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Cheng J, Liu O, Bin X, Tang Z. FBXO2 as a switch guides a special fate of tumor clones evolving into a highly malignant transcriptional subtype in oral squamous cell carcinoma. Apoptosis 2025; 30:167-184. [PMID: 39487312 DOI: 10.1007/s10495-024-02033-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/13/2024] [Indexed: 11/04/2024]
Abstract
Tumors comprise a heterogeneous collection of tumor cells with distinct genetic and phenotypic characteristics that differentially promote malignant progression. Therefore, it is essential to depict the heterogeneous landscape of clones for understanding the cancer biology and overcoming the resistance of cancer therapy. To determine the dynamic clonal feature of OSCC, we constructed the evolutionary trajectory of tumor cells based on single-cell RNA sequencing data. A special transcriptional states of clones with distinct highly malignant features was identified, and FBXO2 was determined as the key switch gene causing the transition of tumor cells into this special state. FBXO2 exhibited a significantly high expression in OSCC than normal samples, especially in those with high clinical stages. The knockdown or overexpression of FBXO2 in OSCC cells correspondingly inhibited or promoted the abilities of proliferation, G1-S phase transition, migration, invasion, EMT, and resisting apoptosis. Moreover, FBXO2 was indicated to be involved in an intricate network to regulate multiple processes, modifying the interactions between tumor cells and other cells and thus defining different functional subtypes of tumor cells to affect tumor progression. These results provide new insights into clonal fate and pave the way for more effective therapy of OSCC.
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Affiliation(s)
- Jingyi Cheng
- Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, 410008, Hunan, China
- Hunan Key Laboratory of Oral Health Research & Hunan Clinical Research Center of Oral Major Diseases and Oral Health & Academician Workstation for Oral-Maxilofacial and Regenerative Medicine, Central South University, Changsha, 410008, Hunan, China
| | - Ousheng Liu
- Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, 410008, Hunan, China
- Hunan Key Laboratory of Oral Health Research & Hunan Clinical Research Center of Oral Major Diseases and Oral Health & Academician Workstation for Oral-Maxilofacial and Regenerative Medicine, Central South University, Changsha, 410008, Hunan, China
| | - Xin Bin
- Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, 410008, Hunan, China.
- Hunan Key Laboratory of Oral Health Research & Hunan Clinical Research Center of Oral Major Diseases and Oral Health & Academician Workstation for Oral-Maxilofacial and Regenerative Medicine, Central South University, Changsha, 410008, Hunan, China.
- Department of Oral and Maxillofacial Surgery, Xiangya Stomatological Hospital of Central South University, Central South University, No.72, Xiangya Road, Changsha, 410008, Hunan, P. R. China.
- Hunan Key Laboratory of Oral Health Research & Hunan 3D Printing Engineering Research Center of Oral Care & Hunan Clinical Research Center of Oral Major Diseases and Oral Health & Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, 410008, Hunan, P. R. China.
| | - Zhangui Tang
- Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, 410008, Hunan, China.
- Hunan Key Laboratory of Oral Health Research & Hunan Clinical Research Center of Oral Major Diseases and Oral Health & Academician Workstation for Oral-Maxilofacial and Regenerative Medicine, Central South University, Changsha, 410008, Hunan, China.
- Department of Oral and Maxillofacial Surgery, Xiangya Stomatological Hospital of Central South University, Central South University, No.72, Xiangya Road, Changsha, 410008, Hunan, P. R. China.
- Hunan Key Laboratory of Oral Health Research & Hunan 3D Printing Engineering Research Center of Oral Care & Hunan Clinical Research Center of Oral Major Diseases and Oral Health & Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, 410008, Hunan, P. R. China.
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Gong D, Jian N, Zhou YT, Wang J. Proteomic analysis of HeLa cells after stable transfection with the Chlamydia trachomatis CT143 gene. Gene 2025; 933:148982. [PMID: 39374816 DOI: 10.1016/j.gene.2024.148982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 09/06/2024] [Accepted: 10/02/2024] [Indexed: 10/09/2024]
Abstract
BACKGROUND The CT143 protein of Chlamydia trachomatis (Ct) is a key immunodominant antigen and candidate type-III secretion substrate. Although CT143 expression has not been detected in the cytosol of infected cells, it is known to interfere with the physiological behavior of HeLa cells. This study aims to investigate how the CT143 protein affects the protein expression profile of HeLa cells, providing a basis for further research into Ct's pathogenic mechanisms. METHODS We constructed a stably transfected HeLa cell line, pCD513B-1-CT143-HeLa, and a control cell line, pCD513B-1-HeLa. Protein expression profiles of these cell lines were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Differentially expressed proteins were identified, constructed into a database, and verified using parallel reaction monitoring (PRM). Bioinformatics software facilitated the preliminary analysis of the biological functions of these differential proteins. RESULTS A total of 221 host proteins were differentially expressed, with 68 upregulated and 153 downregulated. These variations influence the regulation of peptidase activity and are crucial in biological processes such as cell secretion and protease activity. Significant changes were noted in protein processing, alcohol dehydrogenase activity, Aldo-Keto reductase activity, and peptidase regulator activity. Furthermore, alterations were observed in cellular components like the plasma membrane and cell periphery. Pathways involving the hematopoietic system, glycosaminoglycan degradation, retinol metabolism, and cytochrome P450-mediated exogenous drug metabolism were notably affected. Indirect interactions among differentially expressed proteins included three key nodal proteins: C3, IFIT3, and IFIT1. CONCLUSION The successful construction of a host differential protein expression profile was achieved through stable transfection of HeLa cells with the CT143 gene. The differential proteins identified are implicated in regulating various biological processes such as intracellular signal transduction, cell secretion, protein processing, hydrolysis, and enzyme activity. These findings suggest that the CT143 protein may influence the host cell's biological behavior by altering host protein expression, potentially hindering Ct growth and development.
