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Carver K, Clark C, Zhong Y, Yang G, Mishra M, Alarcon C, Perera M. MeQTL Mapping in African American Hepatocytes Reveals Shared Genetic Regulators of DNA Methylation and Gene Expression. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.23.634506. [PMID: 39896509 PMCID: PMC11785176 DOI: 10.1101/2025.01.23.634506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
Methylation quantitative trait loci (meQTL) mapping can provide insight into the genetic architecture underlying the epigenome by identifying single-nucleotide polymorphisms (SNPs) associated with differential methylation at methylation sites (CpGs) across the genome. Given that the epigenetic architecture underlying differences in gene expression can vary across racial populations, performing epigenomic studies in African Americans is crucial for understanding the interplay between genetic variation, DNA methylation, and gene expression in this understudied group. By performing cis-meQTL mapping in African American hepatocytes, we identified 410,186 cis-meQTLs associated with methylation at 24,425 CpGs in the liver. Through colocalization analysis, we found that 18,206 of these meQTLs are also colocalized with known liver eQTLs. Additionally, we found that using African American eQTL data results in an increased ability to detect additional colocalized variants that exhibit strong differences in allele frequency between people of European and African ancestry. Furthermore, the presence of smaller linkage disequilibrium blocks in African Americans allows us to identify narrower genomic regions of potentially causal variants compared to when data from Europeans is used. Importantly, these colocalized SNPs are significantly enriched for genetic associations with lipid and inflammatory traits in the GWAS catalog, suggesting that DNA methylation may contribute to the etiologies of these diseases. Furthermore, while it is generally presumed that the genetic regulation of DNA methylation is shared between blood and liver, we found that only 5.4% of African American liver meQTLs colocalize with blood meQTLs. Overall, our results reveal that studying African American populations results in the identification of additional genetic and epigenetic factors that may regulate gene expression in the liver, thereby expanding our understanding of gene regulation in African Americans.
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Affiliation(s)
- Kathryn Carver
- Department of Pharmacology, Center for Pharmacogenetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611
| | - Carolina Clark
- Department of Pharmacology, Center for Pharmacogenetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611
| | - Yizhen Zhong
- Department of Pharmacology, Center for Pharmacogenetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611
| | - Guang Yang
- Department of Pharmacology, Center for Pharmacogenetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611
- Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN
| | - Mrinal Mishra
- Department of Pharmacology, Center for Pharmacogenetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611
| | - Cristina Alarcon
- Department of Pharmacology, Center for Pharmacogenetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611
| | - Minoli Perera
- Department of Pharmacology, Center for Pharmacogenetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611
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Xie J, Wei J, Shi H, Lin Z, Lu J, Zhang X, Wan C. A deep learning approach for early prediction of breast cancer neoadjuvant chemotherapy response on multistage bimodal ultrasound images. BMC Med Imaging 2025; 25:26. [PMID: 39849366 PMCID: PMC11758756 DOI: 10.1186/s12880-024-01543-7] [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: 08/11/2024] [Accepted: 12/19/2024] [Indexed: 01/25/2025] Open
Abstract
Neoadjuvant chemotherapy (NAC) is a systemic and systematic chemotherapy regimen for breast cancer patients before surgery. However, NAC is not effective for everyone, and the process is excruciating. Therefore, accurate early prediction of the efficacy of NAC is essential for the clinical diagnosis and treatment of patients. In this study, a novel convolutional neural network model with bimodal layer-wise feature fusion module (BLFFM) and temporal hybrid attention module (THAM) is proposed, which uses multistage bimodal ultrasound images as input for early prediction of the efficacy of neoadjuvant chemotherapy in locally advanced breast cancer (LABC) patients. The BLFFM can effectively mine the highly complex correlation and complementary feature information between gray-scale ultrasound (GUS) and color Doppler blood flow imaging (CDFI). The THAM is able to focus on key features of lesion progression before and after one cycle of NAC. The GUS and CDFI videos of 101 patients collected from cooperative medical institutions were preprocessed to obtain 3000 sets of multistage bimodal ultrasound image combinations for experiments. The experimental results show that the proposed model is effective and outperforms the compared models. The code will be published on the https://github.com/jinzhuwei/BLTA-CNN .
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Affiliation(s)
- Jiang Xie
- School of Computer Engineering and Science, Shanghai University, Shanghai, 200444, China
| | - Jinzhu Wei
- School of Medicine, Shanghai University, Shanghai, 200444, China
| | - Huachan Shi
- School of Computer Engineering and Science, Shanghai University, Shanghai, 200444, China
| | - Zhe Lin
- School of Computer Engineering and Science, Shanghai University, Shanghai, 200444, China
| | - Jinsong Lu
- Department of Ultrasound, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
| | - Xueqing Zhang
- Department of Pathology, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
| | - Caifeng Wan
- Department of Ultrasound, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
- Department of Breast Surgery, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China.
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Huang J, Zhen W, Ma X, Ge S, Ma L. MiR-301b-3p targets and regulates EBF3 to impact the stem-like phenotype of breast cancer cells through glycolysis. J Clin Biochem Nutr 2025; 76:25-34. [PMID: 39896160 PMCID: PMC11782780 DOI: 10.3164/jcbn.23-131] [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: 12/27/2023] [Accepted: 05/18/2024] [Indexed: 02/04/2025] Open
Abstract
BACKGROUND Cancer stem cells are essential for the development of tumors, their recurrence, metastasis, and resistance to treatment. Previous studies have shown that the silencing of EBF3 promotes the progression of malignant tumors, but its impact on the stem-like phenotype of tumor cells remains unexplored. Therefore, this work aims to investigate the influence of EBF3 on the stem-like phenotype of breast cancer (BC) cells and its underlying molecular mechanisms. METHODS Bioinformatics analysis was utilized to predict EBF3 and miR-301b-3p expression and their binding sites in BC tissues. qRT-PCR was conducted to assess EBF3 and miR-301b-3p expression in BC cells. Cell viability was assessed using CCK-8 assay, while sphere-forming ability was assayed by sphere formation experiments. Western blot analysis was employed to assess the expression of stem cell-related markers and proteins associated with the glycolysis metabolic pathway. ECAR experiments and analysis of glycolysis metabolite production were performed to evaluate cellular glycolysis capacity. Dual-luciferase reporter assays and RIP were utilized to validate the binding relationship between EBF3 and miR-301b-3p. RESULTS EBF3 was downregulated in BC tissues and cells, and overexpression of EBF3 repressed the glycolysis capacity of BC cells, thereby suppressing stem-like phenotype. Furthermore, miR-301b-3p was identified as a direct target of EBF3, and its expression was increased in BC. Cell experiments revealed that miR-301b-3p suppressed EBF3 expression, thereby promoting the glycolysis capacity and stem-like phenotype of BC cells. CONCLUSION miR-301b-3p enhanced glycolysis and promoted the stem-like phenotype of BC cells by targeting EBF3. These findings can offer new therapeutic approaches for BC.
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Affiliation(s)
- Jiankang Huang
- Department of Thyroid and Breast Surgery, Anhui No.2 Provincial People’s Hospital, 1868 Dangshan Road, North 2nd Ring Road, Yaohai District, Hefei City, Anhui Province, 230000, China
| | - Weidong Zhen
- Department of Thyroid and Breast Surgery, Anhui No.2 Provincial People’s Hospital, 1868 Dangshan Road, North 2nd Ring Road, Yaohai District, Hefei City, Anhui Province, 230000, China
| | - Xiaokai Ma
- Department of Thyroid and Breast Surgery, Anhui No.2 Provincial People’s Hospital, 1868 Dangshan Road, North 2nd Ring Road, Yaohai District, Hefei City, Anhui Province, 230000, China
| | - Suxia Ge
- Department of Thyroid and Breast Surgery, Anhui No.2 Provincial People’s Hospital, 1868 Dangshan Road, North 2nd Ring Road, Yaohai District, Hefei City, Anhui Province, 230000, China
| | - Ling Ma
- Department of Gynecology, Anhui No.2 Provincial People’s Hospital, 1868 Dangshan Road, North 2nd Ring Road, Yaohai District, Hefei City, Anhui Province, 230000, China
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4
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Wang L, Guo X, Qin J, Jin Z, Liu Q, Sun C, Sun K, Li L, Wei X, Zhang Y. Assessing the causal relationship between plasma proteins and osteoporosis: novel insights into pathological mechanisms and therapeutic implications. Osteoporos Int 2024; 35:1973-1987. [PMID: 39120624 DOI: 10.1007/s00198-024-07225-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 08/02/2024] [Indexed: 08/10/2024]
Abstract
Identifying dysregulated plasma proteins in osteoporosis (OP) progression offers insights into prevention and treatment. This study found 8 such proteins associated with OP, suggesting them as therapy targets. This discovery may cut drug development costs and improve personalized treatments. PURPOSE This study aims to identify potential therapeutic targets for OP using summary data-based Mendelian randomization (SMR) and colocalization analysis methods. Furthermore, we seek to explore the biological significance and pharmacological value of these drug targets. METHODS To identify potential therapeutic targets for OP, we conducted SMR and colocalization analysis. Plasma protein (pQTL, exposure) data were sourced from the study by Ferkingstad et al. (n = 35,559). Summary statistics for bone mineral density (BMD, outcome) were obtained from the GWAS Catalog (n = 56,284). Additionally, we utilized enrichment analysis, protein-protein interaction (PPI) network analysis, drug prediction, and molecular docking to further analyze the biological significance and pharmacological value of these drug targets. RESULTS In the SMR analysis, while 20 proteins showed significance, only 8 potential drug targets (GCKR, ERBB3, CFHR1, GPN1, SDF2, VTN, BET1L, and SERPING1) received support from colocalization (PP.H4 > 0.8). These proteins are closely associated with immune function in terms of biological significance. Molecular docking also demonstrated favorable binding of drugs to proteins, consistent with existing structural data, further substantiating the pharmacological value of these targets. CONCLUSIONS The study identified 8 potential drug targets for OP. These prospective targets are believed to have a higher chance of success in clinical trials, thus aiding in prioritizing OP drug development and reducing development costs.
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Affiliation(s)
- Liang Wang
- School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China
| | - Xiangyun Guo
- School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China
| | - Jinran Qin
- School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China
| | - Zikai Jin
- Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, 100102, China
| | - Qingqing Liu
- School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China
| | - Chuanrui Sun
- Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, 100102, China
| | - Kai Sun
- Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, 100102, China
| | - Linghui Li
- Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, 100102, China
| | - Xu Wei
- Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, 100102, China.
| | - Yili Zhang
- School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China.
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5
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Zhang YF, Lin S, Zhen X, Ho M. A proteomic atlas of glypican-3 interacting partners: Identification of alpha-fetoprotein and other extracellular proteins as potential immunotherapy targets in liver cancer. PROTEOGLYCAN RESEARCH 2024; 2:e70004. [PMID: 39822733 PMCID: PMC11737099 DOI: 10.1002/pgr2.70004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Accepted: 08/31/2024] [Indexed: 01/19/2025]
Abstract
Antibody and cell-based therapeutics targeting cell surface receptors have emerged as a major class of immune therapeutics for treating cancer. However, the number of cell surface targets for cancer immunotherapy remains limited. Glypican-3 (GPC3) is a cell surface proteoglycan and an oncofetal antigen. In this study, we report a large-scale tumor-associated GPC3 co-immunoprecipitation (CoIP)-proteomic study using liver cancer xenograft tumors in mice. We identified 153 GPC3-associated proteins through mass spectrometry. To identify potential drug targets, we categorized GPC3-associated proteins based on their subcellular locations using UniProt annotations, with a focus on extracellular proteins. Additionally, we annotated differentially expressed proteins in hepatocellular carcinoma (HCC) versus non-tumor liver samples based on the literature, analyzed expression levels in tumor versus normal tissues using TCGA and GTEx databases via GEPIA, and identified prognostic liver cancer markers according to GEPIA. Among GPC3-associated proteins, Immunoglobulin Superfamily Member 1 (IGSF1), alpha-fetoprotein (AFP), FAT Atypical Cadherin 1 (FAT1), Formin 1 (FMN1), and Guanylate Cyclase 2C (GUCY2C), were identified as potential therapeutic targets. Furthermore, we validated the direct protein interaction between GPC3 and AFP through immunoprecipitation with purified proteins and through co-localization imaging using immunofluorescence microscopy. This study provides large proteomic datasets related to GPC3-associated proteins, enhancing our understanding of glypican biology in cancer cells and offering a new approach to identifying immunotherapy targets.
