Antithrombotic Effects of a FXI Antisense Oligonucleotide in Mice

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3076-3076
Author(s):  
Hong Zhang ◽  
Chenguang Zhao ◽  
Jeff Crosby ◽  
Curt Mazur ◽  
Susan M. Freier ◽  
...  
Keyword(s):  
Mouse Model ◽  
Dose Range ◽  
Safety Margin ◽  
Mrna Levels ◽  
Vessel Occlusion ◽  
Antithrombotic Activity ◽  
Protein Levels ◽  
2Nd Generation ◽  
Vessel Injury ◽  
Antithrombotic Effects

Abstract FXI, a component of the intrinsic pathway of coagulation, contributes to the generation of thrombin and is also activated by thrombin on the surface of platelets, resulting in further amplification of the coagulation process. Reports have shown that FXI deficiency in mice or in humans is generally not associated with major bleeding yet is associated with reduced risk for thromboembolic disease. To determine whether targeting FXI with antisense oligonucleotides (ASOs) can produce antithrombotic activity without increasing risk of bleeding, a series of 2nd Generation 2′-O-methoxyethyl modified ASOs were identified that specifically reduce levels of FXI in mice and were evaluated for antithrombotic activity and bleeding potential. Mice were dosed with FXI ASO (ISIS 404071) subcutaneously for three weeks. FXI ASO treatment resulted in a dosedependent and specific reduction in FXI mRNA levels in liver and FXI protein levels in plasma with an ED50 of 3.2 mg/kg. These reductions in FXI levels correlated well with a prolongation of aPTT with no effects on PT prolongation. The anticoagulant effect of FXI ASO treatment also correlated well with antithrombotic activity in a 10% FeCl3 induced IVC thrombosis mouse model across a wide dose range. Furthermore, FXI ASO treatment was generally well tolerated and no prolongation of tail bleeding time was observed at any dose tested, indicating a broad safety margin for FXI ASO targeting. Additional studies using intravital microscopy to study the effects of FXI ASO treatment on thrombosis formation in the mesenteric vein following 10% FeCl3 injury demonstrated that FXI ASO treatment significantly impeded platelet aggregation at the site of vessel injury, thrombus growth and vessel occlusion. Studies to further evaluate the safety of FXI targeting were conducted using a mouse model of intracerebral hemorrhage induced by intracranial injection of collagenase. In this model, FXI ASO treatment had no effect on hemorrhagic size, neurologic deficit score, or mortality at doses well above that needed to produce maximal antithrombotic activity. These results strongly suggest that FXI is an effective and safe target for antithrombotic therapy and that antisense drug technology could be an attractive approach to specifically target FXI for the treatment of thrombotic disorders.

FXII Antisense Oligonucleotide Mediated Depletion Results In Effective Anticoagulation without Bleeding Risk.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1149-1149
Author(s):  
Jeff R. Crosby ◽  
Dacao Gao ◽  
Chenguang Zhao ◽  
Chris May ◽  
Robert MacLeod ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Dose Range ◽  
Safety Margin ◽  
Vena Cava ◽  
Bleeding Risk ◽  
Coagulation Factors ◽  
Bleeding Tendency ◽  
Mrna Levels ◽  
Clotting Factors ◽  
Antithrombotic Activity

