Targeting HOXA11-AS to mitigate prostate cancer via the glycolytic metabolism: In vitro and in vivo.

As oncogenes or oncogene suppressors, long-stranded non-coding RNAs are essential for the formation and progression of human tumours. However, the mechanisms behind the regulatory role of RNA HOXA11-AS in prostate cancer (PCa) are unclear. PCa is a common malignant tumour worldwide, and an increasing number of studies have focused on its metabolic profile. Studies have shown that the long non-coding RNA (lncRNA) HOXA11-AS is aberrantly expressed in many tumours. However, the role of HOXA11-AS in PCa is unclear. This work aimed to determine how HOXA11-AS regulated PCa in vitro and in vivo. We first explored the clinical role of HOXA11-AS in PCa using bioinformatics methods, including single sample gene set enrichment analysis (ssGSEA), weighted gene co-expression network analysis (WGCNA), and least absolute shrinkage and selection operator (LASSO)-logistics systematically. In this study, PCa cell lines were selected to assess the PCa regulatory role of HOXA11-AS overexpression versus silencing in vitro, and tumour xenografts were performed in nude mice to assess tumour suppression by HOXA11-AS silencing in vivo. HOXA11-AS expression was significantly correlated with clinicopathological factors, epithelial-mesenchymal transition (EMT) and glycolysis. Moreover, key genes downstream of HOXA11-AS exhibited good clinical diagnostic properties for PCa. Furthermore, we studied both in vitro and in vivo effects of HOXA11-AS expression on PCa. Overexpression of HOXA11-AS increased PCa cell proliferation, migration and EMT, while silencing HOXA11-AS had the opposite effect on PCa cells. In addition, multiple metabolites were downregulated by silencing HOXA11-AS via the glycolytic pathway. HOXA11-AS silencing significantly inhibited tumour development in vivo. In summary, silencing HOXA11-AS can inhibit PCa by regulating glucose metabolism and may provide a future guidance for the treatment of PCa.

Predictive power of lipid-related indicators for testosterone deficiency: a comparative analysis, NHANES 2011-2016.

BACKGROUND: Studies have shown that lipid-related indicators are associated with testosterone deficiency. However, it is difficult to determine which indicator is the most accurate predictor of testosterone deficiency. We aimed to identify the lipid-related indicators most predictive of testosterone deficiency in adults in the United States. METHODS: This observational research was conducted on a population aged ≥ 20 years. By plotting the receiver operating characteristic curve (ROC) and obtaining the corresponding area under the curve (AUC) value, we assessed the predictive capacity of TyG, WTI, LAP, and VAI for testosterone deficiency. We compared the area under the curve (AUC) values of these measures to determine if there were any statistically significant differences. The relationship between lipid-related indices and testosterone hormones was investigated using regression modeling, eXtreme Gradient Boosting (XGBoost) modeling, and sensitivity analysis. RESULTS: A total of 3,272 eligible participants were included in the study. Testosterone deficiency was found to exist in 20.63% of the participants. Subjects with higher lipid-related markers were more likely to have lower testosterone levels. LAP was the best predictor of testosterone deficiency in ROC analysis over other indicators (AUC = 0.7176, (95% CI: 0.6964-0.7389)). CONCLUSION: LAP is the most straightforward and convenient indicator for identifying testosterone deficiency in clinical practice.

Association of TyG index with prostate-specific antigen (PSA) in American men: results from NHANES, 2003-2010.

BACKGROUND: In recent years, triglyceride-glucose index (TyG) was a new indicator of insulin resistance, and it has been widely reported that it may be associated with serum prostate-specific antigen (PSA) concentrations. AIMS: We intended to investigate the possible connection between serum PSA concentration and the TyG index. METHODS: This is a cross-sectional study of adults with complete data on TyG and serum PSA concentrations (ng/ml) from the NHANES, 2003-2010. The TyG index is obtained by the formula below: TyG = Ln [triglycerides (mg/dL) × fasting glucose(mg/dL)/2]. Multivariate regression analysis and subgroup analysis were used to examine the connection between the TyG index and serum PSA levels. RESULTS: Multiple regression analysis of the weighted linear model showed that individuals with a higher TyG index had lower PSA levels. Subgroup analyses and interaction tests showed no apparent dependence on age, race/ethnicity, BMI, household income ratio, education level, and marital status on this negative association (all interactions p > 0.05). CONCLUSIONS: TyG index is related to lower serum PSA concentrations in adult men from the USA. Further comprehensive prospective studies are needed to confirm our findings.