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Affiliation(s)
- Yi-Fan Zhang
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA
| | - Shaoli Lin
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA
| | - Xiao Zhen
- Laboratory of Proteomics and Analytical Technologies, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA
| | - Mitchell Ho
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA
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6
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Macdonald JK, Taylor HB, Wang M, Delacourt A, Edge C, Lewin DN, Kubota N, Fujiwara N, Rasha F, Marquez CA, Ono A, Oka S, Chayama K, Lewis S, Taouli B, Schwartz M, Fiel MI, Drake RR, Hoshida Y, Mehta AS, Angel PM. The Spatial Extracellular Proteomic Tumor Microenvironment Distinguishes Molecular Subtypes of Hepatocellular Carcinoma. J Proteome Res 2024; 23:3791-3805. [PMID: 38980715 PMCID: PMC11385377 DOI: 10.1021/acs.jproteome.4c00099] [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: 02/12/2024] [Revised: 05/31/2024] [Accepted: 06/15/2024] [Indexed: 07/10/2024]
Abstract
Hepatocellular carcinoma (HCC) mortality rates continue to increase faster than those of other cancer types due to high heterogeneity, which limits diagnosis and treatment. Pathological and molecular subtyping have identified that HCC tumors with poor outcomes are characterized by intratumoral collagenous accumulation. However, the translational and post-translational regulation of tumor collagen, which is critical to the outcome, remains largely unknown. Here, we investigate the spatial extracellular proteome to understand the differences associated with HCC tumors defined by Hoshida transcriptomic subtypes of poor outcome (Subtype 1; S1; n = 12) and better outcome (Subtype 3; S3; n = 24) that show differential stroma-regulated pathways. Collagen-targeted mass spectrometry imaging (MSI) with the same-tissue reference libraries, built from untargeted and targeted LC-MS/MS was used to spatially define the extracellular microenvironment from clinically-characterized, formalin-fixed, paraffin-embedded tissue sections. Collagen α-1(I) chain domains for discoidin-domain receptor and integrin binding showed distinctive spatial distribution within the tumor microenvironment. Hydroxylated proline (HYP)-containing peptides from the triple helical regions of fibrillar collagens distinguished S1 from S3 tumors. Exploratory machine learning on multiple peptides extracted from the tumor regions could distinguish S1 and S3 tumors (with an area under the receiver operating curve of ≥0.98; 95% confidence intervals between 0.976 and 1.00; and accuracies above 94%). An overall finding was that the extracellular microenvironment has a high potential to predict clinically relevant outcomes in HCC.
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Affiliation(s)
- Jade K. Macdonald
- Department
of Cell and Molecular Pharmacology, Medical
University of South Carolina, Charleston, South Carolina 29425, United States
| | - Harrison B. Taylor
- Department
of Cell and Molecular Pharmacology, Medical
University of South Carolina, Charleston, South Carolina 29425, United States
| | - Mengjun Wang
- Department
of Cell and Molecular Pharmacology, Medical
University of South Carolina, Charleston, South Carolina 29425, United States
| | - Andrew Delacourt
- Department
of Cell and Molecular Pharmacology, Medical
University of South Carolina, Charleston, South Carolina 29425, United States
| | - Christin Edge
- Department
of Cell and Molecular Pharmacology, Medical
University of South Carolina, Charleston, South Carolina 29425, United States
| | - David N. Lewin
- Department
of Cell and Molecular Pharmacology, Medical
University of South Carolina, Charleston, South Carolina 29425, United States
| | - Naoto Kubota
- Liver
Tumor Translational Research Program, Simmons Comprehensive Cancer
Center, Division of Digestive and Liver Diseases, Department of Internal
Medicine, University of Texas Southwestern
Medical Center, Dallas, Texas 75390, United States
| | - Naoto Fujiwara
- Liver
Tumor Translational Research Program, Simmons Comprehensive Cancer
Center, Division of Digestive and Liver Diseases, Department of Internal
Medicine, University of Texas Southwestern
Medical Center, Dallas, Texas 75390, United States
| | - Fahmida Rasha
- Liver
Tumor Translational Research Program, Simmons Comprehensive Cancer
Center, Division of Digestive and Liver Diseases, Department of Internal
Medicine, University of Texas Southwestern
Medical Center, Dallas, Texas 75390, United States
| | - Cesia A. Marquez
- Liver
Tumor Translational Research Program, Simmons Comprehensive Cancer
Center, Division of Digestive and Liver Diseases, Department of Internal
Medicine, University of Texas Southwestern
Medical Center, Dallas, Texas 75390, United States
| | - Atsushi Ono
- Department
of Gastroenterology, Graduate School of
Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan
| | - Shiro Oka
- Department
of Gastroenterology, Graduate School of
Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan
| | - Kazuaki Chayama
- Hiroshima
Institute of Life Sciences, Hiroshima 734-8553, Japan
- Collaborative
Research Laboratory of Medical Innovation, Research Center for Hepatology
and Gastroenterology, Hiroshima University, Hiroshima 734-8553, Japan
- RIKEN Center
for Integrative Medical Sciences, Yokohama 230-0045, Japan
| | - Sara Lewis
- Department
of Radiology, Icahn School of Medicine at
Mount Sinai, New York, New York 10029, United States
| | - Bachir Taouli
- Department
of Radiology, Icahn School of Medicine at
Mount Sinai, New York, New York 10029, United States
| | - Myron Schwartz
- Department
of Radiology, Icahn School of Medicine at
Mount Sinai, New York, New York 10029, United States
- Department
of Surgery, Icahn School of Medicine at
Mount Sinai, New York, New York 10029, United States
| | - M Isabel Fiel
- Department
of Radiology, Icahn School of Medicine at
Mount Sinai, New York, New York 10029, United States
- Department
of Pathology, Icahn School of Medicine at
Mount Sinai, New York, New York 10029, United States
| | - Richard R. Drake
- Department
of Cell and Molecular Pharmacology, Medical
University of South Carolina, Charleston, South Carolina 29425, United States
| | - Yujin Hoshida
- Liver
Tumor Translational Research Program, Simmons Comprehensive Cancer
Center, Division of Digestive and Liver Diseases, Department of Internal
Medicine, University of Texas Southwestern
Medical Center, Dallas, Texas 75390, United States
| | - Anand S. Mehta
- Department
of Cell and Molecular Pharmacology, Medical
University of South Carolina, Charleston, South Carolina 29425, United States
| | - Peggi M. Angel
- Department
of Cell and Molecular Pharmacology, Medical
University of South Carolina, Charleston, South Carolina 29425, United States
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Ahmed F, Mishra NK, Alghamdi OA, Khan MI, Ahmad A, Khan N, Rehan M. Deciphering KDM8 dysregulation and CpG methylation in hepatocellular carcinoma using multi-omics and machine learning. Epigenomics 2024; 16:961-983. [PMID: 39072393 PMCID: PMC11370911 DOI: 10.1080/17501911.2024.2374702] [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: 11/23/2023] [Accepted: 06/25/2024] [Indexed: 07/30/2024] Open
Abstract
Aim: This study investigates the altered expression and CpG methylation patterns of histone demethylase KDM8 in hepatocellular carcinoma (HCC), aiming to uncover insights and promising diagnostics biomarkers.Materials & methods: Leveraging TCGA-LIHC multi-omics data, we employed R/Bioconductor libraries and Cytoscape to analyze and construct a gene correlation network, and LASSO regression to develop an HCC-predictive model.Results: In HCC, KDM8 downregulation is correlated with CpGs hypermethylation. Differential gene correlation analysis unveiled a liver carcinoma-associated network marked by increased cell division and compromised liver-specific functions. The LASSO regression identified a highly accurate HCC prediction signature, prominently featuring CpG methylation at cg02871891.Conclusion: Our study uncovers CpG hypermethylation at cg02871891, possibly influencing KDM8 downregulation in HCC, suggesting these as promising biomarkers and targets.
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Affiliation(s)
- Firoz Ahmed
- Department of Biological Sciences, College of Science, University of Jeddah, Jeddah, Saudi Arabia
| | - Nitish Kumar Mishra
- Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, 38015, USA
| | - Othman A Alghamdi
- Department of Biological Sciences, College of Science, University of Jeddah, Jeddah, Saudi Arabia
| | - Mohammad Imran Khan
- Research Center, King Faisal Specialist Hospital & Research Centre, Jeddah, Saudi Arabia
- Department of Biochemistry & Molecular Medicine, College of Medicine, Al-Faisal University, Riyadh, Saudi Arabia
| | - Aamir Ahmad
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, 3050, Qatar
| | - Nargis Khan
- Snyder Institute of Chronic Diseases, Health Research & Innovation Center, Cumming School of Medicine, University of Calgary, Alberta, Canada
- Department of Microbiology, Immunology & Infectious Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada
| | - Mohammad Rehan
- Snyder Institute of Chronic Diseases, Health Research & Innovation Center, Cumming School of Medicine, University of Calgary, Alberta, Canada
- Department of Microbiology, Immunology & Infectious Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada
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8
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Feng S, Wang Z, Jin Y, Xu S. TabDEG: Classifying differentially expressed genes from RNA-seq data based on feature extraction and deep learning framework. PLoS One 2024; 19:e0305857. [PMID: 39037985 PMCID: PMC11262683 DOI: 10.1371/journal.pone.0305857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 06/05/2024] [Indexed: 07/24/2024] Open
Abstract
Traditional differential expression genes (DEGs) identification models have limitations in small sample size datasets because they require meeting distribution assumptions, otherwise resulting high false positive/negative rates due to sample variation. In contrast, tabular data model based on deep learning (DL) frameworks do not need to consider the data distribution types and sample variation. However, applying DL to RNA-Seq data is still a challenge due to the lack of proper labeling and the small sample size compared to the number of genes. Data augmentation (DA) extracts data features using different methods and procedures, which can significantly increase complementary pseudo-values from limited data without significant additional cost. Based on this, we combine DA and DL framework-based tabular data model, propose a model TabDEG, to predict DEGs and their up-regulation/down-regulation directions from gene expression data obtained from the Cancer Genome Atlas database. Compared to five counterpart methods, TabDEG has high sensitivity and low misclassification rates. Experiment shows that TabDEG is robust and effective in enhancing data features to facilitate classification of high-dimensional small sample size datasets and validates that TabDEG-predicted DEGs are mapped to important gene ontology terms and pathways associated with cancer.
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Affiliation(s)
- Sifan Feng
- School of Mathematics and Statistics, Guangdong University of Technology, Guangzhou, Guangdong, China
| | - Zhenyou Wang
- School of Mathematics and Statistics, Guangdong University of Technology, Guangzhou, Guangdong, China
| | - Yinghua Jin
- School of Mathematics and Statistics, Guangdong University of Technology, Guangzhou, Guangdong, China
| | - Shengbin Xu
- School of Mathematics and Statistics, Guangdong University of Technology, Guangzhou, Guangdong, China
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9
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Schmidt R, Hamm CA, Rueger C, Xu H, He Y, Gottwald LA, Gebauer B, Savic LJ. Decision-Tree Models Indicative of Microvascular Invasion on MRI Predict Survival in Patients with Hepatocellular Carcinoma Following Tumor Ablation. J Hepatocell Carcinoma 2024; 11:1279-1293. [PMID: 38974016 PMCID: PMC11227855 DOI: 10.2147/jhc.s454487] [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: 12/16/2023] [Accepted: 04/18/2024] [Indexed: 07/09/2024] Open
Abstract
Purpose Histological microvascular invasion (MVI) is a risk factor for poor survival and early recurrence in hepatocellular carcinoma (HCC) after surgery. Its prognostic value in the setting of locoregional therapies (LRT), where no tissue samples are obtained, remains unknown. This study aims to establish CT-derived indices indicative of MVI on liver MRI with superior soft tissue contrast and evaluate their association with patient survival after ablation via interstitial brachytherapy (iBT) versus iBT combined with prior conventional transarterial chemoembolization (cTACE). Patients and Methods Ninety-five consecutive patients, who underwent ablation via iBT alone (n = 47) or combined with cTACE (n = 48), were retrospectively included between 01/2016 and 12/2017. All patients received contrast-enhanced MRI prior to LRT. Overall (OS), progression-free survival (PFS), and time-to-progression (TTP) were assessed. Decision-tree models to determine Radiogenomic Venous Invasion (RVI) and Two-Trait Predictor of Venous Invasion (TTPVI) on baseline MRI were established, validated on an external test set (TCGA-LIHC), and applied in the study cohorts to investigate their prognostic value for patient survival. Statistics included Fisher's exact and t-test, Kaplan-Meier and cox-regression analysis, area under the receiver operating characteristic curve (AUC-ROC) and Pearson's correlation. Results OS, PFS, and TTP were similar in both treatment groups. In the external dataset, RVI showed low sensitivity but relatively high specificity (AUC-ROC = 0.53), and TTPVI high sensitivity but only low specificity (AUC-ROC = 0.61) for histological MVI. In patients following iBT alone, positive RVI and TTPVI traits were associated with poorer OS (RVI: p < 0.01; TTPVI: p = 0.08), PFS (p = 0.04; p = 0.04), and TTP (p = 0.14; p = 0.03), respectively. However, when patients with combined cTACE and iBT were stratified by RVI or TTPVI, no differences in OS (p = 0.75; p = 0.55), PFS (p = 0.70; p = 0.43), or TTP (p = 0.33; p = 0.27) were observed. Conclusion The study underscores the role of non-invasive imaging biomarkers indicative of MVI to identify patients, who would potentially benefit from embolotherapy via cTACE prior to ablation rather than ablation alone.
