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.

Cancer on motors: How kinesins drive prostate cancer progression?

Prostate cancer causes numerous male deaths annually. Although great progress has been made in the diagnosis and treatment of prostate cancer during the past several decades, much about this disease remains unknown, especially its pathobiology. The kinesin superfamily is a pivotal group of motor proteins, that contains a microtubule-based motor domain and features an adenosine triphosphatase activity and motility characteristics. Large-scale sequencing analyses based on clinical samples and animal models have shown that several members of the kinesin family are dysregulated in prostate cancer. Abnormal expression of kinesins could be linked to uncontrolled cell growth, inhibited apoptosis and increased metastasis ability. Additionally, kinesins may be implicated in chemotherapy resistance and escape immunologic cytotoxicity, which creates a barrier to cancer treatment. Here we cover the recent advances in understanding how kinesins may drive prostate cancer progression and how targeting their function may be a therapeutic strategy. A better understanding of kinesins in prostate cancer tumorigenesis may be pivotal for improving disease outcomes in prostate cancer patients.

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.

Research hotspots of prostate cancer at the international conferences on urology in 2022. / 2022å¹´æ³Œå°¿å¤–ç§‘å›½é™ ä¼šè®®å‰åˆ—è ºç™Œç›¸å ³ç ”ç©¶çƒ­ç‚¹.

The American Urological Association (AUA), European Association of Urology (EUA) and International Urological Society (SIU) annual meetings were held in 2022. Studies on prostate cancer reported in the meetings mainly focus on the advances of diagnostic biomarkers (such as α-2, 3-1inked sialylation of terminal N-glycan on free PSA density, SelectMDx) and imaging techniques [such as multiparametric magnetic resonance imaging, prostate specific membrane antigen(PSMA)-PET/CT], the new method for prostate biopsy, the new treatments of prostate cancer including [177Lu] Ludotadipep and DROP-IN PSMA probe, and the prognosis assessment of prostate cancer (such as AR-V7). This article provides an overview on the research hotspots of three international academic meetings.

A robust activatable two-photon fluorescent probe for endogenous formaldehyde biomarker visualization diagnosis and evaluation of diabetes mellitus.

Diabetes mellitus and its complications are one of the largest healthcare burdens in the world and are increasing every year. However, the lack of effective biomarkers and non-invasive real-time monitoring tools remains a great challenge for the early diagnosis of diabetes mellitus. Endogenous formaldehyde (FA) represents a key reactive carbonyl species in biological systems, and altered metabolism and functions of FA have been closely related to the pathogenesis and maintenance of diabetes. Among various noninvasive biomedical imaging techniques, the identification-responsive fluorescence (FL) imaging could greatly benefit the comprehensive multi-scale assessment of some diseases such as diabetes. Herein, we have designed a robust activatable two-photon probe DM-FA for the first highly selective monitoring of fluctuations in FA levels during diabetes mellitus. Through the density functional theory (DFT) theoretical calculations, we elucidated the rationality of the activatable fluorescent probe DM-FA turning on the FL before and after the reaction with FA. In addition, DM-FA has excellent high selectivity, high growth factor and good photostability in the process of recognizing FA. Due to the brilliant two-photon and one-photon FL imaging capabilities of DM-FA, it has been successfully used to visualize of exogenous and endogenous FA in cells and mice. Remarkably, as a powerful FL imaging visualization tool, DM-FA was introduced for the first time to visually diagnose and explore diabetes through the fluctuation of FA content. The successful application of DM-FA in two-photon and one-photon FL imaging experiments found elevated FA levels in high glucose-stimulated diabetic cell models. We successfully visualized upregulation of FA levels in diabetic mice and decreased of FA levels in diabetic mice scavenged by NaHSO3 from multiple perspectives using multiple imaging modalities. This work may provide a novel strategy for the initial diagnosis of diabetes mellitus and the evaluation of the efficacy of drug therapy for treating diabetes mellitus, which will likely have a positive impact on clinical medicine.

