Co-transcriptional R-loops-mediated epigenetic regulation drives growth retardation and docetaxel chemosensitivity enhancement in advanced prostate cancer.

R-loops are prevalent three-stranded nucleic acid structures, comprising a DNA-RNA hybrid and a displaced single-stranded DNA, that frequently form during transcription and may be attributed to genomic stability and gene expression regulation. It was recently discovered that RNA modification contributes to maintain the stability of R-loops such as N6-methyladenosine (m6A). Yet, m6A-modified R-loops in regulating gene transcription remains poorly understood. Here, we demonstrated that insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) recognize R-loops in an m6A-dependent way. Consequently, IGF2BPs overexpression leads to increased overall R-loop levels, cell migration inhibition, and cell growth retardation in prostate cancer (PCa) via precluding the binding of DNA methyltransferase 1(DNMT1) to semaphorin 3 F (SEMA3F) promoters. Moreover, the K homology (KH) domains of IGF2BPs are required for their recognition of m6A-containing R-loops and are required for tumor suppressor functions. Overexpression of SEMA3F markedly enhanced docetaxel chemosensitivity in prostate cancer via regulating Hippo pathway. Our findings point to a distinct R-loop resolution pathway mediated by IGF2BPs, emphasizing the functional importance of IGF2BPs as epigenetic R-loop readers in transcriptional genetic regulation and cancer biology.The manuscript summarizes the new role of N6-methyladenosine in epigenetic regulation, we introduce the distinct R-loop resolution mediated by IGF2BP proteins in an m6A-dependent way, which probably lead to the growth retardation and docetaxel chemotherapy resistance in prostate cancer. Moreover, our findings first emphasized the functional importance of IGF2BPs as epigenetic R-loop readers in transcriptional genetic regulation and cancer biology. In addition, our research provides a novel RBM15/IGF2BPs/DNMT1 trans-omics regulation m6A axis, indicating the new crosstalk between RNA m6A methylation and DNA methylation in prostate cancer.

Dietary fiber intake and the risk of bladder cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) cohort.

Dietary fiber intake has been implicated as a protective factor for several human cancers in multiple epidemiologic studies. However, little is known about the effect of fiber intake on bladder cancer. This study examines the association between dietary fiber intake and bladder cancer risk among participants in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. A total of 101 721 participants were included in this study as they completed both the baseline questionnaire and the diet history questionnaire (cancer free before completion of the diet history questionnaire). Hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were estimated using the Cox proportional hazards regression model. After a median of 12.5 years of follow-up, 776 new cases of bladder cancer were identified. Higher intake of total fiber, insoluble fiber and soluble fiber were not significantly associated with a reduced risk of bladder cancer. The multi-adjusted HRs (95 CIs) of highest versus lowest tertile of intake were 0.83 (0.66-1.04) for total fiber (P for trend = 0.098), 0.83 (95% CI: 0.67-1.03) for insoluble fiber (P for trend = 0.092) and 0.86 (95% CI: 0.68-1.08) for soluble fiber (P for trend = 0.168), respectively. There was no significant interaction of potential confounders, including education, body mass index and smoking status, with total fiber intake on bladder cancer risk. In summary, the findings of this prospective study show that there is no obvious evidence for a link between dietary fiber consumption and bladder cancer risk. Further large cohort studies are warranted to confirm these findings.

[Diagnosis and treatment of prostatic malignant mesenchymal tumors: Analysis of 20 cases].

