SIRT4 silencing in tumor-associated macrophages promotes HCC development via PPARδ signalling-mediated alternative activation of macrophages

Abstract Background The activation of tumour-associated macrophages (TAMs) contributes to the progression of hepatocellular carcinoma (HCC). SIRT4 acts as a tumour suppressor of tumour growth by regulating cell metabolism, inflammation, and anti-tumourigenesis. However, the involvement of SIRT4 in the activation of TAMs is unknown. Based on previous findings, the expression of SIRT4 in distinct groups of TAMs as well as the effect of SIRT4 silencing on macrophage polarization was investigated. Methods The expression of SIRT4 in HCC tissues and peritumour tissues was tested by qRT-PCR, western blotting and histological analysis. A Kaplan-Meier survival curve was generated based on the expression of SIRT4 in the HCC samples. Next, immunofluorescence staining was used to evaluate distinct groups of TAMs in human HCC samples, and the expression of SIRT4 in M1 and M2 TAMs was examined by flow cytometry. A homograft mouse model was used to assess the effect of SIRT4 silencing in TAMs on the development of HCC cells. Results SIRT4 was significantly downregulated in HCC tumour tissues, and the expression of SIRT4 in peritumour tissues was positively associated with survival in patients. We further found that downregulation of SIRT4 was associated with increased macrophage infiltration and a high ratio of M2/M1 macrophages in HCC peritumour tissues. Using gene interference, we found that SIRT4 silencing in TAMs significantly modulated the alternative activation of macrophages and promoted in vitro and in vivo HCC cell growth. Mechanistically, we revealed that HCM restricted the expression of SIRT4 in macrophages and promoted alternative activation of macrophages via the FAO-PPARδ-STAT3 axis. Furthermore, we also revealed that elevated MCP-1 expression induced by SIRT4 downregulation was responsible for increased TAM infiltration in peritumour tissues. Conclusions Overall, our results demonstrate that downregulation of SIRT4 in TAMs modulates the alternative activation of macrophages and promotes HCC development via the FAO-PPARδ-STAT3 axis. These results could provide a new therapeutic target for the treatment of HCC.

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DDRE-26. INHIBITION OF PRMT5 SENSITIZES GLIOBLASTOMA MODELS TO TRAMETINIB TREATMENT

Neuro-Oncology ◽

10.1093/neuonc/noab196.310 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi79-vi80

Author(s):

Yesh Banasavadi ◽

Sriya Namagiri ◽

yoshihiro Otani ◽

Shilpa Thammegowda ◽

Hannah Sur ◽

...

Keyword(s):

Cell Cycle Progression ◽

Survival Curve ◽

Oral Gavage ◽

Cycle Progression ◽

Arginine Methyltransferase ◽

Tumor Bearing ◽

Nsg Mice ◽

Kaplan Meier ◽

Meier Survival Curve

Abstract With limited effective therapeutic strategies, the prognosis for glioblastoma (GBM) is very poor. Our previous study shows that the expression of Protein Arginine Methyltransferase 5 (PRMT5) is upregulated in GBM; its inhibition promotes apoptosis and senescence in differentiated and stem-like tumor cells, respectively. MEK inhibitors, including trametinib, are currently under investigation for GBM therapy. In this study, we tested whether inhibition of PRMT5 can enhance the anti-GBM efficacy of trametinib. Patient-derived primary GBM neurospheres (GBMNS) with transient PRMT5 knockdown were treated with trametinib and cell viability, proliferation, cell cycle progression, ELISA, and western blot analysis were conducted. In vivo, PRMT5-intact and -depleted GBMNS were intracranially implanted in NSG mice and treated with trametinib by daily oral gavage, and tumor progression and mice survival rate were analyzed by MRI and Kaplan-Meier survival curve, respectively. Depletion of PRMT5 increased the cytotoxic effect of trametinib in GBMNS. Trametinib treatment increased the activity of ERBB3 and AKT; With PRMT5 knockdown, the activity of both AKT and ERBB3 decreased significantly. But, inhibition of ERBB3 alone failed to block the trametinib-induced AKT activity suggesting that even though PRMT5 regulates the activity of both ERBB3 and AKT, the enhanced antitumor effect imparted by PRMT5 knockdown in trametinib treated GBMNS is because of AKT inhibition alone. In vivo, PRMT5-depletion extended the survival of the tumor-bearing mice that further increased in combination with trametinib treatment. Interestingly, trametinib treatment alone had no survival benefit.

