International Journal of Biological Sciences
·
2024
·Vol. 20
·期 2
·516-536
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IF 8.2
Tian Shaoping,Wang Rui,Wang Yiting,Chen Ruibing,Lin Tianyu,Xiao Xuesong,Liu Xinyu,Ideozu Justin Eze,Geng Hua,Wang Yong,Yue Dan
A key player in mitochondrial respiration, p32, often referred to as C1QBP, is mostly found in the mitochondrial matrix. Previously, we showed that p32 interacts with DLAT in the mitochondria. Here, we found that p32 expression was reduced in ccRCC and suppressed progression and metastasis in ccRCC animal models. We observed that increasing p32 expression led to an increase in oxidative phosphorylation by interacting with DLAT, thus, regulating the activation of the pyruvate dehydrogenase complex (PDHc). Mechanistically, reduced p32 expression, in concert with DLAT, suppresses PDHc activity and the TCA cycle. Furthermore, our research discovered that p32 has a direct binding affinity for copper, facilitating the copper-induced oligomerization of lipo-DLAT specifically in ccRCC cells. This finding reveals an innovative function of the p32/DLAT/copper complex in regulating glycometabolism and the TCA cycle in ccRCC. Importantly, our research provides important new understandings of the underlying molecular processes causing the abnormal mitochondrial metabolism linked to this cancer.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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代谢紊乱
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产品关联
DOI
PubMed
高影响因子
Biomarkers in Medicine
·
2020
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IF 2.479
Mingfeng Xiang,Feng Du,Jing Dai,Ling Chen,Ruijin Geng,Huiming Huang,Baogang Xie
Aim: The discrimination of renal cell carcinoma from renal angiomyolipoma (RAML) is crucial for the effective treatment of each. Materials & methods: Serum samples were analyzed by nuclear magnetic resonance spectroscopy-based metabolomics and a number of metabolites were further quantified by HPLC–UV. Results: Clear-cell renal carcinoma (ccRCC) was characterized by drastic disruptions in energy, amino acids, creatinine and uric acid metabolic pathways. A logistic model for the differential diagnosis of RAML from ccRCC was established using the combination of serum levels of uric acid, the ratio of uric acid to hypoxanthine and the ratio of hypoxanthine to creatinine as variables with area under the curve of the receiver operating characteristic curve value of 0.907. Conclusion: Alterations in serum purine metabolites may be used as potential metabolic markers for the differential diagnosis of ccRCC and RAML.
研究领域:
肿瘤学
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代谢组学
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医学诊断
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DOI
高影响因子
Cell Death & Disease
·
2026
·
IF 12.2
Song Wei,Zhang Houliang,Wang Yidi,Xu Tianyuan,Ni Jinliang,Wang Guangchun,Zhang Haipeng,Mao Weipu,Wang Keyi,Peng Bo
Clear cell renal cell carcinoma (ccRCC) is a common urological malignancy with limited therapeutic options for advanced disease. Aberrant DNA methylation and dysregulated ferroptosis have both been implicated in ccRCC progression, yet the mechanisms connecting these processes remain incompletely defined. Here, we identify ZBTB10 as a suppressor of ccRCC progression that transcriptionally represses GPX4, a central inhibitor of ferroptosis. Mechanistically, ZBTB10 recruits DNMT1 to the GPX4 promoter, thereby increasing promoter methylation and silencing GPX4 expression. We further define a self-regulatory ZBTB10/DNMT1/FBXW4 loop that maintains this epigenetic state. FBXW4 acts as an E3 ubiquitin ligase that promotes DNMT1 degradation and directly ubiquitinates ZBTB10 to reduce its stability. In turn, ZBTB10 recruits DNMT1 to the FBXW4 promoter, increases promoter methylation, and suppresses FBXW4 transcription. This self-regulatory circuit stabilizes both ZBTB10 and DNMT1, sustains low GPX4 expression, and promotes ferroptosis in ccRCC cells, as evidenced by increased lipid peroxidation and reactive oxygen species accumulation. Together, these findings reveal an epigenetic mechanism linking ZBTB10 to ferroptosis in ccRCC and suggest that targeting the ZBTB10/DNMT1/FBXW4/GPX4 axis may provide a therapeutic strategy for limiting ccRCC progression.
