articles meeting the requirements were found and included 450 patients. Meta-analysis showed that the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) score [mean difference (MD) =-1.76, 95% confidence interval (CI): (-3.35 to -0.17), and P=0.03], pain score [MD =-2.24, 95% CI: (-3.65 to -0.83), and P=0.002], voiding symptom score [MD =-1.21, 95% CI: (-2.06 to -0.35), and P=0.006], and quality of life score [MD =-1.40, 95% CI: (-1.48 to -1.33), and P<0.00001] for patients in the experimental group were lower in contrast to those in the control group after the treatment. DISCUSSION: The use of α-ARB could significantly improve the treatment effect of patients with prostatitis and improve their quality of life.