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Affiliation(s)
- Ding Gong
- Department of Immunology, Xiangya School of Medicine, Central South University, Changsha 410078, China
| | - Ni Jian
- Department of Immunology, Xiangya School of Medicine, Central South University, Changsha 410078, China
| | - Yu-Tong Zhou
- Department of Immunology, Xiangya School of Medicine, Central South University, Changsha 410078, China
| | - Jie Wang
- Department of Immunology, Xiangya School of Medicine, Central South University, Changsha 410078, China.
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Alur V, Vastrad B, Raju V, Vastrad C, Kotturshetti S. The identification of key genes and pathways in polycystic ovary syndrome by bioinformatics analysis of next-generation sequencing data. MIDDLE EAST FERTILITY SOCIETY JOURNAL 2024; 29:53. [DOI: 10.1186/s43043-024-00212-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 11/17/2024] [Indexed: 01/02/2025] Open
Abstract
Abstract
Background
Polycystic ovary syndrome (PCOS) is a reproductive endocrine disorder. The specific molecular mechanism of PCOS remains unclear. The aim of this study was to apply a bioinformatics approach to reveal related pathways or genes involved in the development of PCOS.
Methods
The next-generation sequencing (NGS) dataset GSE199225 was downloaded from the gene expression omnibus (GEO) database and NGS dataset analyzed is obtained from in vitro culture of PCOS patients’ muscle cells and muscle cells of healthy lean control women. Differentially expressed gene (DEG) analysis was performed using DESeq2. The g:Profiler was utilized to analyze the gene ontology (GO) and REACTOME pathways of the differentially expressed genes. A protein–protein interaction (PPI) network was constructed and module analysis was performed using HiPPIE and cytoscape. The miRNA-hub gene regulatory network and TF-hub gene regulatory network were constructed. The hub genes were validated by using receiver operating characteristic (ROC) curve analysis.
Results
We have identified 957 DEG in total, including 478 upregulated genes and 479 downregulated gene. GO terms and REACTOME pathways illustrated that DEG were significantly enriched in regulation of molecular function, developmental process, interferon signaling and platelet activation, signaling, and aggregation. The top 5 upregulated hub genes including HSPA5, PLK1, RIN3, DBN1, and CCDC85B and top 5 downregulated hub genes including DISC1, AR, MTUS2, LYN, and TCF4 might be associated with PCOS. The hub gens of HSPA5 and KMT2A, together with corresponding predicted miRNAs (e.g., hsa-mir-34b-5p and hsa-mir-378a-5p), and HSPA5 and TCF4 together with corresponding predicted TF (e.g., RCOR3 and TEAD4) were found to be significantly correlated with PCOS.
Conclusions
These study uses of bioinformatics analysis of NGS data to obtain hub genes and key signaling pathways related to PCOS and its associated complications. Also provides novel ideas for finding biomarkers and treatment methods for PCOS and its associated complications.
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Guo W, Ren Y, Qiu X. FBXO2 promotes the progression of papillary thyroid carcinoma through the p53 pathway. Sci Rep 2024; 14:22574. [PMID: 39343799 PMCID: PMC11439943 DOI: 10.1038/s41598-024-73455-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Accepted: 09/17/2024] [Indexed: 10/01/2024] Open
Abstract
Emerging evidence have demonstrated that F-box only protein 2 (FBXO2) is intimately associated with malignant tumor development and occurrence. However, neither the functions nor the molecular mechanisms underlying FBXO2 have been determined in the papillary thyroid carcinoma (PTC). The quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry were carried out to detect the FBXO2 expression in PTC tissues. CCK-8 assay, EdU assay and flow cytometry were used to assess cell proliferation, cell cycle and apoptosis. The trans-well assay was conducted to determine the cell invasiveness. The effect of FBXO2 on PTC cell proliferation in vivo was observed through a subcutaneous tumor formation experiment in nude mice. Immunoprecipitation were conducted to detect the interaction between FBXO2 and p53. The ubiquitination assays were conducted to assess the regulation of p53 ubiquitination by FBXO2. FBXO2 was overexpressed in both PTC tissues and cell lines. FBXO2 expression positively correlated with PTC tumor size, lymphatic metastasis, and extramembranous invasion. Furthermore, silencing FBXO2 inhibited PTC cell proliferation and promoted apoptosis. The overexpression of FBXO2 significantly promotes PTC cell proliferation. Mechanistic studies revealed that FBXO2 could directly bind to p53 and promote its ubiquitination degradation. Knockdown of p53 partially reversed the progression arrest induced by FBXO2 Knockdown in PTC cells. FBXO2 knockdown inhibited PTC cell proliferation and promoted apoptosis by targeting p53 for ubiquitination and degradation. This process represents a research foundation for its diagnostic and therapeutic applications.
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Affiliation(s)
- Wenke Guo
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yaoqiang Ren
- Department of Urology, Fenyang Hospital of Shanxi Province, Lüliang, Shanxi, China
| | - Xinguang Qiu
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
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Wei X, Xiong X, Wang P, Zhang S, Peng D. SIRT1-mediated deacetylation of FOXO3 enhances mitophagy and drives hormone resistance in endometrial cancer. Mol Med 2024; 30:147. [PMID: 39266959 PMCID: PMC11391609 DOI: 10.1186/s10020-024-00915-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 08/28/2024] [Indexed: 09/14/2024] Open
Abstract
BACKGROUND The complex interplay between Sirtuin 1 (SIRT1) and FOXO3 in endometrial cancer (EC) remains understudied. This research aims to unravel the interactions of deacetylase SIRT1 and transcription factor FOXO3 in EC, focusing on their impact on mitophagy and hormone resistance. METHODS High-throughput sequencing, cell experiments, and bioinformatics tools were employed to investigate the roles and interactions of SIRT1 and FOXO3 in EC. Co-immunoprecipitation (Co-IP) assay was used to assess the interaction between SIRT1 and FOXO3 in RL95-2 cells. Functional assays were used to assess cell viability, proliferation, migration, invasion, apoptosis, and the expression of related genes and proteins. A mouse model of EC was established to evaluate tumor growth and hormone resistance under different interventions. Immunohistochemistry and TUNEL assays were used to assess protein expression and apoptosis in tumor tissues. RESULTS High-throughput transcriptome sequencing revealed a close association between SIRT1, FOXO3, and EC development. Co-IP showed a protein-protein interaction between SIRT1 and FOXO3. Overexpression of SIRT1 enhanced FOXO3 deacetylation and activity, promoting BNIP3 transcription and PINK1/Parkin-mediated mitophagy, which in turn promoted cell proliferation, migration, invasion, and inhibited apoptosis in vitro, as well as increased tumor growth and hormone resistance in vivo. These findings highlighted SIRT1 as an upstream regulator and potential therapeutic target in EC. CONCLUSION This study reveals a novel molecular mechanism underlying the functional relevance of SIRT1 in regulating mitophagy and hormone resistance through the deacetylation of FOXO3 in EC, thereby providing valuable insights for new therapeutic strategies.