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DOI
高影响因子
APOPTOSIS
·
2024
·
IF 6.1
Li Ziyao,Tian Ye,Zong Huafeng,Wang Xuelei,Li Dongyang,Keranmu Adili,Xin Shiyong,Ye Bowen,Bai Rong,Chen Weihua,Yang Guosheng,Ye Lin,Wang Siyan
Dysregulation of deubiquitination contributes to various diseases, including cancer, and aberrant expression of deubiquitinating enzymes is involved in carcinoma progression. As a member of the ovarian tumor (OTU) deubiquitinases, OTUD4 is considered a tumor suppressor in many kinds of malignancies. The biological characteristics and mechanisms of OTUD4 in clear cell renal cell carcinoma (ccRCC) remain unclear. The downregulation of OTUD4 in ccRCC was confirmed based on the TCGA database and a validation cohort of 30-paired ccRCC and para-carcinoma samples. Moreover, OTUD4 expression was detected by immunohistochemistry in 50 cases of ccRCC tissues, and patients with lower levels of OTUD4 showed larger tumor size ( p = 0.015). TCGA data revealed that patients with high expression of OTUD4 had a longer overall survival rate. In vitr o and in vivo studies revealed that downregulation of OTUD4 was essential for tumor cell growth and metastasis in ccRCC, and OTUD4 overexpression inhibited these malignant phenotypes. We further found that OTUD4 sensitized ccRCC cells to Erastin-induced ferroptosis, and ferrostain-1 inhibited OTUD4-induced ferroptotic cell death. Mechanistic studies indicated that OTUD4 functioned as an anti-proliferative and anti-metastasic factor through the regulation of RNA-binding protein 47 (RBM47)-mediated activating transcription factor 3 (ATF3). OTUD4 directly interacted with RBM47 and promoted its stability via deubiquitination events. RBM47 was critical in ccRCC progression by regulating ATF3 mRNA stability, thereby promoting ATF3-mediated ferroptosis. RBM47 interference abolished the suppressive role of OTUD4 overexpression in ccRCC. Our findings provide mechanistic insight into OTUD4 of ccRCC progression and indicate a novel critical pathway OTUD4/RBM47/ATF3 may serve as a potential therapeutic pathway for ccRCC.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
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肿瘤学
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DOI
PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2024
·Vol. 28
·期 6
·e18186
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IF 4.3
Bo Guan,Ming Li,Di Cui,Chen Shen,Zongyao Hao,Xiaowei Li
Clear cell renal cell carcinoma (ccRCC) represents a significant challenge in oncology, primarily due to its resistance to conventional therapies. Understanding the tumour microenvironment (TME) is crucial for developing new treatment strategies. This study focuses on the role of amyloid precursor protein (APP) in tumour-associated macrophages (TAMs) within the ccRCC TME, exploring its potential as a prognostic biomarker. Basing TAM-related genes, the prognostic model was important to constructed. Employing advanced single-cell transcriptomic analysis, this research dissects the TME of ccRCC at an unprecedented cellular resolution. By isolating and examining the gene expression profiles of individual cells, particularly focusing on TAMs, the study investigates the expression levels of APP and their association with the clinical outcomes of ccRCC patients. The analysis reveals a significant correlation between the expression of APP in TAMs and patient prognosis in ccRCC. Patients with higher APP expression in TAMs showed differing clinical outcomes compared to those with lower expression. This finding suggests that APP could serve as a novel prognostic biomarker for ccRCC, providing insights into the disease progression and potential therapeutic targets. This study underscores the importance of single-cell transcriptomics in understanding the complex dynamics of the TME in ccRCC. The correlation between APP expression in TAMs and patient prognosis highlights APP as a potential prognostic biomarker. However, further research is needed to validate these findings and explore the regulatory mechanisms and therapeutic implications of APP in ccRCC.
