Progression Of Renal Cell Carcinoma Research Articles

Dimethyl fumarate promotes the degradation of HNF1B and suppresses the progression of clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is the most lethal subtype of renal cancer, and its treatment options remain limited. Therefore, there is an urgent need to discover therapeutic agents for ccRCC treatment. Here, we demonstrate that dimethyl fumarate (DMF), an approved medication for multiple sclerosis [1] and psoriasis, can inhibit the proliferation of ccRCC cells. Mechanistically, hepatocyte nuclear factor 1β (HNF1B), a transcription factor highly expressed in ccRCC, is succinated by DMF at cysteine residues, leading to its proteasomal degradation. Furthermore, HNF1B interacts with and stabilizes Yes-associated protein (YAP), thus DMF-mediated HNF1B degradation decreases YAP protein level and the expression of its target genes, resulting in the suppression of ccRCC cell proliferation. Importantly, oral administration of DMF sensitizes ccRCC to sunitinib treatment and enhances its efficacy in mice. In summary, we provide evidences supporting DMF as a potential drug for clinical treatment of ccRCC by targeting HNF1B and reveal a previously unrecognized role of HNF1B in regulating YAP in ccRCC.

Design, Synthesis, and In Silico Insights of new 4-Piperazinylquinolines as Antiproliferative Agents against NCI Renal Cancer Cell Lines.

In the search for new anticancer compounds, quinoline and piperazine moieties represent the most promising pharmacophoric fragments for the development of more effective drugs. A particularly interesting approach in medicinal chemistry is molecular hybridization, where different known components are integrated into a single chemical entity, resulting in hybrid molecules with enhanced biological activity. In this study, we have developed a new series of 4-(4-benzoylpiperazin-1-yl)-6-nitroquinoline-3-carbonitrile compounds (8 a-l), with potential anticancer effect, by combining the quinoline, the piperazinyl and the benzoylamino moieties. The rationalized compounds (8 a-l) were first evaluated in silico to assess the ADMET and drug-likeness profiles, synthesized using appropriate synthetic strategies and then tested in vitro under the National Cancer Institute DTP-NCI60 program. The entire series exhibited potent anticancer activity against the renal cell carcinoma (RCC) cell line UO-31, with compounds 8 c and 8 g effectively inhibiting cancer cell growth without excessive cytotoxic effects (growth percentages of -7 and -19, respectively). In silico induced fit docking (IFD) and molecular dynamics (MD) studies provided further insights into the putative mechanisms of action for both compounds, which were predicted to strongly bind key oncogenic proteins involved in RCC progression. The promising in vitro and in silico results herein presented provide a solid foundation for the development of a new series of small heterocyclic molecules with anticancer activity.

Kidney cancer: From tumor biology to innovative therapeutics.

Renal cell carcinoma (RCC) constitutes the most frequent kidney cancer of the adult population and one of the most lethal malignant tumors worldwide. RCC often presents without early symptoms, leading to late diagnosis. Prognosis varies widely based on the stage of cancer at diagnosis. In the early-stage, localized RCC has a relatively good prognosis, while advanced or metastatic RCC has a poor outcome. Obesity, smoking, genetic mutations and family history are all considered risk factors for RCC, while inherited disorders, such as Tuberous Sclerosis and von Hippel-Lindau syndrome, are causally associated with RCC development. Genetic screening, deep sequencing analysis, quantitative proteomics and immunostaining analysis on RCC tissues, biological fluids and blood samples have been employed to identify novel biomarkers, predisposing factors and therapeutic targets for RCC with important clinical implications for patient treatment. Combined approaches of gene-targeting strategies coupled to a deep functional analysis of cancer cell biology, both in vitro and in appropriate animal models of RCC, significantly contributed to identify and characterize relevant pathogenic mechanisms underlying development and progression of RCC. These studies provided also important cues for the generation of novel target-specific therapeutics that selectively restore deranged cancer cell signalling and dysfunctional immune checkpoints, positively impacting on the survival rate of treated RCC patients. In this review, we will describe the recent discoveries concerning the most relevant pathogenic mechanisms of RCC and will highlight novel therapeutic strategies that interrupt oncogenic pathways and restore immune defences in RCC patients.

