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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]