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Affiliation(s)
- Xuehua Wei
- Obstetrics and Gynecology Center, Department of Gynecology, Zhujiang Hospital, Southern Medical University, No. 253, Industry Avenue, Haizhu District, Guangzhou, 510280, Guangdong, China
| | - Xiangpeng Xiong
- Department of Gynecology, Jiangxi Maternal and Child Health Hospital, Nanchang, 336000, China
| | - Pingping Wang
- Obstetrics and Gynecology Center, Department of Gynecology, Zhujiang Hospital, Southern Medical University, No. 253, Industry Avenue, Haizhu District, Guangzhou, 510280, Guangdong, China
| | - Shufang Zhang
- Department of Gynecology, Southern University of Science and Technology Hospital, Shenzhen, 518000, China
| | - Dongxian Peng
- Obstetrics and Gynecology Center, Department of Gynecology, Zhujiang Hospital, Southern Medical University, No. 253, Industry Avenue, Haizhu District, Guangzhou, 510280, Guangdong, China.
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Lai W, Xie R, Chen C, Lou W, Yang H, Deng L, Lu Q, Tang X. Integrated analysis of scRNA-seq and bulk RNA-seq identifies FBXO2 as a candidate biomarker associated with chemoresistance in HGSOC. Heliyon 2024; 10:e28490. [PMID: 38590858 PMCID: PMC10999934 DOI: 10.1016/j.heliyon.2024.e28490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 03/19/2024] [Accepted: 03/20/2024] [Indexed: 04/10/2024] Open
Abstract
Background High-grade serous ovarian carcinoma (HGSOC) is the most prevalent and aggressive histological subtype of epithelial ovarian cancer. Around 80% of individuals will experience a recurrence within five years because of resistance to chemotherapy, despite initially responding well to platinum-based treatment. Biomarkers associated with chemoresistance are desperately needed in clinical practice. Methods We jointly analyzed the transcriptomic profiles of single-cell and bulk datasets of HGSOC to identify cell types associated with chemoresistance. Copy number variation (CNV) inference was performed to identify malignant cells. We subsequently analyzed the expression of candidate biomarkers and their relationship with patients' prognosis. The enrichment analysis and potential biological function of candidate biomarkers were explored. Then, we validated the candidate biomarker using in vitro experiments. Results We identified 8871 malignant epithelial cells in a single-cell RNA sequencing dataset, of which 861 cells were associated with chemoresistance. Among these malignant epithelial cells, FBXO2 (F-box protein 2) is highly expressed in cells related to chemoresistance. Moreover, FBXO2 expression was found to be higher in epithelial cells from chemoresistance samples compared to those from chemosensitivity samples in a separate single-cell RNA sequencing dataset. Patients exhibiting elevated levels of FBXO2 experienced poorer outcomes in terms of both overall survival (OS) and progression-free survival (PFS). FBXO2 could impact chemoresistance by influencing the PI3K-Akt signaling pathway, focal adhesion, and ECM-receptor interactions and regulating tumorigenesis. The 50% maximum inhibitory concentration (IC50) of cisplatin decreased in A2780 and SKOV3 ovarian carcinoma cell lines with silenced FBXO2 during an in vitro experiment. Conclusions We determined that FBXO2 is a potential biomarker linked to chemoresistance in HGSOC by combining single-cell RNA-seq and bulk RNA-seq dataset. Our results suggest that FBXO2 could serve as a valuable prognostic marker and potential target for drug development in HGSOC.
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Affiliation(s)
- Wenwen Lai
- Department of Organ Transplantation, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, Jiangxi, China
- Department of Biostatistics and Epidemiology, School of Public Health, Nanchang University, Nanchang, Jiangxi, China
| | - Ruixiang Xie
- School of Life Science, Nanchang University, Nanchang University, Nanchang, China
| | - Chen Chen
- College of Basic Medical Science, Nanchang University, Nanchang, China
| | - Weiming Lou
- Academic Affairs Office, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Haiyan Yang
- Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, Jiangxi, China
- Department of Biostatistics and Epidemiology, School of Public Health, Nanchang University, Nanchang, Jiangxi, China
| | - Libin Deng
- Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, Jiangxi, China
- Department of Biostatistics and Epidemiology, School of Public Health, Nanchang University, Nanchang, Jiangxi, China
| | - Quqin Lu
- Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, Jiangxi, China
- Department of Biostatistics and Epidemiology, School of Public Health, Nanchang University, Nanchang, Jiangxi, China
| | - Xiaoli Tang
- College of Basic Medical Science, Nanchang University, Nanchang, China
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Li L, Huang J, Liu Y. The extracellular matrix glycoprotein fibrillin-1 in health and disease. Front Cell Dev Biol 2024; 11:1302285. [PMID: 38269088 PMCID: PMC10806136 DOI: 10.3389/fcell.2023.1302285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 12/19/2023] [Indexed: 01/26/2024] Open
Abstract
Fibrillin-1 (FBN1) is a large, cysteine-rich, calcium binding extracellular matrix glycoprotein encoded by FBN1 gene. It serves as a structural component of microfibrils and provides force-bearing mechanical support in elastic and nonelastic connective tissue. As such, mutations in the FBN1 gene can cause a wide variety of genetic diseases such as Marfan syndrome, an autosomal dominant disorder characterized by ocular, skeletal and cardiovascular abnormalities. FBN1 also interacts with numerous microfibril-associated proteins, growth factors and cell membrane receptors, thereby mediating a wide range of biological processes such as cell survival, proliferation, migration and differentiation. Dysregulation of FBN1 is involved in the pathogenesis of many human diseases, such as cancers, cardiovascular disorders and kidney diseases. Paradoxically, both depletion and overexpression of FBN1 upregulate the bioavailability and signal transduction of TGF-β via distinct mechanisms in different settings. In this review, we summarize the structure and expression of FBN1 and present our current understanding of the functional role of FBN1 in various human diseases. This knowledge will allow to develop better strategies for therapeutic intervention of FBN1 related diseases.