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Thioholgamide A, a New Anti-Proliferative Anti-Tumor Agent, Modulates Macrophage Polarization and Metabolism

Cancers ◽

10.3390/cancers12051288 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1288 ◽

Cited By ~ 2

Author(s):

Charlotte Dahlem ◽

Wei Xiong Siow ◽

Maria Lopatniuk ◽

William K. F. Tse ◽

Sonja M. Kessler ◽

...

Keyword(s):

Tumor Microenvironment ◽

Tumor Cells ◽

Cell Metabolism ◽

Macrophage Polarization ◽

Human Monocyte ◽

Live Cell ◽

Hallmarks Of Cancer ◽

Culture Models

Natural products represent powerful tools searching for novel anticancer drugs. Thioholgamide A (thioA) is a ribosomally synthesized and post-translationally modified peptide, which has been identified as a product of Streptomyces sp. MUSC 136T. In this study, we provide a comprehensive biological profile of thioA, elucidating its effects on different hallmarks of cancer in tumor cells as well as in macrophages as crucial players of the tumor microenvironment. In 2D and 3D in vitro cell culture models thioA showed potent anti-proliferative activities in cancer cells at nanomolar concentrations. Anti-proliferative actions were confirmed in vivo in zebrafish embryos. Cytotoxicity was only induced at several-fold higher concentrations, as assessed by live-cell microscopy and biochemical analyses. ThioA exhibited a potent modulation of cell metabolism by inhibiting oxidative phosphorylation, as determined in a live-cell metabolic assay platform. The metabolic modulation caused a repolarization of in vitro differentiated and polarized tumor-promoting human monocyte-derived macrophages: ThioA-treated macrophages showed an altered morphology and a modulated expression of genes and surface markers. Taken together, the metabolic regulator thioA revealed low activities in non-tumorigenic cells and an interesting anti-cancer profile by orchestrating different hallmarks of cancer, both in tumor cells as well as in macrophages as part of the tumor microenvironment.

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The biology of nematode- and IL4Rα-dependent murine macrophage polarization in vivo as defined by RNA-Seq and targeted lipidomics

Blood ◽

10.1182/blood-2012-07-442640 ◽

2012 ◽

Vol 120 (25) ◽

pp. e93-e104 ◽

Cited By ~ 33

Author(s):

Graham D. Thomas ◽

Dominik Rückerl ◽

Benjamin H. Maskrey ◽

Phillip D. Whitfield ◽

Mark L. Blaxter ◽

...

Keyword(s):

Transcriptional Activation ◽

Expression Profiles ◽

Macrophage Polarization ◽

Peritoneal Macrophages ◽

Mitochondrial Metabolism ◽

Alternative Activation ◽

Alternatively Activated Macrophages ◽

Transcription Start Sites

Abstract Alternatively activated macrophages (AAMφ) are a major component of the response to helminth infection; however, their functions remain poorly defined. To better understand the helminth-induced AAMφ phenotype, we performed a systems-level analysis of in vivo derived AAMφ using an established mouse model. With next-generation RNA sequencing, we characterized the transcriptomes of peritoneal macrophages from BALB/c and IL4Rα−/− mice elicited by the nematode Brugia malayi, or via intraperitoneal thioglycollate injection. We defined expression profiles of AAMφ-associated cytokines, chemokines, and their receptors, providing evidence that AAMφ contribute toward recruitment and maintenance of eosinophilia. Pathway analysis highlighted complement as a potential AAMφ-effector function. Up-regulated mitochondrial genes support in vitro evidence associating mitochondrial metabolism with alternative activation. We mapped macrophage transcription start sites, defining over-represented cis-regulatory motifs within AAMφ-associated promoters. These included the binding site for PPAR transcription factors, which maintain mitochondrial metabolism. Surprisingly PPARγ, implicated in the maintenance of AAMφ, was down-regulated on infection. PPARδ expression, however, was maintained. To explain how PPAR-mediated transcriptional activation could be maintained, we used lipidomics to quantify AAMφ-derived eicosanoids, potential PPAR ligands. We identified the PPARδ ligand PGI2 as the most abundant AAMφ-derived eicosanoid and propose a PGI2-PPARδ axis maintains AAMφ during B malayi implantation.