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Affiliation(s)
- Robin Schmidt
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Radiology, Berlin, 13353, Germany
- Experimental Clinical Research Center (ECRC) at Charité - Universitätsmedizin Berlin and Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, 13125, Germany
| | - Charlie Alexander Hamm
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Radiology, Berlin, 13353, Germany
- Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, 10117, Germany
| | - Christopher Rueger
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Radiology, Berlin, 13353, Germany
| | - Han Xu
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Radiology, Berlin, 13353, Germany
| | - Yubei He
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Radiology, Berlin, 13353, Germany
- Experimental Clinical Research Center (ECRC) at Charité - Universitätsmedizin Berlin and Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, 13125, Germany
| | | | - Bernhard Gebauer
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Radiology, Berlin, 13353, Germany
| | - Lynn Jeanette Savic
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Radiology, Berlin, 13353, Germany
- Experimental Clinical Research Center (ECRC) at Charité - Universitätsmedizin Berlin and Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, 13125, Germany
- Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, 10117, Germany
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10
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Wan R, Tan Z, Qian H, Li P, Zhang J, Zhu X, Xie P, Ren L. Prognostic Value of S100 Family mRNA Expression in Hepatocellular Carcinoma. THE TURKISH JOURNAL OF GASTROENTEROLOGY : THE OFFICIAL JOURNAL OF TURKISH SOCIETY OF GASTROENTEROLOGY 2024; 35:316-334. [PMID: 39128058 PMCID: PMC11114241 DOI: 10.5152/tjg.2024.22658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Accepted: 10/27/2023] [Indexed: 08/13/2024]
Abstract
BACKGROUND/AIMS The S100 family contains more than 20 Ca2+-binding proteins that participate in numerous cellular biological processes. However, the prognostic value of individual S100s in hepatocellular carcinoma (HCC) remains unclear. Therefore, we comprehensively assessed the prognostic value of S100s in HCC. MATERIALS AND METHODS The mRNA level of S100s in distinct types of cancer was analyzed through Oncomine. The clinical prognostic significance of each S100 was evaluated using Kaplan-Meier plotter and OncoLnc. The expression and mutation of S100s were determined through cBioPortal. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were used to predict the functions and pathways of S100s. RESULTS The analyses revealed that, relative to normal tissues, liver cancer tissues showed aberrant mRNA expression of most S100s. In the survival analysis with Kaplan-Meier plotter, elevated expression levels of S100PBP, S100A2, S100A7, S100A10, and S100A13 were related to shorter overall survival (OS), whereas increased S100A5 expression was associated with longer OS. Moreover, results obtained using OncoLnc showed that increased expression levels of S100P, S100PBP, S100A13, S100A11, S100A10, and S100A2 were related to shorter OS. Thus, S100PBP, S100A13, S100A10, and S100A2 exhibited the same prognostic trend in the 2 databases. However, all S100 member gene mutational changes had no considerable prognostic value in OS and disease-free survival of HCC patients. CONCLUSION Although the findings need to be further confirmed by experiments, they provide new evidence for the prognostic significance of the S100s in HCC.
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Affiliation(s)
- Renrui Wan
- Department of Hepatobiliary Surgery, Huzhou Central Hospital, Zhejiang University Huzhou Hospital, Affiliated Central Hospital of Huzhou Teachers College, Huzhou, Zhejiang, China
| | - Zhenhua Tan
- Department of Hepatobiliary Surgery, Huzhou Central Hospital, Zhejiang University Huzhou Hospital, Affiliated Central Hospital of Huzhou Teachers College, Huzhou, Zhejiang, China
| | - Hai Qian
- Department of Hepatobiliary Surgery, Huzhou Central Hospital, Zhejiang University Huzhou Hospital, Affiliated Central Hospital of Huzhou Teachers College, Huzhou, Zhejiang, China
| | - Peng Li
- Department of Operating Room, Huzhou Central Hospital, Affiliated Central Hospital Huzhou Teachers College, Huzhou, Zhejiang, China
| | - Jian Zhang
- Department of Hepatobiliary Surgery, Huzhou Central Hospital, Zhejiang University Huzhou Hospital, Affiliated Central Hospital of Huzhou Teachers College, Huzhou, Zhejiang, China
| | - Xiaofeng Zhu
- Department of Hepatobiliary Surgery, Huzhou Central Hospital, Zhejiang University Huzhou Hospital, Affiliated Central Hospital of Huzhou Teachers College, Huzhou, Zhejiang, China
| | - Ping Xie
- Department of Hepatobiliary Surgery, Huzhou Central Hospital, Zhejiang University Huzhou Hospital, Affiliated Central Hospital of Huzhou Teachers College, Huzhou, Zhejiang, China
| | - Lingyan Ren
- Department of Nephrology, the First Affiliated Hospital of Huzhou Teachers College, the First People’s Hospital of Huzhou, Huzhou, Zhejiang, China
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11
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Lu M, Yin R, Chen XS. Ensemble methods of rank-based trees for single sample classification with gene expression profiles. J Transl Med 2024; 22:140. [PMID: 38321494 PMCID: PMC10848444 DOI: 10.1186/s12967-024-04940-2] [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: 12/16/2023] [Accepted: 01/27/2024] [Indexed: 02/08/2024] Open
Abstract
Building Single Sample Predictors (SSPs) from gene expression profiles presents challenges, notably due to the lack of calibration across diverse gene expression measurement technologies. However, recent research indicates the viability of classifying phenotypes based on the order of expression of multiple genes. Existing SSP methods often rely on Top Scoring Pairs (TSP), which are platform-independent and easy to interpret through the concept of "relative expression reversals". Nevertheless, TSP methods face limitations in classifying complex patterns involving comparisons of more than two gene expressions. To overcome these constraints, we introduce a novel approach that extends TSP rules by constructing rank-based trees capable of encompassing extensive gene-gene comparisons. This method is bolstered by incorporating two ensemble strategies, boosting and random forest, to mitigate the risk of overfitting. Our implementation of ensemble rank-based trees employs boosting with LogitBoost cost and random forests, addressing both binary and multi-class classification problems. In a comparative analysis across 12 cancer gene expression datasets, our proposed methods demonstrate superior performance over both the k-TSP classifier and nearest template prediction methods. We have further refined our approach to facilitate variable selection and the generation of clear, precise decision rules from rank-based trees, enhancing interpretability. The cumulative evidence from our research underscores the significant potential of ensemble rank-based trees in advancing disease classification via gene expression data, offering a robust, interpretable, and scalable solution. Our software is available at https://CRAN.R-project.org/package=ranktreeEnsemble .
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Affiliation(s)
- Min Lu
- Division of Biostatistics, Department of Public Health Sciences, Miller School of Medicine, University of Miami, 1120 NW 14th Street, Miami, FL, 33136, USA.
| | - Ruijie Yin
- Division of Biostatistics, Department of Public Health Sciences, Miller School of Medicine, University of Miami, 1120 NW 14th Street, Miami, FL, 33136, USA
| | - X Steven Chen
- Division of Biostatistics, Department of Public Health Sciences, Miller School of Medicine, University of Miami, 1120 NW 14th Street, Miami, FL, 33136, USA.
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, 1475 NW 12th Ave, Miami, FL, 33136, USA.
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12
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Zhu Y, Wang Q, Xie X, Ma C, Qiao Y, Zhang Y, Wu Y, Gao Y, Jiang J, Liu X, Chen J, Li C, Ge G. ZBTB7B is a permissive regulator of hepatocellular carcinoma initiation by repressing c-Jun expression and function. Cell Death Dis 2024; 15:55. [PMID: 38225233 PMCID: PMC10789742 DOI: 10.1038/s41419-024-06441-y] [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: 07/25/2023] [Revised: 01/02/2024] [Accepted: 01/05/2024] [Indexed: 01/17/2024]
Abstract
Hepatocarcinogenesis is a multi-step process. However, the regulators of hepatocellular carcinoma (HCC) initiation are understudied. Adult liver-specific gene expression was globally downregulated in HCC. We hypothesize that adult liver-specific genes, especially adult liver-enriched transcription factors may exert tumor-suppressive functions in HCC. In this study, we identify ZBTB7B, an adult liver-enriched transcription factor as a permissive regulator of HCC initiation. ZBTB7B is highly expressed in hepatocytes in adult livers, compared to fetal livers. To evaluate the functions of ZBTB7B in hepatocarcinogenesis, we performed hepatocyte-specific ZBTB7B knockout in hydrodynamic oncogene transfer-induced mouse liver cancer models. Hepatocyte-specific knockout of ZBTB7B promotes activated Akt and N-Ras-induced HCC development. Moreover, ZBTB7B deficiency sensitizes hepatocytes to a single oncogene Akt-induced oncogenic transformation and HCC initiation, which is otherwise incompetent in inducing HCC. ZBTB7B deficiency accelerates HCC initiation by down-regulating adult liver-specific gene expression and priming livers to a fetal-like state. The molecular mechanism underlying ZBTB7B functions in hepatocytes was investigated by integrated transcriptomic, phosphoproteomic, and chromatin immunoprecipitation-sequencing analyses. Integrative multi-omics analyses identify c-Jun as the core signaling node in ZBTB7B-deficient liver cancer initiation. c-Jun is a direct target of ZBTB7B essential to accelerated liver cancer initiation in ZBTB7B-deficient livers. Knockdown of c-Jun expression or dominant negative c-Jun expression delays HCC development in ZBTB7B-deficient livers. In addition, ZBTB7B competes with c-Jun for chromatin binding. Ectopic ZBTB7B expression attenuates the tumor-promoting functions of c-Jun. Expression of ZBTB7B signature, composed of 140 genes co-regulated by ZBTB7B and c-Jun, is significantly downregulated in early-stage HCCs compared to adjacent normal tissues, correlates to liver-specific gene expression, and is associated with good prognosis in human HCC. Thus, ZBTB7B functions as a permissive regulator of HCC initiation by directly regulating c-Jun expression and function.
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Affiliation(s)
- Yue Zhu
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Qinqin Wang
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Xinyu Xie
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Cuihong Ma
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yuemei Qiao
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yu Zhang
- State Key Laboratory of Molecular Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yanjun Wu
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yuan Gao
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Jing Jiang
- Genome Tagging Project (GTP) Center, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Xin Liu
- State Key Laboratory of Molecular Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Jianfeng Chen
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China
| | - Chen Li
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Gaoxiang Ge
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
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Song Y, Liu H, Xian Q, Gui C, Xu M, Zhou Y. Mechanistic insights into UHRF1‑mediated DNA methylation by structure‑based functional clarification of UHRF1 domains (Review). Oncol Lett 2023; 26:542. [PMID: 38020304 PMCID: PMC10660443 DOI: 10.3892/ol.2023.14129] [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: 03/04/2023] [Accepted: 10/16/2023] [Indexed: 12/01/2023] Open
Abstract
Epigenetic modification is crucial for transmitting genetic information, while abnormalities in DNA methylation modification are primarily associated with cancer and neurological diseases. As a multifunctional epigenetic modifier, ubiquitin like with PHD and ring finger domains 1 (UHRF1) mainly affects cell energy metabolism and cell cycle control. It also inhibits the transcription of tumor suppressor genes through DNA and/or histone methylation modifications, promoting the occurrence and development of cancer. Therefore, comprehensively understanding the molecular mechanism of the epigenetic modification of UHRF1 in tumors will help identify targets for inhibiting the expression and function of UHRF1. Notably, each domain of UHRF1 functions as a whole and differently. Thus, the abnormality of any domain can lead to a change in phenotype or disease. However, the specific regulatory mechanism and proteins of each domain have not been fully elucidated. The present review aimed to contribute to the study of the regulatory mechanism of UHRF1 to a greater extent in different cancers and provide ideas for drug research by clarifying the function of UHRF1 domains.