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Affiliation(s)
- Li Li
- State Key Laboratory of Organ Failure Research, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, Guangzhou, China
| | - Junxin Huang
- State Key Laboratory of Organ Failure Research, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, Guangzhou, China
| | - Youhua Liu
- State Key Laboratory of Organ Failure Research, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, Guangzhou, China
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Liu Z, Chen NY, Zhang Z, Zhou S, Hu SY. F-box only protein 2 exacerbates non-alcoholic fatty liver disease by targeting the hydroxyl CoA dehydrogenase alpha subunit. World J Gastroenterol 2023; 29:4433-4450. [PMID: 37576703 PMCID: PMC10415968 DOI: 10.3748/wjg.v29.i28.4433] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/19/2023] [Accepted: 07/11/2023] [Indexed: 07/26/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a major health burden with an increasing global incidence. Unfortunately, the unavailability of knowledge underlying NAFLD pathogenesis inhibits effective preventive and therapeutic measures. AIM To explore the molecular mechanism of NAFLD. METHODS Whole genome sequencing (WGS) analysis was performed on liver tissues from patients with NAFLD (n = 6) and patients with normal metabolic conditions (n = 6) to identify the target genes. A NAFLD C57BL6/J mouse model induced by 16 wk of high-fat diet feeding and a hepatocyte-specific F-box only protein 2 (FBXO2) overexpression mouse model were used for in vivo studies. Plasmid transfection, co-immunoprecipitation-based mass spectrometry assays, and ubiquitination in HepG2 cells and HEK293T cells were used for in vitro studies. RESULTS A total of 30982 genes were detected in WGS analysis, with 649 up-regulated and 178 down-regulated. Expression of FBXO2, an E3 ligase, was upregulated in the liver tissues of patients with NAFLD. Hepatocyte-specific FBXO2 overexpression facilitated NAFLD-associated phenotypes in mice. Overexpression of FBXO2 aggravated odium oleate (OA)-induced lipid accumulation in HepG2 cells, resulting in an abnormal expression of genes related to lipid metabolism, such as fatty acid synthase, peroxisome proliferator-activated receptor alpha, and so on. In contrast, knocking down FBXO2 in HepG2 cells significantly alleviated the OA-induced lipid accumulation and aberrant expression of lipid metabolism genes. The hydroxyl CoA dehydrogenase alpha subunit (HADHA), a protein involved in oxidative stress, was a target of FBXO2-mediated ubiquitination. FBXO2 directly bound to HADHA and facilitated its proteasomal degradation in HepG2 and HEK293T cells. Supplementation with HADHA alleviated lipid accumulation caused by FBXO2 overexpression in HepG2 cells. CONCLUSION FBXO2 exacerbates lipid accumulation by targeting HADHA and is a potential therapeutic target for NAFLD.
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Affiliation(s)
- Zhi Liu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Ning-Yuan Chen
- Department of General Surgery, Shandong Provincial Qian Foshan Hospital, Shandong University, Jinan 250014, Shandong Province, China
| | - Zhao Zhang
- Department of General Surgery, Shandong Provincial Qian Foshan Hospital, Shandong University, Jinan 250014, Shandong Province, China
| | - Sai Zhou
- Department of General Surgery, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, Shandong Province, China
| | - San-Yuan Hu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
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R I A, Vatsyayan A, Damodaran D, Sivadas A, Van der Speeten K. Multi-omics Analysis Classifies Colorectal Cancer into Distinct Methylated Immunogenic and Angiogenic Subtypes Based on Anatomical Laterality. Indian J Surg Oncol 2023; 14:209-219. [PMID: 37359923 PMCID: PMC10284779 DOI: 10.1007/s13193-023-01760-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 04/25/2023] [Indexed: 06/28/2023] Open
Abstract
We employed supervised machine learning algorithms to a cohort of colorectal cancer patients from the NCI to differentiate and classify the heterogenous disease based on anatomical laterality and multi-omics stratification, in a first of its kind. Multi-omics integrative analysis shows distinct clustering of left and right colorectal cancer with disentangled representation of methylome and delineation of transcriptome and genome. We present novel multi-omics findings consistent with augmented hypermethylation of genes in right CRC, epigenomic biomarkers on the right in conjunction with immune-mediated pathway signatures, and lymphocytic invasion which unlocks unique therapeutic avenues. Contrarily, left CRC multi-omics signature is found to be marked by angiogenesis, cadherins, and epithelial-mesenchymal transition (EMT). An integrated multi-omics molecular signature of RNF217-AS1, hsa-miR-10b, and panel of FBX02, FBX06, FBX044, MAD2L2, and MIIP copy number altered genes have been found by the study. Overall survival analysis reveals genomic biomarkers ABCA13 and TTN in 852 LCRC cases, and SOX11 in 170 RCRC cases that predicts a significant survival benefit. Our study exemplifies the translational competence and robustness of machine learning in effective translational bridging of research and clinic. Supplementary Information The online version contains supplementary material available at 10.1007/s13193-023-01760-6.
