Progression Of Renal Cell Carcinoma Research Articles

Expression analysis of leptin in nephrogenesis and renal carcinogenesis

The complex phenomenon of renal development involves several signaling molecules. Any alteration in the developmental process could largely influence the organogenesis, thus predisposing to several adulthood diseases. Leptin is a pleiotropic gene secreted by adipose cells. However, the purview of its actions is much beyond merely the extent of human adipose reserve. It regulates several cellular mechanisms such as cell proliferation, inflammation, vasculogenesis, and the production of collagen fibres. Further leptins are thought to play a putative role in embryogenesis and tumorigenesis. The aim of thIS study was to investigate the localization of the protein in fetal and cancer kidney in an attempt to understand the role of the protein in fetal kidney development and in renal cancer. Leptin expression was evaluated by subjecting tissue sections from paraffin-embedded blocks of renal tissues (fetal, adult and cancer) to immunohistochemistry staining. The tissues were scored based on the staining pattern and percentage of immunoreactive cells. The tissues were subjected to haematoxylin and eosin stain before performing immunohistochemistry. The images were analyzed and photographed. Mild staining for leptin was observed in the tubules of fetal and adult kidneys. Mild to moderate staining was seen in membranes of renal cell carcinoma tissues. It appears such that leptin may not be a key factor or rather a temporary factor in the developmental process of the kidney. The low levels of leptin in normal adult renal tissues may be physiologically significant. The role of leptin in the renal cell carcinoma progression is sceptible.

VHL mutation drives human clear cell renal cell carcinoma progression through PI3K/AKT-dependent cholesteryl ester accumulation

Cholesteryl ester (CE) accumulation in intracellular lipid droplets (LDs) is an essential signature of clear cell renal cell carcinoma (ccRCC), but its molecular mechanism and pathological significance remain elusive. Enabled by the label-free Raman spectromicroscopy, which integrated stimulated Raman scattering microscopy with confocal Raman spectroscopy on the same platform, we quantitatively analyzed LD distribution and composition at the single cell level in intact ccRCC cell and tissue specimens in situ without any processing or exogenous labeling. Since we found that commonly used ccRCC cell lines actually did not show the CE-rich signature, primary cancer cells were isolated from human tissues to retain the lipid signature of ccRCC with CE level as high as the original tissue, which offers a preferable cell model for the study of cholesterol metabolism in ccRCC. Moreover, we established a patient-derived xenograft (PDX) mouse model that retained the CE-rich phenotype of human ccRCC. Surprisingly, our results revealed that CE accumulation was induced by tumor suppressor VHL mutation, the most common mutation of ccRCC. Moreover, VHL mutation was found to promote CE accumulation by upregulating HIFα and subsequent PI3K/AKT/mTOR/SREBPs pathway. Inspiringly, inhibition of cholesterol esterification remarkably suppressed ccRCC aggressiveness invitro and invivo with negligible toxicity, through the reduced membrane cholesterol-mediated downregulations of integrin and MAPK signaling pathways. Collectively, our study improves current understanding of the role of CE accumulation in ccRCC and opens up new opportunities for treatment. This work was supported by National Natural Science Foundation of China (No. U23B2046 and No. 62027824), National Key R&D Program of China (No. 2023YFC2415500), Fundamental Research Funds for the Central Universities (No. YWF-22-L-547), PKU-Baidu Fund (No. 2020BD033), Peking University First Hospital Scientific and Technological Achievement Transformation Incubation Guidance Fund (No. 2022CX02), and Beijing Municipal Health Commission (No. 2020-2Z-40713).

Macrophage-Derived Nanosponges Adsorb Cytokines and Modulate Macrophage Polarization for Renal Cell Carcinoma Immunotherapy.

