Autophagy-related long non-coding RNAs act as prognostic biomarkers and associate with tumor microenvironment in prostate cancer.

Aberrant autophagy could promote cancer cells to survive and proliferate in prostate cancer (PCa). LncRNAs play key roles in autophagy regulatory network. We established a prognostic model, which autophagy-related lncRNAs (au-lncRNAs) were used as biomarkers to predict prognosis of individuals with PCa. Depending on au-lncRNAs from the Cancer Genome Atlas and the Human Autophagy Database, a risk score model was created. To evaluate the prediction accuracy, the calibration, Kaplan-Meier, and receiver operating characteristic curves were used. To clarify the biological function, gene set enrichment analyses (GSEA) were performed. Quantitative real-time PCR (qRT-PCR) was employed to determine the au-lncRNAs expression in PCa cell lines and healthy prostate cells for further confirmation. We identified five au-lncRNAs with prognostic significance (AC068580.6, AF131215.2, LINC00996, LINC01125 and LINC01547). The development of a risk scoring model required the utilization of multivariate Cox analysis. According to the model, we categorized PCa individuals into low- and high-risk cohorts. PCa subjects in the high-risk group had a worse disease-free survival rate than those in the low-risk group. The 1-, 3-, and 5-year periods had corresponding areas under curves (AUC) of 0.788, 0.794, and 0.818. The prognosis of individuals with PCa could be predicted by the model with accuracy. Further analysis with GSEA showed that the prognostic model was associated with the tumor microenvironment, including immunotherapy, cancer-related inflammation, and metabolic reprogramming. Four lncRNAs expression in PCa cell lines was greater than that in healthy prostate cells. The au-lncRNA prognostic model has significant clinical implications in prognosis of PCa patient.

YTHDC1 as a tumor progression suppressor through modulating FSP1-dependent ferroptosis suppression in lung cancer.

Ferroptosis is a regulated cell death process initiated by iron-dependent phospholipid peroxidation and is mainly suppressed by GPX4-dependent and FSP1-dependent surveillance mechanisms. However, how the ferroptosis surveillance system is regulated during cancer development remains largely unknown. Here, we report that the YTHDC1-mediated m6A epigenetic regulation of FSP1 alleviates the FSP1-dependent ferroptosis suppression that partially contributes to the tumor suppressive role of YTHDC1 in lung cancer progression. YTHDC1 knockdown promoted the lung tumor progression and upregulated FSP1 protein level that resulted in ferroptosis resistance of lung cancer cells. Silencing FSP1 abrogated YTHDC1 knockdown-induced proliferation increase and ferroptosis resistance. Mechanistically, YTHDC1 binding to the m6A sites in the FSP1 3'-UTR recruited the alternative polyadenylation regulator CSTF3 to generate a less stable shorter 3'-UTR contained FSP1 mRNA, whereas YTHDC1 downregulation generated the longer 3'-UTR contained FSP1 mRNA that is stabilized by RNA binding protein HuR and thus led to the enhanced FSP1 protein level. Therefore, our findings identify YTHDC1 as a tumor progression suppressor in lung cancer and a ferroptosis regulator through modulating the FSP1 mRNA stability and thus suggest a ferroptosis-related therapeutic option for YTHDC1high lung cancer.

Downregulation of N6-methyladenosine-modified LINC00641 promotes EMT, but provides a ferroptotic vulnerability in lung cancer.

The prognosis of lung cancer is poor with few effective therapies. Targeting ferroptosis is a new promising strategy for cancer therapy. LINC00641 has been involved in several cancers, however, its specific roles in lung cancer treatment remain largely unknown. Here, we reported that LINC00641 was down-regulated in tumor tissues and its downregulation was associated with poor outcomes in lung adenocarcinoma. LINC00641 was localized primarily in the nucleus and was modified by m6A. The nuclear m6A reader YTHDC1 regulated LINC00641 expression by affecting its stability. We demonstrated that LINC00641 suppressed lung cancer by inhibiting migration and invasion in vitro and metastasis in vivo. Knockdown of LINC00641 upregulated HuR protein level (especially in the cytoplasm), which subsequently increased N-cadherin levels by stabilizing its mRNA, then ultimately promoted EMT. Interestingly, LINC00641 knockdown in lung cancer cells increased the arachidonic acid metabolism and promoted ferroptosis sensitivity. Our findings identified LINC00641 as a tumor suppressor through inhibiting EMT. In another aspect, low expression of LINC00641 caused a ferroptotic vulnerability in lung cancer cells, which may serve as a potential ferroptosis-related therapeutic target for lung cancer.

A potassium-chloride co-transporter promotes tumor progression and castration resistance of prostate cancer through m6A reader YTHDC1.

SLC12A5, a neuron-specific potassium-chloride co-transporter, has been reported to promote tumor progression, however, the underlying mechanism remains unclear. Here we report that SLC12A5 functions as an oncogene to promote tumor progression and castration resistance of prostate cancer through the N6-methyladenosine (m6A) reader YTHDC1 and the transcription factor HOXB13. We have shown that the level of SLC12A5 was increased in prostate cancer, in comparison to its normal counterparts, and further elevated in castration-resistant prostate cancer (CRPC). The enhanced expression of SLC12A5 mRNA was associated with neuroendocrine prostate cancer (NEPC) progression and poor survival in prostate cancer. Furthermore, we demonstrated that SLC12A5 promoted the castration resistance development of prostate cancer in addition to the cell proliferation and migration. Interestingly, SLC12A5 was detected in the cell nucleus and formed a complex with nuclear m6A reader YTHDC1, which in turn upregulated HOXB13 to promote the prostate cancer progression. Therefore, our findings reveal a mechanism that how the potassium-chloride cotransporter SLC12A5 promotes the tumor progression and provide a therapeutic opportunity for prostate cancer to apply the neurological disorder drug SLC12A5 inhibitors.