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Affiliation(s)
- Anu R I
- Department of Cancer Biology and Therapeutics, MVR Cancer Center and Research Institute, Calicut, Kerala India
- Department of Clinical Biochemistry, MVR Cancer Center and Research Institute, Calicut, Kerala India
| | - Aastha Vatsyayan
- CSIR Institute of Genomics and Integrative Biology (CSIR-IGIB), New Delhi, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Dileep Damodaran
- Department of Surgical Oncology, MVR Cancer Center and Research Institute, Calicut, Kerala India
| | - Ambily Sivadas
- Division of Nutrition, St. John’s Research Institute, Bangalore, India
| | - Kurt Van der Speeten
- Department of Surgical Oncology, Ziekenhuis Oost-Limburg, Genk, Belgium
- Faculty of Medicine and Life Sciences, BIOMED Research Institute, University Hasselt, Hasselt, Belgium
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Shen NN, Lin JH, Liu PP. EBF1 Promotes the Sensitivity of Cervical Cancer Cells to Cisplatin via Activating FBN1 Transcription. Mol Biol 2023. [DOI: 10.1134/s0026893323030093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2023]
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Wu X, Yang X, Tian Y, Xu P, Yue H, Sang N. Bisphenol B and bisphenol AF exposure enhances uterine diseases risks in mouse. ENVIRONMENT INTERNATIONAL 2023; 173:107858. [PMID: 36881955 DOI: 10.1016/j.envint.2023.107858] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 01/26/2023] [Accepted: 02/26/2023] [Indexed: 06/18/2023]
Abstract
Bisphenol A (BPA) analogs, bisphenol B (BPB) and bisphenol AF (BPAF) have been widely detected in the environment and human products with increasing frequency. However, uterine health risks caused by BPB and BPAF exposure need to be further elucidated. The study aimed to explore whether BPB or BPAF exposure will induce adverse outcomes in uterus. Female CD-1 mice were continuously exposed to BPB or BPAF for 14 and 28 days. Morphological examination showed that BPB or BPAF exposure caused endometrial contraction, decreased epithelial height, and increased number of glands. Bioinformatics analysis indicated that both BPB and BPAF disturbed the immune comprehensive landscape of the uterus. In addition, survival and prognosis analysis of hub genes and tumor immune infiltration evaluation were performed. Finally, the expression of hub genes was verified by quantitative real-time PCR (qPCR). Disease prediction found that eight of the BPB and BPAF co-response genes, which participated in the immune invasion of the tumor microenvironment, were associated with uterine corpus endometrial carcinoma (UCEC). Importantly, the gene expression levels of Srd5a1 after 28-day BPB and BPAF exposure were 7.28- and 25.24-fold higher than those of the corresponding control group, respectively, which was consistent with the expression trend of UCEC patients, and its high expression was significantly related to the poor prognosis of patients (p = 0.003). This indicated that Srd5a1 could be a valuable signal of uterus abnormalities caused by BPA analogs exposure. Our study revealed the key molecular targets and mechanisms of BPB or BPAF exposure induced uterine injury at the transcriptional level, providing a perspective for evaluating the safety of BPA substitutes.
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Affiliation(s)
- Xiaoyun Wu
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, PR China
| | - Xiaowen Yang
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, PR China
| | - Yuchai Tian
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, PR China
| | - Pengchong Xu
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, PR China
| | - Huifeng Yue
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, PR China.
| | - Nan Sang
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, PR China
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12
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Hong X, Ma N, Li D, Zhang M, Dong W, Huang J, Ci X, Zhang S. UBE2E2 enhances Snail-mediated epithelial-mesenchymal transition and Nrf2-mediated antioxidant activity in ovarian cancer. Cell Death Dis 2023; 14:100. [PMID: 36765041 PMCID: PMC9918489 DOI: 10.1038/s41419-023-05636-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 01/29/2023] [Accepted: 01/31/2023] [Indexed: 02/12/2023]
Abstract
Dissemination of ovarian cancer (OvCa) cells can lead to inoperable metastatic lesions in the bowel and omentum, which have a poor prognosis despite surgical and chemotherapeutical options. A better understanding of the mechanisms underlying metastasis is urgently needed. In this study, bioinformatics analyses revealed that UBE2E2, a less-studied ubiquitin (Ub)-conjugating enzyme (E2), was upregulated in OvCa and was associated with poor prognosis. Subsequently, we performed western blot analysis and IHC staining with 88 OvCa and 26 normal ovarian tissue samples, which further confirmed that UBE2E2 protein is highly expressed in OvCa tissue but weakly expressed in normal tissue. Furthermore, the silencing of UBE2E2 blocked OvCa cell migration, epithelial-mesenchymal transition (EMT) and metastasis in vitro, whereas UBE2E2 overexpression exerted the opposite effects. Mechanistically, UBE2E2 promoted p62 accumulation and increased the activity of the Nrf2-antioxidant response element (ARE) system, which ultimately activated the Snail signaling pathway by inhibiting the ubiquitin-mediated degradation of Snail. Additionally, co-IP and immunofluorescence demonstrated that a direct interaction exists between UBE2E2 and Nrf2, and the N-terminal of UBE2E2 (residues 1-52) is required and sufficient for its interaction with Nrf2 protein. Mutations in the active site cysteine (Cys139) impaired both the function and cellular distribution of UBE2E2. More importantly, the deletion of UBE2E2 reduced tumorigenicity and metastasis in xenograft OvCa mouse models. Taken together, our findings reveal the role of the UBE2E2-Nrf2-p62-Snail signaling axis in OvCa and thus provides novel therapeutic targets for the prevention of OvCa metastasis.
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Affiliation(s)
- Xiaoling Hong
- Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, 130021, Jilin, China
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Ning Ma
- Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Danjie Li
- Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Mengwen Zhang
- Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Wenqiuzi Dong
- Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Jie Huang
- Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Xinxin Ci
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, 130021, Jilin, China.
| | - Songling Zhang
- Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, 130021, Jilin, China.