Renal cell carcinoma (RCC) is a hot tumor infiltrated by large numbers of CD8+ T cells and is highly sensitive to immunotherapy. However, tumor-associated macrophages (TAMs), mainly M2 macrophages, tend to undermine the efficacy of immunotherapy and promote the progression of RCC. Here, macrophage-derived nanosponges are fabricated by M2 macrophage membrane-coated poly（lactic-co-glycolic acid）（PLGA）, which could chemotaxis to the CXC and CC chemokine subfamily-enriched RCC microenvironment via corresponding membrane chemokine receptors. Subsequently, the nanosponges act like cytokine decoys to adsorb and neutralize broad-spectrum immunosuppressive cytokines such as colony stimulating factor-1(CSF-1), transforming growth factor-β（TGF-β）, and Lnterleukin-10（IL-10）, thereby reversing the polarization of M2-TAMs toward the pro-inflammatory M1 phenotype, and enhancing the anti-tumor effect of CD8+ T cells. To further enhance the polarization reprogramming efficiency of TAMs, DSPE-PEG-M2pep is conjugated on the surface of macrophage-derived nanosponges for specific recognition of M2-TAMs, and the toll like receptors 7/8（TLR7/8） agonist, R848, is encapsulated in these nanosponges to induce M1 polarization, which result in significant efficacy against RCC. In addition, these nanosponges exhibit undetectable biotoxicity, making them suitable for clinical applications. In summary, a promising and facile strategy is provided for immunomodulatory therapies, which are expected to be used in the treatment of tumors, autoimmune diseases, and inflammatory diseases.

CDCA5-EEF1A1 interaction promotes progression of clear cell renal cell carcinoma by regulating mTOR signaling

BackgroundCell division cycle associated 5 (CDCA5) plays ontogenetic role in various human cancers. However, its specific function and regulatory mechanism in ccRCC remain uncertain.MethodsImmunohistochemistry and western blots were performed to investigate the expression of CDCA5 in ccRCC tissues. Genetic knockdown and upregulation of CDCA5 were performed to investigate its functional roles in ccRCC proliferation, migration, apoptosis and sunitinib resistance. Furthermore, Co-IP assay and LC–MS/MS were performed to investigate the underlying mechanisms.ResultsWe found that CDCA5 expression is frequently upregulated in ccRCC tumors and is associated with poor prognosis of ccRCC patients. Functionally, CDCA5 promotes proliferation, migration, and sunitinib resistance, while inhibiting apoptosis in ccRCC cells. In vivo mouse xenograft model confirms that silencing of CDCA5 drastically inhibits the growth of ccRCC. Mechanistically, we discovered that CDCA5 interacts with Eukaryotic Translation Elongation Factor 1 Alpha 1 (EEF1A1) to regulate mTOR signaling pathway, thereby promoting ccRCC progression.ConclusionsTaken together, our results demonstrate the significant role of CDCA5 in ccRCC progression. The findings may provide insights for the development of new treatment strategies targeting CDCA5 for ccRCC patients.

MOICS, a novel classier deciphering immune heterogeneity and aid precise management of clear cell renal cell carcinoma at multiomics level

ABSTRACT Recent studies have indicated that the tumor immune microenvironment plays a pivotal role in the initiation and progression of clear cell renal cell carcinoma (ccRCC). However, the characteristics and heterogeneity of tumor immunity in ccRCC, particularly at the multiomics level, remain poorly understood. We analyzed immune multiomics datasets to perform a consensus cluster analysis and validate the clustering results across multiple internal and external ccRCC datasets; and identified two distinctive immune phenotypes of ccRCC, which we named multiomics immune-based cancer subtype 1 (MOICS1) and subtype 2 (MOICS2). The former, MOICS1, is characterized by an immune-hot phenotype with poor clinical outcomes, marked by significant proliferation of CD4+ and CD8+ T cells, fibroblasts, and high levels of immune inhibitory signatures; the latter, MOICS2, exhibits an immune-cold phenotype with favorable clinical characteristics, characterized by robust immune activity and high infiltration of endothelial cells and immune stimulatory signatures. Besides, a significant negative correlation between immune infiltration and angiogenesis were identified. We further explored the mechanisms underlying these differences, revealing that negatively regulated endopeptidase activity, activated cornification, and neutrophil degranulation may promote an immune-deficient phenotype, whereas enhanced monocyte recruitment could ameliorate this deficiency. Additionally, significant differences were observed in the genomic landscapes between the subtypes: MOICS1 exhibited mutations in TTN, BAP1, SETD2, MTOR, MUC16, CSMD3, and AKAP9, while MOICS2 was characterized by notable alterations in the TGF-β pathway. Overall, our work demonstrates that multi-immune omics remodeling analysis enhances the understanding of the immune heterogeneity in ccRCC and supports precise patient management.