A prospective multi-center randomized comparative trial evaluating outcomes of transrectal ultrasound (TRUS)-guided 12-core systematic biopsy, mpMRI-targeted 12-core biopsy, and artificial intelligence ultrasound of prostate (AIUSP) 6-core targeted biopsy for prostate cancer diagnosis.

BACKGROUND: Artificial intelligence ultrasound of prostate (AIUSP)-targeted biopsy has been used for prostate cancer (PCa) diagnosis. The objective of this prospective multi-center head-to-head clinical randomized comparative trail (RCT) is to compare PCa detection rate in the TRUS-guided 12-core standard systematic biopsy (TRUS-SB) group and cognitive fused mpMRI-guided 12-core biopsy (mpMRI) group against AIUSP group. METHODS: Four hundred patients were randomized to three arms and underwent biopsies by TRUS-SB (n = 133), mpMRI (n = 134), and AIUSP (n = 133) between January 2015 and December 2017. In TRUS-SB group, a standard 12-core systematic biopsy was performed. In mpMRI group, mpMRI-suspicious lesions (PI-RADS 3-5) were targeted by 2-core biopsy followed by a 10-core systematic biopsy. Otherwise, 12-core systematic biopsy was performed. In AIUSP group, a 6-core targeted biopsy was performed. The primary endpoint was PCa detection rate. RESULTS: AIUSP detected the highest rate of PCa (66/133, 49.6%) compared to TRUS-SB (46/133, 34.6%, p = 0.036) and mpMRI (48/134, 35.8%, p = 0.052). Compared to TRUS-SB (35/133, 26.3%) and mpMRI (31/134, 23.1%) groups, clinically significant PCa (csPCa) detection rate was 32.3% (43/133) in AIUSP group. Overall biopsy core positive rate in the TRUS-SB group (11.0%, 176/1598) and in the mpMRI group (12.7%, 204/1608) was significantly lower than that in the AIUSP group (22.7%, 181/798, p < 0.001). CONCLUSIONS: AIUSP detected the highest rate of overall and significant PCa compared to TRUS-SB and mpMRI, and could be used as an alternative to systematic biopsy in the future. REGISTRATION: This trial was registered in ISRCTN (ISRCTN18033113).

In vivo confocal microscopy of sub-basal corneal nerves and corneal densitometry after three kinds of refractive procedures for high myopia.

PURPOSE: To observe corneal nerve fibers and densitometry after small incision lenticule extraction (SMILE), femtosecond laser-assisted laser in situ keratomileusis (FS-LASIK) and laser-assisted subepithelial keratomileusis (LASEK) for high myopia. METHODS: This is a prospective, cross-sectional research study. Patients with high myopia (equivalent spherical lens: -6.00 and -11.00D) who underwent laser corneal refractive surgery were divided into three groups: SMILE, FS-LASIK and LASEK. Scheimpflug imaging of corneal nerves in five areas was observed by confocal microscopy before and 6, 12 months after surgery. Corneal densitometry was measured by Pentacam anterior segment analysis system. RESULTS: Overall, 59 patients were enrolled. The nerve density in the central area did not recover to the preoperative level in three groups until 12 months. The density and length of corneal nerves in central and lower area were better in the SMILE group 6 months postoperatively (p = 0.01), while nerve density did not differ significantly among three groups 12 months postoperatively (p = 0.18). Nerve fibers in central and temporal region were wider in LASEK than that in other two groups at 6- and 12-month follow-up. Corneal densitometry in the central 6 mm diameter was significantly higher in the LASEK group compared with other two groups 6 months postoperatively (p = 0.04). Twelve months postoperatively, corneal densitometry in range of all zone was lower in SMILE than in FS-LASIK and LASEK (p = 0.01, 0.03, 0.04). CONCLUSIONS: Compared with FS-LASIK and LASEK, SMILE-treated eyes with high myopia had certain advantages in nerve density, length and nerve connection way and had better corneal transparency after operation.