OBJECTIVE: To explore the diagnosis, treatment, and prognosis of prostatic malignant mesenchymal tumors (PMMT). METHODS: We retrospectively analyzed the clinical and follow-up data about 20 cases of PMMT and reviewed the literature relevant to the diagnosis, treatment, and prognosis of the disease. RESULTS: Based on the results of pathology and immunohistochemistry, the 20 PMMT cases included leiomyosarcoma (n = 7), rhabdomyosarcoma (n = 5), prostatic stromal sarcoma (n = 3), chondrosarcoma (n = 1), and undifferentiated PMMT (n = 4). Twelve of the patients were treated by radical prostatectomy (3 concurrently by sigmoid colostomy and 1 by cystostomy), 2 by pelvic tumor resection following arterial embolization, 1 by total pelvic exenteration, 1 by colostomy with pelvic lymph node biopsy, and 4 by conservative therapy because of metastasis to the lung, pelvis and bone. Of the 20 patients, 9 died of systemic metastasis within 3 months after treatment, 3 died at 6, 7, and 14 months, respectively, 3 survived with tumor for 5, 11, and 12 months, respectively, 2 survived without tumor for 12 and 24 months so far, all subjected to periodic chemotherapy postoperatively, and 3 lost to follow-up. CONCLUSION: PMMT is a tumor of high malignancy and rapid progression, for which transrectal ultrasound-guided biopsy remains the main diagnostic method. The clinical stage of the tumor is an important factor influencing its prognosis and the survival rate of the patients can be improved by early diagnosis and combined therapy dominated by radical prostatectomy.

Downregulation of microRNA-182-5p contributes to renal cell carcinoma proliferation via activating the AKT/FOXO3a signaling pathway.

BACKGROUND: Emerging evidence has suggested that dysregulation of miR-182-5p may contribute to tumor development and progression in several types of human cancers. However, its role in renal cell carcinoma (RCC) is still unknown. METHODS: Quantitative RT-PCR was used to quantify miR-182-5p expression in RCC clinical tissues. Bisulfite sequencing PCR was used for DNA methylation analysis. The CCK-8, colony formation, flow cytometry, and a xenograft model were performed. Immunohistochemistry was conducted using the peroxidase and DAB methods. A miR-182-5p target was determined by luciferase reporter assays, quantitative RT-PCR, and Western blotting. RESULTS: miR-182-5p is frequently down-regulated in human RCC tissues. Epigenetic modulation may be involved in the regulation of miR-182-5p expression. Enforced expression of miR-182-5p in RCC cells significantly inhibited the proliferation and tumorigenicity in vitro and in vivo. Additionally, overexpression of miR-182-5p induced G1-phase arrest via inhibition of AKT/FOXO3a signaling. Moreover, FLOT1 was confirmed as a target of miR-182-5p. Silencing FLOT1 by small interfering RNAs phenocopied the effects of miR-182-5p overexpression, whereas restoration of FLOT1 in miR-182-5p -overexpressed RCC cells partly reversed the suppressive effects of miR-182-5p. CONCLUSIONS: These findings highlight an important role for miR-182-5p in the pathogenesis of RCC, and restoration of miR-182-5p could be considered as a potential therapeutic strategy for RCC therapy.

[Comparison of ultrasound-guided transrectal and transperineal prostate biopsies in clinical application].

OBJECTIVE: To compare the positive rates and complications of ultrasound-guided transrectal and transperineal prostate biopsies. METHODS: We retrospectively analyzed 156 cases of ultrasound-guided transrectal (n = 97) and transperineal (n = 59) prostate biopsy, and compared the positive rate and post-biopsy complications between the two approaches. RESULTS: The positive rates in the transrectal and transperineal groups were 48.4% and 44.1%, respectively, with no significant difference between the two approaches according to different PSA levels (P >0.05). No statistically significant differences were observed between the transrectal and transperineal groups in the post-biopsy incidence rates of such complications as hematuria (54.6% vs 42.4%, P >0.05), lower urinary tract symptoms (17.5% vs 22.0%, P >0.05), dysuria (9.3% vs 6.8%, P >0.05), and acute urinary retention (7.2% vs 6.8%, P >0.05). However, the incidence rates of post-biopsy infection and rectal bleeding were remarkably higher (15.5% vs 3.4%, P<0.05 and 50.5% vs 3.4%, P >0.01) while that of perineal swelling markedly lower in the former than in the latter (3.1% vs 13.6%, P <0.05). CONCLUSION: Transrectal and transperineal biopsies are both effective for the diagnosis of prostate cancer. Since their complications vary, the choice between the two methods depends on the specific condition of the patient.

PRIORITI: Phase 4 study of triptorelin or active surveillance in high-risk prostate cancer.