[Retracted] lncRNA ROR promotes the progression of renal cell carcinoma through the miR‑206/VEGF axis.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the Transwell cell invasion and migration assay data shown in Fig. 2D and F on p. 3786 were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes, which had already been published. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 20: 3782‑3792, 2019; DOI: 10.3892/mmr.2019.10636].

Exploring the role of coagulation-related genes in renal cell carcinoma: Implications for tumor microenvironment and prognostic biomarkers

PurposeClear cell renal cell carcinoma (ccRCC) frequently progresses to advanced stages due to tumor thrombus (TTs) formation. In this study, we aimed to investigate the role of coagulation-related pathway activation in the progression of ccRCC. MethodsConsensus clustering was used to identify coagulation-related molecular clusters of ccRCC patients from The Cancer Genome Atlas Program (TCGA) database. The function of coagulation and its correlation with the immune microenvironment were investigated. Protein-protein interactions and differential expression analysis were used to identify the key gene, which was verified by external experiments. The coagulation-associated risk score was constructed by cox proportional hazards regression. ResultsNotable disparities were detected in immune characteristics, prognostic differentiation and drug sensitivity between two coagulation-related clusters. Through the integration of clinical stage significance and protein-protein interactions, the key gene MMP9 was screened and it was significantly correlated with CD4+T cells, CD8+T cells and Treg cells. A coagulation-related risk score prognostic model was developed in the Cancer Genome Atlas (TCGA) cohort for risk stratification and prognosis prediction. The prognostic predictive values of the coagulation-related risk score were further authenticated in both TCGA-KIRC and E-MTAB-1980 cohorts. ConclusionThere is an obvious correlation between the coagulation and the tumor microenvironment in ccRCC. As a key coagulation-related gene, MMP9 may promote the progression of renal cell carcinoma by influencing immune infiltration of CD8+T cells and Treg cells. Additionally, the risk score could be used as a durable prognostic biomarker, which could assist in clinical decision making for ccRCC patients.

LncRNA-SERB promotes vasculogenic mimicry (VM) formation and tumor metastasis in renal cell carcinoma.

A growing body of evidence shows that vasculogenic mimicry (VM) is closely related to the invasion and metastasis of many tumor cells. Although the estrogen receptor (ER) can promote initiation and progression of renal cell carcinoma (RCC), how downstream biomolecules are involved, and the detailed mechanisms of how ER expression is elevated in RCC remain to be further elucidated. Here, we discovered that LncRNA-SERB is highly expressed in tumor cells of RCC patients. We used multiple RCC cells and an in vivo mouse model for our study, and results indicated that LncRNA-SERB could boost RCC VM formation and cell invasion in vitro and in vivo. Although a previous report showed that ER beta (ERβ) can affect the VM formation in RCC, it is unclear which factor could up-regulate ERβ. This is the first study to show LncRNA-SERB can be the upstream regulator of ERβ to control RCC progression. Mechanistically, LncRNA-SERB may increase ERβ via binding to the promoter area, and ERβ functions through transcriptional regulation of Zinc finger E-box binding homeobox 1 (ZEB1) to regulate VM formation. These results suggest that LncRNA-SERB promotes RCC cell VM formation and invasion by upregulating the ERβ/ZEB1 axis and that therapeutic targeting of this newly identified pathway may better inhibit RCC progression.