Multifunctional chitosan/gelatin@tannic acid cryogels decorated with in situ reduced silver nanoparticles for wound healing.

Background: Most traditional wound dressings only partially meet the needs of wound healing because of their single function. Patients usually suffer from the increasing cost of treatment and pain resulting from the frequent changing of wound dressings. Herein, we have developed a mutifunctional cryogel to promote bacterial infected wound healing based on a biocompatible polysaccharide. Methods: The multifunctional cryogel is made up of a compositive scaffold of chitosan (CS), gelatin (Gel) and tannic acid (TA) and in situ formed silver nanoparticles (Ag NPs). A liver bleeding rat model was used to evaluate the dynamic hemostasis performance of the various cryogels. In order to evaluate the antibacterial properties of the prepared cryogels, gram-positive bacterium Staphylococcus aureus (S. aureus) and gram-negative bacterium Escherichia coli (E. coli) were cultured with the cryogels for 12 h. Meanwhile, S. aureus was introduced to cause bacterial infection in vivo. After treatment for 2 days, the exudates from wound sites were dipped for bacterial colony culture. Subsequently, the anti-inflammatory effect of the various cryogels was evaluated by western blotting and enzyme-linked immunosorbent assay. Finally, full-thickness skin defect models on the back of SD rats were established to assess the wound healing performances of the cryogels. Results: Due to its porous structure, the multifunctional cryogel showed fast liver hemostasis. The introduced Ag NPs endowed the cryogel with an antibacterial efficiency of >99.9% against both S. aureus and E. coli. Benefited from the polyphenol groups of TA, the cryogel could inhibit nuclear factor-κB nuclear translocation and down-regulate inflammatory cytokines for an anti-inflammatory effect. Meanwhile, excessive reactive oxygen species could also be scavenged effectively. Despite the presence of Ag NPs, the cryogel did not show cytotoxicity and hemolysis. Moreover, in vivo experiments demonstrated that the biocompatible cryogel displayed effective bacterial disinfection and accelerated wound healing. Conclusions: The multifunctional cryogel, with fast hemostasis, antibacterial and anti-inflammation properties and the ability to promote cell proliferation could be widely applied as a wound dressing for bacterial infected wound healing.

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.

Novel Prognosis and Therapeutic Response Model of Immune-Related lncRNA Pairs in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common type of renal carcinoma. It is particularly important to accurately judge the prognosis of patients. Since most tumor prediction models depend on the specific expression level of related genes, a better model therefore needs to be constructed. To provide an immune-related lncRNA (irlncRNAs) tumor prognosis model that is independent of the specific gene expression levels, we first downloaded and sorted out the data on ccRCC in the TCGA database and screened irlncRNAs using co-expression analysis and then obtained the differently expressed irlncRNA (DEirlncRNA) pairs by means of univariate analysis. In addition, we modified LASSO penalized regression. Subsequently, the ROC curve was drawn, and we compared the area under the curve, calculated the Akaike information standard value of the 5-year receiver operating characteristic curve, and determined the cut-off point to establish the best model to distinguish the high- or low-disease-risk group of ccRCC. Subsequently, we reassessed the model from the perspectives of survival, clinic-pathological characteristics, tumor-infiltrating immune cells, chemotherapeutics efficacy, and immunosuppressed biomarkers. A total of 17 DEirlncRNAs pairs (AL031710.1|AC104984.5, AC020907.4|AC127-24.4,AC091185.1|AC005104.1, AL513218.1|AC079015.1, AC104564.3|HOXB-AS3, AC003070.1|LINC01355, SEMA6A-AS1|CR936218.1, AL513327.1|AS005785.1, AC084876.1|AC009704.2, IGFL2-AS1|PRDM16-DT, AC011462.4|MMP25-AS1, AL662844.3I|TGB2-AS1, ARHGAP27P1|AC116914.2, AC093788.1|AC007098.1, MCF2L-AS1|AC093001.1, SMIM25|AC008870.2, and AC027796.4|LINC00893) were identified, all of which were included in the Cox regression model. Using the cut-off point, we can better distinguish patients according to different factors, such as survival status, invasive clinic-pathological features, tumor immune infiltration, whether they are sensitive to chemotherapy or not, and expression of immunosuppressive biomarkers. We constructed the irlncRNA model by means of pairing, which can better eliminate the dependence on the expression level of the target genes. In other words, the signature established by pairing irlncRNA regardless of expression levels showed promising clinical prediction value.

