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TAR-DNA-binding protein-43 (TDP-43) is a member of hnRNP family and acts as both RNA and DNA binding regulator, mediating RNA metabolism and transcription regulation in various diseases. Currently, emerging evidence gradually elucidates the crucial role of TDP-43 in human cancers like it is previously widely researched in neurodegeneration diseases. A series of RNA metabolism events, including mRNA alternative splicing, transport, stability, miRNA processing, and ncRNA regulation, are all confirmed to be closely involved in various carcinogenesis and tumor progressions, which are all partially regulated and interacted by TDP-43. Herein we conducted the first overall review about TDP-43 and cancers to systematically summarize the function and precise mechanism of TDP-43 in different human cancers. We hope it would provide basic knowledge and concepts for tumor target therapy and biomarker diagnosis in the future. [ABSTRACT FROM AUTHOR]

Background: Emerging evidence suggests that miR‐501‐3p plays an important role in the pathogenesis and progression of various carcinomas. However, its role and underlying mechanisms in renal cell carcinoma (RCC) remain to be elucidated. Methods: Quantitative RT‐PCR, western blot, and bioinformatics methods were used to evaluate the expression of miR‐501‐3p and Wilms' tumor 1‐associating protein (WTAP) in RCC cell lines and clinical tissues. The effects of miR‐501‐3p on the proliferation of RCC cells were investigated using flow cytometric, colony formation, and CCK8 assays. The target gene of miR‐501‐3p was confirmed by western blotting, qRT‐PCR, and dual‐luciferase reporter assays. The levels of RNA methylation with N6‐methyladenosine (m6A) following miR‐501‐3p overexpression or knockdown of its target gene were quantified using a dot‐blot assay. Results: miR‐501‐3p expression was significantly downregulated in human RCC cell lines and tissues. In contrast, its overexpression markedly inhibited cancer cell proliferation in vitro by inducing G1 phase arrest. Moreover, WTAP was verified as a direct target gene of miR‐501‐3p. WTAP gene knockdown alone efficiently produced the same cancer‐inhibiting effects as miR‐501‐3p overexpression, with the level of m6A in RCC cells being decreased under both scenarios. The intermolecular interaction between miR‐501‐3p and WTAP was further substantiated by rescue experiments. Conclusion: RCC progression is regulated via the miR‐501‐3p/WTAP/CDK2 axis and is inhibited by the overexpression of miR‐501‐3p. [ABSTRACT FROM AUTHOR]

Emerging research indicates that miRNAs can regulate cancer progression by influencing molecular pathways. Here, we studied miR-665, part of the DLK1-DIO3 miRNA cluster, which is downregulated by upstream methylation in bladder cancer. MiR-665 overexpression significantly downregulated the expression of SMAD3, phospho-SMAD3, and SNAIL, reversed epithelial–mesenchymal transition progression, and inhibited the migration of bladder cancer cells. To predict potential targets of miR-665, we used online databases and subsequently determined that miR-665 binds directly to the 3ʹ untranslated region of SMAD3. Moreover, silencing of SMAD3 with small interfering RNAs phenocopied the effect of miR-665 overexpression, and overexpression of SMAD3 restored miR-665-overexpression-induced metastasis. This study revealed the role of the miR-665/SMAD3/SNAIL axis in bladder cancer, as well as the potential of miR-665 as a promising therapeutic target. [ABSTRACT FROM AUTHOR]

Background: Tumor-associated macrophages (TAMs) are the major immune cells in tumor microenvironment. The prognostic significance of TAMs has been confirmed in various tumors. However, whether TAMs can be prognostic factors in clear cell renal cell carcinoma (ccRCC) is unclear. In this study, we aimed to clarify the prognostic value of TAMs in ccRCC. Methods: We searched PubMed, Embase, and the Web of Science for relevant published studies before December 19, 2020. Evidence from enrolled studies were pooled and analyzed by a meta-analysis. Hazard ratios (HRs) and odd ratios (ORs) with 95% confidence intervals (CIs) were computed to evaluate the pooled results. Results: Both of high CD68+ TAMs and M2-TAMs were risk factors for poor prognosis in ccRCC patients. The pooled HRs indicated that elevated CD68+ TAMs correlated with poor OS and PFS (HR: 3.97, 95% CI 1.39–11.39; HR: 5.73, 95% CI 2.36–13.90, respectively). For M2-TAMs, the pooled results showed ccRCC patients with high M2-TAMs suffered a worse OS and shorter PFS, with HR 1.32 (95% CI 1.16–1.50) and 1.40 (95% CI 1.14–1.72), respectively. Also, high density of TAMs was associated with advanced clinicopathological features in ccRCC. Conclusions: TAMs could be potential biomarkers for prognosis and novel targets for immunotherapy in ccRCC. Further researches are warranted to validate our results. [ABSTRACT FROM AUTHOR]

