Emerging discoveries of dynamic and reversible N6-methyladenosine (m6A) modification on RNA in mammals have revealed the key roles of the modification in human tumorigenesis. As known m6A readers, insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) are upregulated in most cancers and mediates the enhancement of m6A-modified mRNAs stability. However, the mechanisms of IGF2BPs in renal cell cancer (RCC) still remain unclear. Bioinformatic analysis and RT-qPCR were performed to evaluate the expression of IGF2BPs and m6A writer Wilms tumor 1-associating protein (WTAP) in RCC samples and its correlation with patient prognosis. In vitro, in vivo biological assays were performed to investigate the functions of IGF2BPs and WTAP in RCC. Chromatin immunoprecipitation-qPCR (ChIP-qPCR) combined with bioinformatics analysis and following western blot assay, dual-luciferase reporter assays were performed to validate the regulatory relationships between transcription factor (TF) early growth response 2 (EGR2) and potential target genes IGF2BPs. RNA sequencing (RNA-seq), methylated RNA immunoprecipitation-qPCR (MERIP-qPCR), RIP-qPCR, m6A dot blot, and dual-luciferase reporter assays combined with bioinformatics analysis were employed to screen and validate the direct targets of IGF2BPs and WTAP. Here, we showed that early growth response 2 (EGR2) transcription factor could increase IGF2BPs expression in RCC. IGF2BPs in turn regulated sphingosine-1-phosphate receptor 3 (S1PR3) expression in an m6A-dependent manner by enhancing the stability of S1PR3 mRNA. They also promoted kidney tumorigenesis via PI3K/AKT pathway. Furthermore, IGF2BPs and WTAP upregulation predicted poor overall survival in RCC. Our studies showed that the EGR2/IGF2BPs regulatory axis and m6A-dependent regulation of S1PR3-driven RCC tumorigenesis, which enrich the m6A-modulated regulatory network in renal cell cancer. Together, our findings provide new evidence for the role of N6-methyladenosine modification in RCC.
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.
Results of a study of lipid peroxidation, antioxidant system components , and cholinergic neurotransmitter system in the organs of experimental rats of different ages exposed to alimentary synthetic estrogen are presented. Given the state of peroxidation processes and AChE activities in female rats exposed to xenoestro-gen, it is possible to assume the possibility of the restructuring of the functioning of mediator and enzyme systems and additional strengthening of pathological symptoms. In the future, such phenomena may trigger the reduction of potential of compensatory mechanisms in compromising the health of the consumers. In puberty, females were more sensitive to nutritional synthetic es-trogen than mature animals, thus proving that age is another factor in xenoestrogen exposure. Because of the changes in the rates of reactions to detoxification but not to the metabolism of estro-gen received into the organism, particularly with food, with age the animals were less susceptible to the effects of these substances.
The aim of this study is to investigate the functions and mechanisms of miR‐608 in prostate cancer (PCa). CISH and qRT‐PCR analysis demonstrated that miR‐608 was low expressed in PCa tissues and cells, which was partly attributed to the methylation of CpG island adjacent to the transcription start site (TSS) of miR‐608 gene. Intracellular miR‐608 overexpression inhibited in vivo PCa tumor growth, and suppressed PCa cell proliferation, G2/M transition, and migration in vitro, which was independent of EMT‐associated mechanisms. Then RAC2, a GTPase previously deemed hematopoiesis‐specific but now discovered to exist and play important roles in PCa, was verified by western blot and dual‐luciferase reporter assays to mediate the effects of miR‐608 through RAC2/PAK4/LIMK1/cofilin pathway. MiR‐608 also promoted the apoptosis of PCa cells through BCL2L1/caspase‐3 pathway by targeting the 3′‐UTR of BCL2L1. Moreover, PAK4, the downstream effector of RAC2, was found to be targeted by miR‐608 at the mRNA coding sequence (CDS) instead of the canonical 3′‐UTR. Knocking down RAC2, PAK4, or BCL2L1 with siRNAs reproduced the antiproliferative, mitosis‐obstructive, antimigratory and proapoptotic effects of miR‐608 in PCa cells, which could be attenuated by downregulating miR‐608. In conclusion, miR‐608 suppresses PCa progression, and its activation provides a new therapeutic option for PCa.
BACKGROUNDAlthough skin avulsions to male external genitalia are rare, they can be both physically and psychologically traumatic. Thus, the necessity for judicious management poses significant challenges to surgeons in order to avoid potential permanent disabilities. We report a case of massive penoscrotal skin avulsion and a composite graft was creatively applied to cover the defect which achieved good results. We believe that this case is of great reference value for fellow surgeons.CASE SUMMARYA 52-year-old male presented with massive traumatic avulsion of the penile and scrotal skin following mishandling of an electric drill. The avulsed skin was missing. The patient was diagnosed with massive skin avulsion of external genitalia. Following initial complete debridement of devitalized or infected tissues, Pelnac dermal substitute was secured to the defect with the assistance of negative-pressure wound closure. In the final step, the silicone layer of Pelnac was removed and a split-thickness skin graft was applied. The defect had healed at the two-month follow-up. The patient now has normal erections and satisfactory sexual function.CONCLUSIONOur experience with this wound repair demonstrated that the combination of a dermal regeneration template and a split-thickness skin graft with vacuum-assisted closure is a safe, well-tolerated and efficient solution for the reconstruction of massive penoscrotal skin defects.
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