AIM: To evaluate the efficacy and safety of triptorelin after radical prostatectomy (RP) in patients with negative lymph nodes. METHODS: PRIORITI (NCT01753297) was a prospective, open-label, randomized, controlled, phase 4 study conducted in China and Russia. Patients with high-risk (Gleason score ≥ 8 and/or pre-RP prostate-specific antigen [PSA] ≥ 20 ng/mL and/or primary tumor stage 3a) prostate adenocarcinoma without evidence of lymph node or distant metastases were randomized to receive triptorelin 11.25 mg at baseline (≤ 8 weeks after RP) and at 3 and 6 months, or active surveillance. The primary endpoint was biochemical relapse-free survival (BRFS), defined as the time from randomization to biochemical relapse (BR; increased PSA > 0.2 ng/mL). Patients were monitored every 3 months for at least 36 months; the study ended when 61 BRs were observed. RESULTS: The intention-to-treat population comprised 226 patients (mean [standard deviation] age, 65.3 [6.4] years), of whom 109 and 117 were randomized to triptorelin or surveillance, respectively. The median BRFS was not reached. The 25th percentile time to BRFS (95% confidence interval) was 39.1 (29.9-not estimated) months with triptorelin and 30.0 (18.6-42.1) months with surveillance (p = 0.16). There was evidence of a lower risk of BR with triptorelin versus surveillance but this was not statistically significant at the 5% level (p = 0.10). Chemical castration was maintained at month 9 in 93.9% of patients who had received triptorelin. Overall, triptorelin was well tolerated and had an acceptable safety profile. CONCLUSION: BRFS was observed to be longer with triptorelin than surveillance, but the difference was not statistically significant.

N6-methyladenosine-modified CircPSMA7 enhances bladder cancer malignancy through the miR-128-3p/MAPK1 axis.

Several studies have indicated that circular RNAs (circRNAs) play vital roles in the progression of various diseases, including bladder cancer (BCa). However, the underlying mechanisms by which circRNAs drive BCa malignancy remain unclear. In this study, we identified a novel circRNA, circPSMA7 (circbaseID:has_circ_0003456), showing increased expression in BCa cell lines and tissues, by integrating the reported information with circRNA-seq and qRT-PCR. We revealed that circPSMA7 is associated with a higher tumor grade and stage in BCa. M6A modification was identified in circPSMA7, and IGF2BP3 recognized this modification and stabilized circPSMA7, subsequently increasing the circPSMA7 expression. In vitro and in vivo experiments showed that circPSMA7 promoted BCa proliferation and metastasis by regulating the cell cycle and EMT processes. CircPSMA7 acted as a sponge for miR-128-3p, which showed antitumor effects in BCa cell lines, increasing the expression of MAPK1. The tumor proliferation and metastasis suppression induced by silencing circPSMA7 could be partly reversed by miR-128-3p inhibition. Thus, the METTL3/IGF2BP3/circPSMA7/miR-128-3p/MAPK1 axis plays a critical role in BCa progression. Furthermore, circPSMA7 may be a potential diagnostic biomarker and novel therapeutic target for patients with BCa.

Long-term tadalafil once daily in Chinese men with erectile dysfunction: a 2-year final analysis of a post-marketing, multicenter, randomized, open-label trial.

The long-term safety and effectiveness of once-daily tadalafil is crucial, but limited data are available in Chinese patients with erectile dysfunction (ED). In this post-marketing, multicenter, randomized, open-label trial with 2-year follow-up, 635 ED cases were randomized to receive daily oral tadalafil 2.5 mg or 5 mg for 3 months, of whom 580 continued once-daily tadalafil 5 mg for 21 months. Treatment-emergent adverse events in the 12-month and 24-month period were similar, with the most common being viral upper respiratory tract infection, upper respiratory tract infection, and headache. Significant improvement from baseline in the International Index of Erectile Function-Erectile Function (IIEF-EF) score was detected at month 12 (least squares mean [LSM] change: 7.9, 95% confidence interval [CI]: 7.5-8.4, P < 0.001) and was maintained to month 24 (LSM change: 8.6, 95% CI: 8.1-9.0, P < 0.001). The proportions of patients regaining normal erectile function (IIEF-EF score ≥26) were 43.7% and 48.0% at months 12 and 24, respectively. Global Assessment Questionnaire results showed improved erection function in 97.5% of patients and improved ability to engage in sexual activity in 95.9% of patients at month 12; these values were 96.1% and 95.0% at month 24, respectively. The quality of sexual life score based on the Sexual Life Quality Questionnaire (SLQQ) was increased by 52.2% at month 12 and by 55.3% at month 24 (both P < 0.001). The treatment satisfaction score determined by SLQQ (mean ± standard deviation) was 62.4 ± 21.0 at month 12 versus 65.9 ± 20.2 at month 24. Two-year daily application of tadalafil 5 mg in Chinese men with ED showed a favorable safety profile and durable improvement in sexual performance and satisfaction.