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Affiliation(s)
- Yiying Song
- Department of Clinical Laboratory Diagnosis, Jinan Central Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Haiting Liu
- Department of Critical Care Medicine, Jinan Zhangqiu Hospital of Traditional Chinese Medicine, Jinan, Shandong 250200, P.R. China
| | - Qingqing Xian
- Department of Clinical Laboratory Diagnosis, Jinan Central Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Chengzhi Gui
- Department of Clinical Laboratory Diagnosis, Shandong First Medical University, Jinan, Shandong 250012, P.R. China
| | - Mingjie Xu
- Medical Research and Laboratory Diagnostic Center, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250013, P.R. China
| | - Yunying Zhou
- Department of Clinical Laboratory Diagnosis, Jinan Central Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
- Department of Clinical Laboratory Diagnosis, Shandong First Medical University, Jinan, Shandong 250012, P.R. China
- Medical Research and Laboratory Diagnostic Center, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250013, P.R. China
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Wang L, Zhang Y, Li J, Guo S, Ren J, Li Z, Zhuang X, Xue J, Lei J. A Nomogram of Magnetic Resonance Imaging for Preoperative Assessment of Microvascular Invasion and Prognosis of Hepatocellular Carcinoma. Dig Dis Sci 2023; 68:4521-4535. [PMID: 37794295 DOI: 10.1007/s10620-023-08022-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 06/23/2023] [Indexed: 10/06/2023]
Abstract
BACKGROUND Microvascular invasion (MVI) is a predictor of recurrence and overall survival in hepatocellular carcinoma (HCC), the preoperative diagnosis of MVI through noninvasive methods play an important role in clinical treatment. AIMS To investigate the effectiveness of radiomics features in evaluating MVI in HCC before surgery. METHODS We included 190 patients who had undergone contrast-enhanced MRI and curative resection for HCC between September 2015 and November 2021 from two independent institutions. In the training cohort of 117 patients, MVI-related radiomics models based on multiple sequences and multiple regions from MRI were constructed. An independent cohort of 73 patients was used to validate the proposed models. A final Clinical-Imaging-Radiomics nomogram for preoperatively predicting MVI in HCC patients was generated. Recurrence-free survival was analyzed using the log-rank test. RESULTS For tumor-extracted features, the performance of signatures in fat-suppressed T1-weighted images and hepatobiliary phase was superior to that of other sequences in a single-sequence model. The radiomics signatures demonstrated better discriminatory ability than that of the Clinical-Imaging model for MVI. The nomogram incorporating clinical, imaging and radiomics signature showed excellent predictive ability and achieved well-fitted calibration curves, outperforming both the Radiomics and Clinical-Radiomics models in the training and validation cohorts. CONCLUSIONS The Clinical-Imaging-Radiomics nomogram model of multiple regions and multiple sequences based on serum alpha-fetoprotein, three MRI characteristics, and 12 radiomics signatures achieved good performance for predicting MVI in HCC patients, which may help clinicians select optimal treatment strategies to improve subsequent clinical outcomes.
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Affiliation(s)
- Lili Wang
- First Clinical Medical School of Lanzhou University, Chengguan District, Donggangxi Road No. 1, Lanzhou, 730000, China
- Department of Radiology, First Hospital of Lanzhou University, Chengguan District, Donggangxi Road No. 1, Lanzhou, 730000, China
| | - Yanyan Zhang
- Department of Radiology, Beijing YouAn Hospital, Capital Medical University, Beijing, 100069, China
| | - Junfeng Li
- First Clinical Medical School of Lanzhou University, Chengguan District, Donggangxi Road No. 1, Lanzhou, 730000, China
- Department of Infectious Diseases, Institute of Infectious Diseases, First Hospital of Lanzhou University, Chengguan District, Donggang Road No. 1, Lanzhou, 730000, China
| | - Shunlin Guo
- First Clinical Medical School of Lanzhou University, Chengguan District, Donggangxi Road No. 1, Lanzhou, 730000, China
- Department of Radiology, First Hospital of Lanzhou University, Chengguan District, Donggangxi Road No. 1, Lanzhou, 730000, China
| | - Jialiang Ren
- GE Healthcare China, Daxing District, Tongji South Road No. 1, Beijing, 100176, China
| | - Zhihao Li
- GE Healthcare China, Yanta District, 12th Jinye Road, Xi'an, 710076, Shanxi, China
| | - Xin Zhuang
- First Clinical Medical School of Lanzhou University, Chengguan District, Donggangxi Road No. 1, Lanzhou, 730000, China
- Department of Radiology, First Hospital of Lanzhou University, Chengguan District, Donggangxi Road No. 1, Lanzhou, 730000, China
| | - Jingmei Xue
- First Clinical Medical School of Lanzhou University, Chengguan District, Donggangxi Road No. 1, Lanzhou, 730000, China
- Department of Radiology, First Hospital of Lanzhou University, Chengguan District, Donggangxi Road No. 1, Lanzhou, 730000, China
| | - Junqiang Lei
- First Clinical Medical School of Lanzhou University, Chengguan District, Donggangxi Road No. 1, Lanzhou, 730000, China.
- Department of Radiology, First Hospital of Lanzhou University, Chengguan District, Donggangxi Road No. 1, Lanzhou, 730000, China.
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15
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Wei H, Huang L, Lu Q, Huang Z, Huang Y, Xu Z, Li W, Pu J. N 6-Methyladenosine-Modified LEAWBIH Drives Hepatocellular Carcinoma Progression through Epigenetically Activating Wnt/β-Catenin Signaling. J Hepatocell Carcinoma 2023; 10:1991-2007. [PMID: 37954496 PMCID: PMC10637240 DOI: 10.2147/jhc.s433070] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Accepted: 10/18/2023] [Indexed: 11/14/2023] Open
Abstract
Purpose N6-methyladenosine (m6A) modification plays an important role in regulating RNA maturation, stability, and translation. Thus, m6A modification is involved in various pathophysiological processes including hepatocellular carcinoma (HCC). However, the direct contribution of m6A modifications to RNA function in HCC remains unclear. Here, we identified LEAWBIH (long non-coding RNA epigenetically activating Wnt/β-catenin signalling in HCC) as an m6A-modified long non-coding RNA (lncRNA) and investigated the effects of m6A on the function of LEAWBIH in HCC. Methods Quantitative polymerase chain reaction was performed to measure the gene expression in tissues and cells. The level of m6A modification was detected using a methylated RNA immunoprecipitation assay and single-base elongation- and ligation-based qPCR amplification method. Cell proliferation was evaluated using the Glo cell viability and CCK-8 assays. Cell migration and invasion were evaluated using Transwell migration and invasion assays. The mechanisms of m6A modified LEAWBIH were investigated using chromatin isolation by RNA purification, chromatin immunoprecipitation, and dual-luciferase reporter assays. Results LEAWBIH was highly expressed and correlated with poor survival in HCC patients. LEAWBIH was identified as a m6A-modified transcript. m6A modification increased LEAWBIH transcript stability. The m6A modification level of LEAWBIH was increased in HCC, and a high m6A modification level of LEAWBIH predicted poor survival. LEAWBIH promotes HCC cell proliferation, migration, and invasion in an m6A modification-dependent manner. Mechanistic investigations revealed that m6A-modified LEAWBIH activated Wnt/β-catenin signaling. m6A-modified LEAWBIH binds to the m6A reader YTHDC1, which further interacts with and recruits H3K9me2 demethylase KDM3B to CTNNB1 promoter, leading to H3K9me2 demethylation and CTNNB1 transcription activation. Functional rescue assays showed that blocking Wnt/β-catenin signaling abolished the role of LEAWBIH in HCC. Conclusion m6A-modified LEAWBIH exerts oncogenic effects in HCC by epigenetically activating Wnt/β-catenin signaling, highlighting m6A-modified LEAWBIH as a promising therapeutic target for HCC.
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Affiliation(s)
- Huamei Wei
- Department of Pathology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, People’s Republic of China
| | - Lizheng Huang
- Graduate College of Youjiang Medical University for Nationalities, Baise, People’s Republic of China
| | - Qi Lu
- Graduate College of Youjiang Medical University for Nationalities, Baise, People’s Republic of China
| | - Zheng Huang
- Graduate College of Youjiang Medical University for Nationalities, Baise, People’s Republic of China
| | - Yanyan Huang
- Graduate College of Youjiang Medical University for Nationalities, Baise, People’s Republic of China
| | - Zuoming Xu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, People’s Republic of China
| | - Wenchuan Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, People’s Republic of China
| | - Jian Pu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, People’s Republic of China
- Guangxi Clinical Medical Research Center of Hepatobiliary Disease, Baise, People’s Republic of China
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Chen PD, Liao YY, Cheng YC, Wu HY, Wu YM, Huang MC. Decreased B4GALT1 promotes hepatocellular carcinoma cell invasiveness by regulating the laminin-integrin pathway. Oncogenesis 2023; 12:49. [PMID: 37907465 PMCID: PMC10618527 DOI: 10.1038/s41389-023-00494-y] [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: 01/17/2023] [Revised: 09/26/2023] [Accepted: 10/11/2023] [Indexed: 11/02/2023] Open
Abstract
Beta1,4-galactosyltransferases (B4GALTs) play a crucial role in several diseases, including cancer. B4GALT1 is highly expressed in the liver, and patients with mutations in B4GALT1 exhibit hepatopathy. However, the role of B4GALT1 in liver cancer remains unclear. Here, we found that B4GALT1 was significantly downregulated in hepatocellular carcinoma (HCC) tissue compared with the adjacent liver tissue, and low B4GALT1 expression was associated with vascular invasion and poor overall survival in patients with HCC. Additionally, silencing or loss of B4GALT1 enhanced HCC cell migration and invasion in vitro and promoted lung metastasis of HCC in NOD/SCID mice. Moreover, B4GALT1 knockdown or knockout increased cell adhesion to laminin, whereas B4GALT1 overexpression decreased the adhesion. Through a mass spectrometry-based approach and Griffonia simplicifolia lectin II (GSL-II) pull-down assays, we identified integrins α6 and β1 as the main protein substrates of B4GALT1 and their N-glycans were modified by B4GALT1. Further, the increased cell migration and invasion induced by B4GALT1 knockdown or knockout were significantly reversed using a blocking antibody against integrin α6 or integrin β1. These results suggest that B4GALT1 downregulation alters N-glycosylation and enhances the laminin-binding activity of integrin α6 and integrin β1 to promote invasiveness of HCC cells. Our findings provide novel insights into the role of B4GALT1 in HCC metastasis and highlight targeting the laminin-integrin axis as a potential therapeutic strategy for HCC with low B4GALT1 expression.
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Affiliation(s)
- Po-Da Chen
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
- Department of Surgical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan
| | - Ying-Yu Liao
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yu-Chia Cheng
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hsin-Yi Wu
- Instrumentation center, National Taiwan University, Taipei, Taiwan
| | - Yao-Ming Wu
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
- Department of Surgical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan.
| | - Min-Chuan Huang
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
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17
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Liu Z, Chen C, Ma Q. Category-aware optimal transport for incomplete data classification. Inf Sci (N Y) 2023. [DOI: 10.1016/j.ins.2023.03.107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2023]
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Azadeh M, Salehzadeh A, Ghaedi K, Talesh Sasani S. Integrated High-Throughput Bioinformatics (Microarray, RNA-Seq, and RNA Interaction) and qRT-PCR Investigation of BMPR1B Axis as a Potential Diagnostic Biomarker of Isfahan Breast Cancer. Adv Biomed Res 2023; 12:120. [PMID: 37434942 PMCID: PMC10331528 DOI: 10.4103/abr.abr_200_22] [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: 06/14/2022] [Revised: 07/17/2022] [Accepted: 07/19/2022] [Indexed: 07/13/2023] Open
Abstract
Background According to the bioinformatics analyses and previous studies, bone morphogenetic protein receptor type 1B (BMPR1B) dysregulation could remarkably affect breast cancer (BC) status as a potential biomarker and tumor suppressor. Therefore, the analysis of the expression level of BMPR1B and other relevant biological factors such as microRNAs, long non-coding RNAs, downstream proteins in the relevant signaling pathways, and finding the accurate biological mechanism of BMPR1B could be helpful for a better understanding of BC pathogenicity and discovering the new treatment methods and drugs. Materials and Methods R Studio software (4.0.2) was used for microarray data analyses. GSE31448 dataset was downloaded by GEOquery package and analyzed by limma package. STRING and miRWalk online databases and Cytoscape software were used for interaction analyses. Quantitative measurement of BMPR1B expression level was performed by qRT-PCR experiment. Result Microarray and real-time PCR analysis revealed that BMPR1B has a significant downregulation in the transforming growth factor (TGF)-beta and bone morphogenic protein (BMP) signaling pathways in BC samples. BMPR1B is a potential diagnostic biomarker, regulated by hsa-miR-181a-5p. Also, BMPR1B regulates the function of BMP2, BMP6, SMAD4, SMAD5, and SMAD6 proteins. Discussion BMPR1B have a significant role in the development of BC by regulating the potential proteins' function, playing the diagnostic biomarker role, and regulation of TGF-beta and BMP signaling pathways. The high amount of BMPR1B protein helps in increasing the survival rate of the patients.