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Enforced Differentiation of Dnmt3a-Null Bone Marrow Leads to Failure with c-Kit Mutations Driving Leukemic Transformation

Blood ◽

10.1182/blood.v124.21.837.837 ◽

2014 ◽

Vol 124 (21) ◽

pp. 837-837

Author(s):

Hamza Celik ◽

Cates Mallaney ◽

Alok Kothari ◽

Christopher A Miller ◽

Jasreet Hundal ◽

...

Keyword(s):

Bone Marrow ◽

Survival Curve ◽

Lymphoblastic Leukemia ◽

Loss Of Function ◽

Wild Type ◽

Leukemic Transformation ◽

Kaplan Meier ◽

Cell Acute Lymphoblastic Leukemia ◽

Meier Survival Curve

Abstract Genome sequencing studies of patient samples have implicated the involvement of various components of the epigenetic machinery in myeloid diseases, including the de novo DNA methyltransferase DNMT3A (Cancer Genome Atlas Research, N Engl J Med, 2013). We have recently shown that Dnmt3a is essential for normal hematopoietic stem cell (HSC) differentiation. Genetic ablation of Dnmt3a resulted in HSCs that showed diminished capacity for peripheral blood generation after serial transplantation (on a per-HSC basis), while phenotypically-defined HSCs accumulated in the bone marrow (Challen et al., Nature Genetics, 2012). Although this differentiation arrest was insufficient to cause overt disease, in these competitive transplants the presence of wild-type whole bone marrow may have suppressed malignant transformation of the mutant HSCs. Dnmt3a-null HSCs were less proliferative than counterpart control HSCs in this transplantation setting, suggesting that the cellular turnover threshold necessary to generate additional genetic and/or epigenetic lesions required for leukemogenesis was not achieved. To further understand the contribution of Dnmt3a loss-of-function in hematopoiesis, we performed non-competitive transplantation of Dnmt3a-null bone marrow. This forces the mutant HSCs to divide in vivoto regenerate the hematopoietic system following lethal irradiation, and should uncover any predispositions to transformation. Mice transplanted with Dnmt3a-null bone marrow in the absence of wild-type support cells succumbed principally to bone marrow failure (median survival 328 days) characteristic of myelodysplastic syndromes (MDS) with symptoms including anemia, neutropenia, bone marrow hypercellularity and splenomegaly with myeloid infiltration. 2/25 mice developed myeloid leukemia with >20% blasts in the blood and bone marrow. 4/25 primary mice succumbed to myeloproliferative disorders, some of which progressed to secondary leukemia after long latency. Exome sequencing was performed to identify co-operating mutations that drove leukemic transformation, and revealed c-Kit mutations found only in the Dnmt3a-null AML samples. As DNMT3A and KIT mutations can co-occur in AML and mastocytosis, we tested whether these two pathways could co-operate in vivo by ectopic introduction of c-Kit variants into hematopoietic progenitors followed by bone marrow transplantation (Figure 1). As previously reported, expression of c-KitD814V in wild-type cells lead to development of B-cell acute lymphoblastic leukemia (B-ALL). However, expression of c-KitD814V in a Dnmt3a-null background lead to acute leukemia with a much shorter latency (median survival 67 days), implicating a synergism between these pathways in vivo. Moreover, the absence of Dnmt3a also distorted the spectrum of leukemia resulting from enforced c-Kit signaling. While some of the mice transplanted with Dnmt3a-null c-KitD814V cells also succumbed to a B-ALL, 4/13 (31%) developed mastocytosis with involvement of myeloid blasts, and 4/13 (31%) mice developed a T-cell acute lymphoblastic leukemia (T-ALL). We show for the first time that these pathways can co-operate to accelerate transformation in vivo. This Dnmt3a/c-Kit disease model resembles the classical “two-hit” model of leukemogenesis in which one mutation in a hematopoietic progenitor cell inhibits differentiation (Dnmt3a loss-of-function), whilst another drives proliferation (c-Kit gain-of-function). Such mouse models present a unique opportunity to study the sequence of early events leading to HSC transformation following Dnmt3a-inactivation. Figure 1 Kaplan-Meier survival curve of mice transplanted with control or Dnmt3a-KO bone marrow progenitor cells transduced with a lentivirus expressing c-KitD814V. *** p <0.001. Figure 1. Kaplan-Meier survival curve of mice transplanted with control or Dnmt3a-KO bone marrow progenitor cells transduced with a lentivirus expressing c-KitD814V. *** p <0.001. Disclosures No relevant conflicts of interest to declare.