MicroRNA-490-5p inhibits proliferation of bladder cancer by targeting c-Fos.

MicroRNAs (miRNAs) are non-protein-coding sequences that play a crucial role in tumorigenesis by negatively regulating gene expression. Here, we found that miR-490-5p is down-regulated in human bladder cancer tissue and cell lines compared to normal adjacent tissue and a non-malignant cell line. To better characterize the function of miR-490-5p in bladder cancer, we over-expressed miR-490-5p in bladder cancer cell lines with chemically synthesized mimics. Enforced expression of miR-490-5p in bladder cancer cells significantly inhibited the cell proliferation via G1-phase arrest. Further studies found the decreased c-Fos expression at both mRNA and protein levels and Luciferase reporter assays demonstrated that c-Fos is a direct target of miR-490-5p in bladder cancer. These findings indicate miR-490-5p to be a novel tumor suppressor of bladder cancer cell proliferation through targeting c-Fos.

MicroRNA-124-3p inhibits cell migration and invasion in bladder cancer cells by targeting ROCK1.

BACKGROUND: Increasing evidence has suggested that dysregulation of certain microRNAs (miRNAs) may contribute to human disease including carcinogenesis and tumor metastasis in human. miR-124-3p is down-regulated in various cancers, and modulates proliferation and aggressiveness of cancer cells. However, the roles of miR-124-3p in human bladder cancer are elusive. Thus, this study was conducted to investigate the biological functions and its molecular mechanisms of miR-124-3p in human bladder cancer cell lines, discussing whether it has a potential to be a therapeutic biomarker of bladder cancer. METHODS: Three human bladder cancer cell lines and samples from ten patients with bladder cancer were analyzed for the expression of miR-124-3p by quantitative RT--PCR. Exogenetic overexpression of miR-124-3p was established by transfecting mimics into T24, UM-UC-3 and J82 cells, after that cell proliferation and cell cycle were assessed by MTT assay, flow cytometry and Colony-forming assay. Cell motility and invasion ability were evaluated by wound healing assay and transwell assay. Tissue microarray, and immunohistochemistry with antibodies against ROCK1, MMP2 and MMP9 was performed using the peroxidase and DAB methods. The target gene of miR-124-3p was determined by luciferase assays, quantitative RT--PCR and western blot. The regulation of epithelial-to-mesenchymal transition by miR-124-3p was analyzed by western blot. RESULTS: miR-124-3p is frequently down-regulated in bladder cancer both in three bladder cancer cell lines, T24, UM-UC-3, J82 and clinical samples. Overexpression of miR-124-3p induced G1-phase arrest in T24, UM-UC-3 and J82 cell lines and suppressed cell growth in colony-forming assay. miR-124-3p significantly repressed the capability of migration and invasion of bladder cancer cells. In addition, ROCK1 was identified as a new target of miR-124-3p. ROCK1, MMP2, MMP9 were up-regulated in bladder cancer tissues. Furthermore, we demonstrated miR-124-3p could inhibit bladder cancer cell epithelial mesenchymal transfer, and regulated the expression of c-Met, MMP2, MMP9. CONCLUSIONS: miR-124-3p can repress the migration and invasion of bladder cancer cells via regulating ROCK1. Our data indicate that miR-124-3p could be a tumor suppressor and may have a potential to be a diagnostics or predictive biomarker in bladder cancer.

Cruciferous vegetables consumption and risk of renal cell carcinoma: a meta-analysis.