Abstract Abstract 1149 Human clinical efficacy has been demonstrated with antisense oligonucleotides (ASOs) in several disease indications, including dyslipidemia, cancer, diabetes and multiple sclerosis. Coagulation factors are attractive targets for antisense therapeutics for several reasons. The liver is principally responsible for production of coagulation factors and is an organ which is highly sensitive to ASO drugs. ASOs are highly specific, and thus we can selectively evaluate multiple coagulation factors to determine their roles in thrombosis, bleeding, and other processes. Employing antisense technology we selectively reduced levels of several individual clotting factors and compared the relative risk/benefit profiles. Antithrombotic activity was determined following ferric chloride induced thrombosis in the inferior vena cava and bleeding tendency was measured by blood volume loss following tail nick. ASOs targeting several clotting factors were studied, including factors FII, FVII, FIX, FXI and FXII. Previously we characterized the beneficial effects of targeting FXI, demonstrating antithrombotic effects without increased bleeding risk. Here, we describe the effects of targeting another member of the intrinsic pathway, FXII. FXII ASO treatment resulted in a dose-dependent and specific reduction in FXII mRNA levels in liver. These reductions in FXII levels correlated well with a prolongation of aPTT with no effects on PT prolongation. The anticoagulant effect of FXII ASO treatment also correlated well with antithrombotic activity in a FeCl3 induced IVC thrombosis mouse model across a wide dose range. In addition to the venous thrombosis model, FXII ASO treatment was effective across a wide dose range in a model of arterial thrombosis. Furthermore, FXII ASO treatment was well tolerated and no prolongation of tail bleeding time was observed at any dose tested, indicating a broad safety margin for FXII ASO targeting (in mice). In addition, FXII inhibition was protective in a mouse TF driven pulmonary embolism model. Inhibiting coagulation factors with ASOs is highly specific and offers an attractive approach to identifying optimal antithrombotic targets as well as human therapeutics for the treatment of coagulation related disorders with the potential for improved safety profiles. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Motor Neuron Disease Mouse Model hSOD1-G93A Presents a Non-canonical Profile of Senescence Biomarkers in The Spinal Cord

2020 ◽  
Author(s):  
Pascual Torres ◽  
Carlos Anerillas ◽  
Mario Encinas ◽  
Monica Povedano ◽  
Pol Andrés-Benito ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mouse Model ◽  
Mrna Levels ◽  
Cryptic Exon ◽  
Protein Levels ◽  
Splicing Variant ◽  
Parkinson’S Diseases ◽  
Secretory Phenotype ◽  
Lumbar Spinal ◽  
Lateral Sclerosis

Abstract Recent evidence demonstrates a pathological role for senescent cells in Alzheimer’s and Parkinson’s diseases. The present study aimed to show senescence mechanisms including senescence-associated secretory phenotype (SASP) in the familial amyotrophic lateral sclerosis (ALS) transgenic mouse model hSOD1-G93A. We evaluated, as senescence biomarkers, the expression of p16 and p21 with reverse-transcriptase quantitative PCR (RT-qPCR), immunofluorescence (IF), and immunohistochemistry (IHC), as well as the senescence-associated β galactosidase (SA-β-gal) activity in the lumbar spinal cords (LSC) of this model. As SASP markers, we quantified the mRNA levels of Il1a, Il6, Ifna, and Ifnb. Furthermore, we explored if an alteration of alternative splicing is associated with senescence phenomena in this model. Thus, we quantified the Adipor2 cryptic exon inclusion levels, a specific splicing variant repressed by TAR-DNA binding of 43 kDa (TDP-43), using RT-qPCR. Our results show an atypical senescence-profile in LSC from transgenic mice, increasing p16 and p21 mRNA and protein levels in glial cells with a mostly cytoplasmic pattern, without the canonical increase in SA-beta-gal activity in these cells. Consistent with enhanced SASP, there is an increase in Il1a and Il6 expression. Also, TDP-43 splicing activity is compromised in this ALS model, in a direct relationship with the increase in p16 expression. However, senolytic drug Navitoclax -with reported benefits in Alzheimer and Parkinson disease mouse models - does not alter the present model’s disease progression. Navitoclax neither eliminates cells expressing senescence and nor represses the expression of SASP related genes. Globally, our findings support the existence of a non-canonical profile of senescence biomarkers in the LSC of the ALS model hSOD1-G93A.

scholarly journals The motor neuron disease mouse model hSOD1-G93A presents a non-canonical profile of senescence biomarkers in the spinal cord