Phospholipase C Beta 2 as a Key Regulator of Tumor Progression and Epithelial-Mesenchymal Transition via PI3K/AKT Signaling in Renal Cell Carcinoma

Background: Renal cell carcinoma (RCC) represents the most common form of invasive kidney cancer in adults. Among the components critical to cellular regulation is Phospholipase C Beta 2 (PLCB2), a member of the phospholipase C enzyme family. This enzyme plays a vital role in managing key cellular functions such as growth, differentiation, migration, and survival. Despite its significant importance, the specific expression patterns and molecular mechanisms of PLCB2 in the progression of RCC are not well understood. Methods: This investigation employed a combination of bioinformatics analyses, scRNA-seq, functional assays, transcriptome sequencing, real-time quantitative PCR (RT-PCR), immunofluorescence, rescue experiments, and Western blotting to explore the regulatory function of PLCB2 in driving the epithelial-mesenchymal transition (EMT) in RCC through the PI3K/AKT signaling pathway. Results: PLCB2 expression is significantly elevated in RCC samples, and this increase is inversely correlated with patient prognosis. The knockdown of PLCB2 in RCC cell lines leads to a marked reduction in cell proliferation, invasion, migration, and EMT. Transcriptome sequencing further revealed that PLCB2 is significantly associated with the PI3K/AKT pathway. Notably, the PI3K activator 740Y-P was able to reverse the reductions in migration, invasion, and EMT caused by the PLCB2 knockdown. Conclusions: Our findings underscore the pivotal role of PLCB2 in regulating RCC invasion and metastasis by modulating the EMT via the PI3K/AKT signaling pathway. This highlights PLCB2 not only as a key prognostic biomarker, but also as a promising therapeutic target in the treatment of advanced-stage RCC, offering new avenues for more effective interventions.

Overexpression of PLCG2 and TMEM38A inhibit tumor progression in clear cell renal cell carcinoma

Clear cell renal cell carcinoma is a prevalent urological malignancy, imposing substantial burdens on both patients and society. In our study, we used bioinformatics methods to select four putative target genes associated with EMT and prognosis and developed a nomogram model which could accurately predicting 5-year patient survival rates. We further analyzed proteome and single-cell data and selected PLCG2 and TMEM38A for the following experiments. Overexpression models of PLCG2 and TMEM38A were generated in Caki-1 and 786-O cell lines using plasmids. The in vitro experiments demonstrated that both of them exerted pro-apoptotic effects on Caki-1 and 786-O cells, inducing G2/M phase arrest, inhibiting proliferation, and suppressing EMT. In summary, we identified potential tumor suppressor factors and stratified ccRCC patients into high-risk and low-risk groups based on these factors. Furthermore, we elucidated the impact of PLCG2 and TMEM38A in Caki-1 and 786-O cell lines, offering novel avenues for therapeutic target exploration.

Endogenous peptide CBDP1 inhibits clear cell renal cell carcinoma progression by targeting USP5/YTHDF2/TRPM5 axis