The causal association between smoking, alcohol consumption and risk of bladder cancer: A univariable and multivariable Mendelian randomization study.

Smoking and alcohol consumption are associated with bladder cancer risk in observational studies. We conducted a two-sample univariable and multivariable Mendelian randomization (MR) analysis to determine whether those associations are causal. We used 21, 126, 360, 39 single nucleotide polymorphisms (SNPs) as instrumental variables for number of cigarettes per day, lifetime smoking index, smoking initiation, and drinks per week, respectively. A total of 1115 cases with bladder cancer and 174 006 noncases from FinnGen consortium and 2883 cases with bladder cancer and 417 955 noncases from UK Biobank study were obtained. Genetic predisposition to cigarettes per day, lifetime smoking index and smoking initiation were positively associated with an increased risk of bladder cancer in both the FinnGen and UK Biobank consortium. The summary odds ratio (OR) of bladder cancer was 1.79 (95% confidence interval [CI], 1.31-2.45; P = .0002), 2.38 (95% CI, 1.45-3.88; P = .0005) and 1.91 (95% CI, 1.46-2.50; P = 1.59 × 10-06 ) for one SD increase in the number of cigarettes per day, lifetime smoking index and smoking initiation, respectively. The genetically instrumented number of drinks per week was not associated with bladder cancer (OR = 0.69; 95% CI, 0.44-1.10; P = .1237). Estimates were consistent in multivariable MR analyses by the adjustments of body mass index and education. Our study suggests a causal potential of the association of smoking but not alcohol consumption with bladder cancer according to current evidence.

Global, regional, and national burden of kidney, bladder, and prostate cancers and their attributable risk factors, 1990-2019.

BACKGROUND: The burden of kidney, bladder, and prostate cancers has changed in recent decades. This study aims to investigate the global and regional burden of, and attributable risk factors for genitourinary cancers during the past 30 years. METHODS: We extracted data of kidney, bladder, and prostate cancers from the Global Burden of Disease 2019 database, including incidence, mortality, disability-adjusted life-years (DALYs), and attributable risk factors from 1990 to 2019. Estimated annual percentage changes (EAPC) were calculated to assess the changes in age-standardized incidence rate, age-standardized mortality rate (ASMR), and age-standardized DALYs rate (ASDR). The associations between cancers burden and socio-demographic index (SDI) were also analyzed. RESULTS: Compared with 1990, the global incident cases in 2019 were higher by 154.78%, 123.34%, and 169.11% for kidney, bladder, and prostate cancers, respectively. During the 30-year study period, there was a downward trend in ASMR and ASDR for bladder cancer (EAPC = - 0.68 and - 0.83, respectively) and prostate cancer (EAPC = - 0.75 and - 0.71, respectively), but an upward trend for kidney cancer (EAPC = 0.35 and 0.12, respectively). Regions and countries with higher SDI had higher incidence, mortality, and DALYs for all three types of cancers. The burden of bladder and prostate cancers was mainly distributed among older men, whereas the burden of kidney cancer increased among middle-aged men. Smoking related mortality and DALYs decreased, but high body mass index (BMI) and high fasting plasma glucose (FPG) related mortality and DALYs increased among kidney, bladder, and prostate cancers during the study period. CONCLUSIONS: Kidney, bladder, and prostate cancers remain major global public health challenges, but with distinct trend for different disease entity across different regions and socioeconomic status. More proactive intervention strategies, at both the administrative and academic levels, based on the dynamic changes, are needed.

Can Routine Blood and Urine Parameters Reveal Clues to Detect Bladder Cancer? A Case-Control Study.

OBJECTIVE: Limited attention has been paid to abnormal blood and urine test results for patients with bladder cancer. The present study aimed to identify whether blood and urine parameters are associated with bladder cancer. METHODS: We used a case-control design and matched each patient with bladder cancer with three healthy controls of the same age and sex. Univariate conditional logistic regression was used to calculate the crude and adjusted odds ratio (OR) and its 95% CI. Multivariate conditional logistic regression was performed for confounders adjustment, and Spearman's correlation coefficient was used to assess the correlation between tumor T stages and urine parameters. RESULTS: Patients with bladder cancer (n = 360) and controls (n = 1050) were recruited. In the univariate conditional logistic analysis, higher urine pH was associated with a decreased risk of bladder cancer (OR = 0.67, 95% CI = 0.57-0.78), while higher values of urine protein (OR = 4.55, 95% CI = 3.36-6.15), urine glucose (OR = 1.56, 95% CI = 1.18-2.05), and urine occult blood (OR = 4.27, 95% CI = 3.44-5.29) were associated with an increased risk of bladder cancer. After adjustment for body mass index, fasting blood glucose, hypertension, red blood cells, white blood cells, lymphocytes, neutrophils, and platelets, significance still remained for urine pH (OR = 0.68, 95% CI = 0.53-0.88), urine protein (OR = 1.97, 95% CI = 1.21-3.19), urine glucose (OR = 2.61, 95% CI = 1.39-4.89), and urine occult blood (OR = 3.54, 95% CI = 2.73-4.58). CONCLUSION: This study indicated that lower urine pH and higher values of urine protein, urine glucose, and urine occult blood might be risk factors for bladder cancer.