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13
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Xia L, Chen J, Huang M, Mei J, Lin M. The functions of long noncoding RNAs on regulation of F-box proteins in tumorigenesis and progression. Front Oncol 2022; 12:963617. [PMID: 35928868 PMCID: PMC9343830 DOI: 10.3389/fonc.2022.963617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 06/27/2022] [Indexed: 11/28/2022] Open
Abstract
Accumulated evidence has revealed that F-box protein, a subunit of SCF E3 ubiquitin ligase complexes, participates in carcinogenesis and tumor progression via targeting its substrates for ubiquitination and degradation. F-box proteins could be regulated by cellular signaling pathways and noncoding RNAs in tumorigenesis. Long noncoding RNA (lncRNA), one type of noncoding RNAs, has been identified to modulate the expression of F-box proteins and contribute to oncogenesis. In this review, we summarize the role and mechanisms of multiple lncRNAs in regulating F-box proteins in tumorigenesis, including lncRNAs SLC7A11-AS1, MT1JP, TUG1, FER1L4, TTN-AS1, CASC2, MALAT1, TINCR, PCGEM1, linc01436, linc00494, GATA6-AS1, and ODIR1. Moreover, we discuss that targeting these lncRNAs could be helpful for treating cancer via modulating F-box protein expression. We hope our review can stimulate the research on exploration of molecular insight into how F-box proteins are governed in carcinogenesis. Therefore, modulation of lncRNAs is a potential therapeutic strategy for cancer therapy via regulation of F-box proteins.
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14
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Buehler M, Yi X, Ge W, Blattmann P, Rushing E, Reifenberger G, Felsberg J, Yeh C, Corn JE, Regli L, Zhang J, Cloos A, Ravi VM, Wiestler B, Heiland DH, Aebersold R, Weller M, Guo T, Weiss T. Quantitative proteomic landscapes of primary and recurrent glioblastoma reveal a protumorigeneic role for FBXO2-dependent glioma-microenvironment interactions. Neuro Oncol 2022; 25:290-302. [PMID: 35802605 PMCID: PMC9925714 DOI: 10.1093/neuonc/noac169] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Recent efforts have described the evolution of glioblastoma from initial diagnosis to post-treatment recurrence on a genomic and transcriptomic level. However, the evolution of the proteomic landscape is largely unknown. METHODS Sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) was used to characterize the quantitative proteomes of two independent cohorts of paired newly diagnosed and recurrent glioblastomas. Recurrence-associated proteins were validated using immunohistochemistry and further studied in human glioma cell lines, orthotopic xenograft models, and human organotypic brain slice cultures. External spatial transcriptomic, single-cell, and bulk RNA sequencing data were analyzed to gain mechanistic insights. RESULTS Although overall proteomic changes were heterogeneous across patients, we identified BCAS1, INF2, and FBXO2 as consistently upregulated proteins at recurrence and validated these using immunohistochemistry. Knockout of FBXO2 in human glioma cells conferred a strong survival benefit in orthotopic xenograft mouse models and reduced invasive growth in organotypic brain slice cultures. In glioblastoma patient samples, FBXO2 expression was enriched in the tumor infiltration zone and FBXO2-positive cancer cells were associated with synaptic signaling processes. CONCLUSIONS These findings demonstrate a potential role of FBXO2-dependent glioma-microenvironment interactions to promote tumor growth. Furthermore, the published datasets provide a valuable resource for further studies.
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Affiliation(s)
| | | | - Weigang Ge
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China,Westlake Intelligent Biomarker Discovery Lab, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China,Westlake Omics Biotechnology Co., Ltd., Hangzhou, Zhejiang, China
| | - Peter Blattmann
- Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland
| | - Elisabeth Rushing
- Department of Neuropathology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Guido Reifenberger
- Department of Neuropathology, Heinrich Heine University, Duesseldorf, Germany,German Cancer Consortium, partner site Essen/Düsseldorf, Duesseldorf, Germany
| | - Joerg Felsberg
- Department of Neuropathology, Heinrich Heine University, Duesseldorf, Germany,German Cancer Consortium, partner site Essen/Düsseldorf, Duesseldorf, Germany
| | - Charles Yeh
- Department of Biology, Institute of Molecular Health Sciences, ETH Zürich, Zürich, Switzerland
| | - Jacob E Corn
- Department of Biology, Institute of Molecular Health Sciences, ETH Zürich, Zürich, Switzerland
| | - Luca Regli
- Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, Zürich, Switzerland
| | - Junyi Zhang
- Microenvironment and Immunology Research Laboratory, Department of Neurosurgery, Medical Center, University of Freiburg, Germany,German Cancer Consortium (DKTK), partner site Freiburg, Freiburg, Germany,Translational Neuro-Oncology Research Group, Medical Center, University of Freiburg, Freiburg, Germany
| | - Ann Cloos
- Microenvironment and Immunology Research Laboratory, Department of Neurosurgery, Medical Center, University of Freiburg, Germany,German Cancer Consortium (DKTK), partner site Freiburg, Freiburg, Germany,Translational Neuro-Oncology Research Group, Medical Center, University of Freiburg, Freiburg, Germany
| | - Vidhya M Ravi
- Microenvironment and Immunology Research Laboratory, Department of Neurosurgery, Medical Center, University of Freiburg, Germany,German Cancer Consortium (DKTK), partner site Freiburg, Freiburg, Germany,Translational Neuro-Oncology Research Group, Medical Center, University of Freiburg, Freiburg, Germany,Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, Freiburg, Germany
| | - Benedikt Wiestler
- Department of Neuroradiology, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
| | - Dieter Henrik Heiland
- Microenvironment and Immunology Research Laboratory, Department of Neurosurgery, Medical Center, University of Freiburg, Germany,German Cancer Consortium (DKTK), partner site Freiburg, Freiburg, Germany
| | - Ruedi Aebersold
- Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland
| | - Michael Weller
- Department of Neurology and Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Tiannan Guo
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China,Westlake Intelligent Biomarker Discovery Lab, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
| | - Tobias Weiss
- Corresponding Author: Tobias Weiss, MD, PhD, Department of Neurology, University Hospital and University of Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland ()
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15
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Bano I, Malhi M, Zhao M, Giurgiulescu L, Sajjad H, Kieliszek M. A review on cullin neddylation and strategies to identify its inhibitors for cancer therapy. 3 Biotech 2022; 12:103. [PMID: 35463041 PMCID: PMC8964847 DOI: 10.1007/s13205-022-03162-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 01/29/2022] [Indexed: 11/01/2022] Open
Abstract
The cullin-RING E3 ligases (CRLs) are the biggest components of the E3 ubiquitin ligase protein family, and they represent an essential role in various diseases that occur because of abnormal activation, particularly in tumors development. Regulation of CRLs needs neddylation, a post-translational modification involving an enzymatic cascade that transfers small, ubiquitin-like NEDD8 protein to CRLs. Many previous studies have confirmed neddylation as an enticing target for anticancer drug discoveries, and few recent studies have also found a significant increase in advancement in protein neddylation, including preclinical and clinical target validation to discover the neddylation inhibitor compound. In the present review, we first presented briefly the essence of CRLs' neddylation and its control, systematic analysis of CRLs, followed by the description of a few recorded chemical inhibitors of CRLs neddylation enzymes with recent examples of preclinical and clinical targets. We have also listed various structure-based pointing of protein-protein dealings in the CRLs' neddylation reaction, and last, the methods available to discover new inhibitors of neddylation are elaborated. This review will offer a concentrated, up-to-date, and detailed description of the discovery of neddylation inhibitors.
