Negative Correlation of Serum Total Bile Acid With Albuminuria in Patients With Type 2 Diabetes Mellitus: A Cross-sectional Study.

Context: The treatment of diabetic nephropathy (DN) is still quite limited. DN remains poorly understood due to the complexity of and differences in its etiology. Therefore, potential biomarkers for diagnosis and targeted treatments are urgently needed. Objective: The study aimed to analyze the associations between circulating total bile acid (TBA) levels and the risk of DN in Chinese patients with type 2 diabetes mellitus (T2DM) and to determine the differences in the TBA levels of males and females, including pre- and postmenopausal women, to find clues for the screening of DN. Design: The research team performed a retrospective study. Setting: The study took place at the Second Affiliated Hospital at the School of Medicine of Zhejiang University in Zhejiang, China. Participants: Participants were 1785 T2DM patients admitted to the hospital between April 2008 and November 2013. Groups: The research team separated participants into three groups: (1) the normoalbuminuria or normal group, with a UACR <30 mg/g·Cr (2) the microalbuminuria (MAU) group, with a UACR of 30-299 mg/g·Cr; and (3) the macroalbuminuria (MAC) group, with a UACR of ≥300 mg/g·Cr. Outcome Measures: Between the three groups, the research team compared: (1) the demographic and clinic characteristics of the normal, MAU, and MAC groups; (2) TBA distribution by age; (3) TBA distribution by gender; and (4) TBA quartiles. The team also examined the associations between TBA and albuminuria, identifying the odds ratios (OR) and relevant 95% confidence intervals (CI) using multiple logistic regression. Results: The study found that: (1) the MAC group's TBA was significantly lower than those of the normal and MAU groups; (2) the TBA of postmenopausal women was significantly higher than that of premenopausal women; (3) the incidence of MAC was obviously increased with TBA levels; (4) the risks for MAU group didn't change significantly with increasing TBA levels; (5) the MAC group's odds ratios (ORs) were 0.61 between Q2 and Q1, 0.44 between Q3 and Q1, and 0.38 between Q4 and Q1; and (6) for men and postmenopausal women, the TBA levels of those in Q3 and Q4 might decrease the risk of MAC, whereas no such correlation existed for MAU. Conclusions: An independent negative association exists between TBA levels and MAC in T2DM. The decrease of circulating TBA might be a prospective clinical factor for determining established DN, especially for males and postmenopausal females.

N6-methyladenosine-modified TRAF1 promotes sunitinib resistance by regulating apoptosis and angiogenesis in a METTL14-dependent manner in renal cell carcinoma.

BACKGROUND: Sunitinib resistance can be classified into primary and secondary resistance. While accumulating research has indicated several underlying factors contributing to sunitinib resistance, the precise mechanisms in renal cell carcinoma are still unclear. METHODS: RNA sequencing and m6A sequencing were used to screen for functional genes involved in sunitinib resistance. In vitro and in vivo experiments were carried out and patient samples and clinical information were obtained for clinical analysis. RESULTS: We identified a tumor necrosis factor receptor-associated factor, TRAF1, that was significantly increased in sunitinib-resistant cells, resistant cell-derived xenograft (CDX-R) models and clinical patients with sunitinib resistance. Silencing TRAF1 increased sunitinib-induced apoptotic and antiangiogenic effects. Mechanistically, the upregulated level of TRAF1 in sunitinib-resistant cells was derived from increased TRAF1 RNA stability, which was caused by an increased level of N6-methyladenosine (m6A) in a METTL14-dependent manner. Moreover, in vivo adeno-associated virus 9 (AAV9) -mediated transduction of TRAF1 suppressed the sunitinib-induced apoptotic and antiangiogenic effects in the CDX models, whereas knockdown of TRAF1 effectively resensitized the sunitinib-resistant CDXs to sunitinib treatment. CONCLUSIONS: Overexpression of TRAF1 promotes sunitinib resistance by modulating apoptotic and angiogenic pathways in a METTL14-dependent manner. Targeting TRAF1 and its pathways may be a novel pharmaceutical intervention for sunitinib-treated patients.

Roles of N6 -methyladenosine (m6 A) RNA modifications in urological cancers.