Previous cohort and case-control studies on the association between cruciferous vegetables consumption and risk of renal cell carcinoma have illustrated conflicting results so far. To demonstrate the potential association between them, a meta-analysis was performed. Eligible studies were retrieved via both computerized searches and review of references. The summary relative risks (RRs) with 95% confidence interval (CI) for the highest vs. the lowest consumption of cruciferous vegetables were calculated. Heterogeneity and publication bias were also evaluated. Stratified analyses were performed as well. Three cohort and 7 case-control studies were included. A significantly decreased risk with renal cell carcinoma was observed in overall cruciferous vegetables consumption group (RR = 0.73; 95% CI, 0.63-0.83) and subgroup of case-control studies (RR = 0.69; 95% CI, 0.60-0.78), but not in cohort studies (RR = 0.96; 95% CI, 0.71-1.21). No heterogeneity and publication bias were detected across studies. Our findings supported that cruciferous vegetables consumption was related to the decreased risk of renal cell carcinoma. Because of the limited number of studies, further well-designed prospective studies and researches need to be conducted to better clarify the protective effect of cruciferous vegetables on renal cell carcinoma and potential mechanism.

A panel of five circulating microRNAs as potential biomarkers for prostate cancer.

BACKGROUND: Circulating microRNA (miRNAs) have been shown to have the potential as noninvasive diagnosis markers in several types of cancers. In this study, we investigated whether circulating miRNAs could be used in the diagnosis of prostate cancer (CaP) in a Chinese patient population. METHODS: Illumina's Human v2 miRNA microarray was used to analyze miRNAs levels in a small set of patients [25 CaP, 17 benign prostatic hyperplasia (BPH)] in an effort to identify CaP-specific miRNAs. The identified miRNAs were further examined by quantitative real-time PCR (qRT-PCR) in the same small set of patients. After the training phase of screening and selecting, the candidate miRNAs were validated in a larger independent cohort (80 CaP, 44 BPH, and 54 healthy controls) with qRT-PCR in the verification phase. RESULTS: Five miRNAs were confirmed by qRT-PCR analysis in validation sets. Receiver operating characteristic (ROC) curve analysis showed all 5 miRNAs had diagnostic value. More importantly, further principal component analysis indicated component 1 extracted from expression data of the 5 miRNAs could differentiate CaP from BPH and healthy controls with high diagnosis performance, with an AUC of 0.924 and 0.860, respectively. CONCLUSIONS: Our data suggested that circulating miRNAs could serve as biomarkers for CaP, and compared to single miRNA, the 5 miRNAs panel can accurately discriminate CaP from BPH and healthy controls with high sensitivity and specificity, and therefore, combined with routine PSA test, these 5 CaP-specific miRNAs may help improve CaP diagnosis in clinical application.

A single-dose, randomized, open-labeled, parallel-group study comparing the pharmacokinetics, pharmacodynamics and safety of leuprolide acetate microspheres 3.75 mg and Enantone® 3.75 mg in healthy male subjects.

Leuprolide acetate microspheres developed by Shanghai Livzon Pharmaceutical Co., Ltd. (T) have been marketed in China for more than 10 years, benefiting a large number of patients, and will continue to play an important role in China. However, as a generic drug, it is unclear whether there is a difference in efficacy between T and the original product Enantone® (R). This study compared the differences in efficacy and safety of two 1-month depot formulations in 48 healthy Chinese male subjects by comparing multiple pharmacokinetic (PK) and pharmacodynamic (PD) parameters. The main research indicators were the PK parameters of leuprolide (Cmax, AUC0-t, AUC0-D7, and AUCD7-t) and the PD parameters of testosterone (Emax, AUEC0-t, AUEC0-D7, and AUECD7-t) after 42 days of administration. The Cmax, AUC0-t, AUC0-D7 and AUCD7-t of leuprolide were slightly higher in the T group than in the R group with 90% confidence intervals (CIs) of 94.43-118.53%, 109.13-141.88%, 109.53-139.54%, and 105.17-145.74%, respectively. No significant differences in the PD parameters (Emax, AUEC0-t, AUEC0-D7, and AUECD7-t) existed between the T and R groups, and 90% CIs were 62.80-93.57%, 88.17-110.55, 95.72%-118.50%, and 79.77-105.63, respectively. At 672 h (D28), the castration rate of T was 91.30% (21/23) and that of R was 60.87% (14/23). The PK characteristics were consistent and the inhibitory effects on testosterone levels were similar in both T and R groups; further, clinical safety was observed for both T and R formulations, suggesting that these two products can replace each other in clinical practice. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml, identifier CTR20200641.