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16
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Liu J, Cui G, Shen S, Gao F, Zhu H, Xu Y. Establishing a Prognostic Signature Based on Epithelial-Mesenchymal Transition-Related Genes for Endometrial Cancer Patients. Front Immunol 2022; 12:805883. [PMID: 35095892 PMCID: PMC8795518 DOI: 10.3389/fimmu.2021.805883] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 12/21/2021] [Indexed: 12/24/2022] Open
Abstract
Backgrounds Epithelial-mesenchymal transition (EMT) is a sequential process where tumor cells develop from the epithelial state to the mesenchymal state. EMT contributes to various tumor functions including initiation, propagating potential, and resistance to therapy, thus affecting the survival time of patients. The aim of this research is to set up an EMT-related prognostic signature for endometrial cancer (EC). Methods EMT-related gene (ERG) expression and clinical data were acquired from The Cancer Genome Atlas (TCGA). The entire set was randomly divided into two sets, one for contributing the risk model (risk score) and the other for validating. Univariate and multivariate Cox proportional hazards regression analyses were applied to the training set to select the prognostic ERGs. The expression of 10 ERGs was confirmed by qRT-PCR in clinical samples. Then, we developed a nomogram predicting 1-/3-/5-year survival possibility combining the risk score and clinical factors. The entire set was stratified into the high- and low-risk groups, which was used to analyze the immune infiltrating, tumorigenesis pathways, and response to drugs. Results A total of 220 genes were screened out from 1,316 ERGs for their differential expression in tumor versus normal. Next, 10 genes were found to be associated with overall survival (OS) in EC, and the expression was validated by qRT-PCR using clinical samples, so we constructed a 10-ERG-based risk score to distinguish high-/low-risk patients and a nomogram to predict survival rate. The calibration plots proved the predictive value of our model. Gene Set Enrichment Analysis (GSEA) discovered that in the low-risk group, immune-related pathways were enriched; in the high-risk group, tumorigenesis pathways were enriched. The low-risk group showed more immune activities, higher tumor mutational burden (TMB), and higher CTAL4/PD1 expression, which was in line with a better response to immune checkpoint inhibitors. Nevertheless, response to chemotherapeutic drugs turned out better in the high-risk group. The high-risk group had higher N 6-methyladenosine (m6A) RNA expression, microsatellite instability level, and stemness indices. Conclusion We constructed the ERG-related signature model to predict the prognosis of EC patients. What is more, it might offer a reference for predicting individualized response to immune checkpoint inhibitors and chemotherapeutic drugs.
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Affiliation(s)
- Jinhui Liu
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Guoliang Cui
- Department of Gastroenterology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Shuning Shen
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Feng Gao
- Department of Orthopedic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hongjun Zhu
- Department of Oncology, Nantong Third People's Hospital Affiliated to Nantong University, Nantong, China
| | - Yinghua Xu
- Department of Radiation Oncology, Nantong Third People's Hospital Affiliated to Nantong University, Nantong, China
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17
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Pang X, Zhang X, Huang Y, Qian S. Development and validation of m6A regulators' prognostic significance for endometrial cancer. Medicine (Baltimore) 2021; 100:e26551. [PMID: 34190193 PMCID: PMC8257909 DOI: 10.1097/md.0000000000026551] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 05/26/2021] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Endometrial cancer (EC) is the sixth most common cancer in women globally. It has been found that the expression levels of m6A regulators can be potentially used for prognostic stratification in some cancers, but the role of m6A regulators in EC prognosis remains unclear. METHODS The data of 584 EC samples were downloaded from The Cancer Genome Atlas and the mRNA expression profiles of 20 m6A regulators were analyzed, followed by functional enrichment analysis, immune infiltration analysis, and least absolute shrinkage and selection operator method-COX regression analysis. RESULTS The mRNA expression levels of 20 m6A regulators were significantly different between cancer samples across different grades. The 548 EC samples could be clearly divided into 2 clusters. Kaplan-Meier survival analysis proved that these two groups had highly different overall survival probabilities. Besides, the univariate regression analysis further reserved eight genes related to overall survival from the 20 m6A regulators. We established a prognostic signature including two genes, that is, IGF2BP1 and YTHDF3, that showed a strong ability for stratifying prognostically different EC patients. We identified 3239 differentially expressed genes between the high- and low-risk groups, involving in multiple biological processes and signaling pathways. Meanwhile, 6 differentially infiltrated immune cell types between the high- and low-risk groups could effectively distinguish the high- and low-risk EC groups. The expressions of immune checkpoints were different between high- and low-risk EC patients. CONCLUSION We first report the prognostic role of m6A regulators in EC, which should contribute to a better understanding of the underlying mechanisms of EC pathogenesis and progression.