Epigenetics has long been a hot topic in the field of scientific research. The scope of epigenetics usually includes chromatin remodelling, DNA methylation, histone modifications, non-coding RNAs and RNA modifications. In recent years, RNA modifications have emerged as important regulators in a variety of physiological processes and in disease progression, especially in human cancers. Among the various RNA modifications, m6 A is the most common. The function of m6 A modifications is mainly regulated by 3 types of proteins: m6 A methyltransferases (writers), m6 A demethylases (erasers) and m6 A-binding proteins (readers). In this review, we focus on RNA m6 A modification and its relationship with urological cancers, particularly focusing on its roles and potential clinical applications.

METTL3/YTHDF2 m6 A axis promotes tumorigenesis by degrading SETD7 and KLF4 mRNAs in bladder cancer.

N6-Methyladenosine (m6 A) modification, the most prevalent modification of eukaryotic messenger RNA (mRNA), is involved in the progression of various tumours. However, the specific role of m6 A in bladder cancer (BCa) is still poorly understood. In this study, we demonstrated the tumour-promoting function and specific regulatory mechanism of m6 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, m6 A methylated RNA immunoprecipitation (MeRIP) and RIP, we determined that the METTL3/YTHDF2 m6 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 m6 A axis. Thus, our findings on the METTL3/YTHDF2/SETD7/KLF4 m6 A axis provide the insight into the underlying mechanism of carcinogenesis and highlight potential therapeutic targets for BCa.

YTHDF2 mediates the mRNA degradation of the tumor suppressors to induce AKT phosphorylation in N6-methyladenosine-dependent way in prostate cancer.

BACKGROUND: N6-methyladenosine (m6A) is the most abundant modification in mRNA of humans. Emerging evidence has supported the fact that m6A is comprehensively involved in various diseases especially cancers. As a crucial reader, YTHDF2 usually mediates the degradation of m6A-modified mRNAs in m6A-dependent way. However, the function and mechanisms of m6A especially YTHDF2 in prostate cancer (PCa) still remain elusive. METHODS: To investigate the functions and mechanisms of YTHDF2 in PCa, in vitro, in vivo biofunctional assays and epigenetics experiments were performed. Endogenous expression silencing of YTHDF2 and METTL3 was established with lentivirus-based shRNA technique. Colony formation, flow cytometry and trans-well assays were performed for cell function identifications. Subcutaneous xenografts and metastatic mice models were combined with in vivo imaging system to investigate the phenotypes when knocking down YTHDF2 and METTL3. m6A RNA immunoprecipitation (MeRIP) sequencing, mRNA sequencing, RIP-RT-qPCR and bioinformatics analysis were mainly used to screen and validate the direct common targets of YTHDF2 and METTL3. In addition, TCGA database was also used to analyze the expression pattern of YTHDF2, METTL3 and the common target LHPP in PCa, and their correlation with clinical prognosis. RESULTS: The upregulated YTHDF2 and METTL3 in PCa predicted a worse overall survival rate. Knocking down YTHDF2 or METTL3 markedly inhibited the proliferation and migration of PCa in vivo and in vitro. LHPP and NKX3-1 were identified as the direct targets of both YTHDF2 and METTL3. YTHDF2 directly bound to the m6A modification sites of LHPP and NKX3-1 to mediate the mRNA degradation. Knock-down of YTHDF2 or METTL3 significantly induced the expression of LHPP and NKX3-1 at both mRNA and protein level with inhibited phosphorylated AKT. Overexpression of LHPP and NKX3-1 presented the consistent phenotypes and AKT phosphorylation inhibition with knock-down of YTHDF2 or METTL3. Phosphorylated AKT was consequently confirmed as the downstream of METTL3/YTHDF2/LHPP/NKX3-1 to induce tumor proliferation and migration. CONCLUSION: We propose a novel regulatory mechanism in which YTHDF2 mediates the mRNA degradation of the tumor suppressors LHPP and NKX3-1 in m6A-dependent way to regulate AKT phosphorylation-induced tumor progression in prostate cancer. We hope our findings may provide new concepts of PCa biology.

Dual regulatory role of CCNA2 in modulating CDK6 and MET-mediated cell-cycle pathway and EMT progression is blocked by miR-381-3p in bladder cancer.