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Affiliation(s)
- Mansoureh Azadeh
- Department of Biology, Rasht Branch, Islamic Azad University, Rasht, Iran
| | - Ali Salehzadeh
- Department of Biology, Rasht Branch, Islamic Azad University, Rasht, Iran
| | - Kamran Ghaedi
- Department of Biology, Rasht Branch, Islamic Azad University, Rasht, Iran
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Sohail J, Zubair M, Hussain K, Faisal M, Ismail M, Haider I, Mumtaz R, Khan AA, Khan MA. Pharmacological activities of Artemisia absinthium and control of hepatic cancer by expression regulation of TGFβ1 and MYC genes. PLoS One 2023; 18:e0284244. [PMID: 37053209 PMCID: PMC10101520 DOI: 10.1371/journal.pone.0284244] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 03/26/2023] [Indexed: 04/14/2023] Open
Abstract
Plant derived compounds have always been an important source of medicines and have received significant attention in recent years due to their diverse pharmacological properties. Millions of plant-based herbal or traditional medicines are used to cure various types of cancers especially due to activation of proliferative genes. The aim of the present study was to characterize the altered and attenuated gene expression of the selected growth factor namely Transforming growth factor Beta -1 (TGFβ1) and MYC in human hepatoma-derived (Huh7) liver cancer cell lines in response to extracts of Artemisia absinthium dissolved in selected organic solvents. Ethanolic, methanolic and acetone extract of different plant parts (leaf, stem and flowers) was used to access the antiproliferative activity by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay. Quantitative Real-Time RT-PCR revealed that the transcript levels of TGFβ1 are induced in the samples treated with methanolic extract of Artemisia absinthium. Furthermore, reduced expression levels of MYC gene was noticed in cancerous cells suggesting antiproliferative properties of the plant. This study further highlights the resistance profile of various microbes by antimicrobial susceptibility test with plant extracts. In addition, antidiabetic effect of Artemisia absinthium have also shown positive results. Our study elucidates the potentials of Artemisia absinthium as a medicinal plant, and highlights the differential expression of genes involved in its mitogenic and anti-proliferative activity with a brief account of its pharmacological action.
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Affiliation(s)
- Jannat Sohail
- Department of Bioinformatics & Biotechnology, Government College University Faisalabad, Faisalabad, Pakistan
| | - Muhammad Zubair
- Department of Bioinformatics & Biotechnology, Government College University Faisalabad, Faisalabad, Pakistan
| | - Khadim Hussain
- Department of Bioinformatics & Biotechnology, Government College University Faisalabad, Faisalabad, Pakistan
| | - Muhammad Faisal
- Institute of Plant Breeding and Biotechnology, MNS-University of Agriculture, Multan, Pakistan
| | - Muhammad Ismail
- Department of Bioinformatics & Biotechnology, Government College University Faisalabad, Faisalabad, Pakistan
| | - Imran Haider
- Institute of Plant Breeding and Biotechnology, MNS-University of Agriculture, Multan, Pakistan
| | - Rabia Mumtaz
- Department of Bioinformatics & Biotechnology, Government College University Faisalabad, Faisalabad, Pakistan
| | - Asif Ali Khan
- Institute of Plant Breeding and Biotechnology, MNS-University of Agriculture, Multan, Pakistan
| | - Muhammad Asaf Khan
- Institute of Plant Breeding and Biotechnology, MNS-University of Agriculture, Multan, Pakistan
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20
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Song J, Song Y, Jang H, Moon J, Kang H, Huh YM, Son HY, Rho HW, Park M, Lim EK, Jung J, Jung Y, Park HG, Lee KG, Im SG, Kang T. Elution-free DNA detection using CRISPR/Cas9-mediated light-up aptamer transcription: Toward all-in-one DNA purification and detection tube. Biosens Bioelectron 2023; 225:115085. [PMID: 36696850 DOI: 10.1016/j.bios.2023.115085] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 12/31/2022] [Accepted: 01/16/2023] [Indexed: 01/18/2023]
Abstract
Accurate and efficient detection of DNA is crucial for disease diagnosis and health monitoring. The traditional methods for DNA analysis involve multiple steps, including sample preparation, lysis, extraction, amplification, and detection. In this study, we present a one-step elution-free DNA analysis method based on the combination of clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated light-up aptamer transcription (CLAT) assay and a DNA-capturing poly(2-dimethylaminomethyl styrene) (pDMAMS)-coated tube. The sample solution and lysis buffer are added to the pDMAMS-coated tube, and the DNA is efficiently captured on the surface via electrostatic interaction and directly detected by CLAT assay. The ability of the CRISPR/Cas9 system to specifically recognize DNA enables direct detection of DNA captured on the pDMAMS-coated tube. The combination of CLAT assay and pDMAMS-coated tube simplifies DNA detection in a single tube without the need for complicated extraction steps, improving sensitivity. Our platform demonstrated attomolar sensitivity in the detection of target DNA in cell lysate (0.92 aM), urine (7.7 aM), and plasma (94.6 aM) samples within 1 h. The practical applicability of this method was further demonstrated in experiments with tumor-bearing mice. We believe that this approach brings us closer to an all-in-one DNA purification and detection tube system and has potential applications in tissue and liquid biopsies, as well as various other DNA sensing applications.
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Affiliation(s)
- Jayeon Song
- Bionanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Younseong Song
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea; Division of Nano-Bio Sensors/Chips Development, National NanoFab Center (NNFC), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Hyowon Jang
- Bionanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Jeong Moon
- Bionanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea; Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Hyunju Kang
- Bionanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea; Department of Chemistry, KAIST, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Yong-Min Huh
- Department of Radiology, College of Medicine, Yonsei University, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea; Department of Biochemistry & Molecular Biology, College of Medicine, Yonsei University, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea; Severance Biomedical Science Institute, College of Medicine, Yonsei University, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea; YUHS-KRIBB Medical Convergence Research Institute, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Hye Young Son
- Department of Radiology, College of Medicine, Yonsei University, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea; Severance Biomedical Science Institute, College of Medicine, Yonsei University, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Hyun Wook Rho
- Department of Radiology, College of Medicine, Yonsei University, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Mirae Park
- Department of Radiology, College of Medicine, Yonsei University, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Eun-Kyung Lim
- Bionanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea; Department of Nanobiotechnology, KRIBB School of Biotechnology, University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon, 34113, Republic of Korea; School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do, 16419, Republic of Korea
| | - Juyeon Jung
- Bionanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea; School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do, 16419, Republic of Korea
| | - Yongwon Jung
- Department of Chemistry, KAIST, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Hyun Gyu Park
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Kyoung G Lee
- Division of Nano-Bio Sensors/Chips Development, National NanoFab Center (NNFC), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea.
| | - Sung Gap Im
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea.
| | - Taejoon Kang
- Bionanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea; School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do, 16419, Republic of Korea.
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Ren Z, Zhang J, Zheng D, Luo Y, Song Z, Chen F, Li A, Liu X. Identification of Prognosis-Related Oxidative Stress Model with Immunosuppression in HCC. Biomedicines 2023; 11:biomedicines11030695. [PMID: 36979675 PMCID: PMC10045103 DOI: 10.3390/biomedicines11030695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 02/10/2023] [Accepted: 02/19/2023] [Indexed: 03/03/2023] Open
Abstract
For hepatocellular carcinoma (HCC) patients, we attempted to establish a new oxidative stress (OS)-related prognostic model for predicting prognosis, exploring immune microenvironment, and predicting the immunotherapy response. Significantly differently expressed oxidative stress-related genes (DEOSGs) between normal and HCC samples from the Cancer Genome Atlas (TCGA) were screened, and then based on weighted gene coexpression network analysis (WGCNA), HCC-related hub genes were discovered. Based on the least absolute shrinkage and selection operator (LASSO) and cox regression analysis, a prognostic model was developed. We validated the prognostic model’s predictive power using an external validation cohort: the International Cancer Genome Consortium (ICGC).Then a nomogram was determined. Furthermore, we also examined the relationship of the risk model and clinical characteristics as well as immune microenvironment. 434 DEOSGs, comprising 62 downregulated and 372 upregulated genes (p < 0.05 and |log2FC| ≥ 1), and 257 HCC-related hub genes were recognized in HCC. Afterward, we built a five-DEOSG (LOX, CYP2C9, EIF2B4, EZH2, and SRXN1) prognostic risk model. Using the nomogram, the risk model was shown to have good prognostic value. Compared to the low risk group, HCC patients with high risk had poorer outcomes, worse pathological grades, and advanced tumor stages (p < 0.05). There were significant increases in LOX, EIF2B4, EZH2, and SRXN1 expression in HCC samples, while CYP2C9 expression was decreased. Finally, Real-time PCR (RT-qPCR) confirmed the mRNA expressions of five genes (CYP2C9, EIF2B4, EZH2, SRXN1, LOX) in HCC cell lines. Our study constructed a prognostic OS-related model with strong predictive power and potential as an immunosuppressive biomarker for HCC leading to improving prediction and providing new insights for HCC immunotherapy.
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Affiliation(s)
- Zhixuan Ren
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
- Cancer Center, Southern Medical University, Guangzhou 510315, China
| | - Jiakang Zhang
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
- Cancer Center, Southern Medical University, Guangzhou 510315, China
| | - Dayong Zheng
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
- Cancer Center, Southern Medical University, Guangzhou 510315, China
| | - Yue Luo
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
- Cancer Center, Southern Medical University, Guangzhou 510315, China
| | - Zhenghui Song
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
- Cancer Center, Southern Medical University, Guangzhou 510315, China
| | - Fengsheng Chen
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
- Cancer Center, Southern Medical University, Guangzhou 510315, China
| | - Aimin Li
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
- Cancer Center, Southern Medical University, Guangzhou 510315, China
- Correspondence: (A.L.); (X.L.)
| | - Xinhui Liu
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
- Cancer Center, Southern Medical University, Guangzhou 510315, China
- Correspondence: (A.L.); (X.L.)
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22
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Chiang CC, Yeh H, Lim SN, Lin WR. Transcriptome analysis creates a new era of precision medicine for managing recurrent hepatocellular carcinoma. World J Gastroenterol 2023; 29:780-799. [PMID: 36816628 PMCID: PMC9932421 DOI: 10.3748/wjg.v29.i5.780] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/23/2022] [Accepted: 01/10/2023] [Indexed: 02/06/2023] Open
Abstract
The high incidence of hepatocellular carcinoma (HCC) recurrence negatively impacts outcomes of patients treated with curative intent despite advances in surgical techniques and other locoregional liver-targeting therapies. Over the past few decades, the emergence of transcriptome analysis tools, including real-time quantitative reverse transcription PCR, microarrays, and RNA sequencing, has not only largely contributed to our knowledge about the pathogenesis of recurrent HCC but also led to the development of outcome prediction models based on differentially expressed gene signatures. In recent years, the single-cell RNA sequencing technique has revolutionized our ability to study the complicated crosstalk between cancer cells and the immune environment, which may benefit further investigations on the role of different immune cells in HCC recurrence and the identification of potential therapeutic targets. In the present article, we summarized the major findings yielded with these transcriptome methods within the framework of a causal model consisting of three domains: primary cancer cells; carcinogenic stimuli; and tumor microenvironment. We provided a comprehensive review of the insights that transcriptome analyses have provided into diagnostics, surveillance, and treatment of HCC recurrence.
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Affiliation(s)
- Chun-Cheng Chiang
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15232, United States
| | - Hsuan Yeh
- School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, United States
| | - Siew-Na Lim
- Department of Neurology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Wey-Ran Lin
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
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23
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Cui S, Chen Y, Guo Y, Wang X, Chen D. Hsa-miR-22-3p inhibits liver cancer cell EMT and cell migration/ invasion by indirectly regulating SPRY2. PLoS One 2023; 18:e0281536. [PMID: 36749775 PMCID: PMC9904474 DOI: 10.1371/journal.pone.0281536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 01/24/2023] [Indexed: 02/08/2023] Open
Abstract
The general mechanism for microRNAs to play biological function is through their inhibition on the expression of their target genes. In cancer, microRNAs may accelerate cell senescence, block angiogenesis, decrease energy supplies, repress tumor cell cycle and promote apoptosis to function as the tumor repressors. On the other hand, microRNAs can modulate tumor suppressor molecules to activate oncogene relevant signaling pathway to initiate tumorigenesis and promote tumor progression. By targeting different genes, miR-22 can function as either a tumor suppressor or a tumor promoter in different types of cancer. In liver cancer, miR-22 mainly functions as a tumor suppressor via its regulation on different genes. In this study, we demonstrated that miR-22 indirectly regulates SPRY2 by inhibiting CBL, an E3 ligase for SPRY2 that has been confirmed. As one of the modulators of the MAPK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase) signaling pathway, SPRY2 plays important roles in many developmental and physiological processes, and its deregulation has been reported in different types of cancer and shown to affect cancer development, progression, and metastasis. By inhibiting the expression of CBL, which stabilizes SPRY2, miR-22 indirectly upregulates SPRY2, thereby suppressing the epithelial-mesenchymal transition (EMT), cell migration, and invasion and decreasing the expression of liver cancer stem cell (CSC) marker genes. The inhibitory effects of miR-22 on EMT, cell migration, and invasion can be blocked by the knockdown of SPRY2 expression in miR-22 overexpressing cells. Additionally, we demonstrated that miR-22 expression inhibits the ERK signaling pathway and that this effect is due to its upregulation of SPRY2. Overall, our study revealed a novel miR-22-3p/CBL/SPRY2/ERK axis that plays an important role in EMT, cell migration, and invasion of liver cancer cells.
