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Aims: To determine the association between collagen type IV alpha 6 (COL4A6) expression levels and prostate cancer invasion and metastasis. Methods: We analyzed three Gene Expression Omnibus (GEO) datasets through the GEO2R online tool to obtain the set of differentially expressed genes (DEGs) between malignant and nonmalignant prostate tissues, and further analyzed the COL4A6 gene's expression in databases. Western blot assays, real-time quantitative polymerase chain reaction analysis, and immunofluorescence staining were used to detect COL4A6 gene expression. Wound healing assays and cell invasion transwell assays were performed to measure cell invasion and siRNA was used to knock down COL4A6 gene expression. Results: Through the use of bioinformatic tools we showed that the COL4A6 gene is one of the highly downregulated genes in prostate cancer; additionally, hypermethylation of the COL4A6 promoter in prostate cancer is correlated with lower expression levels. We also showed that downregulation of COL4A6, which activates the p-FAK/MMP-9 signaling pathway in prostate cancer cells, is associated with prostate cancer cell metastasis based on data retrieved from The Cancer Genome Atlas (TCGA) and GEO databases. Finally, we found that the COL4A6 protein is localized extracellularly and its expression is positively correlated with disease-free survival of prostate cancer patients. Conclusion: Our results indicate that downregulation of COL4A6 may promote prostate cancer progression and invasion. Additionally, COL4A6 and its promoter methylation status could be valuable markers for prostate cancer prognoses. [ABSTRACT FROM AUTHOR]

Metabolic alteration drives renal cell carcinoma (RCC) development, while the impact of melatonin (MLT), a neurohormone secreted during darkness, on RCC cell growth and underlying mechanisms remains unclear. We detected concentration of metabolites through metabolomic analyses using UPLC-MS/MS, and the oxygen consumption rate was determined using the Seahorse Extracellular Flux analyzer. We observed that MLT effectively inhibited RCC cell growth both in vitro and in vivo. Additionally, MLT increased ROS levels, suppressed antioxidant enzyme activity, and induced apoptosis. Furthermore, MLT treatment upregulated key TCA cycle metabolites while reducing aerobic glycolysis products, leading to higher oxygen consumption rate, ATP production, and membrane potential. Moreover, MLT treatment suppressed phosphorylation of Akt, mTOR, and p70 S6 Kinase as well as the expression of HIF-1α/VEGFA in RCC cells; these effects were reversed by NAC (ROS inhibitors). Conversely, MLT synergistically inhibited cell growth with sunitinib and counteracted the Warburg effect induced by sunitinib in RCC cells. In conclusion, our results indicate that MLT treatment reverses the Warburg effect and promotes intracellular ROS production, which leads to the suppression of Akt/mTOR/S6K signaling pathway, induction of cell apoptosis, and synergistically inhibition of cell growth with sunitinib in RCC cells. Overall, this study provides new insights into the mechanisms underlying anti-tumor effect of MLT in RCC cells, and suggests that MLT might be a promising therapeutic for RCC. [ABSTRACT FROM AUTHOR]

Tumor angiogenesis is a major characteristic of renal cell carcinoma (RCC). Herein, we report a novel mechanism of how lncRNA and androgen receptor (AR) drive the Hedgehog pathway to promote tumor angiogenesis in RCC. We found that the high expression of lncRNA HOTAIR in RCC is associated with poor prognosis. Moreover, HOTAIR and AR form a feedback loop to promote the expression of each other. Interestingly, we also found that in RCC, HOTAIR is associated with the Hedgehog pathway, especially GLI2, via bioinformatics analysis. Furthermore, HOTAIR promotes GLI2 expression in the presence of AR. Mechanistically, HOTAIR interacts with AR and they cooperatively bind to GLI2 promoter and increase its transcription activity. We further confirmed how HOTAIR-AR axis regulates GLI2 expression by analyzing its function in RCC cells and found that HOTAIR and AR synergistically enhanced the expression of GLI2 downstream genes, such as VEGFA, PDGFA, and cancer stem cell transcription factors, and promoted tumor angiogenesis and cancer stemness in RCC cells both in vitro and in tumor xenografts. Overall, these findings suggest that HOTAIR and GLI2 could be novel therapeutic targets against RCC. [ABSTRACT FROM AUTHOR]

Abstract During evolution, animals optimize their reproductive strategies to increase offspring survival. Seasonal breeders reproduce only during certain times of the year. In mammals, reproduction is tightly controlled by hypothalamus-pituitary-gonad axis. Although pathways regulating gametogenesis in non-seasonal model species have been well established, molecular insights into seasonal reproduction are severely limited. Using the Plateau pika (Ochotona curzoniae), a small rodent animal species native to the Qinghai-Tibetan plateau, as a model, here we report that seasonal spermatogenesis is governed at the level of spermatogonial differentiation. In testis of the reproductively dormant animals, undifferentiated spermatogonia failed to differentiate and accumulated in the seminiferous tubules. RNA-seq analyses of the active and dormant testes revealed that genes modulating retinoic acid biogenesis and steriodogenesis were differentially regulated. A single injection of all-trans retinoic acid (ATRA) reinitiated spermatogenesis and inhibition the function of RA-degrading enzyme CYP26B1 for 10 days induced spermatogonial differentiation. Strikingly, testosterone injection reinitiated spermatogenesis in short day adapted animals. Testosterone provides a permissive environment of RA biogenesis and actions in testis, therefore, indirectly controls spermatogonial differentiation. Collectively, these findings provide a key mechanistic insight regarding the molecular regulation of seasonal reproduction in mammals. Graphical abstract Image 1 Highlights • Seasonal spermatogenesis is governed at the phase of sprematogonial differentiation in the Plateau Pika. • Genes modulating retinoic acid biogenesis were differentially regulated in the reproductively dormant testis. • A single injection of all-trans retinoic acid induced spermatogonial differentiation and resumption of spermatogenesis. • Testosterone is the master regulator of seasonal spermatogenesis by regulating retinoic acid biogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Increasing evidence suggests that interleukin-10 (IL-10) gene −592 C/A polymorphism may be associated with an increased risk of type 2 diabetes mellitus (T2DM). To provide a quantitative assessment of the association between this variant and risk of T2DM, we performed this meta-analysis. Systematic searches of electronic databases PubMed, Embase, Web of Science, CBMdisc and CNKI, as well as hand searching of the references of identified articles were performed. A total of 2698 T2DM cases and 2622 controls in seven case–control studies were included in this meta-analysis. The results showed no evidence for significant association between IL-10 gene −592 C/A polymorphism and T2DM risk (for A allele vs. C allele: OR=0.94, 95% CI=0.69–1.29, p =0.69; for A/A vs. C/C: OR=0.88, 95% CI=0.39–1.98, p =0.75; for A/A vs. A/C+C/C: OR=1.04, 95% CI=0.59–1.82, p =0.89; for A/A+A/C vs. C/C: OR=1.11, 95% CI=0.73–1.69, p =0.61). In addition, the similar results were obtained in the subgroup analysis based on the ethnicity. In summary, results from this meta-analysis suggest that the IL-10 gene −592 C/A polymorphism is not associated with T2DM risk. [Copyright &y& Elsevier]