N6‐Methyladenosine (m6A) modification, the most prevalent modification of eukaryotic messenger RNA (mRNA), is involved in the progression of various tumours. However, the specific role of m6A in bladder cancer (BCa) is still poorly understood. In this study, we demonstrated the tumour‐promoting function and specific regulatory mechanism of m6A axis, consisting of the core 'writer' protein METTL3 and the major reader protein YTHDF2. Depletion of METTL3 impaired cancer proliferation and cancer metastasis in vitro and in vivo. Through transcriptome sequencing, m6A methylated RNA immunoprecipitation (MeRIP) and RIP, we determined that the METTL3/YTHDF2 m6A axis directly degraded the mRNAs of the tumour suppressors SETD7 and KLF4, contributing to the progression of BCa. In addition, overexpression of SETD7 and KLF4 revealed a phenotype consistent with that induced by depletion of the m6A axis. Thus, our findings on the METTL3/YTHDF2/SETD7/KLF4 m6A axis provide the insight into the underlying mechanism of carcinogenesis and highlight potential therapeutic targets for BCa. [ABSTRACT FROM AUTHOR]

Objectives: Downregulation of miR‐502‐5p has emerged as a critical factor in tumour progression in several cancers. Herein, we elucidated the role of miR‐502‐5p in bladder cancer. Materials and methods: RT‐qPCR was performed to examine the expression of miR‐502‐5p in bladder cancer. And DNA methylation analysis showed that epigenetic mechanisms may contribute to the downregulation of miR‐502‐5p. Then, wound‐healing assay, transwell assay, colony formation assay, CCK8 assay and flow cytometry analysis were applied to evaluate the function of miR‐502‐5p in bladder cancer cell lines. Western blot was conducted to measure the protein levels of related genes. Furthermore, dual‐luciferase reporter assay, in vivo tumorigenesis assay and immunohistochemical staining were also conducted as needed. Results: MiR‐502‐5p is frequently downregulated in BCa. Meanwhile, hypermethylation of CpG islands contributes to the downregulation of miR‐502‐5p. Functionally, overexpression of miR‐502‐5p inhibited cell proliferation and migration in vitro and repressed tumour growth in vivo. CCND1, DNMT3B and NOP14 were identified as direct targets of miR‐502‐5p. Interestingly, DNMT3B and miR‐502‐5p established a positive feedback loop in the regulation of bladder cancer. In addition, rescue experiments further validated the direct molecular interaction between miR‐502‐5p and its targets. Conclusions: Our study proposed and demonstrated that the miR‐502‐5p–mediated regulatory network is critical in bladder cancer; this network may be useful in the development of more effective therapies against bladder cancer. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are a novel class of noncoding RNAs, which are mainly formed as a loop structure at the exons caused by noncanonical splicing; they are much more stable than linear transcripts; recent reports have suggested that the dysregulation of circRNAs is associated with the occurrence and development of diseases, especially various human malignancies. Emerging evidence demonstrated that a large number of circRNAs play a vital role in a series of biological processes such as tumor cell proliferation, migration, drug resistance, and immune escape. Additionally, circRNAs were also reported to be potential prognostic and diagnostic biomarkers in cancers. In this work, we systematically summarize the biogenesis and characteristics of circRNAs, paying special attention to potential mechanisms and clinical applications of circRNAs in urological cancers, which may help develop potential therapy targets for urological cancers in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang, Ying, Ma, Wang, Wang and Xie.)

Clear cell renal cell carcinoma (ccRCC) is one of the tumor types with sensitivity to ferroptosis, and immunotherapy has emerged as a standard pillar for metastatic ccRCC treatment, while it remains largely obscure whether ferroptosis influences the tumor immune microenvironment in ccRCC. Based on available data in The Cancer Genome Atlas, divergent expression profiles of ferroptosis regulators were noted in ccRCC and normal tissues, and we also found that the ferroptosis regulators correlated with the PD-L1 expression. Two independent subtypes were determined by consensus clustering analysis according to the expression level of ferroptosis regulators in ccRCC. Cluster 1 showed lower histological tumor stage and grade, more favorable prognosis, and higher PD-L1 expression compared to cluster 2. CIBERSORT analysis revealed that cluster 2 harbored higher infiltrated levels of CD8+ T cell, Tregs, and T follicular helper cell, while cluster 1 more correlated with the monocyte, M1 macrophage, and M2 macrophage. Gene set enrichment analysis indicated that the ERBB signaling and JAK_STAT signaling pathways were significantly enriched in cluster 1. We subsequently identified CARS as the potentially key immune infiltration-related ferroptosis regulator, whose high expression showed dismal prognosis and was positively correlated with PD-L1 expression in ccRCC. We also verified the upregulation of CARS in ccRCC tissues and cell lines via qRT-PCR method. Additionally, a pan-cancer analysis demonstrated that CARS closely related to the expression of immune checkpoint-related genes (especially PD-L1) and an unfavorable prognosis in diverse cancer types. In summary, our study suggested the crucial role of ferroptosis in immune infiltration of ccRCC, and CARS is a potentially novel prognostic biomarker and potential target for cancer immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang, Chen, Ying, Ma, Shen, Li, Wang, Lin, Liu, Zheng and Xie.)