Background: Clear cell renal cell carcinoma (ccRCC) has a high incidence rate and poor prognosis, and currently lacks effective therapies. Recently, peptide-based drugs have shown promise in cancer treatment. In this research, a new endogenous peptide called CBDP1 was discovered in ccRCC and its potential anti-cancer properties were examined. Methods: Peptide expression in ccRCC was analyzed using peptidomics technology to screen for potential antitumor peptides. The effects of the peptide on ccRCC growth and migration were studied through Colony Formation Assay, CCK-8 assay, Transwell Assays, Wound Healing Assay, and animal experiments. Further investigation into the antitumor mechanisms of the peptide was conducted using lentivirus transduction, Western Blot Analysis, qRT-PCR, Immunoprecipitation, Immunofluorescence, and Immunohistochemistry. Results: Our findings reveal that Cathepsin B Derived Peptide 1 (CBDP1) can inhibit the progression of ccRCC both in vitro and in vivo. Through mechanistic investigations, it was revealed that CBDP1 facilitates the interaction between YTHDF2 and the deubiquitinase USP5, thereby impeding the ubiquitination and degradation of YTHDF2. The upregulated YTHDF2 then binds to TRPM3 mRNA and promotes its degradation, ultimately reducing TRPM3 expression levels. These molecular events collectively contribute to the anti-cancer properties of CBDP1. Conclusion: These data indicate that CBDP1 exerts its antitumor effects by regulating the USP5/YTHDF2/TRPM3 axis. CBDP1 emerges as a promising candidate for the treatment of ccRCC.

Hypoxia-triggered ERRα acetylation enhanced its oncogenic role and promoted progression of renal cell carcinoma by coordinating autophagosome-lysosome fusion

Estrogen-related receptor α (ERRα) is dysregulated in many types of cancer and exhibits oncogenic activity by promoting tumorigenesis and metastasis of cancer cells. However, its defined role in renal cell carcinoma (RCC) has not been fully elucidated. To reveal the biological function of ERRα and determine the underlying regulatory mechanism in RCC, the quantitative proteomics analysis and mechanism investigation were conducted. The results demonstrated that ERRα promoted the proliferation and tumorigenesis of RCC cells by maintaining lysosome-dependent autophagy flux. ERRα inhibition impaired the transcriptional expression of LAMP2 and VAMP8 and blocked the fusion of autophagosomes with lysosomes, causing the impairment of the autophagy-lysosome pathway and tumor repression in RCC. Moreover, VHL mutant-induced hyperactive hypoxia signaling in RCC triggered p300/CBP-mediated acetylation at the DNA-binding domain of ERRα, and this acetylation promoted its affinity toward targeting DNA and Parkin-mediated ubiquitination and proteasome-dependent degradation. This regulatory model enhanced ERRα transactivation on the expression of LAMP2 and VAMP8, which then maintained autophagy flux and RCC progression. Pharmaceutical inhibition on ERRα acetylation-mediated autophagy-lysosome pathway led to growth repression and sunitinib sensitivity of RCC cells. Taken together, this study uncovered a novel regulatory mechanism of acetylation contributing to the transcriptional performance and the oncogenic role of ERRα in RCC progression by modulating the autophagy-lysosome pathway. These findings might provide a novel approach for the clinical diagnosis and resolution of sunitinib resistance of RCC.

Integrative Analysis of Radiation-Induced Senescence-Associated Secretory Phenotype Factors in Kidney Cancer Progression.

Ionizing radiation (IR) is a well-known inducer of cellular senescence and the senescence-associated secretory phenotype (SASP). SASP factors play dual roles in cancer, either promoting or inhibiting its development. This study investigates IR-induced SASP factors specifically secreted by renal cortical epithelial (RCE) cells and their role in promoting renal cell carcinoma (RCC) progression. Proteomic data from the SASP Atlas were analyzed to identify IR-induced factors unique to RCE cells, with subsequent evaluations performed at both the gene and protein levels. Thirty-seven proteins were identified as exclusively upregulated and secreted by senescent RCE cells. Gene expression analysis of these RCE-specific SASP factors was conducted using the Gene Expression database of Normal and Tumor tissues (GENT2) and The Cancer Genome Atlas (TCGA). To assess their prognostic relevance in RCC, the corresponding proteins were further analyzed using the Human Protein Atlas (HPA), emphasizing the relationship between SASP factor expression and RCC progression. ALDH18A1 and ASPH emerged as key RCE-specific SASP factors with significant upregulation at both the gene and protein levels (Log2 ratio > 1.15, p < 0.05). These proteins are implicated in pro-cancer activities and are strongly associated with poor prognostic outcomes in RCC. Their critical roles in RCC progression underscore their potential as promising therapeutic targets for the prevention and treatment of the disease. This study provides novel insights into the role of IR-induced SASP in renal carcinogenesis, marking the first identification of ALDH18A1 and ASPH as specific secreted proteins associated with tumor progression in RCC. This study suggests that ALDH18A1 and ASPH hold promise as early biomarkers for RCC and as therapeutic targets for disease prevention and treatment.