Tumor Supplying Artery Injection of Liposome@Sunitinib Could Effectively Inhibit the Progression of Kidney Tumor.

Renal cell carcinoma (RCC) is one of the most common malignancies in the urinary system and is not sensitive to chemotherapy or radiotherapy in its advanced stages. Sunitinib is recommended as a first-line target drug for unresectable and metastatic RCC by targeting tyrosine kinase-related signaling pathways, but its therapeutic effect is unsatisfactory. Recently, nanomaterials have shown great prospects in the medical field because of their unique physicochemical properties. Particularly, liposomes are considered as ideal drug delivery systems due to their biodegradability, biocompatibility, and ideal drug-loading efficiency. Considering that tumor supplying artery injection can directly distribute drugs into tumor tissues, in this study, liposomes were employed to encapsulate water-insoluble sunitinib to construct the liposome@sunitinib (Lipo@Suni) complex, so that the drug could directly target and distribute into tumor tissue, and effectively trapped in tumor tissues after tumor supplying artery injection for the advantage of the physicochemical properties of liposomes, thereby achieving a better therapeutic effect on advanced RCC. Here, we found that compared with the peripheral intravenous administration, trans-renal arterial administration increases the content and prolongs the retention time of liposomes in tumor tissues; accordingly, more sunitinib is dispersed and retained in tumor tissues. Ultimately, trans-renal arterial administration of Lipo@Suni exerts a better suppressive effect on RCC progression than peripheral intravenous administration, even better than the conventional oral administration of sunitinib.

Tumor-associated macrophages impair NK cell IFN-γ production and contribute to tumor progression in clear cell renal cell carcinoma.

Tumor-associated macrophages (TAM) are abundant in several tumor types and usually correlate with poor prognosis. Previously, we demonstrated that anti-inflammatory macrophages (M2) inhibit NK cell effector functions. Here, we explored the impact of TAM on NK cells in the context of clear-cell renal cell carcinoma (ccRCC). Bioinformatics analysis revealed that an exhausted NK cell signature strongly correlated with an M2 signature. Analysis of TAM from human ccRCC samples confirmed that they exhibited an M2-skewed phenotype and inhibited IFN-γ production by NK cells. Moreover, human M0 macrophages cultured with conditioned media from ccRCC cell lines generated macrophages with an M2-skewed phenotype (TAM-like), which alike TAM, displayed suppressive activity on NK cells. Moreover, TAM depletion in the mouse Renca ccRCC model resulted in delayed tumor growth and reduced volume, accompanied by an increased frequency of IFN-γ-producing tumor-infiltrating NK cells that displayed heightened expression of T-bet and NKG2D and reduced expression of the exhaustion-associated co-inhibitory molecules PD-1 and TIM-3. Therefore, in ccRCC, the tumor microenvironment polarizes TAM toward an immunosuppressive profile that promotes tumor-infiltrating NK cell dysfunction, contributing to tumor progression. In addition, immunotherapy strategies targeting TAM may result in NK cell reinvigoration, thereby counteracting tumor progression.

CCDC25 suppresses clear cell renal cell carcinoma progression by LATS1/YAP-mediated regulation of the hippo pathway