Development of an activatable hydrogen sulfide-specific two-photon fluorescent probe for bioimaging in an air pouch inflammation model.

Inflammation caused by traumatic, ischemic, infectious, autoimmune or toxic injury may further trigger cancer and even death. Overexpression of hydrogen sulfide (H2S) in vivo has been identified as a biomarker for various types of inflammation. Identification-responsive fluorescence imaging probes have broad application prospects for in vivo diagnosis of inflammation. However, it is a challenge to design an imaging probe that concurrently responds to the target molecules to improve the sensitivity and specificity of inflammation detection. Herein, we designed and synthesized an activatable two-photon fluorescent probe to detect H2S. Fl-H2S had high selectivity, excellent photostable signals and low detection limit for recognizing H2S. In addition, Fl-H2S showed excellent two-photon fluorescence properties in cell and liver tissue visualization experiments, with a penetration depth of up to 126 µm in liver tissue. Most importantly, the unique probe Fl-H2S was the first probe to monitor H2S levels in a mouse air pouch inflammation model by fluorescence imaging technology. We expect Fl-H2S to become an effective tool for longitudinal monitoring of inflammation, diagnosis of inflammation and prediction of underlying pathogenesis of related diseases by detecting H2S.

SMAD3 and FTO are involved in miR-5581-3p-mediated inhibition of cell migration and proliferation in bladder cancer.

Previous research evidence suggests that microRNAs (miRNAs) play an indispensable role in onset and progression of bladder cancer (BCa). Here, we explored the functions and mechanisms of miR-5581-3p in BCa. miR-5581-3p, as a tumor suppressor in BCa, was detected at a lower expression level in BCa tissue and cells in contrast with the non-malignant bladder tissue and cells. Over-expression of miR-5581-3p remarkably dampened the migration and proliferation of BCa in vitro and in vivo. SMAD3 and FTO were identified as the direct targets of miR-5581-3p by online databases prediction and mRNA-seq, which were further verified. SMAD3 as a star molecule in modulating EMT progress of BCa had been formulated in former studies. Meanwhile, FTO proved as an N6-methyladenosine (m6A) demethylase in decreasing m6A modification was confirmed to regulate the migration and proliferation in BCa. In addition, we conducted rescue experiments and confirmed overexpressing miR-5581-3p partially rescued the effects of the overexpressing SMAD3 and FTO in BCa cells. In conclusion, our studies exhibit that miR-5581-3p is a novel tumor inhibitor of BCa.

Fe(III)-Chelated Polydopamine Nanoparticles for Synergistic Tumor Therapies of Enhanced Photothermal Ablation and Antitumor Immune Activation.