Obesity alters the fitness of peritumoral adipose tissue, exacerbating tumor invasiveness in renal cancer through the induction of ADAM12 and CYP1B1.

Obesity exacerbates the risk and aggressiveness of many types of cancer. Adipose tissue (AT) represents a prevalent component of the tumor microenvironment (TME) and contributes to cancer development and progression. Reciprocal communication between cancer and adipose cells leads to the generation of cancer-associated adipocytes (CAAs), which in turn foster tumor invasiveness by producing paracrine metabolites, adipocytokines, and growth factors. Interfering with the crosstalk between CAAs and cancer cells is of key relevance in the prevention of tumor progression. The present study aimed to analyze the contribution of peritumoral AT in renal cell carcinoma (RCC) progression in lean versus overweight or obese patients. By isolating human adipose-derived stromal/stem cells from the three groups of patients and performing conditioned medium studies with RCC cells along with in vivo xenograft experiments, we found that peritumoral adipocytes from the three groups show a distinct expression profile of genes. In particular, ADAM metallopeptidase domain 12 (ADAM12) and cytochrome P450 family 1 subfamily B member 1 (CYP1B1) were found to be upregulated in obesity and their silencing reduced RCC cell invasiveness. In conclusion, high ADAM12 and CYP1B1 expressions in the peritumoral adipocytes boost tumor invasiveness and may serve as an indicator of poor prognosis in RCC.

MiR-507 Acts as a Tumor Suppressor in Renal Cell Carcinoma Cells by Targeting STEAP3.

In recent years, there has been a rise in the incidence of renal cell carcinoma (RCC), with metastatic RCC being a prevalent and significant contributor to mortality. While a regulatory role for microRNAs (miRNAs) in the development and progression of RCC has been recognized, their precise functions, molecular mechanisms, and potential clinical implications remain inadequately elucidated. Hence, this study aimed to explore the role of miR-507 in RCC and identify STEAP3 as a downstream target of miR-507. Bioinformatics analysis was used to analyze the expression of miR-507 and STEAP3 in RCC specimens. CCK-8, Transwell, and flow cytometry assays were used to assess the function of miR-507 in RCC cells. The connection between miR-507 and STEAP3 was confirmed through a luciferase reporter assay. The expression level of STEAP3, p53, and xCT was analyzed by western blotting. Bioinformatics analysis showed that miR-507 was expressed at low levels in RCC tissues and was linked to poor overall survival. STEAP3 was found to be significantly upregulated in RCC. Further, STEAP3 was shown to be targeted by miR-507. High levels of miR-507 reduced the expression of STEAP3, leading to stagnant cell viability, apoptosis, and migrative capacity. Whereas miR-507 knockdown reverted such a tendency. The study also discovered that miR-507 exerted its inhibitory effect through the op53/xCT pathway. Within RCC, miR-507 modulates the expression of SETAP3/p53/xCT axis, exhibiting a tumor suppressive effect. These discoveries offer present prospective biomarkers for both surveillance and treatment of RCC.