Emerging evidence has elucidated that microRNAs (miRNAs) transcribed from miRNA cluster at DLK-DIO3 imprinted domain are involved in various cancers. However, as one member of this cluster, the underlying mechanisms and functions of miR-381-3p in bladder cancer (BCa) still remains elusive. Here we demonstrate that the hypermethylated status of upstream maternally expressed gene 3 divergent methylation region reduces the expression of miR-381-3p in BCa by bisulfite-sequencing PCR. In vitro and in vivo experiments indicate that overexpression of miR-381-3p significantly inhibits cell proliferation via inducing G1 phase arrest and migration via down-regulating MET and CCNA2 induced EMT progression. CDK6/CCNA2/MET are all identified as the direct targets of miR-381-3p by bioinformatics analysis and dual-luciferase reporter assay. Furthermore, inhibition of CCNA2 mediated by miR-381-3p as the crucial biregulator not only participates in the proliferation regulation with CDK6 in cell cycle but also modulates the EMT progression via ROCK/AKT/ß-catenin/SNAIL pathway, which establishes an EMT circuit combined with miR-381-3p/MET/AKT/GSK-3ß/SNAIL pathway, and SNAIL is the last confocal target to induce EMT progression. To conclude, we propose 2 novel regulatory circuits mediated by miR-381-3p in BCa, which may assist in the development of more effective therapies against BCa in the future.-Li, J., Ying, Y., Xie, H., Jin, K., Yan, H., Wang, S., Xu, M., Xu, X., Wang, X., Yang, K., Zheng, X., Xie, L. Dual regulatory role of CCNA2 in modulating CDK6 and MET-mediated cell-cycle pathway and EMT progression is blocked by miR-381-3p in bladder cancer.

The dual role of N6-methyladenosine modification of RNAs is involved in human cancers.

As the most abundant and reversible RNA modification in eukaryotic cells, m6 A triggers a new layer of epi-transcription. M6 A modification occurs through a methylation process modified by "writers" complexes, reversed by "erasers", and exerts its role depending on various "readers". Emerging evidence shows that there is a strong association between m6 A and human diseases, especially cancers. Herein, we review bi-aspects of m6 A in regulating cancers mediated by the m6 A-associated proteins, which exert vital and specific roles in the development of various cancers. Generally, the m6 A modification performs promotion or inhibition functions (dual role) in tumorigenesis and progression of various cancers, which suggests a new concept in cancer regulations. In addition, m6 A-targeted therapies including competitive antagonists of m6 A-associated proteins may provide a new tumour intervention in the future.

m6Am Methyltransferase PCIF1 Promotes LPP3 Mediated Phosphatidic Acid Metabolism and Renal Cell Carcinoma Progression.

N6-methyl-2'-O-methyladenosine (m6Am), occurring adjacent to the 7-methylguanosine (m7G) cap structure and catalyzed by the newly identified writer PCIF1 (phosphorylated CTD interacting factor 1), has been implicated in the pathogenesis of various diseases. However, its involvement in renal cell carcinoma (RCC) remains unexplored. Here, significant upregulation of PCIF1 and m6Am levels in RCC tissues are identified, unveiling their oncogenic roles both in vitro and in vivo. Mechanically, employing m6Am-Exo-Seq, LPP3 (phospholipid phosphatase 3) mRNA is identified as a key downstream target whose translation is enhanced by m6Am modification. Furthermore, LPP3 is revealed as a key regulator of phosphatidic acid metabolism, critical for preventing its accumulation in mitochondria and facilitating mitochondrial fission. Consequently, Inhibition of the PCIF1/LPP3 axis significantly altered mitochondrial morphology and reduced RCC tumor progression. In addition, depletion of PCIF1 sensitizes RCC to sunitinib treatment. This study highlights the intricate interplay between m6Am modification, phosphatidic acid metabolism, and mitochondrial dynamics, offering a promising therapeutic avenue for RCC.

Effects of contrasting N-enriched biochar applications on paddy soil and rice leaf phosphorus fractions in subtropical China.