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18
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Peng X, Zhang Z, Mo Y, Liu J, Wang S, Liu H. Bioinformatics Analysis of Choriocarcinoma-Related MicroRNA-Transcription Factor-Target Gene Regulatory Networks and Validation of Key miRNAs. Onco Targets Ther 2021; 14:3903-3919. [PMID: 34234459 PMCID: PMC8254590 DOI: 10.2147/ott.s311291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 06/15/2021] [Indexed: 11/23/2022] Open
Abstract
Objective The aim of the current research was to construct a miRNA-transcription factor (TF)-target gene regulatory network in order to investigate the mechanism underlying choriocarcinoma and to verify the network through the overexpression or silencing of hub miRNAs in vitro. Materials and Methods A mRNA expression dataset and two miRNA expression datasets were analysed to identify differentially expressed genes (DEGs) and miRNAs (DEMs) between normal cells and choriocarcinoma cells. The top 400 upregulated and downregulated DEGs were identified as candidate DEGs, which were then mapped to construct protein–protein interaction (PPI) networks and select hub genes. Moreover, the DGIdb database was utilized to select candidate drugs for hub genes. Moreover, DEM target genes were predicted through the miRWalk2.0 database and overlaid with candidate DEGs to identify the differentially expressed target genes (DETGs). Furthermore, we established miRNA-TF-target gene regulatory networks and performed functional enrichment analysis of hub DEMs. Finally, we transfected mimics or inhibitors of hub DEMs into choriocarcinoma cells and assessed cell proliferation and migration to verify the vital role of hub DEMs in choriocarcinoma. Results A total of 140 DEMs and 400 candidate DEGs were screened from choriocarcinoma cells and normal cells. A PPI network of 400 candidate DEGs was established. Twenty-nine hub genes and 99 associated small molecules were identified to provide potential target drugs for choriocarcinoma treatment. We obtained 70 DETGs of DEMs derived from the intersection between predicted miRNA target genes and candidate DEGs. Subsequently, 3 hub DEMs were selected, and miRNA-TF-target gene regulatory networks containing 4 TFs, 3 TFs and 3 TFs for each network were constructed. The RT-PCR results confirmed that miR-29b-3p was highly expressed and that miR-519c-3p and miR-520a-5p were expressed at low levels in choriocarcinoma cells. The overexpression or silencing results suggested that 3 dysregulated hub DEMs jointly accelerated the proliferation and migration of choriocarcinoma. Conclusion Association of miRNA-TF-target gene regulatory networks may help us explore the underlying mechanism and provide potential targets for the diagnosis and treatment of choriocarcinoma.
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Affiliation(s)
- Xiaotong Peng
- Department of Gynaecology and Obstetrics, Xiangya Hospital, Central South University, Changsha, 410008, People's Republic of China
| | - Zhirong Zhang
- Department of Gynaecology and Obstetrics, Xiangya Hospital, Central South University, Changsha, 410008, People's Republic of China
| | - Yanqun Mo
- Department of Gynaecology and Obstetrics, Xiangya Hospital, Central South University, Changsha, 410008, People's Republic of China
| | - Junliang Liu
- Department of Gynaecology and Obstetrics, Xiangya Hospital, Central South University, Changsha, 410008, People's Republic of China
| | - Shuo Wang
- Department of Orthopaedics, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233, People's Republic of China
| | - Huining Liu
- Department of Gynaecology and Obstetrics, Xiangya Hospital, Central South University, Changsha, 410008, People's Republic of China
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19
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Jian F, Che X, Zhang J, Liu C, Liu G, Tang Y, Feng W. The long-noncoding RNA SOCS2-AS1 suppresses endometrial cancer progression by regulating AURKA degradation. Cell Death Dis 2021; 12:351. [PMID: 33824269 PMCID: PMC8024384 DOI: 10.1038/s41419-021-03595-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 02/02/2021] [Accepted: 02/19/2021] [Indexed: 12/12/2022]
Abstract
Aberrant long-noncoding RNA (lncRNA) expression has been shown to be involved in the pathogenesis of endometrial cancer (EC). Herein, we report a novel tumor suppressor lncRNA SOCS2-AS1 in EC. Quantitative real-time PCR was performed to detect RNA expression. In situ hybridization and nuclear/cytoplasmic fractionation assays were used to detect the subcellular location. We found that SOCS2-AS1 was downregulated in EC tissues. Its reduced expression was correlated with advanced clinical stage and poor prognosis. Forced expression of SOCS2-AS1 suppressed EC cell proliferation and induced cell-cycle arrest and apoptosis. SOCS2-AS1-binding proteins were detected using RNA pull-down assay and mass spectrometry. Mechanistically, SOCS2-AS1 bound to Aurora kinase A (AURKA) and increased its degradation through the ubiquitin-proteasome pathway. In conclusion, SOCS2-AS1 may thus serve as a prognostic predictor and a biomarker for AURKA-inhibitor treatment in EC patients.
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Affiliation(s)
- Fangfang Jian
- Department of obstetrics and gynecology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Xiaoxia Che
- Department of obstetrics and gynecology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.,Obstetrics and gynecology hospital, Fudan University, Shanghai, 200011, China
| | - Jingjing Zhang
- Department of obstetrics and gynecology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Chang Liu
- Department of obstetrics and gynecology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Gedan Liu
- Department of obstetrics and gynecology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yujing Tang
- Department of obstetrics and gynecology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Weiwei Feng
- Department of obstetrics and gynecology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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