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Affiliation(s)
- Shuaishuai Cui
- School of Life Sciences and Medicine, Shandong University of Technology, Zibo, China
| | - Yuanyuan Chen
- School of Life Sciences and Medicine, Shandong University of Technology, Zibo, China
| | - Yunfei Guo
- School of Life Sciences and Medicine, Shandong University of Technology, Zibo, China
| | - Xing Wang
- School of Life Sciences, Jiangsu Normal University, Xuzhou, China
| | - Dahu Chen
- School of Life Sciences and Medicine, Shandong University of Technology, Zibo, China
- * E-mail:
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24
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Clinical significance of cylindromatosis expression in primary hepatocellular carcinoma. Arab J Gastroenterol 2023; 24:58-64. [PMID: 36720665 DOI: 10.1016/j.ajg.2022.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 08/16/2022] [Accepted: 11/28/2022] [Indexed: 01/30/2023]
Abstract
BACKGROUND AND STUDY AIM There is currently a lack of sensitive biomarkers for the diagnosis of hepatocellular carcinoma (HCC). Low expression of cylindromatosis (CYLD), a tumor suppressor gene that encodes a deubiquitinase, is associated with the development of HCC. The present study, therefore, aimed to determine the clinical utility of measuring CYLD expression in the early diagnosis of HCC. PATIENTS AND METHODS The present study comprised 257 patients from the Affiliated Hospital of Qingdao University including 90 patients with HCC, 41 patients with liver cirrhosis (LC), 46 patients with hepatitis B (HB), and 80 healthy controls. qPCR was used to measure the amounts of CYLD mRNA in stored blood samples. The sensitivity and specificity of CYLD mRNA in diagnosing HCC was analyzed using receiver operator characteristic (ROC) curves. We also obtained HCC data from the Oncomine database to further verify our results. RESULTS The relative levels of CYLD mRNA in peripheral blood from patients with HCC (median, 0.060; interquartile range [IQR], 0.019-0.260) was significantly lower than in blood from patients with LC (median, 3.732; IQR, 0.648-14.573), HB (median, 0.419; IQR, 0.255-1.809) and healthy controls (median, 1.262; IQR, 0.279-3.537; P < 0.05). CYLD mRNA levels in peripheral blood were significantly higher in patients with LC compared to healthy controls and patients with HB. Oncomine data demonstrated that CYLD mRNA expression levels in HCC tissues were significantly lower than in normal liver tissues. ROC analysis demonstrated that the combined use of peripheral blood levels of CYLD and AFP had the greatest diagnostic accuracy for HCC (area under the curve (AUC), 0.897; 95 % confidence interval [CI], 0.853-0.942). CYLD had utility as a supplementary marker to AFP for diagnosing HCC. CONCLUSION Circulating levels of CYLD mRNA are significantly decreased in patients with HCC, indicating CYLD may have utility as a biomarker of HCC. Combined measurement of CYLD mRNA and AFP protein had the greatest diagnostic accuracy.
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25
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Gárate-Rascón M, Recalde M, Rojo C, Fernández-Barrena MG, Ávila MA, Arechederra M, Berasain C. SLU7: A New Hub of Gene Expression Regulation—From Epigenetics to Protein Stability in Health and Disease. Int J Mol Sci 2022; 23:ijms232113411. [PMID: 36362191 PMCID: PMC9658179 DOI: 10.3390/ijms232113411] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 10/28/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022] Open
Abstract
SLU7 (Splicing factor synergistic lethal with U5 snRNA 7) was first identified as a splicing factor necessary for the correct selection of 3′ splice sites, strongly impacting on the diversity of gene transcripts in a cell. More recent studies have uncovered new and non-redundant roles of SLU7 as an integrative hub of different levels of gene expression regulation, including epigenetic DNA remodeling, modulation of transcription and protein stability. Here we review those findings, the multiple factors and mechanisms implicated as well as the cellular functions affected. For instance, SLU7 is essential to secure liver differentiation, genome integrity acting at different levels and a correct cell cycle progression. Accordingly, the aberrant expression of SLU7 could be associated with human diseases including cancer, although strikingly, it is an essential survival factor for cancer cells. Finally, we discuss the implications of SLU7 in pathophysiology, with particular emphasis on the progression of liver disease and its possible role as a therapeutic target in human cancer.
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Affiliation(s)
- María Gárate-Rascón
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
| | - Miriam Recalde
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
| | - Carla Rojo
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
| | - Maite G. Fernández-Barrena
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
| | - Matías A. Ávila
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
| | - María Arechederra
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
| | - Carmen Berasain
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-948-194700; Fax: +34-948-194717
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Comprehensive analyses of prognostic biomarkers and immune infiltrates among histone lysine demethylases (KDMs) in hepatocellular carcinoma. Cancer Immunol Immunother 2022; 71:2449-2467. [DOI: 10.1007/s00262-022-03167-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Accepted: 01/31/2022] [Indexed: 10/18/2022]
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27
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Wang SY, Huang YH, Liang YJ, Wu JC. Gene coexpression network analysis identifies hubs in hepatitis B virus-associated hepatocellular carcinoma. J Chin Med Assoc 2022; 85:972-980. [PMID: 35801949 DOI: 10.1097/jcma.0000000000000772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related death worldwide. The molecular pathogenesis of HCC involves multiple signaling pathways. This study utilizes systems and bioinformatic approaches to investigate the pathogenesis of HCC. METHODS Gene expression microarray data were obtained from 50 patients with chronic hepatitis B and HCC. There were 1649 differentially expressed genes inferred from tumorous and nontumorous datasets. Weighted gene coexpression network analysis (WGCNA) was performed to construct clustered coexpressed gene modules. Statistical analysis was used to study the correlation between gene coexpression networks and demographic features of patients. Functional annotation and pathway inference were explored for each coexpression network. Network analysis identified hub genes of the prognostic gene coexpression network. The hub genes were further validated with a public database. RESULT Five distinct gene coexpression networks were identified by WGCNA. A distinct coexpressed gene network was significantly correlated with HCC prognosis. Pathway analysis of this network revealed extensive integration with cell cycle regulation. Ten hub genes of this gene network were inferred from protein-protein interaction network analysis and further validated in an external validation dataset. Survival analysis showed that lower expression of the 10-gene signature had better overall survival and recurrence-free survival. CONCLUSION This study identified a crucial gene coexpression network associated with the prognosis of hepatitis B virus-related HCC. The identified hub genes may provide insights for HCC pathogenesis and may be potential prognostic markers or therapeutic targets.
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Affiliation(s)
- Shen-Yung Wang
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, MacKay Memorial Hospital, Taipei, Taiwan, ROC
| | - Yen-Hua Huang
- Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Center for Systems and Synthetic Biology, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Yuh-Jin Liang
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Jaw-Ching Wu
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
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28
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Chen E, Yi J, Ren Q, Mi Y, Gan Z, Liu J. Overexpression of SRD5A3 in Hepatocellular Carcinoma and Its Molecular Mechanism: A Study of Bioinformatics Exploration Analysis with Experimental Verification. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:7853168. [PMID: 36159555 PMCID: PMC9507747 DOI: 10.1155/2022/7853168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 08/07/2022] [Accepted: 09/06/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and more prevalent among males than females. However, the biological role of enzyme 5α-reductase (SRD5A3), which plays a critical role in the androgen receptor signaling pathway during HCC development, remains poorly understood. METHODS ONCOMINE, GEPIA, UALCAN, and Kaplan-Meier Plotter were used to analyze the expression and prognostic value of SRD5A3 in HCC. STRING and Metascape were applied to analyze potential target and molecular pathways underlying SRD5A3 in HCC. A real-time quantitative reverse transcription-polymerase chain reaction was used to validate the downstream target expression of SRD5A3. RESULTS The expression of SRD5A3 was significantly overexpressed in HCC tissues compared with normal tissues, while the expression of SRD5A1 and SRD5A2 were downregulated in multiple public datasets. It may be that the low methylation of the SRD5A3 promoter leads to its overexpression. The level of SRD5A3 tended to be higher expressed in clinical samples with advanced stage and positive node metastasis. Furthermore, the patients with higher SRD5A3 were remarkably associated with poorer overall survival and disease-free survival in the TCGA data. In addition, the increased mRNA expression of SRD5A3 could predict poorer overall survival in Kaplan-Meier Plotter database including different patient cohorts. Moreover, HCC patients with higher level of SRD5A3 had significantly shorter recurrence-free survival, progression-free survival, and disease-specific survival. Furthermore, enrichment analysis demonstrated that multiple processes, such as steroid hormone biosynthesis, lipid biosynthetic process, and androgen metabolic process, were affected by SRD5A1-3 alterations. In vitro experiments showed that the expression of SRD5A3 was increased in HCC tissues than that in adjacent tissues. SRD5A3 silencing promoted the expression of DOLK in two HCC cell lines. CONCLUSIONS This study identified SRD5A3/DOLK as a novel axis to regulate HCC development.
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Affiliation(s)
- Erbao Chen
- Department of Hepatobiliary and Pancreatic Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong, China
- School of Medicine, Southern University of Science and Technology, Shenzhen 518055, Guangdong, China
| | - Jing Yi
- Department of Hepatobiliary and Pancreatic Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong, China
| | - Qingqi Ren
- Department of Hepatobiliary and Pancreatic Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong, China
| | - Yuanna Mi
- Department of Hepatobiliary and Pancreatic Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong, China
| | - Zhe Gan
- Department of Hepatobiliary and Pancreatic Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong, China
| | - Jikui Liu
- Department of Hepatobiliary and Pancreatic Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong, China
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RPNs Levels Are Prognostic and Diagnostic Markers for Hepatocellular Carcinoma. JOURNAL OF ONCOLOGY 2022; 2022:7270541. [PMID: 36072976 PMCID: PMC9444382 DOI: 10.1155/2022/7270541] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 05/04/2022] [Accepted: 05/23/2022] [Indexed: 11/17/2022]
Abstract
The ribophorin family (RPN) is an essential regulatory subunit of the proteasome. By influencing the ubiquitin-proteasome system activity, ribophorins (RPNs) are responsible for almost all physiology and pathology processes of mammalian cells. Nevertheless, little is known about the role of RPNs in HCC. In this work, we first evaluated the transcriptional levels and the prognostic and diagnostic value of RPNs based on the public database. Firstly, we found all RPNs were surprisingly consistently upregulated in HCC tissues. Moreover, the RPNs' expression pattern is correlated with HCC tumor grade. The TCGA HCC platforms' data indicated that RPN2, RPN3, RPN6, RPN9, RPN10, RPN11, and RPN12 have robust diagnosis values. Then, survival analysis revealed that the high expression of RPN1, RPN2, RPN4, RPN5, RPN6, RPN9, and RPN11 was correlated with unfavourable HCC overall survival. Then, genetic alteration, immune infiltration feature, gene-genes network, and functional enrichment for RPNs indicated that RPNs have many potential biosynthesis activities expert for UPS functions. Moreover, western blot and qRT-PCR results confirmed these results. The silencing of RPN6 and RPN9 significantly reduced HCC cells' proliferation, migration, and invasion ability in vitro. An in vivo tumor model further validated the oncogene effect of RPN6 on HCC cell growth. Moreover, RPN6 and RPN9 could promote cell migratory and invasive potential by affecting the epithelial-mesenchymal transition (EMT) process. In summary, this study suggests that the RPN family has the potential to be potential biomarkers and targets for HCC.
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Cai C, Zhang Y, Hu X, Yang S, Ye J, Wei Z, Chu T. Spindle and Kinetochore-associated Family Genes are Prognostic and Predictive Biomarkers in Hepatocellular Carcinoma. J Clin Transl Hepatol 2022; 10:627-641. [PMID: 36062274 PMCID: PMC9396317 DOI: 10.14218/jcth.2021.00216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 09/07/2021] [Accepted: 10/08/2021] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND AND AIMS Hepatocellular carcinoma (HCC) is one of the most frequent malignant tumors. Spindle and kinetochore-associated (SKA) family genes are essential for the maintenance of the metaphase plate and spindle checkpoint silencing during mitosis. Recent studies have indicated that dysregulation of SKA family genes induces tumorigenesis, tumor progression, and chemoresistance via modulation of cell cycle and DNA replication. However, the differential transcription of SKAs in the context of HCC and its prognostic significance has not been demonstrated. METHODS Bioinformatics analyses were performed using TCGA, ONCOMINE, HCCDB, Kaplan-Meier plotter, STRING, GEPIA databases. qRT-PCR, western blot, and functional assays were utilized for in vitro experiments. RESULTS We found remarkable upregulation of transcripts of SKA family genes in HCC samples compared with normal liver samples on bioinformatics analyses and in vitro validation. Interaction analysis and enrichment analysis showed that SKA family members were mainly related to microtubule motor activity, mitosis, and cell cycle. Immuno-infiltration analysis showed a correlation of all SKA family genes with various immune cell subsets, especially T helper 2 (Th2) cells. Transcriptional levels of SKA family members were positively associated with histologic grade, T stage, and α-fetoprotein in HCC patients. Receiver operating characteristic curve analysis demonstrated a strong predictive ability of SKA1/2/3 for HCC. Increased expression of these SKAs was associated with unfavorable overall survival, progression-free survival, and disease-specific survival. On Cox proportional hazards regression analyses, SKA1 upregulation and pathological staging were independent predictors of overall survival and disease-specific survival of HCC patients. Finally, clinical tissue microarray validation and in vitro functional assays revealed SKA1 acts an important regulatory role in tumor malignant behavior. CONCLUSIONS SKA family members may potentially serve as diagnostic and prognostic markers in the context of HCC. The correlation between SKAs and immune cell infiltration provides a promising research direction for SKA-targeted immunotherapeutics for HCC.