Both the low energy density of near-infrared (NIR) photothermal conversion during treatment and the recurrence and metastasis after local treatment have been the main obstacles and conundrums in polydopamine-mediated tumor photothermal therapy (PTT). Herein, On the basis of the enhancement of NIR absorption by ligand to metal charge transfer (LMCT) in transition-metal complexes and the activation of antitumor immunity by an appropriate concentration of Fe(III) ions, Fe(III)-chelated PDA nanoparticles (Fe-PDA NPs) with high loading and responsive release of iron ions were synthesized through a prechelation-polymerization method. First, Fe(III) chelated with the catechol groups in DA to form a mono-dopa-Fe(III) chelate, and then the polymerization of dopamine was initiated under alkaline conditions. The results revealed that the mono-dopa-Fe(III) chelate was still the main form of the Fe ion existing in Fe-PDA and was able to greatly enhance the light absorption behaviors of PDA in NIR, resulting a superior photothermal conversion ability (η = 55.5%). Moreover, the existence of Fe(III) also gave Fe-PDA a T1-weighted MRI contrast-enhancement performance (r1 = 7.668 mM-1 s-1) and it would enable the accurate ablation of primary tumors in vivo with Fe-PDA under NIR irradiation by means of the guidance of MRI and thermal imaging. Furthermore, Fe-PDA exhibited better H2O2-responsive biodegradability in comparison to PDA and easily released Fe ions in tumors, which could effectively promote the tumor-associated macrophage (TAM) repolarization to the M1 mode. TAM repolarization combined with the immunogenic cell death (ICD) induced by PTT could effectively enhance the efficacy of immunotherapy, preventing tumor recurrence and metastasis. The design of Fe-PDA nanoparticles should provide more inspiration for structural and functional improvements of melanin-based materials in tumor suppression.

Early Diagnosis and Treatment of Nine Patients with Severe Multiple Injuries Accompanied by Traumatic Aortic Dissection during Emergency Treatment.

Objective: This study is aimed at investigating the early diagnosis and efficacy of emergency treatments of nine patients with severe multiple injuries accompanied by traumatic aortic dissection (TAD). Methods: Patients who sustained severe multiple injuries accompanied by TAD following a car accident (n = 6) and falls from a height (n = 3) were treated in the emergency department of our hospital from October 2017 to July 2021. Data of these patients, including seven men and two women (average age, 53 ± 15.2 years; range, 18-83 years) were analysed retrospectively. Upon hospital arrival, the multidisciplinary treatment (MDT) trauma team, composed of doctors and nurses, immediately performed resuscitation following the Green Channel Consultation and Treatment Process for Severe Multiple Injuries. Life-threatening injuries were managed urgently. Blood tests and blood preparation and bedside B-scan ultrasonography and CT were performed. Aortic computed tomography angiography (CTA) was conducted decisively in patients suspected of TAD so that endovascular graft exclusion (EVGE) with the aortic covered stent can be performed promptly, followed by emergency management, second-stage surgery, and intensive care according to the injury control strategy. Results: This study included nine patients suffering from severe multiple injuries accompanied by Stanford type B TAD, with injury severity scores ranging from 35 to 43 points. Six patients underwent EVGE while receiving emergency treatment, whereas two patients who also had intracranial haemorrhage underwent selective EVGE. One case of TAD missed in the emergency department was detected 13 days after hospitalisation; therefore, the patient promptly underwent EVGE. Emergency procedures performed included exploratory laparotomy and splenectomy (n = 2), thoracic closed drainage (n = 5), haemothoracotomy (n = 3), second-stage fracture surgery (n = 4), and tracheotomy (n = 1). Postinjury complications included haemorrhagic shock, coagulation disorders, hyoxaemia, pulmonary infection, renal insufficiency, and hypoproteinaemia; however, all patients recovered after intensive care treatment. Aortic CTA after EVGE revealed the disappearance of the dissection and the resorption of the intermural haematoma. However, varying degrees of stenosis or occlusion were observed in the left subclavian artery. Nine patients with severe multiple injuries were treated satisfactorily by the MDT, without fatalities, and all patients were discharged for rehabilitation. Conclusion: In this study, procedures including resuscitation, urgent aortic CTA for definitive diagnosis, prompt EVGE, emergency injury control surgery, second-stage definitive surgery, intensive care treatment, and rehabilitation were rationally performed by the emergency MDT trauma team. Overall, this continuous and seamless process is a key factor for the successful treatment of patients with severe multiple injuries accompanied by TAD.

Highly efficient enrichment of intact phosphoproteins by a cadmium ion-based co-precipitation strategy.