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Anti-Inflammatory Effect of Curcumin on the Mouse Model of Myocardial Infarction through Regulating Macrophage Polarization

Mediators of Inflammation ◽

10.1155/2021/9976912 ◽

2021 ◽

Vol 2021 ◽

pp. 1-19

Author(s):

Shaoxi Yan ◽

Mo Zhou ◽

Xiaoyun Zheng ◽

Yuanyuan Xing ◽

Juan Dong ◽

...

Keyword(s):

Myocardial Infarction ◽

Ventricular Remodeling ◽

Macrophage Polarization ◽

M2 Macrophage ◽

M1 Macrophages ◽

Macrophage Marker ◽

M1 Macrophage ◽

Anti Inflammatory

Inflammation causes tissue damage and promotes ventricular remodeling after myocardial infarction (MI), and the infiltration and polarization of macrophages play an important role in regulating inflammation post-MI. Here, we investigated the anti-inflammatory function of curcumin after MI and studied its relationship with macrophage polarization. In vivo, curcumin not only attenuated ventricular remodeling 3 months after MI but also suppressed inflammation during the first 7 days post-MI. Importantly, the results of qPCR and immunochemistry showed that curcumin decreased M1 (iNOS, CCL2, and CD86) but increased M2 macrophage (Arg1, CD163, and CD206) marker expression in the myocardium of MI mice during the first 7 days post-MI. And flow cytometry analysis indicated that curcumin suppressed M1 (CD45+Gr-1-CD11b+iNOS+ cells) but enhanced M2 macrophage (CD45+Gr-1-CD11b+Arg+ cells) expansion in the myocardium of MI mice during the first 7 days post-MI. In vitro, curcumin decreased LPS/IFNγ-elevated M1 macrophage marker (iNOS and CD86) expression and the proportion of M1 macrophages (iNOS+F4/80+ cells) but increased LPS/IFNγ-suppressed M2 macrophage marker (Arg1 and CD206) expression and the proportion of M2 macrophages (Arg1+F4/80+ cells). In addition, curcumin modulates M1/M2 macrophage polarization partly via AMPK. In conclusion, curcumin suppressed the MI-induced inflammation by modulating macrophage polarization partly via the AMPK pathway.

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Lymphangiogenesis in renal fibrosis arises from macrophages via VEGF-C/VEGFR3-dependent autophagy and polarization

Cell Death and Disease ◽

10.1038/s41419-020-03385-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Ying Zhang ◽

Conghui Zhang ◽

Lixi Li ◽

Xinjun Liang ◽

Peng Cheng ◽

...

Keyword(s):

Renal Fibrosis ◽

Macrophage Polarization ◽

Lymphatic Vessels ◽

Macrophage Phenotype ◽

M1 Macrophages ◽

M1 Macrophage ◽

Close Relationship ◽

Stage Renal Disease

AbstractInflammation plays a crucial role in the occurrence and development of renal fibrosis, which ultimately results in end-stage renal disease (ESRD). There is new focus on lymphangiogenesis in the field of inflammation. Recent studies have revealed the association between lymphangiogenesis and renal fibrosis, but the source of lymphatic endothelial cells (LECs) is not clear. It has also been reported that macrophages are involved in lymphangiogenesis through direct and indirect mechanisms in other tissues. We hypothesized that there was a close relationship between macrophages and lymphatic endothelial progenitor cells in renal fibrosis. In this study, we demonstrated that lymphangiogenesis occurred in a renal fibrosis model and was positively correlated with the degree of fibrosis and macrophage infiltration. Compared to resting (M0) macrophages and alternatively activated (M2) macrophages, classically activated (M1) macrophages predominantly transdifferentiated into LECs in vivo and in vitro. VEGF-C further increased M1 macrophage polarization and transdifferentiation into LECs by activating VEGFR3. It was suggested that VEGF-C/VEGFR3 pathway activation downregulated macrophage autophagy and subsequently regulated macrophage phenotype. The induction of autophagy in macrophages by rapamycin decreased M1 macrophage polarization and differentiation into LECs. These results suggested that M1 macrophages promoted lymphangiogenesis and contributed to newly formed lymphatic vessels in the renal fibrosis microenvironment, and VEGF-C/VEGFR3 signaling promoted macrophage M1 polarization by suppressing macrophage autophagy and then increased the transdifferentiation of M1 macrophages into LECs.