BackgroundClear cell renal cell carcinoma (ccRCC) is one of the most prevalent renal cancers, and the molecular mechanisms underlying its progression are still not fully understood. The expression of CCDC25, a notably underexpressed gene in many tumors, has been understudied in ccRCC. This research aims to explore the role of CCDC25 in ccRCC's clinical outcomes and uncover the molecular pathways influenced by it.MethodsA multi-tiered approach was adopted involving bioinformatic analysis, tissue sample evaluation, in vitro and in vivo experiments. CCDC25 expression levels in tumor vs. normal tissues were quantified using Western blot and immunofluorescence studies. Cell proliferation and migration were analyzed using CCK8, EDU, Transwell assays, and wound healing assays. RNA sequencing was performed to elucidate the molecular pathways affected, followed by detailed protein–protein interaction studies and mouse xenograft models.ResultsCCDC25 was predominantly underexpressed in ccRCC tumors and associated with advanced clinical stages and poor prognosis. Overexpression of CCDC25 in renal cancer cell lines resulted in reduced proliferation and migration. RNA sequencing revealed significant alterations in the Hippo pathway. Overexpression of CCDC25 inhibited the expression of downstream Hippo pathway proteins ITGA3 and CCND1 and promoted YAP phosphorylation. Mechanistic studies showed that CCDC25 interacts with YAP and influences YAP phosphorylation through LATS1. In vivo, CCDC25 overexpression inhibited tumor growth and promoted apoptosis.ConclusionCCDC25 acts as a potential tumor suppressor in ccRCC by inhibiting cell proliferation and migration, potentially through regulating the Hippo signaling pathway. These findings highlight the potential of CCDC25 as a therapeutic target in ccRCC treatment.Graphical

Retraction: Enhanced IMP3 Expression Activates NF-кB Pathway and Promotes Renal Cell Carcinoma Progression.

Retraction: Enhanced IMP3 Expression Activates NF-кB Pathway and Promotes Renal Cell Carcinoma Progression.

TRIB3 promotes the progression of renal cell carcinoma by upregulating the lipid droplet-associated protein PLIN2

Abnormal lipid metabolism and lipid accumulation are characteristic hallmarks of renal cell carcinoma (RCC). While there is prior evidence closely linking such lipid accumulation within RCC cells and consequent tumorigenesis, the mechanisms underlying this process remain incompletely understood. In this study, a series of bioinformatics analyses were initially performed by screening RCC databases and gene sets, ultimately leading to the identification of TRIB3 as an oncogene that functions as a central regulator of lipid metabolism. TRIB3 overexpression was observed in both RCC patient tumor tissues and cell lines, and this upregulation was correlated with a worse RCC patient prognosis. When TRIB3 was knocked down, this resulted in a reduction in lipid accumulation and the consequent induction of endoplasmic reticulum (ER) stress-related apoptotic cell death. At the molecular level, interactions between TRIB3 and PLIN2 were found to abrogate TEB4-mediated PLIN2 ubiquitination and consequent degradation, thus maintaining higher PLIN2 expression levels. This simultaneously helps facilitate the accumulation of lipids while preserving ER homeostasis, thus driving accelerated RCC tumor progression. This TRIB3-PLIN2 axis thus represents a promising new target for efforts to treat RCC.

AURKA promotes renal cell carcinoma progression via regulation of CCNB1 transcription

AURKA is a member of the serine/threonine kinase family and its kinase activity is crucial for the progression of mitosis. Recent studies have highlighted the therapeutic significance of AURKA inhibition in multiple cancer types. However, the specific mechanisms by which AURKA contributes to the progression of renal cell carcinoma (RCC) have not been fully elucidated. In this study, AURKA expression level was identified in human RCC tissues by immunohistochemical (IHC) staining. The function of AURKA on cell malignant phenotypes was evaluated in vitro after AURKA inhibition. The subcutaneous xenograft was conducted to confirm the in vivo effect of AURKA knockdown on growth of RCC cells. Finally, Co-IP, luciferase assay and ChIP experiments were performed to reveal the regulatory mechanism of AURKA on CCNB1. Our results showed a significant upregulation of AURKA in RCC tissues and cell lines, and a high AURKA expression was associated with poor prognosis. AURKA knockdown inhibited RCC cell proliferation and migration, induced cell apoptosis, and led to G1/G2 phase arrest. This effect was further confirmed by the use of an AURKA inhibitor. Mechanistically, AURKA interacted with E2F1, and subsequently recruited it to the promoter region of CCNB1. CCNB1 expression was essential for AURKA-induced RCC progression. Collectively, our results suggested that AURKA plays an important role in development of RCC via regulating CCNB1 transcription.