Comprehensive analysis of the importance of PLAUR in the progression and immune microenvironment of renal clear cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is a common type of kidney cancer with a high mortality rate, and the discovery of new therapeutic markers is essential to improve patient survival. The plasminogen activator urokinase receptor (PLAUR) plays key roles in tissue remodeling and extracellular matrix degradation, which contribute to invasion and metastasis, a major feature of tumor malignancy. The role of PLAUR in ccRCC pathology has not been deeply studied. In this study, we collected the mRNA expression data of 33 tumor types, each derived from human patients obtained from TCGA database, and comprehensively analyzed the correlation between the expression of PLAUR in tumors and prognosis. Then, we studied the relationship between PLAUR expression in ccRCC and specific clinical features of ccRCC patients. In addition, we analyzed the function and mechanism of PLAUR in ccRCC. Our results showed that PLAUR was significantly overexpressed in ccRCC and that both PLAUR levels and PLAUR methylation levels significantly correlated with poor prognosis. Our results also suggest that PLAUR is involved in the progression of ccRCC. The results of functional and mechanistic analysis of PLAUR showed that PLAUR is involved in inflammatory and immune-related pathways in ccRCC; other data showed that PLAUR expression may affect the infiltration of multiple immune cell types in ccRCC and that PLAUR levels were significantly and positively correlated with the expression of immune checkpoints. In conclusion, our findings suggest that high PLAUR expression can promote the progression of ccRCC to poor prognosis, and thus PLAUR may serve as both a potential marker for predicting macrophage infiltration and immune microenvironment status and as an important immunotherapy target for ccRCC.

Silencing of LINC01963 enhances the chemosensitivity of prostate cancer cells to docetaxel by targeting the miR-216b-5p/TrkB axis.

Docetaxel (DTX) treatment effectively prolongs the overall survival of patients with prostate cancer. However, most patients eventually develop resistance to chemotherapy and experience tumor progression or even death. Long noncoding RNAs (lncRNAs) affect docetaxel chemosensitivity. However, the biological role and regulatory mechanisms of lncRNAs in docetaxel-resistant prostate cancer remain unclear. Differences in lncRNAs were evaluated by lncRNA sequencing and evaluated using quantitative real-time polymerase chain reaction, and TrkB expression was measured through western blot analysis. Proliferation was measured using the MTS, while apoptosis and cell cycle were measured using flow cytometry. In addition, migration and invasion were measured using transwell assays. Forty-eight female BALB/c nude mice were used for subcutaneous tumorigenicity and lung metastasis assays. We found that LINC01963 was overexpressed in the PC3-DR cells. LINC01963 silencing enhanced the chemosensitivity of PC3-DR to docetaxel and inhibited tumorigenicity and lung metastasis, while LINC01963 overexpression enhanced the chemoresistance of PC3 cells to docetaxel. It was found that LINC01963 bind to miR-216b-5p. The miR-216b-5p inhibitor reversed the suppressive effect of sh-LINC01963 on PC3-DR cell proliferation, migration, and invasion. Furthermore, miR-216b-5p can bind to the 3'-UTR of NTRK2 and inhibit TrkB protein levels. TrkB enhances docetaxel resistance in prostate cancer and reverses the effects of LINC01963 silencing and miR-216b-5p overexpression. In conclusion, silencing LINC01963 inhibited TrkB protein level to enhance the chemosensitivity of PC3-DR to docetaxel by means of competitively binding to miR-216b-5p. This study illustrates that LINC01963 is a novel therapeutic target for treating prostate cancer patients with DTX resistance.

CircSERPINA3 regulates SERPINA3-mediated apoptosis, autophagy and aerobic glycolysis of prostate cancer cells by competitively binding to MiR-653-5p and recruiting BUD13.

BACKGROUND: Prostate cancer (PCa) belongs to an epithelial malignancy that occurs in the prostate gland and is the most common malignancy of the male genitourinary system. Referring to related literature, circSERPINA3 has been reported to be up-regulated in PCa. However, its biological function remains unclear. PURPOSE: This study aimed to reveal the specific role and relevant molecular mechanism of circSERPINA3 in PCa. METHODS: RT-qPCR was used to examine gene expression and functional analyses were conducted to verify the effect of circSERPINA3 on cell apoptosis, autophagy and aerobic glycolysis in PCa cells. Mechanism assays were applied to evaluate the relationship among circSERPINA3/miR-653-5p/SERPINA3/BUD13. RESULTS: CircSERPINA3 was verified to be up-regulated in PCa cells and to inhibit cell apoptosis while promoting aerobic glycolysis and autophagy in PCa cells. CircSERPINA3 and SERPINA3 were also testified to bind to miR-653-5p through a line of mechanism experiments. Moreover, it was discovered that circSERPINA3 could stabilize SERPINA3 mRNA via recruiting BUD13. Additionally, SERPINA3 was verified to inhibit cell apoptosis, while promoting aerobic glycolysis and autophagy in PCa cells. CONCLUSIONS: Our study suggested that circSERPINA3 regulated apoptosis, autophagy and aerobic glycolysis of PCa cells by competitively binding to miR-653-5p and recruiting BUD13.

The long non-coding RNA LINC00473 contributes to cell proliferation via JAK-STAT3 signaling pathway by regulating miR-195-5p/SEPT2 axis in prostate cancer.