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Affiliation(s)
| | | | | | | | | | | | - Tongwei Chu
- Correspondence to: Tongwei Chu, Department of Orthopedics, Xinqiao Hospital, Third Military Medical University (Army Medical University), No.83 Xinqiao Main Street, Shapingba District, Chongqing 400037, China. ORCID: https://orcid.org/0000-0003-0309-7082. Tel: +86-13708388336, E-mail:
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The Prognostic Value of AT-Rich Interaction Domain (ARID) Family Members in Patients with Hepatocellular Carcinoma. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:1150390. [PMID: 36034939 PMCID: PMC9410793 DOI: 10.1155/2022/1150390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 07/19/2022] [Indexed: 12/24/2022]
Abstract
Objective Hepatocellular carcinoma (HCC) is one of the most lethal malignancies with a poor prognosis. The AT-rich interaction domain (ARID) family plays an essential regulatory role in the pathogenesis and progression of cancers. This study aims to evaluate the prognostic value and clinical significance of human ARID family genes in HCC. Methods ONCOMINE and The Cancer Genome Atlas (TCGA) databases were employed to retrieve ARIDs expression profile and clinicopathological information of HCC. Kaplan–Meier plotter and MethSurv were applied to the survival analysis of patients with HCC. CBioPortal was used to analyze genetic mutations of ARIDs. Gene Expression Profiling Interactive Analysis (GEPIA) and Metascape were used to perform hub gene identification and functional enrichment. Results Expression levels of 11 ARIDs were upregulated in HCC, and 2 ARIDs were downregulated. Also, 4 ARIDs and 5 ARIDs were correlated with pathologic stages and histologic grades, respectively. Furthermore, higher expression of ARID1A, ARID1B, ARID2, ARID3A, ARID3B, ARID5B, KDM5A, KDM5B, KDM5C, and JARID2 was remarkably correlated with worse overall survival of patients with HCC, and the high ARID3C/KDM5D expression was related to longer overall survival. Multivariate Cox analysis indicated that ARID3A, KDM5C, and KDM5D were independent risk factors for HCC prognosis. Moreover, ARIDs mutations and 127 CpGs methylation in all ARIDs were observed to be significantly associated with the prognosis of HCC patients. Besides, our data showed that ARIDs could regulate tumor-related pathways and distinct immune cells in the HCC microenvironment. Conclusions ARIDs present the potential prognostic value for HCC. Our findings suggest that ARID3A, KDM5C, and KDM5D may be the prognostic biomarkers for patients with HCC.
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Prognostic Values of BolA Family Member Expression in Hepatocellular Carcinoma. BIOMED RESEARCH INTERNATIONAL 2022; 2022:8360481. [PMID: 36017386 PMCID: PMC9398796 DOI: 10.1155/2022/8360481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/21/2022] [Accepted: 07/25/2022] [Indexed: 12/31/2022]
Abstract
The BolA gene family member (BOLA1-3) plays an important role in regulating normal and pathological biological processes including liver tumorigenesis. However, their expression patterns as prognostic factors in hepatocellular carcinoma (HCC) patients have not to be elucidated. We examined the transcriptional expressions and survival data of BolA family member in patients with HCC from online databases including ONCOMINE, TCGA, UALCAN, Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan-Meier plotter, SurvExpress, cBioPortal, and Exobase. Network molecular interaction views of BolA family members and their neighborhoods were constructed by the IntAct web server. In our research, we had found that the expression levels of BolA /2/3 mRNA were higher in HCC tissue than in normal liver tissues from TGCA databases. Moreover, the BolA family gene expression level is significantly associated with distinct tumor pathological grade, TMN stage, and overall survival (OS). The BolA family can be considered as prognostic risk biomarkers of HCC. A small number of BolA gene-mutated samples were detected in the HCC tissue. IntAct analysis revealed that BolA1/2/3 was closely associated with the GLRX3 expression in HCC, which is implicated in the regulation of the cellular iron homeostasis and tumor growth. Furthermore, prognostic values of altered BolAs and their neighbor GLRX3 gene in HCC patients were validated by SurvExpress analysis. In conclusion, the membrane BolA family identified in this study provides very useful information for the mechanism of hepatic tumorigenesis.
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Lan F, Chen X, Xiong Z, Cao Z, Lu L, Zhong Y, Zhan X, Yang Y, Shao Y, Li M, Han Z, Zhu X. Comprehensive transcriptomic and co-expression analysis of ABL1 gene and molecularly targeted drugs in hepatocellular carcinoma based on multi-database mining. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 39:146. [PMID: 35834027 DOI: 10.1007/s12032-022-01730-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 04/05/2022] [Indexed: 11/28/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. Consequently, it is essential to identify biomarkers for treatment response and the prognosis prediction. We investigated whether ABL1 can function as a biomarker or a drug target for HCC. We assessed the ABL1 expression, genetic alterations and patients' survival from LinkedOmics, GEO, TCGA and Human Protein Atlas. We analyzed PPI, GO and KEGG pathways. GSEA was analyzed for functional comparison. The current drugs targeting ABL1 were statistically analyzed using DRUGSURV and DGIdb database. We found ABL1 is overexpressed in HCC and its higher expression reduces survival probability. Genetic changes of ABL1 are not frequent. We screened out 25 differentially expressed genes correlated with ABL1. The top functions of ABL1 are biological regulation, metabolic process, protein-containing, and protein binding. KEGG pathways showed that ABL1 and correlated with ABL1 significantly genes markedly enriched in the ErbB signaling pathway, and pathways in cancer. We counted the existing drugs targeting ABL1, which indicates that inhibiting ABL1 expression may improve the survival probability of HCC. In conclusion, ABL1 plays a crucial role in the development and progression of this cancerization and is a potential drug target.
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Affiliation(s)
- Feifei Lan
- Medical Genetics Center, Guangdong Women and Children Hospital, Guangzhou, China
| | - Xinqia Chen
- Zhu's Team, Guangdong Medical University, Zhanjiang, China
| | - Zhuolong Xiong
- Zhu's Team, Guangdong Medical University, Zhanjiang, China
| | - Zitong Cao
- Zhu's Team, Guangdong Medical University, Zhanjiang, China
| | - Liangzong Lu
- Zhu's Team, Guangdong Medical University, Zhanjiang, China
| | - Yueyuan Zhong
- Zhu's Team, Guangdong Medical University, Zhanjiang, China
| | - Xuliang Zhan
- Zhu's Team, Guangdong Medical University, Zhanjiang, China
| | - Yue Yang
- Zhu's Team, Guangdong Medical University, Zhanjiang, China
| | - Yingqi Shao
- Zhu's Team, Guangdong Medical University, Zhanjiang, China
| | - Minhua Li
- Zhu's Team, Guangdong Medical University, Zhanjiang, China
| | - Zenglei Han
- Department of Pathology, Qingdao Municipal Hospital, Qingdao, China.
| | - Xiao Zhu
- Zhu's Team, Guangdong Medical University, Zhanjiang, China. .,School of Laboratory Medicine and Biomedical Engineering, Hangzhou Medical College, Hangzhou, China.
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Grudlewska-Buda K, Wiktorczyk-Kapischke N, Budzyńska A, Kwiecińska-Piróg J, Przekwas J, Kijewska A, Sabiniarz D, Gospodarek-Komkowska E, Skowron K. The Variable Nature of Vitamin C—Does It Help When Dealing with Coronavirus? Antioxidants (Basel) 2022; 11:antiox11071247. [PMID: 35883738 PMCID: PMC9312329 DOI: 10.3390/antiox11071247] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 06/21/2022] [Accepted: 06/22/2022] [Indexed: 02/06/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still spreading worldwide. For this reason, new treatment methods are constantly being researched. Consequently, new and already-known preparations are being investigated to potentially reduce the severe course of coronavirus disease 2019 (COVID-19). SARS-CoV-2 infection induces the production of pro-inflammatory cytokines and acute serum biomarkers in the host organism. In addition to antiviral drugs, there are other substances being used in the treatment of COVID-19, e.g., those with antioxidant properties, such as vitamin C (VC). Exciting aspects of the use of VC in antiviral therapy are its antioxidant and pro-oxidative abilities. In this review, we summarized both the positive effects of using VC in treating infections caused by SARS-CoV-2 in the light of the available research. We have tried to answer the question as to whether the use of high doses of VC brings the expected benefits in the treatment of COVID-19 and whether such treatment is the correct therapeutic choice. Each case requires individual assessment to determine whether the positives outweigh the negatives, especially in the light of populational studies concerning the genetic differentiation of genes encoding the solute carriers responsible forVC adsorption. Few data are available on the influence of VC on the course of SARS-CoV-2 infection. Deducing from already-published data, high-dose intravenous vitamin C (HDIVC) does not significantly lower the mortality or length of hospitalization. However, some data prove, among other things, its impact on the serum levels of inflammatory markers. Finally, the non-positive effect of VC administration is mainly neutral, but the negative effect is that it can result in urinary stones or nephropathies.
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Affiliation(s)
- Katarzyna Grudlewska-Buda
- Department of Microbiology, Ludwik Rydygier Collegium Medicum, Nicolaus Copernicus University in Toruń, 85-094 Bydgoszcz, Poland; (K.G.-B.); (N.W.-K.); (A.B.); (J.K.-P.); (J.P.); (E.G.-K.)
| | - Natalia Wiktorczyk-Kapischke
- Department of Microbiology, Ludwik Rydygier Collegium Medicum, Nicolaus Copernicus University in Toruń, 85-094 Bydgoszcz, Poland; (K.G.-B.); (N.W.-K.); (A.B.); (J.K.-P.); (J.P.); (E.G.-K.)
| | - Anna Budzyńska
- Department of Microbiology, Ludwik Rydygier Collegium Medicum, Nicolaus Copernicus University in Toruń, 85-094 Bydgoszcz, Poland; (K.G.-B.); (N.W.-K.); (A.B.); (J.K.-P.); (J.P.); (E.G.-K.)
| | - Joanna Kwiecińska-Piróg
- Department of Microbiology, Ludwik Rydygier Collegium Medicum, Nicolaus Copernicus University in Toruń, 85-094 Bydgoszcz, Poland; (K.G.-B.); (N.W.-K.); (A.B.); (J.K.-P.); (J.P.); (E.G.-K.)
| | - Jana Przekwas
- Department of Microbiology, Ludwik Rydygier Collegium Medicum, Nicolaus Copernicus University in Toruń, 85-094 Bydgoszcz, Poland; (K.G.-B.); (N.W.-K.); (A.B.); (J.K.-P.); (J.P.); (E.G.-K.)
| | - Agnieszka Kijewska
- Department of Immunobiology and Environmental Biology, Institute of Maritime and Tropical Medicine, Medical University of Gdansk, 80-211 Gdansk, Poland;
| | | | - Eugenia Gospodarek-Komkowska
- Department of Microbiology, Ludwik Rydygier Collegium Medicum, Nicolaus Copernicus University in Toruń, 85-094 Bydgoszcz, Poland; (K.G.-B.); (N.W.-K.); (A.B.); (J.K.-P.); (J.P.); (E.G.-K.)
| | - Krzysztof Skowron
- Department of Microbiology, Ludwik Rydygier Collegium Medicum, Nicolaus Copernicus University in Toruń, 85-094 Bydgoszcz, Poland; (K.G.-B.); (N.W.-K.); (A.B.); (J.K.-P.); (J.P.); (E.G.-K.)
- Correspondence: ; Tel.: +48-(52)-585-38-38
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Li FP, Liu GH, Zhang XQ, Kong WJ, Mei J, Wang M, Dai YH. Overexpressed SNRPB/D1/D3/E/F/G correlate with poor survival and immune infiltration in hepatocellular carcinoma. Am J Transl Res 2022; 14:4207-4228. [PMID: 35836882 PMCID: PMC9274562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 05/23/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Prior reports have indicated that the abnormal expression of small nuclear ribonucleoproteins (snRNPs) genes is related to malignant tumors. However, in hepatocellular carcinoma (HCC), the precise role of snRNPs is not well understood. Therefore, the purpose of this study was to evaluate the prognostic roles of SNRPB/D1/D2/D3/E/F/G and their correlation to immune infiltration in HCC. METHODS The study was carried out via the following databases, software, and experimental validation: ONCOMINE, GEPIA2, UALCAN, The Cancer Genome Atlas, Gene Expression Omnibus, ArrayExpress, Kaplan-Meier plotter, cBioPortal, STRING, DAVID 6.8, TIMER, Cytoscape software, and immunohistochemistry experiments. RESULTS Overexpressed SNRPB/D1/D2/D3/E/F/G proteins were found in HCC tissues. The transcription levels of 7 snRNPs genes were related to the TP53 mutation and tumor grades. SNRPB/D1/D2/D3/F/G expression was significantly correlated with cancer staging, whereas SNRPE was not. Moreover, Kaplan-Meier survival analysis showed that upregulation of SNRPB/D1/D2/E/G was relevant to worse OS in HCC patients, especially in patients with alcohol consumption and those without viral hepatitis. Multivariate Cox regression analysis indicated that expression of SNRPB/D1/D3/E/F/G were independent prognostic factors for unfavorable OS in HCC. In addition, a high mutation rate of snRNPs genes (44%) was also found in HCC. The mRNA expression levels of snRNPs were meaningfully and positively related to six types of infiltrating immune cells (B cells, CD4+ T cells, CD8+ T cells, neutrophil, macrophage, and dendritic cells). Also, SNRPB/D1/G genes were significantly associated with molecular markers of various immune cells in HCC. CONCLUSIONS SNRPB/D1/D3/E/F/G are potential prognostic biomarkers for a short OS in HCC, and SNRPB/D1/G were novel immune therapy targets in HCC patients.