Transcription Factor E3/Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin Axis in Renal Cell Carcinoma Affects Tumor Microenvironment

The role of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in renal cell carcinoma (RCC) progression, metastasis, and resistance to therapies has not been investigated thoroughly. Transcription factor E3 (TFE3) expression is related to a poorer prognosis and tumor microenvironment in patients with RCC. This study aimed to determine the relationship between TFE3 and the PI3K/Akt pathway. TFE3 down-regulation was achieved by transient transfection of siRNA and shRNA in UOK146 cells. TFE3 overexpression was induced by transient transfection with pcDNA3.1 encoding the constitutively active form of TFE3. The cells were treated with mammalian target of rapamycin and PI3K inhibitors. Western blot was performed to detect TFE3, programmed death-ligand 1, phospho-Akt, and Akt. Phospho-Akt expression increased significantly upon TFE3 down-regulation, and decreased significantly upon up-regulation. When RCC cells were treated with a PI3K inhibitor (LY294002), TFE3 expression increased and phospho-Akt expression decreased. TFE3 is related to the PI3K/Akt pathway in RCC, and the results of this study suggest that PI3K/Akt inhibitors potentially may aid in treatment of patients with RCC by affecting the tumor microenvironment.

Calcium saccharate/DUSP6 suppresses renal cell carcinoma glycolytic metabolism and boosts sunitinib efficacy via the ERK-AKT pathway

Current therapeutic options for renal cell carcinoma (RCC) are very limited, which is largely due to inadequate comprehension of molecular pathological mechanisms as well as RCC's resistance to chemotherapy. Dual-specificity phosphatase 6 (DUSP6) has been associated with numerous human diseases. However, its role in RCC is not well understood. Here, we show that diminished DUSP6 expression is linked to RCC progression and unfavorable prognosis. Mechanistically, DUSP6 serves as a tumor suppressor in RCC by intervening the TAF10 and BSCL2 via the ERK-AKT pathway. Further, DUSP6 is also transcriptionally regulated by HNF-4a. Moreover, docking experiments have indicated that DUSP6 expression is enhanced when bound by Calcium saccharate, which also inhibits RCC cell proliferation, metabolic rewiring, and sunitinib resistance. In conclusion, our study identifies Calcium saccharate as a prospective pharmacological therapeutic approach for RCC.

Exosomes in renal cell carcinoma: challenges and opportunities.

Renal cell carcinoma (RCC) is the most common type of kidney cancer that accounts for approximately 2-3% of adult malignancies. Among the primary treatment methods for this type of cancer are surgery and targeted treatment. Still, due to less than optimal effectiveness, there are problems such as advanced distant metastasis, delayed diagnosis, and drug resistance that continue to plague patients. In recent years, therapeutic advances have increased life expectancy and effective treatment in renal cell carcinoma patients. One of these methods is the use of stem cells. Although the therapeutic effects of stem cells, especially mesenchymal stem cells, are still impressive, today, extracellular vesicles (EVs) as carrying molecules and various mediators in intercellular communications, having a central role in tumorigenesis, metastasis, immune evasion, and drug response, and on the other hand, due to its low immunogenicity and strong regulatory properties of the immune system, has received much attention from researchers and doctors. Despite the increasing interest in exosomes as the most versatile type of EVs, the heterogeneity of their efficacy presents challenges and, on the other hand, exciting opportunities for diagnostic and clinical interventions.In the upcoming article, we will review the various aspects of exosomes' effects in the prevention, treatment, and progress of renal cell carcinoma and also ways to optimize them to strengthen their positive sides.

Retraction: RASA1 inhibits the progression of renal cell carcinoma by decreasing the expression of miR-223-3p and promoting the expression of FBXW7.

Retraction: RASA1 inhibits the progression of renal cell carcinoma by decreasing the expression of miR-223-3p and promoting the expression of FBXW7.