研究领域:
肿瘤学
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分子生物学
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转录组学
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癌症免疫学
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DOI
PubMed
高影响因子
Genes & Genomics
·
2022
·Vol. 45
·期 1
·1-11
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IF 2.164
Cao Qingfei,Ma Jiaji,Li Weitao,Hong Peng,Shen Tong,Tong Ming
Background Guanine nucleotide-binding protein 2 (GNBP2) is a GTPase that has critical roles in host immunity and some types of cancer, but its function in clear cell renal cell carcinoma (ccRCC) is not fully understood. Objective This work explored the role of GNBP2 in ccRCC progression and the underlying molecular mechanism. Methods Two public human cancer databases TNMplot and TISIDB were employed to analyze the expression pattern of GNBP2 during ccRCC progression and the correlation between GNBP2 expression and clinical features of ccRCC patients. GNBP2 functions in ccRCC cells were determined by EdU staining, flow cytometry, scratch wound assay, transwell assay, and xenograft model. Gene expression was evaluated using qPCR, Western blot, immunofluorescence staining, and immunohistochemical staining. Results GNBP2 expression was significantly elevated in ccRCC tissues and increased gradually with the increasing tumor grades. Patients with higher GNBP2 expression had shorter overall survival times. Knockdown of GNBP2 suppressed tumor cell proliferation and cell cycle progression and reduced the capability of migration and invasion, while GNBP2 overexpression exhibited protumor effects. GNBP2 silencing by RNA interference significantly inhibited the tumor growth of tumor-bearing nude mice and decreased the proliferation marker Ki67. Mechanistically, GNBP2 downregulation suppressed the STAT3 signaling transduction, as it reduced the phosphorylation of STAT3 and modulated the expression of the target genes, including c-Myc, MMP2, N-cadherin, and E-cadherin. Conclusion These findings reveal that GNBP2 promotes ccRCC progression by regulating STAT3 signaling transduction, indicating that GNBP2 might be a promising molecular target for ccRCC therapy.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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癌症生物学
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产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
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2024
·
IF 10
Xiaotong Xu,Huimin Li,Binghua Tong,Weijie Zhang,Xiaofei Wang,Yue Wang,Geng Tian,Zhaowei Xu,Guilong Zhang
Herein, we designed a ccRCC targeting nanodrug to enhance chemodynamic therapy (CDT) as well as activate cuproptosis and tumor immunotherapy via ccRCC cell membrane modifying CuO@Gd 2 O 3 yolk-like particles (CGYL) loaded with lactate oxidase (LOx) (mCGYL-LOx). Benefiting from the homologous targeting effect of Renca cell membranes, the mCGYS-LOx could be effectively internalized by Renca cells, opened the “gate”, and then released LOx and copper ions. LOx could catalyze excessive lactate in Renca cells into H 2 O 2 , following that the produced H 2 O 2 was further converted by copper ions to the highly toxic ·OH, contributing to tumor CDT. Meanwhile, the excessive copper ions effectively triggered tumor cuproptosis. These synergistic effects induced the release of damage associated molecular patterns and activated immunogenic cell death, leading to DC maturation and infiltration of immune effector cells. Moreover, LOx-mediated lactate consumption downregulated the expression of PD-L1, crippling tumor immune escape. In addition, the mCGYL-LOx improved T 1 -weighted MRI signal, allowing for accurate diagnosis of ccRCC. This study demonstrated that the mCGYL-LOx had great potential for improving therapy of ccRCC via the synergistic actions of CDT and cuproptosis as well as immunotherapy. This article is protected by copyright. All rights reserved
研究领域:
肿瘤学
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纳米技术
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免疫疗法
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生物医学工程
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分子生物学
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产品关联
DOI
PubMed
高影响因子
International Journal of Biological Sciences
·
2022
·
IF 10.75
Wuping Yang,Kenan Zhang,Zedan Zhang,Jingcheng Zhou,Lei Li,Yawei Xu,Jianhui Qiu,Lin Cai,Yanqing Gong,Kan Gong
Our previous study has proved that down-regulation of CLDN10 (Claudin-10) in ccRCC (clear cell renal cell carcinoma) was closely related to tumor metastasis and predicted an unfavorable prognosis by analyzing TCGA-KIRC data. However, the effects of CLDN10 on the progression of ccRCC and its mechanisms of action remain elusive. During the study, a large number of clinical samples were utilized to verify the reduced expression of CLDN10 in ccRCC and its association with tumor metastasis and poor prognosis, and our results confirmed that lower CLDN10 expression was an independent predictor of shorter OS (HR: 4.0860, 95%CI: 2.4737-6.7490, P<0.0001) and DFS (HR: 4.3680, 95%CI: 2.2800-8.3700, P<0.0001) in metastatic ccRCC patients. CLDN10 overexpression accelerated cell apoptosis and restrained cell proliferation, migration and invasion in vitro . Besides, CLDN10 overexpression suppressed ccRCC growth and lung metastasis and promoted apoptosis in orthotopic models. Mechanistically, we found that CLDN10 overexpression up-regulated the acetylation and expression levels of ATP5O (ATP synthase subunit O, mitochondrial), leading to the dysfunction of mitochondrial, thereby suppressing the growth and metastasis of ccRCC through increasing the levels of NDUFS2, ROS, Cleaved-Caspase 3, E-cadherin and SDHB and decreasing the levels of N-cadherin and mitochondrial membrane potential. Moreover, knockdown of ATP5O expression based on the overexpression of CLDN10 could reverse the increase in NDUFS2, ROS, Cleaved-Caspase 3, E-cadherin and SDHB levels, the decrease in N-cadherin and mitochondrial membrane potential levels and the inhibition of ccRCC phenotypes caused by CLDN10 overexpression. Taken together, these findings for the first time illuminate the mechanism by which CLDN10 overexpression suppresses the growth and metastasis of ccRCC.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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癌症研究
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DOI
PubMed
高影响因子
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