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CSIG-17. PRMT5 INHIBITION SENSITIZES GLIOBLASTOMA MODELS TO TRAMETINIB TREATMENT

Neuro-Oncology ◽

10.1093/neuonc/noaa215.129 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii31-ii31

Author(s):

Yoshihiro Otani ◽

Sriya Namagiri ◽

Shilpa Thammegowda ◽

Hannah Sur ◽

Ashis Chowdhury ◽

...

Keyword(s):

Cell Cycle Progression ◽

Survival Curve ◽

Primary Brain Tumor ◽

Oral Gavage ◽

Cycle Progression ◽

Tumor Bearing ◽

Nsg Mice ◽

Kaplan Meier ◽

Meier Survival Curve

Abstract INTRODUCTION Glioblastoma (GBM) is the most common malignant primary brain tumor. With limited effective therapeutic strategies, prognosis for GBM is very poor. Our previous study shows that the expression of Protein Arginine Methyltransferase 5 (PRMT5) is upregulated in GBM; its inhibition promotes anti-GBM effect through apoptosis and senescence of mature and immature tumor cells, respectively. In GBM, RAS-RAF- MEK-ERK signaling is aberrantly activated and promotes tumor growth. Therefore, MEK inhibitors, including trametinib are currently under investigation for GBM therapy. In this study, we tested whether inhibition of PRMT5 can enhance the anti-tumor efficacy of trametinib in GBM. METHODS Patient-derived primary GBM neurospheres (GBMNS) with transient PRMT5 knockdown were treated with trametinib and cell viability, proliferation, cell cycle progression, and western blot analysis were conducted. In vivo, PRMT5-intact and -depleted GBMNS were intracranially implanted in NSG mice and treated with trametinib by daily oral gavage, and tumor progression and mice survival rate were analyzed by MRI and Kaplan-Meier survival curve, respectively. RESULTS Trametinib treatment upregulated the expression of PRMT5 in GBMNS. Depletion of PRMT5 increased the cytotoxic effect of trametinib in GBMNS. In concurrence with the trametinib-induced PRMT5 upregulation, trametinib treatment increased the activity of AKT that was blocked with PRMT5 knockdown. In vivo, PRMT5-depletion extended the survival of the tumor bearing mice that further increased in combination with trametinib treatment. Interestingly, trametinib treatment alone had no survival benefit. CONCLUSION Trametinib treatment induces PRMT5 expression. Depletion of trametinib-induced PRMT5 expression sensitizes GBMNS for trametinib by inhibiting AKT activity.

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Reprogrammed M1 macrophages with inhibited STAT3, STAT6 and/or SMAD3 extends lifespan of mice with experimental carcinoma

ZHurnal «Patologicheskaia fiziologiia i eksperimental`naia terapiia» ◽

10.25557/0031-2991.2017.02.4-9 ◽

2017 ◽

pp. 4-9

Author(s):

С.В. Калиш ◽

С.В. Лямина ◽

А.А. Раецкая ◽

И.Ю. Малышев

Keyword(s):

Tumor Growth ◽

Culture Medium ◽

Ehrlich Carcinoma ◽

Macrophage Phenotype ◽

M1 Macrophages ◽

M1 Macrophage ◽

Ec Cells ◽

Experimental Carcinoma

Цель исследования. Репрограммирование М1 фенотипа макрофагов с ингибированными факторами транскрипции М2 фенотипа STAT3, STAТ6 и SMAD и оценка их влияния на развитие карциномы Эрлиха (КЭ) in vitro и in vivo. Методика. Рост опухоли иницировали in vitro путем добавления клеток КЭ в среду культивирования RPMI-1640 и in vivo путем внутрибрюшинной инъекции клеток КЭ мышам. Результаты. Установлено, что M1макрофаги и in vitro, и in vivo оказывают выраженный противоопухолевый эффект, который превосходит антиопухолевые эффекты М1, M1, M1 макрофагов и цисплатина. Заключение. М1 макрофаги с ингибированными STAT3, STAT6 и/или SMAD3 эффективно ограничивают рост опухоли. Полученные данные обосновывают разработку новой технологии противоопухолевой клеточной терапии. Objective. Reprogramming of M1 macrophage phenotype with inhibited M2 phenotype transcription factors, such as STAT3, STAT6 and SMAD and assess their impact on the development of Ehrlich carcinoma (EC) in vitro and in vivo . Methods. Tumor growth in vitro was initiated by addition of EC cells in RPMI-1640 culture medium and in vivo by intraperitoneal of EC cell injection into mice. Results. It was found that M1 macrophages have a pronounced anti-tumor effect in vitro , and in vivo , which was greater than anti-tumor effects of M1, M1, M1 macrophages and cisplatin. Conclusion. M1 macrophages with inhibited STAT3, STAT6 and/or SMAD3 effectively restrict tumor growth. The findings justify the development of new anti-tumor cell therapy technology.