2021 ◽  
Author(s):  
Pascual Torres ◽  
Carlos Anerillas ◽  
Mario Encinas ◽  
Monica Povedano ◽  
Pol Andrés-Benito ◽  
...  
Keyword(s):  
Mouse Model ◽  
Mrna Levels ◽  
Cryptic Exon ◽  
Protein Levels ◽  
Splicing Variant ◽  
Parkinson’S Diseases ◽  
Secretory Phenotype ◽  
Lumbar Spinal ◽  
Lateral Sclerosis ◽  
P16 Expression

Abstract Recent evidence demonstrates a pathological role for senescent cells in Alzheimer’s and Parkinson’s diseases. The present study aimed to show senescence mechanisms including senescence-associated secretory phenotype (SASP) in the familial amyotrophic lateral sclerosis (ALS) transgenic mouse model hSOD1-G93A. We evaluated, as senescence biomarkers, the expression of p16 and p21 with reverse-transcriptase quantitative PCR (RT-qPCR), immunofluorescence (IF), and immunohistochemistry (IHC), as well as the senescence-associated b galactosidase (SA-b-gal) activity in the lumbar spinal cords (LSC) of this model. As SASP markers, we quantified the mRNA levels of Il1a, Il6, Ifna, and Ifnb. Furthermore, we explored if an alteration of alternative splicing is associated with senescence phenomena in this model. Thus, we quantified the Adipor2 cryptic exon inclusion levels, a specific splicing variant repressed by TAR-DNA binding of 43 kDa (TDP-43), using RT-qPCR. Our results show an atypical senescence-profile in LSC from transgenic mice, increasing p16 and p21 mRNA and protein levels in glial cells with a mostly cytoplasmic pattern, without the canonical increase in SA-beta-gal activity in these cells. Consistent with enhanced SASP, there is an increase in Il1a and Il6 expression. Also, TDP-43 splicing activity is compromised in this ALS model, in a direct relationship with the increase in p16 expression. However, senolytic drug Navitoclax -with reported benefits in Alzheimer and Parkinson disease mouse models - does not alter the present model’s disease progression. Navitoclax neither eliminates cells expressing senescence and nor represses the expression of SASP related genes. Globally, our findings support the existence of a non-canonical profile of senescence biomarkers in the LSC of the ALS model hSOD1-G93A.

scholarly journals Acute Exposure to Cigarette Smoking Followed by Myocardial Infarction Aggravates Renal Damage in an In Vivo Mouse Model

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Firas Kobeissy ◽  
Abdullah Shaito ◽  
Abdullah Kaplan ◽  
Lama Baki ◽  
Hassan Hayek ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cigarette Smoking ◽  
Mouse Model ◽  
Renal Dysfunction ◽  
Renal Damage ◽  
Smooth Muscle Actin ◽  
Tissue Growth ◽  
Mrna Levels ◽  
Protein Levels

Cigarette smoking (S) is a risk factor for progressive chronic kidney disease, renal dysfunction, and renal failure. In this study, the effect of smoking on kidney function was investigated in a mouse model of myocardial infarction (MI) using 4 groups: control (C), smoking (S), MI, and S+MI. Histological analysis of S+MI group showed alterations in kidney structure including swelling of the proximal convoluted tubules (PCTs), thinning of the epithelial lining, focal loss of the brush border of PCTs, and patchy glomerular retraction. Molecular analysis revealed that nephrin expression was significantly reduced in the S+MI group, whereas sodium-hydrogen exchanger-1 (NHE-1) was significantly increased, suggesting altered glomerular filtration and kidney functions. Moreover, S+MI group, but not S alone, showed a significant increase in the expression of connective tissue growth factor (CTGF) and fibrotic proteins fibronectin (FN) and α-smooth muscle actin (SMA), in comparison to controls, in addition to a significant increase in mRNA levels of IL-6 and TNF-α inflammatory markers. Finally, reactive oxygen species (ROS) production was significantly accentuated in S+MI group concomitant with a significant increase in NOX-4 protein levels. In conclusion, smoking aggravates murine acute renal damage caused by MI at the structural and molecular levels by exacerbating renal dysfunction.

scholarly journals The Motor Neuron Disease Mouse Model hSOD1-G93A Presents a Non-canonical Profile of Senescence Biomarkers in the Spinal Cord