Abstract 3457: Distinct signatures of tumor-associated macrophage subpopulations predict survival in renal cell carcinoma

Abstract Background: Comprising 90% of renal cancer cases in adults, renal cell carcinoma (RCC) is marked by significant heterogeneity in its tumor microenvironment. This study aims to test the hypothesis that tumor-associated macrophages (TAMs) play a role in modulating RCC progression and patient response to treatment. We explored the prognostic implications of TAM signatures on RCC survival, leveraging immunomics to decipher TAM-related alterations in the tumor microenvironment. Methods: Utilizing independent single-cell RNA-seq data from human RCC samples, we crafted 8 distinct RCC TAM signatures reflective of TAM presence. A LASSO Cox regression model was developed to prognosticate survival, tested against the TCGA dataset and independently validated across multiple RCC cohorts. Model performance was corroborated through Kaplan-Meier survival plots, receiver operating characteristic (ROC) curves, principal component analysis, and t-SNE analyses. Results: We identified two TAM signatures that correlate positively with patient survival, indicative of the abundance of specific subsets of TAMs in RCC. These signatures showed a strong association of specific TAM markers and macrophage infiltration. Survival analysis demonstrated that specific TAM signature gene expressions are significant prognostic markers. Forest plots underscored their prognostic relevance. A 32-gene risk score model was established, successfully stratifying patients into distinct risk categories, with low-risk patients exhibiting markedly improved overall survival. Conclusions: The study underscores the positive association between abundance of specific TAM subsets of and RCC patient survival. The precision of our LASSO Cox regression model, informed by novel abundance markers of specific TAM subsets, advances our understanding of TAM roles in TIME and RCC progression. These TAM signatures could potentially provide additional insights and targets to enhance the efficacy of RCC treatments. Keywords: Tumor associated macrophage, renal cell carcinoma, prognosis, tumor microenvironment, immunomics. Citation Format: Youngsoo Han, Aidan Shen, Zhaohui Wang, Aliesha Garrett, Chongming Jiang. Distinct signatures of tumor-associated macrophage subpopulations predict survival in renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3457.

MicroRNA-141-3p Suppressed the Progression of the Clear Cell Renal Cell Carcinoma by Targeting Transforming Growth Factor Beta 2 Gene Expression.

Clear cell renal cell carcinoma (ccRCC) is a malignant tumor of kidney epithelial cells, one of the most common tumors in the world. Transforming growth factor beta (TGFβ)1 is a crucial factor that induces epithelial-mesenchymal transition (EMT) in cancer cells. microRNA-141-3p (miR-141-3p) is a microRNA that is considered a tumor suppressor. However, the role and mechanism of miR-141-3p in TGFβ1-induced ccRCC cells are not fully understood. This study investigated the roles of miR-141-3p and its target gene in regulating EMT in ccRCC development. 786-0 and Caki-1cells were treated with TGFβ1 to induce EMT. The levels of miR-141-3p and TGFβ2 were determined by quantitative real-time polymerase chain reaction and Western blotting. The progression of EMT was evaluated by E-cadherin detection by immunofluorescence, and E-cadherin, N-cadherin, and vimentin detection by Western blotting. Furthermore, migration and invasion capacities were assessed using a Transwell system. The direct binding of miR-141-3p with the target gene TGFβ2 was confirmed by dual luciferase reporter gene assay. Results indicated that TGFβ1 treatment decreased the protein abundance of E-cadherin while increasing the protein expression of N-cadherin and vimentin, indicating TGFβ1-induced EMT was constructed successfully. Moreover, TGFβ1 treatment repressed the expression of miR-141-3p. miR-141-3p mimics reversed the effect of TGFβ1 on the migration, invasion, and expression of E-cadherin, N-cadherin, and vimentin. The miR-141-3p directly binds with the 3' untranslated region of TGFβ2 mRNA and suppresses its expression. Furthermore, TGFβ2 overexpression abrogated the above changes regulated by miR-141-3p mimics. Taken together, miR-141-3p inhibited TGFβ1-induced EMT by suppressing the migration and invasion of ccRCC cells via directly targeting TGFβ2 gene expression.