Targeting mTOR Complex 2 in Castration-Resistant Prostate Cancer with Acquired Docetaxel Resistance.

Purpose: Mammalian Target of rapamycin (mTOR) plays a central role in regulating cell growth, proliferation, and cell cycle. The key component of mTORC2 is highly expressed in docetaxel-resistant prostate cells. However, the underlying molecular effects on prostate cells remain unclear. Methods: A docetaxel-resistant human prostate cell line (PC-3/DTX) was constructed to investigate the role of mTORC2 in docetaxel resistance. The lentivirus was transfected into cells to knock down the expression of Rictor, and cell viability was measured by Cell Counting Kit 8 (CCK-8). Flow cytometry was used to analyze the cell cycle, and the changes in related signal cascades were assessed by immunohistochemistry (IHC) staining and Western blot. Results: Docetaxel showed the lowest IC50 (50% inhibitory concentration) in PC-3/DTX cells with sh-RNA. Decreased Rictor expression resulted in a larger proportion of arrested cells in the G0/G1 phase in PC-3/DTX cells. The IC50 values of the AZD8055 group were lower than in the Rapamycin group when treated with docetaxel again. Furthermore, a larger proportion of PC-3/DTX cells were arrested in the G0/G1 phase in the AZD8055 group compared to the Rapamycin group. The IHC results of the prostate cancer tissues from a CRPC patient revealed the over expression of Rictor only, while Raptor expression was unaffected. Conclusion: We investigated the role of mTORC2 signaling on the acquired docetaxel -resistant PC-3 cells to identify potential methods for clinical treatment. MTORC2 expression is essential for docetaxel drug resistance of PC-3 cells. The mTORC1/2 inhibitor AZD8055 caused more significant disruption of mTORC2 kinase activity than the mTORC1 inhibitor Rapamycin, which lead to decreased docetaxel-mediated resistance. Therefore, reversing docetaxel resistance, may become a therapeutic option in the treatment of mCRPC patients.

FTO promotes clear cell renal cell carcinoma progression via upregulation of PDK1 through an m6A dependent pathway.

FTO, as an m6A mRNA demethylase, is involved in various cancers. However, the role of FTO in clear cell renal cell carcinoma (ccRCC) remains unclear. In the present study, we discovered FTO is upregulated in ccRCC. Functionally, knockdown of FTO significantly impairs the proliferation and migration ability of ccRCC cells. Mechanistically, our data suggest FTO promotes the proliferation and migration of ccRCC through preventing degradation of PDK1 mRNA induced by YTHDF2 in an m6A-dependent mechanism. Overall, our results identify the protumorigenic role of FTO through the m6A/YTHDF2/PDK1 pathway, which could be a promising therapeutic target for ccRCC.

Testicular and Spermatic Cord Metastases from Gastric Adenocarcinoma: An Unusual Case.

The metastasis of gastric cancer to the testis or spermatic cord is very rare; however, simultaneous testicular and spermatic cord metastases are even rarer. Here, we report an unusual case of a 54-year-old male patient who had undergone radical gastrectomy for gastric adenocarcinoma more than two years before. He complained of palpable painful masses in the right scrotum and inguinal area occurring for more than half a year. Enhanced computed tomography (CT) separately showed an enhanced soft tissue mass in the right testicular and spermatic cord areas. Therefore, a right radical orchiectomy was conducted. The pathology was consistent with the metastases of gastric adenocarcinoma.

circKDM4C enhances bladder cancer invasion and metastasis through miR-200bc-3p/ZEB1 axis.