MiR-9-5p/HMMR regulates the tumorigenesis and progression of clear cell renal cell carcinoma through EMT and JAK1/STAT1 signaling pathway

BackgroundThe most common malignant type of kidney cancer is clear cell renal cell carcinoma (ccRCC). The expression levels of hyaluronan-mediated motility receptor (HMMR) in many tumor types are significantly elevated. HMMR is closely associated with tumor-related progression, treatment resistance, and poor prognosis, and has yet to be fully investigated in terms of its expression patterns and molecular mechanisms of action in ccRCC. Further research is imperative to elucidate these aspects.MethodsWe used The Cancer Genome Atlas (TCGA) database to preliminarily investigate HMMR expression and function in ccRCC and the data for 19 samples from the NCBI GEO database (GSE207493) for single-cell analysis. We assessed the differential expression level of HMMR between ccRCC cancerous tissues and their matched non-tumor tissues. Subsequently, a series of in vivo and in vitro experiments were designed to elucidate the biological function of HMMR in ccRCC, including Transwell assays, CCK-8 assays, clone formation assays and subcutaneous xenograft experiments in nude mice. Through bioinformatics analysis, we identified potential microRNAs (miRNAs) that may regulate HMMR, as well as the possible signaling pathways involved. Finally, we conducted a series of cellular functional experiments to validate our hypotheses regarding the HMMR axis.ResultsHMMR expression was significantly up-regulated in tumor tissues of ccRCC patients, and elevated HMMR expression level showed a strong correlation with ccRCC progression and adverse prognoses of patients. Knocking down HMMR inhibited the proliferative and migratory abilities of ccRCC cells, while its overexpression amplified these oncogenic properties. In nude mice model, reduced HMMR expression inhibited ccRCC tumor proliferation in vivo. Furthermore, overexpression of an upstream transcriptional regulator, miR-9-5p, effectively downregulated HMMR expression and thus impeded ccRCC cells proliferation and migration. HMMR might influence ccRCC growth via the Epithelial-Mesenchymal Transition (EMT) pathway and the Janus Kinase 1/Signal Transducer and Activator of Transcription 1 (JAK1/STAT1) pathway.ConclusionsHMMR is overexpressed in ccRCC, and there is a significant link between high HMMR expression and tumor progression, as well as poor patient prognosis. Specifically, HMMR could be targeted and inhibited by miR-9-5p and might modulate the tumorigenesis and progression of ccRCC through both EMT and JAK1/STAT1 signaling pathway.

Monotropein attenuates renal cell carcinoma cell progression and M2 macrophage polarization by weakening NF-κB.

The study aimed to investigate the effect and mechanism of monotropein on renal cell carcinoma (RCC). After monotropein and NF-κB receptor activator (RANKL) treatment, cell proliferation, invasion, and apoptosis were evaluated using CCK-8, Transwell, and flow cytometry. Primary macrophages co-cultured with monotropein-treated RCC cells were analyzed to evaluate macrophage polarization using qRT-PCR, western blot, and ELISA assays by detecting the expression of M2 markers (CD206, CD168) and cytokines (IL-10, TGF-β). Additionally, the therapeutic efficacy of monotropein was examined using an RCC mouse xenograft model. Monotropein could inhibit the proliferation, invasion, and M2 macrophage polarization and accelerate the apoptosis of RCC cells. Mechanistically, monotropein suppressed NF-κB pathway activation in RCC cells and reduced the expression of NF-κB downstream targets, including Bcl-2, c-Myc, and MMP9. RANKL could eliminate the effect of monotropein on RCC progression. In primary macrophages co-cultured with monotropein-treated RCC cells, monotropein downregulated M2 polarization markers and cytokines, further supporting its role in modulating the tumor microenvironment. In mouse models, monotropein reduced RCC tumor growth, induced apoptosis, and blocked NF-κB pathway. Monotropein prevents RCC malignant progression and reduces M2 macrophage polarization by suppressing the NF-κB pathway, suggesting that monotropein may serve as a potential therapeutic agent for RCC by targeting both tumor cells and the tumor microenvironment.