2020 ◽  
Author(s):  
Pascual Torres ◽  
Carlos Anerillas ◽  
Mario Encinas ◽  
Monica Povedano ◽  
Pol Andrés-Benito ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mouse Model ◽  
Mrna Levels ◽  
Cryptic Exon ◽  
Protein Levels ◽  
Splicing Variant ◽  
Parkinson’S Diseases ◽  
Secretory Phenotype ◽  
Lumbar Spinal ◽  
Lateral Sclerosis

Abstract Recent evidence demonstrates a pathological role for senescent cells in Alzheimer’s and Parkinson’s diseases. The present study aimed to show senescence mechanisms including senescence-associated secretory phenotype (SASP) in the familial amyotrophic lateral sclerosis (ALS) transgenic mouse model hSOD1-G93A. We evaluated, as senescence biomarkers, the expression of p16 and p21 with reverse-transcriptase quantitative PCR (RT-qPCR), immunofluorescence (IF), and immunohistochemistry (IHC), as well as the senescence-associated β galactosidase (SA-β-gal) activity in the lumbar spinal cords (LSC) of this model. As SASP markers, we quantified the mRNA levels of Il1a, Il6, Ifna, and Ifnb. Furthermore, we explored if an alteration of alternative splicing is associated with senescence phenomena in this model. Thus, we quantified the Adipor2 cryptic exon inclusion levels, a specific splicing variant repressed by TAR-DNA binding of 43 kDa (TDP-43), using RT-qPCR. Our results show an atypical senescence-profile in LSC from transgenic mice, increasing p16 and p21 mRNA and protein levels in glial cells with a mostly cytoplasmic pattern, without the canonical increase in SA-beta-gal activity in these cells. Consistent with enhanced SASP, there is an increase in Il1a and Il6 expression. Also, TDP-43 splicing activity is compromised in this ALS model, in a direct relationship with the increase in p16 expression. However, senolytic drug Navitoclax -with reported benefits in Alzheimer and Parkinson disease mouse models - does not alter the present model’s disease progression. Navitoclax neither eliminates cells expressing senescence and nor represses the expression of SASP related genes. Globally, our findings support the existence of a non-canonical profile of senescence biomarkers in the LSC of the ALS model hSOD1-G93A.

Antisense Oligonucleotide Mediated Depletion of Factor XI Prevents Vascular Occlusion in An Experimental Thrombosis Model in Primates

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2250-2250
Author(s):  
Jeff R. Crosby ◽  
Ulla M Marzec ◽  
Chenguang Zhao ◽  
Dacao Gao ◽  
Alexey S Revenko ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Subcutaneous Administration ◽  
Vascular Occlusion ◽  
Mrna Levels ◽  
Antithrombotic Effect ◽  
Antithrombotic Activity ◽  
Protein Levels ◽  
Thrombosis Model ◽  
Intravascular Thrombosis ◽  
Increased Risk