Circular RNAs (circRNAs) play essential roles in human bladder cancer (BCa) development, however, unusual expression patterns and functional dysfunction of circRNAs in BCa have not been evaluated. In this study, we validated that circKDM4C (hsa_circ_0001839), derived from the KDM4C gene, is elevated in BCa cell lines as well as tissues. Functionally, overexpression of circKDM4C significantly enhances, and silencing of circKDM4C suppresses migration and invasion capabilities of BCa cells. Mechanistically, circKDM4C can directly interact with miR-200b-3p and miR-200c-3p as a miRNA sponge, which enhances the expression of ZEB1 and promotes mesenchymal phenotype. Conclusively, our findings indicate that circKDM4C may act as a pro-oncogenic factor in BCa invasion and metastasis via the circKDM4C/miR-200bc-3p/ZEB1 axis, which is a potential biomarker or therapeutic target for bladder cancer.

Perspectives on Circular RNAs as Prostate Cancer Biomarkers.

High throughput RNA sequencing has revealed the existence of abundant circular RNAs (circRNAs) that are cell lineage-specific and have been implicated in human diseases. CircRNAs are resistant to exonuclease digestion, can carry genetic information of oncogenes, and are enriched in exosome to be transported from tissues into various body fluids. These properties make circRNAs ideal non-invasive diagnostic biomarkers for disease detection. Furthermore, many circRNAs have been demonstrated to possess biological functions in relevant cells, suggesting that they may also be potential therapeutic targets and reagents. However, our knowledge of circRNAs is still at an infant stage and far from being translated into clinics. Here, we review circRNAs in the disease setting of prostate cancer. We start by introducing the basic knowledge of circRNAs, followed by summarizing opportunities of circRNAs to be prostate cancer biomarkers, and discuss current challenges in circRNA research and outlook of future directions in translating current knowledge about circRNA into clinical practice.

Dietary inflammatory index and bladder cancer risk: a prospective study.

BACKGROUND: Dietary factors may play a role in bladder cancer etiology through modulation of inflammation. The purpose of this study was to examine the relationship between the inflammatory potential of diet, as estimated by the Dietary Inflammatory Index (DII®), and bladder cancer risk. METHODS: Energy-adjusted DII (E-DIITM) scores were computed among 101,721 participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) study. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression analysis stratified by sex, with adjustment for smoking status and other confounding. RESULTS: Over a median of 12.5 years of follow-up, 776 bladder cancer cases were diagnosed. E-DII scores were not associated with bladder cancer risk in the multivariable models. The HRs (95% CIs) in the highest compared with the lowest E-DII quintile were 0.90 (0.70-1.17) and 1.22 (0.72-2.06) for men and women, respectively. The associations did not differ when DII score was set as a continuous variable. The HRs (95% CIs) of one-unit increment in the E-DII for bladder cancer risk were 0.99 (0.96-1.02) and 1.01 (0.94-1.10) for men and women, respectively. CONCLUSIONS: Our study does not support an association between inflammatory potential of diet, as estimated by the E-DII, and bladder cancer risk.

STAT3 activates MSK1-mediated histone H3 phosphorylation to promote NFAT signaling in gastric carcinogenesis.

Epigenetic abnormalities contribute significantly to the development and progression of gastric cancer. However, the underlying regulatory networks from oncogenic signaling pathway to epigenetic dysregulation remain largely unclear. Here we showed that STAT3 signaling, one of the critical links between inflammation and cancer, acted as a control pathway in gastric carcinogenesis. STAT3 aberrantly transactivates the epigenetic kinase mitogen- and stress-activated protein kinase 1 (MSK1), thereby phosphorylating histone H3 serine10 (H3S10) and STAT3 itself during carcinogen-induced gastric tumorigenesis. We further identified the calcium pathway transcription factor NFATc2 as a novel downstream target of the STAT3-MSK1 positive-regulating loop. STAT3 forms a functional complex with MSK1 at the promoter of NFATc2 to promote its transcription in a H3S10 phosphorylation-dependent way, thus affecting NFATc2-related inflammatory pathways in gastric carcinogenesis. Inhibiting the STAT3/MSK1/NFATc2 signaling axis significantly suppressed gastric cancer cell proliferation and xenograft tumor growth, which provides a potential novel approach for gastric carcinogenesis intervention by regulating aberrant epigenetic and transcriptional mechanisms.