Glycine Decarboxylase Regulates Renal Carcinoma Progression via Interferon Stimulated Gene Factor 3-Mediated Pathway.

Renal cell carcinoma (RCC) is considered as a "metabolic disease" due to various perturbations in metabolic pathways that could drive cancer development. Glycine decarboxylase (GLDC) is a mitochondrial enzyme that takes part in the oxidation of glycine to support nucleotide biosynthesis via transfer of one-carbon units. Herein, we aimed to investigate the potential role of GLDC in RCC development. We found that GLDC depletion diminished nucleotide synthesis and promoted reactive oxygen species (ROS) generation to repress RCC progression, which was reversed by repletion of deoxynucleosides. Additionally, in vitro and in vivo studies revealed that GLDC plays an important role in regulation of proliferation and tumor growth via interferon stimulated gene factor 3 (ISGF3)-mediated pathway. Expressions of interferon regulatory factor 9 (IRF9) and signal transducer and activator of transcription 2 (STAT2) were elevated in GLDC knock-downed cells and decreased in GLDC over-expressed cells. Double knock-down of STAT2 and IRF9 in GLDC-deficient cells rescued GLDC depletion-induced decrease in cell proliferation. Furthermore, GLDC depletion increased cisplatin-and doxorubicin-induced DNA damage through ISGF3 pathway, leading to cell cycle dysregulation and increased mitotic catastrophe. These findings reveal that GLDC regulates RCC progression via ISFG3-mediated pathway and offers a promising strategy for RCC treatment.

Human leukocyte antigen DR alpha inhibits renal cell carcinoma progression by promoting the polarization of M2 macrophages to M1 via the NF-κB pathway

Human leukocyte antigen DR alpha (HLA-DRA) is recognized for its inhibitory effect on the progression of clear cell renal cell carcinoma (ccRCC); high HLA-DRA expression levels are positively correlated with improved prognosis in patients with ccRCC. In this study, we evaluated HLA-DRA expression in ccRCCs, its effects on tumor-associated macrophage recruitment, and the influence of polarization. Clinical cohort analyses revealed that elevated HLA-DRA expression in ccRCC cells was correlated with enhanced tumor infiltration by M1-type macrophages. In addition, ccRCC prognosis was predicted by combining HLA-DRA expression level analysis and the M1/M2 macrophage ratio. In vitro studies demonstrated that ccRCC cells with increased HLA-DRA expression promoted THP-1 cell migration and induced macrophage polarization toward the M1 phenotype. The effect was further substantiated in a mouse xenograft model in which an increase in M1 macrophages was observed. In addition, co-culturing macrophages with the supernatant from cells overexpressing HLA-DRA induced the expression of proteins associated with both M1 and M2 macrophage polarization. HLA-DRA was intricately linked to the expression and secretion of chemokines, including CCL2, CCL5, MIP-1ɑ, and CXCL-10. Moreover, the NF-κB pathway activation promoted polarization to M1 macrophages. This study shows that HLA-DRA and the M1/M2 ratio are indicators of favorable prognosis in patients with ccRCC. HLA-DRA promotes M1-like polarization by regulating NF-κB, which can be used as a therapeutic target to enhance anti-tumor immunity.

ERβ-regulated circATP2B1/miR-204-3p/TWIST1 positive feedback loop facilitates epithelial to mesenchymal transition in clear cell renal cell carcinoma.