Prostate cancer is a kind of male malignant tumor, which has brought tremendous health threat to men. Prostate cancer is difficult to be cured because of high incidence and metastasis rate. Thereby, it is of great urgency to elucidate the underlying molecular mechanism of prostate cancer for the treatment of this cancer. LINC00473 dysregulation has been observed in many cancers. However, the role of LINC00473 was unknown in prostate cancer. In the present study, we discovered that prostate cancer cells presented high expression of LINC00473, and LINC00473 inhibition limited cell proliferation and the expression of proteins in JAK-STAT3 signaling pathway. Additionally, LINC00473 acted as an up-stream factor for miR-195-5p to negatively modulate miR-195-5p expression. Moreover, SEPT2 interacted with miR-195-5p in prostate cancer and SEPT2 expression was positively modulated by LINC00473 and negatively regulated by miR-195-5p. Last, the inhibitory effect of LINC00473 knockdown on cell proliferation and expression of proteins of JAK-STAT3 signaling pathway was restored by SEPT2 overexpression. All in all, LINC00473 contributed to cell proliferation via JAK-STAT3 signaling pathway by regulating miR-195-5p/SEPT2 axis in prostate cancer, which provided a novel therapeutic tactic for prostate cancer patients.

CTCF-induced upregulation of HOXA11-AS facilitates cell proliferation and migration by targeting miR-518b/ACTN4 axis in prostate cancer.

BACKGROUND: Testified as crucial participators in different types of human malignancies, long noncoding RNAs (lncRNAs) have been revealed to exert a significant effect on the complicated courses of tumor progression. Although existing literatures have revealed the oncogenic role of lncRNA homeobox A11 antisense RNA (HOXA11-AS) in multiple cancers, the underlying role of HOXA11-AS in prostate cancer (PCa) and its potential molecular mechanism remains poorly understood. AIM: To decipher the molecular performance of HOXA11-AS in PCa. METHODS: The expression of HOXA11-AS, miR-518b and actinin alpha 4 (ACTN4) was detected by a real-time quantitative polymerase chain reaction. Colony formation, EdU, flow cytometry, wound healing, and transwell assays were utilized to explore the biological role of HOXA11-AS in PCa. The interaction between RNAs (CCCTC-binding factor [CTCF], HOXA11-AS, miR-518b, and ACTN4) was tested via chromatin immunoprecipitation, luciferase reporter and RNA immunoprecipitation assays. RESULTS: HOXA11-AS in PCa cells was expressed at high levels. Silenced HOXA11-AS in PCa cells could lead to a significant elevation in the abilities of cell proliferation and migration whereas a remarkable declination in cell apoptosis capability. Subsequent molecular mechanism assays confirmed that HOXA11-AS bound with miR-518b and negatively regulates miR-518b expression. Besides, HOXA11-AS could regulate the expression of ACTN4 by sponging miR-518b. Moreover, rescued-function assays revealed that miR-518b inhibition or ACTN4 upregulation reversed the repressive effect of HOXA11-AS knockdown on PCa progression. Furthermore, CTCF was validated to activate HOXA11-AS transcription in PCa cells. CONCLUSIONS: CTCF-induced upregulation of HOXA11-AS facilitates PCa progression via miR-518b/ACTN4 axis, providing a new target for PCa treatment.

Tyrosine receptor kinase B silencing inhibits anoikis­resistance and improves anticancer efficiency of sorafenib in human renal cancer cells.

Renal cell carcinoma (RCC) is the most common solid neoplasm of adult kidney, and the major treatment for metastatic RCC (mRCC) is molecular targeted therapy. Sorafenib, as a multi-targeted tyrosine kinase inhibitor (TKI), has significantly improved clinical outcomes of mRCC patients. However, complete or long-term remissions are rarely achieved due to intolerance to dose-related adverse effects. It is therefore, necessary to explore novel target molecules for treatment or to enhance the therapeutic efficiency of present TKI for mRCC treatment. Anoikis is a specific type of apoptosis that plays a vital physiological role in regulating tissue homoeostasis. Anoikis-resistance is of critical importance for metastasis of various human cancers including mRCC. However, the precise mechanisms on anoikis-resistance in mRCC are still unclear. Tyrosine receptor kinase B (TrkB) belongs to the Trk family of neurotrophin receptors. Previous investigations have implied that activation or overexpression of TrkB promoted proliferation, survival, angiogenesis, anoikis-resistance and metastasis in human cancers. Yet, the correlation between TrkB and anoikis-resistance in mRCC has rarely been reported. The aim of the present study was to explore the impact of TrkB on anoikis-resistance and targeted therapy in mRCC. Our data revealed that anoikis-resistant ACHN cells presented with tolerance to detachment-induced apoptosis, excessive proliferation and aggressive invasion, accompanied by upregulation of TrkB expression in contrast to parental cells. Furthermore, TrkB silencing caused apoptosis, inhibited proliferation, retarded invasion as well as improved anticancer efficiency of sorafenib in anoikis-resistant ACHN cells through inactivation of PI3K/Akt and MEK/ERK pathways. Our data may offer a novel potential therapeutic strategy for mRCC.