Abstract Abstract 2250 It has recently been demonstrated that the intrinsic pathway is an important contributor to pathologic intravascular thrombosis, suggesting that targeting this pathway may yield effective antithrombotic agents. Furthermore, FXI deficiency is not associated with spontaneous bleeding in humans, and deficiency of a contact factor does not cause abnormal bleeding. We have previously shown that treatment with FXI Antisense Oligonucleotides (ASOs) produces potent, dose-dependent antithrombotic activity in various venous and arterial murine thrombosis models. In the current study we characterize the antithrombotic effects of FXI ASOs in a non-human primate model. Subcutaneous administration of FXI ASOs in cynomologus monkeys resulted in a dose-and time-dependant decrease in FXI mRNA levels in liver (up to 90%), decreased FXI protein and activity levels measured in plasma, and prolonged activated partial thromboplastin times (aPTT). Importantly, FXI depletion in monkeys was not associated with an increased risk of bleeding. Recent studies demonstrated that complete inhibition (>99%) of FXI by a monoclonal antibody reduced thrombin generation and prevented vascular occlusion in a collagen-coated graft inserted into a baboon arteriovenous shunt (Tucker et al., Blood 2009). In the present study, we set out to determine the relationship between FXI levels and antithrombotic activity, and in particular, the minimal level of FXI reduction required to produce an antithrombotic effect in a baboon thrombosis model. Using the FXI monoclonal antibody, we demonstrate that ∼50% inhibition of FXI levels produces antithrombotic activity in baboons. Next we applied baboon-specific FXI ASOs and demonstrated reductions in FXI protein levels and activity, with corresponding increases in aPTT levels. Baboons were then treated with FXI ASOs in a manner that would produce ∼50% reduction of FXI protein levels and measured anti-thrombotic activity. Similar to the antibody approach, ASO-mediated reduction of FXI plasma levels ≥ 50% resulted in a potent antithrombotic effect. Furthermore, reductions in FXI levels do not increase bleeding times in baboons. These results further support the development of FXI ASOs for antithrombotic therapy with the potential for a superior safety profile compared to currently available anticoagulants. Disclosures: Crosby: Isis Pharmaceuticals: Employment. Zhao:Isis Pharmaceuticals: Employment. Gao:Isis Pharmaceuticals: Employment. Revenko:Isis Pharmaceuticals: Employment. MacLeod:Isis Pharmaceuticals: Employment. Gruber:Aronora, LLC: Consultancy, Equity Ownership. Monia:Isis Pharmaceuticals: Employment.

scholarly journals The Motor Neuron Disease Mouse Model hSOD1-G93A Presents a Non-canonical Profile of Senescence Biomarkers in the Spinal Cord

2020 ◽  
Author(s):  
Pascual Torres ◽  
Carlos Anerillas ◽  
Mario Encinas ◽  
Monica Povedano ◽  
Pol Andrés-Benito ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mouse Model ◽  
Mrna Levels ◽  
Cryptic Exon ◽  
Protein Levels ◽  
Splicing Variant ◽  
Parkinson’S Diseases ◽  
Secretory Phenotype ◽  
Lumbar Spinal ◽  
Lateral Sclerosis

Abstract Recent evidence demonstrates a pathological role for senescent cells in Alzheimer’s and Parkinson’s diseases. The present study aimed to show senescence mechanisms including senescence-associated secretory phenotype (SASP) in the familial amyotrophic lateral sclerosis (ALS) transgenic mouse model hSOD1-G93A. We evaluated, as senescence biomarkers, the expression of p16 and p21 with reverse-transcriptase quantitative PCR (RT-qPCR), immunofluorescence (IF), and immunohistochemistry (IHC), as well as the senescence-associated β galactosidase (SA-β-gal) activity in the lumbar spinal cords (LSC) of this model. As SASP markers, we quantified the mRNA levels of Il1a, Il6, Ifna, and Ifnb. Furthermore, we explored if an alteration of alternative splicing is associated with senescence phenomena in this model. Thus, we quantified the Adipor2 cryptic exon inclusion levels, a specific splicing variant repressed by TAR-DNA binding of 43 kDa (TDP-43), using RT-qPCR. Our results show an atypical senescence-profile in LSC from transgenic mice, increasing p16 and p21 mRNA and protein levels in glial cells with a mostly cytoplasmic pattern, without the canonical increase in SA-beta-gal activity in these cells. Consistent with enhanced SASP, there is an increase in Il1a and Il6 expression. Also, TDP-43 splicing activity is compromised in this ALS model, in a direct relationship with the increase in p16 expression. However, senolytic drug Navitoclax -with reported benefits in Alzheimer and Parkinson disease mouse models - does not alter the present model’s disease progression. Navitoclax neither eliminates cells expressing senescence and nor represses the expression of SASP related genes. Globally, our findings support the existence of a non-canonical profile of senescence biomarkers in the LSC of the ALS model hSOD1-G93A.