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Hypoxic glioma-derived exosomes promote M2-like macrophage polarization by enhancing autophagy induction

Cell Death and Disease ◽

10.1038/s41419-021-03664-1 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Jianye Xu ◽

Jian Zhang ◽

Zongpu Zhang ◽

Zijie Gao ◽

Yanhua Qi ◽

...

Keyword(s):

Macrophage Polarization ◽

Autophagy Induction ◽

Antitumor Immunotherapy ◽

Novel Biomarkers ◽

And Migration ◽

Immunosuppressive Microenvironment ◽

Proliferation And Migration ◽

Glioma Progression

AbstractExosomes participate in intercellular communication and glioma microenvironment modulation, but the exact mechanisms by which glioma-derived exosomes (GDEs) promote the generation of the immunosuppressive microenvironment are still unclear. Here, we investigated the effects of GDEs on autophagy, the polarization of tumor-associated macrophages (TAMs), and glioma progression. Compared with normoxic glioma-derived exosomes (N-GDEs), hypoxic glioma-derived exosomes (H-GDEs) markedly facilitated autophagy and M2-like macrophage polarization, which subsequently promoted glioma proliferation and migration in vitro and in vivo. Western blot and qRT-PCR analyses indicated that interleukin 6 (IL-6) and miR-155-3p were highly expressed in H-GDEs. Further experiments showed that IL-6 and miR-155-3p induced M2-like macrophage polarization via the IL-6-pSTAT3-miR-155-3p-autophagy-pSTAT3 positive feedback loop, which promotes glioma progression. Our study clarifies a mechanism by which hypoxia and glioma influence autophagy and M2-like macrophage polarization via exosomes, which could advance the formation of the immunosuppressive microenvironment. Our findings suggest that IL-6 and miR-155-3p may be novel biomarkers for diagnosing glioma and that treatments targeting autophagy and the STAT3 pathway may contribute to antitumor immunotherapy.

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TRIM27 interacts with Iκbα to promote the growth of human renal cancer cells through regulating the NF-κB pathway

BMC Cancer ◽

10.1186/s12885-021-08562-5 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Chengwu Xiao ◽

Wei Zhang ◽

Meimian Hua ◽

Huan Chen ◽

Bin Yang ◽

...

Keyword(s):

Cell Lines ◽

Prognostic Indicator ◽

The Cancer Genome Atlas ◽

Mrna Levels ◽

Loss Of Function ◽

Protein Levels ◽

Kaplan Meier ◽

Cancer Genome Atlas

Abstract Background The tripartite motif (TRIM) family proteins exhibit oncogenic roles in various cancers. The roles of TRIM27, a member of the TRIM super family, in renal cell carcinoma (RCC) remained unexplored. In the current study, we aimed to investigate the clinical impact and roles of TRIM27 in the development of RCC. Methods The mRNA levels of TRIM27 and Kaplan–Meier survival of RCC were analyzed from The Cancer Genome Atlas database. Real-time PCR and Western blotting were used to measure the mRNA and protein levels of TRIM27 both in vivo and in vitro. siRNA and TRIM27 were exogenously overexpressed in RCC cell lines to manipulate TRIM27 expression. Results We discovered that TRIM27 was elevated in RCC patients, and the expression of TRIM27 was closely correlated with poor prognosis. The loss of function and gain of function results illustrated that TRIM27 promotes cell proliferation and inhibits apoptosis in RCC cell lines. Furthermore, TRIM27 expression was positively associated with NF-κB expression in patients with RCC. Blocking the activity of NF-κB attenuated the TRIM27-mediated enhancement of proliferation and inhibition of apoptosis. TRIM27 directly interacted with Iκbα, an inhibitor of NF-κB, to promote its ubiquitination, and the inhibitory effects of TRIM27 on Iκbα led to NF-κB activation. Conclusions Our results suggest that TRIM27 exhibits an oncogenic role in RCC by regulating NF-κB signaling. TRIM27 serves as a specific prognostic indicator for RCC, and strategies targeting the suppression of TRIM27 function may shed light on future therapeutic approaches.

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