N6-Methyladenosine (m 6 A) modification, the most prevalent modification of eukaryotic messenger RNA (mRNA), is involved in the progression of various tumours. However, the specific role of m 6 A in bladder cancer (BCa) is still poorly understood. In this study, we demonstrated the tumour-promoting function and specific regulatory mechanism of m 6 A axis, consisting of the core 'writer' protein METTL3 and the major reader protein YTHDF2. Depletion of METTL3 impaired cancer proliferation and cancer metastasis in vitro and in vivo. Through transcriptome sequencing, m 6 A methylated RNA immunoprecipitation (MeRIP) and RIP, we determined that the METTL3/YTHDF2 m 6 A axis directly degraded the mRNAs of the tumour suppressors SETD7 and KLF4, contributing to the progression of BCa. In addition, overexpression of SETD7 and KLF4 revealed a phenotype consistent with that induced by depletion of the m 6 A axis. Thus, our findings on the METTL3/YTHDF2/SETD7/KLF4 m 6 A axis provide the insight into the underlying mechanism of carcinogenesis and highlight potential therapeutic targets for BCa., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Curcumin induces apoptosis and autophagy in different cancer cells. Moreover, chemical and biological experiments have evidenced that curcumin is a biologically active iron chelator and induces cytotoxicity through iron chelation. We thus hypothesized that curcumin may induce apoptosis and autophagy in castration-resistant prostate cancer (CRPC) cells through its iron-chelating properties., Materials and Methods: CRPC cells were loaded with curcumin alone or in combination with ferric ammonium citrate (FAC). Cytotoxicity was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was assessed by flow cytometry, terminal deoxynucleotidyl transferase nick end labeling (TUNEL) assay and caspase activity. Autophagy status was analyzed by the detection of autophagosomes and light chain 3-II (LC3-II) using transmission electron microscopy and Western blot. Iron-binding activity of curcumin was assessed by spectrophotometry and MTT assay. The expression levels of transferrin receptor 1 (TfR1) and iron regulatory protein 1 (IRP1) were examined by Western blot., Results: Curcumin induced apoptosis and autophagy in CRPC cells. Combining curcumin with autophagy inhibitors (3-methyladenine [3-MA]) synergized the apoptotic effect of curcumin. Moreover, curcumin bound to FAC at a ratio of ~1:1, as assessed by spectrophotometry and MTT assay. Apoptosis and autophagy induced by curcumin were counteracted by equal amounts of FAC. At apoptosis- and autophagy-inducing concentrations, curcumin enhanced the expression levels of TfR1 and IRP1, indicative of iron deprivation induced by curcumin., Conclusion: Together, our results indicate that curcumin induces apoptosis and protective autophagy in CRPC cells, which are at least partially dependent on its iron-chelating properties., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Bladder neck preservation (BNP) during radical prostatectomy (RP) may improve postoperative urinary continence, although its overall effectiveness remains controversial. We systematically searched PubMed, Ovid Medline, Embase, CBM and the Cochrane Library to identify studies published before February 2016 that assessed associations between BNP and post-RP urinary continence. Thirteen trials (1130 cases and 1154 controls) assessing BNP versus noBNP (or with bladder neck reconstruction, BNR) were considered suitable for meta-analysis, including two randomized controlled trials (RCT), six prospective and five retrospective studies. Meta-analysis demonstrated that BNP improved early urinary continence rates (6 mo, OR = 1.66; 95% CI, 1.21-2.27; P = 0.001) and long-term urinary continence outcomes (>12 mo, OR = 3.99; 95% CI, 1.94-8.21; P = 0.0002). Patients with BNP also had lower bladder neck stricture frequencies (OR = 0.49; 95% CI, 0.29-0.81; P = 0.006). Anastomotic leak rates, positive surgical margins and biochemical failure rates were comparable between the two groups (P>0.05). There were no differences in baseline characteristics except for a smaller average prostate volume (WMD = -2.24 ml; 95% CI, -4.27 to -0.22; P = 0.03) in BNP patients. Our analyses indicated that BNP during RP improved early recovery and overall long-term (1 year) urinary continence and decreased bladder neck stricture rates without compromising oncologic control.