Our previous studies have shown that estrogen receptor beta (ERβ) can promote the progression of clear cell renal cell carcinoma (ccRCC) by downregulating the expression of circATP2B1 and miR-204-3p. Here, we found that ERβ might promote the epithelial-mesenchymal transition(EMT) of ccRCC by modulating the circATP2B1/miR-204-3p/TWIST1(Twist family basic helix-loop-helix transcription factor 1) signaling pathway. We utilized bioinformatics analysis to determine the clinical significance of TWIST1 in ccRCC. The expression of TWIST1 in ccRCC tissues and cells was examined using immunohistochemistry, real-time quantitative polymerase chain reaction and western blotting assay. Chromatin Immunoprecipitation assay were conducted to validate the relationship between ERβ and TWIST1. Luciferase reporter gene assays were employed to validate the binding targets of TWIST1 and miR-204-3p. The role of TWIST1 in ccRCC was studied through in vitro and in vivo experiments. Transwell assays and wound healing assays were used to assess the impact of TWIST1 on the invasive and migratory abilities of ccRCC cells. Mechanism analysis revealed that miR-204-3p can inhibit TWIST1 by targeting its 3' untranslated region. Additionally, TWIST1 can promote ERβ transcription by directly binding to transcription factor binding site in the ERβ promoter region, forming a positive feedback loop. These in vitro data were further validated in an in vivo mouse model. Importantly, analysis of data from the TCGA-KIRC database further confirmed the above in vitro/in vivo findings. Together, our results suggest that ERβ/circATP2B1/miR-204-3p/TWIST1 can promote EMT by forming a positive feedback loop, thus promoting the progression of ccRCC. Targeting this newly identified signaling pathway may more effectively control the progression of ccRCC.

The 7-Methylguanosine (m7G) methylation METTL1 acts as a potential biomarker of clear cell renal cell carcinoma progression.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer. 7-Methylguanosine (m7G), one of the most prevalent RNA modifications, has been reported to play an important role in ccRCC progression; however, the specific regulators of m7G modification that are involved in this function remain unclear. This study aimed to explore the correlation between regulators of m7G methylation and ccRCC progression using unsupervised machine learning methods. Transcriptome and clinical data of ccRCC were retrieved from The Cancer Genome Atlas (TCGA) database to identify differentially expressed m7G-related genes associated with the overall survival of patients with ccRCC. To construct and validate a prognostic risk model, TCGA dataset samples were divided into training and test sets. A multiple-gene risk signature was constructed using least absolute shrinkage and selection operator Cox regression analysis, and its prognostic significance was assessed using Cox regression and survival analyses. Finally, immunohistochemistry was performed to verify the prognostic significance of this signature. In total, 537 patients with ccRCC were included in this study. We found that 26 m7G RNA methylation regulators that were significantly differentially expressed. Univariate and multifactorial Cox regression analyses revealed that METTL1 expression was associated with ccRCC progression. METTL1 associated with m7G may serve as a potential biomarker for ccRCC prognosis and diagnosis. Moreover, it may affect the prognosis of ccRCC by regulating the tumor immune microenvironment, providing a potential therapeutic target for immunotherapy. These results provide a new perspective on the role of M7G-related RNAs in ccRCC pathogenesis.

Copper Drives Remodeling of Metabolic State and Progression of Clear Cell Renal Cell Carcinoma.

The work establishes a requirement for glucose-dependent coordination between energy production and redox homeostasis, which is fundamental for the survival of cancer cells that accumulate Cu and contributes to tumor growth.

Response Gene to Complement 32 is associated with poor patient survival and an inflamed tumor-immune microenvironment in clear cell renal cell carcinoma.

It has been well established that tumor-infiltrating lymphocytes (TILs) play a critical role in the pathogenesis and progression of clear cell renal cell carcinoma (ccRCC). However, the mechanism on the interactions between TILs and tumor cells in the tumor-immune microenvironment remains unclear. In the present study, the expression of Response Gene to Complement 32 (RGC-32) was evaluated using immunohistochemistry. We analyzed the associations of RGC-32 expression with patient characteristics and survival. We also assessed TILs and their subsets (CD3+, CD4+, CD8+ and PD-1+) in the tumor nest. The level of RGC-32 expression was positively correlated with ISUP grade and Ki67 expression and was an independent poor prognosis factor of patients with ccRCC. RGC-32 expression was negatively correlated with the infiltration of TIL and CD3+T cells, but positively correlated with infiltration of PD-1+cells. In vitro studies showed that RGC-32 expression in renal cancer cells was downregulated by activated immune cells. Further investigation revealed that RGC-32 expression in renal cancer cells was inhibited by TNF-α and IL-1β secreted by activated immune cells. Collectively, these data indicate that RGC-32 could be a novel prognostic and druggable target related to the tumor-immune microenvironment in renal cancer.