Selective separation and enrichment of phosphoproteins are essential for understanding their important functions in almost all cellular processes. Here, taking advantage of the feature that cadmium ion (Cd2+ ) has an overwhelming preference for phosphates, we developed a robust and simple Cd2+ co-precipitation strategy for the selective isolation of intact phosphoproteins. After evaluating the feasibility of Cd2+ in phosphoprotein precipitation, we compared the washing protocols for the removal of non-specific binding proteins and then used the best-performing protocol for the isolation of phosphoproteins from different complex samples. It was found that phosphoproteins can be specifically enriched from artificial protein mixtures containing α-casein, ß-casein, and bovine serum albumin or plasma, in which bovine serum albumin or plasma were served as interferences with very high molar ratios. Applying this method to enrich phosphoproteins from complex cell lysates, a high specificity was confirmed by western blotting analysis with a phosphoprotein-specific kit. Finally, we successfully applied this method to the purification of caseins from drinking milk, highlighting its potential application in the studies where purified phosphoproteins were required. In a word, this Cd2+ co-precipitation method enables universal and effective capture, enrichment, and detection of intact phosphoproteins, making it a powerful tool for the comprehensive analysis of the phosphoproteome.

The Regulatory Role of RNA Metabolism Regulator TDP-43 in Human Cancer.

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.

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.

MicroRNA-501-3p inhibits the proliferation of kidney cancer cells by targeting WTAP.

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 (m6 A) 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 m6 A 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.

Ion release behavior of vanadium-doped mesoporous bioactive glass particles and the effect of the released ions on osteogenic differentiation of BMSCs via the FAK/MAPK signaling pathway.

Vanadium is an important trace element in bone and is involved in bone metabolism, bone formation, and bone growth, but the roles of various vanadium ions, especially of pentavalent vanadium, in bone tissue regenerative repair have been underestimated and even misinterpreted for a long time. The main purposes of this study are to investigate the release profile of Si, Ca, P, and V ions from vanadium doped mesoporous bioactive glass (V-MBG) particles and to explore the effect of pentavalent vanadium ions on proliferation and osteogenic differentiation of BMSCs as well as the corresponding osteogenic signaling pathway. On the basis of preparations of V-MBG particles with different pentavalent vanadium contents, the ion release behavior from V-MBG in distilled water and simulated body fluid was systemically investigated. Furthermore, the cytocompatibility and osteogenic effect of V-MBG extracts were studied in rBMSCs, and the related molecular mechanisms were preliminarily discussed. The results of dissolution experiments showed that the V ionic concentration exhibited a burst increase and then a sustained slow increase in the two media. The resultant V ions from 1.0V-MBG, 4.0V-MBG and 10.0V-MBG at 21 days were about 1.1, 5.8, and 12.5 mg L-1 in water, respectively, and 1.6, 4.8 and 12.8 mg L-1 in SBF, respectively. The release behaviors of Si, Ca, P, and V ions were evidently affected by high contents of incorporated vanadium. The cellular results indicated that compared to the control and MBG groups, the V(V) ions in V-MBG extracts at about 19.4 µM markedly promoted the proliferation, the gene and protein expression of BMP-2 and COL-I, and the ALP activity of rBMSCs in non-osteoinductive media, but insignificantly stimulated the OCN protein synthesis. More deeply, V(V) ions at about 19.4 µM significantly upregulated the gene and protein expressions of Itga 2b, FAK, and pERK1/2, demonstrating that V(V) ions could regulate osteogenic differentiation of rBMSCs through the activation of the Itga 2b-FAK-MAPK (pERK1/2) signaling pathway. The in vivo results further confirmed that V-MBG induced and promoted new bone formation in the defect area compared to the PGC and PGC/V-M0 groups. These results would contribute to modify the perception about the biocompatibility and osteogenic promotion of pentavalent vanadium at an appropriate concentration.

Comprehensive Analysis of Ferroptosis Regulators With Regard to PD-L1 and Immune Infiltration in Clear Cell Renal Cell Carcinoma.

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.