Biochar has been proved to be an important soil amendment to alleviate soil phosphorus (P) in the paddy crops. However, the role of specially prepared biochar (N-enriched biochar) on the distribution and transformation of P soil in and rice leaves needs to be revealed. In this study, we studied in a field experiment the effects of two different levels of application of N-enriched biochar on the P fractions of soil and leaves. The results showed that: (1) in early rice, both rates of N-enriched biochar increased soil concentrations of labile inorganic P (Pi) (+51.5 % and +66.2 %, respectively) and labile organic P (Po) (+167 % and + 76.9 %, respectively) and moderately labile Pi (+37.8 % and +27.8 %, respectively) and decreased soil concentration of moderately labile Po (-17.0 % and -52.7 %, respectively) in the 0-15 cm layer. Soil total P concentration was positively correlated with soil labile P fractions and moderately labile Pi concentrations (p < 0.05); (2) in early and late rice, application of the biochar at 4 t ha-1 increased rice leaf concentration of inorganic (+13.3 % and +34.8 %, respectively), nucleic acid (+24.2 % and +13.0 %, respectively) (p < 0.05). The foliar inorganic and nucleic acid P concentrations were positively correlated with foliar total P concentrations; (3) redundancy analysis showed that with the application of N-enriched biochar, soil total carbon (C), nitrogen (N) and P concentration were important factors affecting the chemical forms of soil P, while soil organic matter, soil total P and leaf total P content were important factors affecting the chemical forms of leaf P; (4) allometric growth models showed that under the application of N-enriched biochar, 0-30 cm soil labile Po concentration was positively related to leaf concentration of nucleic acid P, 0-15 cm soil moderately labile Pi concentration was positively related to leaf concentration of inorganic P and nucleic acid P. Thus, this study provides evidence that N-enriched biochar increase the soil P-availability of labile and moderately labile P that in turn improved rice plants P use efficiency.

Ligand-dependent CD36 functions in cancer progression, metastasis, immune response, and drug resistance.

CD36, a multifunctional glycoprotein, has been shown to play critical roles in tumor initiation, progression, metastasis, immune response, and drug resistance. CD36 serves as a receptor for a wide range of ligands, including lipid-related ligands (e.g., long-chain fatty acid (LCFA), oxidized low-density lipoprotein (oxLDL), and oxidized phospholipids), as well as protein-related ligands (e.g., thrombospondins, amyloid proteins, collagens I and IV). CD36 is overexpressed in various cancers and may act as an independent prognostic marker. While it was initially identified as a mediator of anti-angiogenesis through its interaction with thrombospondin-1 (TSP1), recent research has highlighted its role in promoting tumor growth, metastasis, drug resistance, and immune suppression. The varied impact of CD36 on cancer is likely ligand-dependent. Therefore, we focus specifically on the ligand-dependent role of CD36 in cancer to provide a critical review of recent advances, perspectives, and challenges.

Exosome-derived circTFDP2 promotes prostate cancer progression by preventing PARP1 from caspase-3-dependent cleavage.

BACKGROUND: Circular RNAs (circRNAs) have been reported to play a significant role in tumorigenesis. However, the detailed function of circRNA in prostate cancer (PCa) is still largely unknown. METHODS: We quantified circTFDP2 expression in PCa tissues and adjacent normal tissues using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Colony formation, Cell Counting Kit-8 (CCK-8), flow cytometry, transwell, and in vivo progression and metastasis assays were applied to reveal the proliferation and metastatic abilities of circTFDP2 in PCa cells. Mass spectrometry, RNA pulldown, RNA-immunoprecipitation (RIP), western blotting and immunofluorescence were used for the mechanistic studies. qRT-PCR and RIP assays were used to explore the regulatory role of eIF4A3 in the biogenesis of circTFDP2. Finally, functional assays showed the effect of circTFDP2-containing exosomes on PCa cell progression. RESULTS: circTFDP2 was upregulated in PCa tissues compared with adjacent normal tissues. Furthermore, high circTFDP2 expression was positively correlated with the Gleason score. Functionally, circTFDP2 promoted PCa cell proliferation and metastasis both in vivo and in vitro. Mechanistically, circTFDP2 interacted with poly(ADP-ribose) polymerase 1 (PARP1) protein in its DNA-binding domain to prevent it from active caspase-3-dependent cleavage, and finally relieved PCa cells from DNA damage. In addition, RNA-binding protein eIF4A3 can interact with the flanking region of circTFDP2 and promote the biogenesis of circTFDP2. Moreover, exosome-derived circTFDP2 promoted PCa cell progression. CONCLUSIONS: In general, our study demonstrated that circTFDP2 promoted PCa cell progression through the PARP1/DNA damage axis, which may be a promising therapeutic target for PCa.

Exosomes in Genitourinary Cancers: Emerging Mediators of Drug Resistance and Promising Biomarkers.

Drug resistance presents a major obstacle in the treatment of genitourinary cancers. Exosomes as the medium of intercellular communication serve important biological functions and play essential roles in pathological processes, including drug response. Through the transfer of bioactive cargoes, exosomes can modulate drug resistance via multiple mechanisms. This review attempts to elucidate the mechanisms of exosomal cargoes with reference to tumor drug resistance, their role in genitourinary cancers, and their potential clinical applications as candidate biomarkers in liquid biopsy.