Redox homeostasis of one-carbon metabolism-dependent reprogramming is critical for RCC progression under exogenous serine/glycine-deprived conditions

BackgroundSerine/glycine are critical for the growth and survival of cancer cells. Some cancer cells are more dependent on exogenous serine/glycine than endogenously synthesized serine/glycine. However, the function and underlying mechanisms of exogenous serine/glycine in renal cell carcinoma (RCC) remain unclear.MethodsWe conducted a comprehensive assessment of RCC progression under conditions of exogenous serine/glycine deprivation and explored the underlying mechanism via immunofluorescence, autophagic flux analysis, extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) measurements.ResultsThe expression of the serine synthesis pathway enzymes was decreased in RCC specimens, the de novo serine synthesis pathway (SSP) was reduced in RCC. And the levels of endogenously synthesized serine/glycine were little. Yet, the exogenous serine/glycine deprivation significantly inhibited the growth of RCC cells both in vitro and in vivo, indicating that exogenous serine/glycine were important for RCC progression. Mechanistically, the deprivation of exogenous serine/glycine disrupted one-carbon metabolism and increased the ratio of NAD(P)+/NAD(P)H, resulting in the accumulation of reactive oxygen species (ROS) and oxidative stress, which induced autophagic flux and enhanced lysosome membrane permeabilization (LMP), leading to the release of lysosomal cathepsins into the cytoplasm, which ultimately triggered lysosomal dependent cell death (LDCD) and inhibited the progression of RCC.ConclusionsOur results indicate that exogenous serine/glycine are critical for RCC progression by maintaining one-carbon metabolism-dependent redox homeostasis, which provides new insights for the development of dietary serine/glycine starvation-based therapeutic approaches for RCC.

BEX4 inhibits the progression of clear cell renal cell carcinoma by stabilizing SH2D4A, which is achieved by blocking SIRT2 activity.

Clear cell renal cell carcinoma (ccRCC) is one of the most common malignancies. Recently, the role of brain-expressed X-linked 4 (BEX4) in cancer progression has received increasing attention. This study aimed to investigate the function of BEX4 in ccRCC and to reveal the underlying mechanisms. We first confirmed that BEX4 was significantly downregulated in ccRCC by bioinformatics analysis and that patients with low BEX4 expression tended to have prolonged overall survival time. Subsequently, we confirmed that BEX4 inhibited ccRCC cell proliferation in vitro and tumorigenesis in vivo through a series of cell function assays and the establishment of a nude mouse xenograft model, respectively. Mechanistically, we found that BEX4 positively regulates the expression of Src homology 2 domain-containing 4A (SH2D4A), an inhibitor of the NOTCH pathway, which further promoted the tumor-suppressive effects of BEX4. In addition, our study confirmed that the promoting effect of BEX4 on SH2D4A was achieved by inhibiting the deacetylase sirtuin 2 (SIRT2) activity. On this basis, we found that there was a competition between acetylation and ubiquitination modifications at the K69 site of SH2DA4 and that BEX4-induced upregulation of acetylation at the k69 site stabilizes SH2D4A protein expression by inhibiting ubiquitination at the same site. In addition, dual-luciferase assays showed that the transcriptional activity of BEX4 was positively regulated by activation transcription factor 3 (ATF3). Our study suggests that BEX4 plays a role in inhibiting tumor progression in ccRCC and maybe a new diagnostic and therapeutic target for ccRCC patients.