The Effects of Vitamin K1 and Warfarin on Prothrombin Expression in Human Hepatoblastoma (HepG2) Cells

1992 ◽  
Vol 68 (01) ◽  
pp. 040-047 ◽  
Author(s):  
C Scott Jamison ◽  
Bryan F Burkey ◽  
Sandra J Friezner Degen
Keyword(s):  
Total Protein ◽  
Hepg2 Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Response Analysis ◽  
Secreted Protein ◽  
Mrna Levels ◽  
Vitamin K1 ◽  
Maximal Increase ◽  
Protein Levels ◽  
Warfarin Treatment

SummaryCultures of human hepatoblastoma (HepG2) cells were treated with vitamin K1 or warfarin and prothrombin antigen and mRNA levels were determined. With 3 and 6 h of 10 µg vitamin K1 treatment secreted prothrombin antigen levels, relative to total secreted protein levels, were increased 1.5-fold and 2.1-fold, respectively, over ethanol-treated control levels as determined by an enzyme-linked immunosorbent assay. Dose-response analysis with 3 h of 25 µg/ml vitamin K1 treatment demonstrated a maximal increase of 2.0-fold in secreted prothrombin antigen levels, relative to total secreted protein levels, over ethanol-treated control levels. Pulse-chase analysis with 35S-methionine and immunoprecipitation of 35S-labelled prothrombin demonstrated that, with vitamin K1 treatment (25 µg/ml, 3 h), the rate of prothrombin secretion increased approximately 2-fold and the total amount (intra- and extracellular) of prothrombin synthesized increased approximately 50% over ethanol-treated control levels. Warfarin treatment (1, 5, or 10 µg/ml, 24 h) resulted in decreases in secreted prothrombin antigen levels, relative to total protein levels to approximately 85%, 87% or 81% of ethanol-treated control levels. Analysis of total RNA isolated from these cultures by Northern and solution hybridization techniques demonstrated that prothrombin mRNA was approximately 2.1 kb and that neither vitamin K1 nor warfarin treatment affected the quantity of prothrombin mRNA (ranging from 240–350 prothrombin mRNA molecules per cell). These results demonstrate that vitamin K1 and warfarin, in addition to effects on γ-carboxylation, affect prothrombin synthesis post-transcriptionally, perhaps influencing translation, post-translational processing and/or secretion mechanisms.

Negative Correlation Between Serum Levels of Homocysteine and Apolipoprotein M

2019 ◽  
Vol 19 (2) ◽  
pp. 120-126
Author(s):  
J. Wei ◽  
Y. Yu ◽  
Y. Feng ◽  
J. Zhang ◽  
Q. Jiang ◽  
...  
Keyword(s):  
Negative Correlation ◽  
Hepg2 Cells ◽  
Serum Levels ◽  
Significant Negative Correlation ◽  
Mrna Levels ◽  
Rt Pcr ◽  
Apolipoprotein M ◽  
Protein Mass ◽  
Protein Levels ◽  
Phosphoinositide 3 Kinase

Background: Homocysteine (Hcy) has been suggested as an independent risk factor for atherosclerosis. Apolipoprotein M (apoM) is a constituent of the HDL particles. The goal of this study was to examine the serum levels of homocysteine and apoM and to determine whether homocysteine influences apoM synthesis. Methods: Serum levels of apoM and Hcy in 17 hyperhomocysteinemia (HHcy) patients and 19 controls were measured and their correlations were analyzed. Different concentrations of homocysteine (Hcy) and LY294002, a specific phosphoinositide 3- kinase (PI3K) inhibitor, were used to treat HepG2 cells. The mRNA levels were determined by RT-PCR and the apoM protein mass was measured by western blot. Results: We found that decreased serum apoM levels corresponded with serum HDL levels in HHcy patients, while the serum apoM levels showed a statistically significant negative correlation with the serum Hcy levels. Moreover, apoM mRNA and protein levels were significantly decreased after the administration of Hcy in HepG2 cells, and this effect could be abolished by addition of LY294002. Conclusions: resent study demonstrates that Hcy downregulates the expression of apoM by mechanisms involving the PI3K signal pathway.

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

BMC Cancer ◽  
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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