HIF1A-repressed PUS10 regulates NUDC/Cofilin1 dependent renal cell carcinoma migration by promoting the maturation of miR-194-5p.

BACKGROUND: Renal cell carcinoma (RCC) is characterized by a high rate of distant metastasis, which leads to poor prognosis in patients with advanced RCC. PUS10 has been recognized as a member of the pseudouridine synthase family, and recently other functions beyond the synthesis of the RNA modification have been uncovered. However, little is known about its role in diseases such as cancer. METHODS: RT-qPCR, western blot and immunohistochemistry were used to measure the expression of PUS10 in RCC tissues. Transwell assay, wound healing assay, and in vivo metastasis model were conducted to determine the function of PUS10 in RCC progression. MicroRNA sequencing and GEO database were used to screen for the downstream microRNAs of PUS10. RNA immunoprecipitation, dual luciferase reporter assay, immunostaining, and rescue experiments were employed to establish the PUS10/miR-194-5p/nuclear distribution protein C(NUDC)/Cofilin1 axis in RCC migration. Chromatin immunoprecipitation and dual luciferase reporter assay were used to verify its upstream transcriptional regulator. RESULTS: The expression of PUS10 was significantly decreased in RCC tissues, and low expression predicted poor prognosis. In vitro and in vivo experiments showed that PUS10 suppressed RCC migration, which, however, was independent of its classical pseudouridine catalytic function. Mechanically, PUS10 promoted the maturation of miR-194-5p, which sequentially inhibited RCC migration via disrupting NUDC-dependent cytoskeleton. Furthermore, hypoxia and HIF-1 A were found involved in the downregulation of PUS10. CONCLUSION: We unraveled PUS10 restrained RCC migration via the PUS10/miR-194-5p/NUDC/Cofilin1 pathway, which independent of its classical catalytic function. Furthermore, a linkage between the critical tumor microenvironment hallmark with malfunction of the forementioned metastasis inhibition mechanism was presented, as demonstrated by repressed expression of PUS10 due to hypoxia and HIF-1A.

Effects of treatments on gender differences in patients with localized muscle-invasive bladder cancer.

PURPOSE: To explore the gender differences in survival under different treatments in localized muscle-invasive bladder cancer (MIBC), and to find clinical strategies to improve the poor prognosis of female with bladder cancer (BC). METHODS: Patients with localized MIBC were collected in the SEER database from 2010 to 2016 to analyze the gender differences in clinical characteristics. Propensity score matching was used to balance the effects of confounding factors. Kaplan-Meier method and Cox proportional hazards regression model were performed to compare the overall survival (OS) and cancer-specific survival (CSS) of patients between different treatment subgroups. RESULTS: The entire cohort included 13,272 T2N0M0 MIBC patients, with a male-to-female incidence of 3:1. Compared with male patients, females had a higher age of onset and more blacks. There were more female patients undergoing bladder-sparing surgery (BSS) alone, and the OS and CSS were worse than those in males. The gender difference showed statistical significance in the BSS group, but not in the radical cystectomy (RC) group. CONCLUSION: The survival of localized MIBC patients can be affected by treatments. Multi-modality treatment and RC may improve the survival prognosis of female patients.

Biofortification Technology for the Remediation of Cadmium-Contaminated Farmland by the Hyperaccumulator Sedum alfredii under Crop Rotation and Relay Cropping Mode.

Soil cadmium (Cd) extraction for hyperaccumulators is one of the most important technologies for the remediation of Cd-contaminated farmland soil. However, a phytoremediation model using a single hyperaccumulator cannot guarantee normal agricultural production in contaminated areas. To solve this problem, a combination of efficient remediation and safe production has been developed. Based on two-period field experiments, this study explored the effect of biofortification on soil Cd remediation using the fruit tree Sedum alfredii Hance and oil sunflower crop rotation and relay cropping mode. BioA and BioB treatments could markedly improve the efficiency of Cd extraction and remediation, and the maximum increase in Cd accumulation was 243.29%. When BioB treatment was combined with papaya-S. alfredii and oil sunflower crop rotation and relay cropping mode, the highest soil Cd removal rate in the two periods was 40.84%, whereas the Cd concentration of papaya fruit was lower than safety production standards (0.05 mg/kg). These results demonstrate that biofortification measures can significantly improve the Cd extraction effect of S. alfredii crop rotation and relay cropping restoration modes, which has guiding significance for Cd pollution remediation and safe production in farmland.

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.

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.

Nitroxoline suppresses metastasis in bladder cancer via EGR1/circNDRG1/miR-520h/smad7/EMT signaling pathway.

Bladder cancer is one of the most common and deadly cancer worldwide. Current chemotherapy has shown limited efficacy in improving outcomes for patients. Nitroxoline, an old and widely used oral antibiotic, which was known to treat for urinary tract infection for decades. Recent studies suggested that nitroxoline suppressed the tumor progression and metastasis, especially in bladder cancer. However, the underlying mechanism for anti-tumor activity of nitroxoline remains unclear. Methods: CircRNA microarray was used to explore the nitroxoline-mediated circRNA expression profile of bladder cancer lines. Transwell and wound-healing assay were applied to evaluate the capacity of metastasis. ChIP assay was chosen to prove the binding of promotor and transcription factor. RNA-pulldown assay was performed to explore the sponge of circRNA and microRNA. Results: We first identified the circNDRG1 (has_circ_0085656) as a novel candidate circRNA. Transwell and wound-healing assay demonstrated that circNDRG1 inhibited the metastasis of bladder cancer. ChIP assay showed that circNDRG1 was regulated by the transcription factor EGR1 by binding the promotor of host gene NDRG1. RNA-pulldown assay proved that circNDRG1 sponged miR-520h leading to the overexpression of smad7, which was a negative regulatory protein of EMT. Conclusions: Our research revealed that nitroxoline may suppress metastasis in bladder cancer via EGR1/circNDRG1/miR-520h/smad7/EMT signaling pathway.

Adding fuel to the fire: The lipid droplet and its associated proteins in cancer progression.

A lipid droplet (LD) is an organelle that consists of a phospholipid monolayer and a neutral lipid core, with proteins embedded in or attached to its surface. Until recently, cancers had long been regarded as genetic disorders with the abnormal activation of oncogenes and inactivation of tumor suppressor genes before their quality of a metabolic disorder began to be recognized. The last decade has witnessed the recognition of several metabolic characteristics of cancer cells, among which one is the accumulation of lipid droplets; therefore, attention has been given to exploring the role of LDs in carcinomas. In addition, there has been a remarkable expansion in understanding the complexity of LD's function in cellular homeostasis, including but not limited to energy supply, endoplasmic reticulum (ER) stress and oxidative stress management, or lipotoxicity alleviation. Thus, lipid droplet-associated proteins, which to a great extent determine the dynamics of a lipid droplet, have attracted the interest of numerous cancer researchers and their potential as cancer diagnostic biomarkers and therapeutic targets has been affirmed by emerging evidence. In this review, we systematically summarize the critical role of LDs in cancer and then focus on four categories of lipid droplet-associated proteins having the most direct influence on LD biosynthesis (diacylglycerol acyltransferase 1 (DGAT1) and diacylglycerol acyltransferase 2 (DGAT2)), degradation (adipose triglyceride lipase (ATGL)), and two renowned protein families on the LD surface (perilipins and cell death-inducing DNA fragmentation factor alpha-like effectors (CIDEs)). In this way, we aim to highlight their important role in tumor progression and their potential in clinical applications.

METTL1 drives tumor progression of bladder cancer via degrading ATF3 mRNA in an m7G-modified miR-760-dependent manner.

7-methylguanosine (m7G) modification is recently found to conservatively exist in RNA internal position besides mRNA caps and mediates the various RNA metabolisms. As the core confirmed transmethylase of m7G modification, METTL1 has been reported in certain human cancers. However, the role of internal m7G at miRNAs and its core writer METTL1 in bladder cancer (BCa) remains to be elucidated. Here, we demonstrated that METTL1 was indispensable for BCa proliferation and metastasis in vitro and in vivo. By combining miRNA sequencing, m7G methylated RNA immunoprecipitation (MeRIP) and RIP, we identified METTL1 promoted the processing of miR-760 in an m7G-dependent manner. Transcription sequencing suggested that METTL1 indirectly degrades tumor suppressor ATF3 mRNA mediated by miR-760. Together, we concluded a regulatory axis composed of METTL1/m7G/miR-760/ATF3 in regulating BCa progression and provided potential therapeutic targets for BCa.