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Affiliation(s)
- Fu-Ping Li
- Department of Clinical Medicine, Shaanxi University of Chinese MedicineXianyang 712046, Shaanxi, China
| | - Gao-Hua Liu
- Department of Oncology, Fujian Medical University Union HospitalFuzhou 350001, Fujian, China
| | - Xue-Qin Zhang
- Jincheng Institute of Sichuan UniversityChengdu 610000, Sichuan, China
| | - Wei-Jie Kong
- Department of Clinical Medicine, Shaanxi University of Chinese MedicineXianyang 712046, Shaanxi, China
| | - Jian Mei
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Fujian Medical UniversityFuzhou 350005, China
| | - Mao Wang
- Department of Surgical Oncology Medicine, Second Affiliated Hospital of Shaanxi University of Chinese MedicineXianyang 712000, Shaanxi, China
| | - Yin-Hai Dai
- Department of Clinical Medicine, Shaanxi University of Chinese MedicineXianyang 712046, Shaanxi, China
- Department of Surgical Oncology Medicine, Second Affiliated Hospital of Shaanxi University of Chinese MedicineXianyang 712000, Shaanxi, China
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Li X, Zhang L, Yi Z, Zhou J, Song W, Zhao P, Wu J, Song J, Ni Q. NUF2 Is a Potential Immunological and Prognostic Marker for Non-Small-Cell Lung Cancer. J Immunol Res 2022; 2022:1161931. [PMID: 35600043 PMCID: PMC9119754 DOI: 10.1155/2022/1161931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 04/09/2022] [Indexed: 11/17/2022] Open
Abstract
Background Globally, non-small-cell lung cancer (NSCLC) is one of the most prevalent tumors. Various studies have investigated its etiology, but the molecular mechanism of NSCLC has not been elucidated. Methods The GSE19804, GSE118370, GSE19188, GSE27262, and GSE33532 microarray datasets were obtained from the Gene Expression Omnibus (GEO) database for the identification of genes involved in NSCLC development as well as progression. Then, the identified differentially expressed genes (DEGs) were subjected to functional enrichment analyses. The protein-protein interaction (PPI) network was built after which module analysis was conducted via the Search Tool for Retrieval of Interacting Genes/Proteins (STRING) and Cytoscape. There were 562 DEGs: 98 downregulated genes and 464 upregulated. These DEGs were established to be enriched in p53 signaling pathway, transendothelial leukocyte migration, cell adhesion molecules, contractions of vascular smooth muscles, coagulation and complement cascades, and axon guidance. Assessment of tumor immunity was performed to determine the roles of hub genes. Results There were 562 dysregulated genes, while 12 genes were hub genes. NUF2 was established to be a candidate immunotherapeutic target with potential clinical implications. The 12 hub genes were highly enriched in the p53 signaling pathway, the cell cycle, progesterone-associated oocyte maturation, cellular senescence, and oocyte meiosis. Survival analysis showed that NUF2 is associated with NSCLC occurrence, invasion, and recurrence. Conclusion The NUF2 gene discovered in this study helps us clarify the pathomechanisms of NSCLC occurrence as well as progression and provides a potential diagnostic and therapeutic target for NSCLC.
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Affiliation(s)
- Xia Li
- Department of General Medicine, The Sixth Affiliated Hospital of Nantong University, Yancheng Third People's Hospital, Jiangsu Province, China
- The Central Laboratory, The Sixth Affiliated Hospital of Nantong University, Yancheng Third People's Hospital, Jiangsu Province, China
| | - Lianlian Zhang
- Department of Ultrasound Imaging, The Fourth Affiliated Hospital of Nantong University, Yancheng First People's Hospital, Jiangsu Province, China
| | - Zhongquan Yi
- The Central Laboratory, The Sixth Affiliated Hospital of Nantong University, Yancheng Third People's Hospital, Jiangsu Province, China
| | - Jing Zhou
- Department of General Medicine, The Sixth Affiliated Hospital of Nantong University, Yancheng Third People's Hospital, Jiangsu Province, China
| | - Wenchun Song
- Department of General Medicine, The Sixth Affiliated Hospital of Nantong University, Yancheng Third People's Hospital, Jiangsu Province, China
| | - Panwen Zhao
- The Central Laboratory, The Sixth Affiliated Hospital of Nantong University, Yancheng Third People's Hospital, Jiangsu Province, China
| | - Jixiang Wu
- Department of Thoracic Surgery, The Sixth Affiliated Hospital of Nantong University, Yancheng Third People's Hospital, Jiangsu Province, China
| | - Jianxiang Song
- Department of Thoracic Surgery, The Sixth Affiliated Hospital of Nantong University, Yancheng Third People's Hospital, Jiangsu Province, China
| | - Qinggan Ni
- Department of Burns and Plastic Surgery, The Fourth Affiliated Hospital of Nantong University, Yancheng First People's Hospital, Jiangsu Province, China
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Comprehensive Landscape of STEAP Family Members Expression in Human Cancers: Unraveling the Potential Usefulness in Clinical Practice Using Integrated Bioinformatics Analysis. DATA 2022. [DOI: 10.3390/data7050064] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
The human Six-Transmembrane Epithelial Antigen of the Prostate (STEAP) family comprises STEAP1-4. Several studies have pointed out STEAP proteins as putative biomarkers, as well as therapeutic targets in several types of human cancers, particularly in prostate cancer. However, the relationships and significance of the expression pattern of STEAP1-4 in cancer cases are barely known. Herein, the Oncomine database and cBioPortal platform were selected to predict the differential expression levels of STEAP members and clinical prognosis. The most common expression pattern observed was the combination of the over- and underexpression of distinct STEAP genes, but cervical and gastric cancer and lymphoma showed overexpression of all STEAP genes. It was also found that STEAP genes’ expression levels were already deregulated in benign lesions. Regarding the prognostic value, it was found that STEAP1 (prostate), STEAP2 (brain and central nervous system), STEAP3 (kidney, leukemia and testicular) and STEAP4 (bladder, cervical, gastric) overexpression correlate with lower patient survival rate. However, in prostate cancer, overexpression of the STEAP4 gene was correlated with a higher survival rate. Overall, this study first showed that the expression levels of STEAP genes are highly variable in human cancers, which may be related to different patients’ outcomes.
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Park B, Lee W, Han K. A New Approach to Deriving Prognostic Gene Pairs From Cancer Patient-Specific Gene Correlation Networks. IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2022; 19:1267-1276. [PMID: 32809942 DOI: 10.1109/tcbb.2020.3017209] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Many of the known prognostic gene signatures for cancer are individual genes or combination of genes, found by the analysis of microarray data. However, many of the known cancer signatures are less predictive than random gene expression signatures, and such random signatures are significantly associated with proliferation genes. With the availability of RNA-seq gene expression data for thousands of human cancer patients, we have analyzed RNA-seq and clinical data of cancer patients and constructed gene correlation networks specific to individual cancer patients. From the patient-specific gene correlation networks, we derived prognostic gene pairs for three types of cancer. In this paper, we propose a new method for inferring prognostic gene pairs from patient-specific gene correlation networks. The main difference of our method from previous ones includes (1) it is focused on finding prognostic gene pairs rather than prognostic genes, (2) it can identify prognostic gene pairs from RNA-seq data even when no significant prognostic genes exist, and (3) prognostic gene pairs can serve as robust prognostic biomarkers in the sense that most prognostic gene pairs show little association with proliferation genes, the major boosting factor of the predictive power of random gene signatures. Evaluation of our method with extensive data of three types of cancer (liver cancer, pancreatic cancer, and stomach cancer) showed that our approach is general and that gene pairs can serve as more reliable prognostic signatures for cancer than genes. Analysis of patient-specific gene networks suggests that prognosis of individual cancer patients is affected by the existence of prognostic gene pairs in the patient-specific network and by the size of the patient-specific network. Although preliminary, our approach will be useful for finding gene pairs to predict survival time of patients and to tailor treatments to individual characteristics. The program for dynamically constructing patient-specific gene networks and for finding prognostic gene pairs is available at http://bclab.inha.ac.kr/LPS.
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Wu G, Zhou J, Zhu X, Tang X, Liu J, Zhou Q, Chen Z, Liu T, Wang W, Xiao X, Wu T. Integrative analysis of expression, prognostic significance and immune infiltration of RFC family genes in human sarcoma. Aging (Albany NY) 2022; 14:3705-3719. [PMID: 35483337 PMCID: PMC9085243 DOI: 10.18632/aging.204039] [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: 02/08/2022] [Accepted: 04/13/2022] [Indexed: 11/25/2022]
Abstract
Objective: To reveal the expression and prognostic value of replication factor C family genes (RFCs) in patients with sarcoma. Results: The results showed that the mRNA expression levels of RFC2, RFC3, RFC4, and RFC5 were increased in sarcoma tissues. In addition, Cancer Cell Line Encyclopedia (CCLE) dataset analysis indicated that RFC1, RFC2, RFC3, RFC4, and RFC5 were elevated expressed in sarcoma cell lines. Moreover, Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan-Meier Plotter showed that highly expressed RFC2-5 were associated with poor overall survival (OS) or relapse-free survival (RFS) in sarcoma patients. The results of the Tumor Immune Estimation Resource (TIMER) database indicated that the expression of RFCs was negatively correlated with the infiltration of CD4+ T cells and macrophages. Conclusions: There were significant differences in the expression of RFCs between normal tissue and sarcoma tissue, and RFC2, RFC3, RFC4, and RFC5 might be promising prognostic biomarkers for sarcoma. Methods: The expression of RFCs was analyzed using the ONCOMINE dataset and GEPIA dataset. CCLE dataset was used to assess the expression of RFCs in the cancer cell line. The prognostic value of RFCs was evaluated by GEPIA and Kaplan-Meier analysis. Furthermore, the association between RFCs and their co-expressed genes were explored via ONCOMINE and GEPIA datasets. We used the TIMER dataset to analyze the immune cell infiltration of RFCs in sarcoma.
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Affiliation(s)
- Gen Wu
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.,Clinical Medicine Eight-Year Program, 02 Class, 2014 Grade, Central South University, Changsha 410013, Hunan Province, China
| | - Jian Zhou
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Xi Zhu
- Department of Internal Medicine III, University Hospital, Ludwig Maximilian University, Munich 81377, Germany
| | - Xianzhe Tang
- Department of Orthopedics, Chenzhou No.1 People's Hospital, Chenzhou 423000, Hunan, China
| | - Jie Liu
- Department of Cardiology, The Fourth Hospital of Changsha, Changsha 410006, Hunan, China
| | - Qiong Zhou
- Department of Cardiology, The Fourth Hospital of Changsha, Changsha 410006, Hunan, China
| | - Ziyuan Chen
- Department of Orthopedics, The First People's Hospital of Changde City, Changde 415003, Hunan, China
| | - Tang Liu
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Wanchun Wang
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Xungang Xiao
- Department of Orthopedics, Chenzhou No.1 People's Hospital, Chenzhou 423000, Hunan, China
| | - Tong Wu
- Department of Emergency, The First Hospital of Changsha, Changsha 410005, Hunan, China
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Fan J, Wang L, Chen M, Zhang J, Li J, Song F, Gu A, Yin D, Yi Y. Analysis of the expression and prognosis for leukocyte immunoglobulin-like receptor subfamily B in human liver cancer. World J Surg Oncol 2022; 20:92. [PMID: 35321724 PMCID: PMC8943947 DOI: 10.1186/s12957-022-02562-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 03/10/2022] [Indexed: 12/24/2022] Open
Abstract
Background Leukocyte immunoglobulin-like receptor subfamily B (LILRB), including 5 subtypes, is a group of inhibitory receptors in the immune system. The LILRB family is known to be involved in the tumor progression of various cancer types, especially liver cancer. However, the expression patterns and prognostic values of LILRB family members in liver cancer tissues remain unclear. Methods We used the Oncomine database, GEPIA database, Kaplan–Meier Plotter, Timer, and TISIDB to assess the expression and prognostic value of the LILRB family in liver cancer patients. We also verified the expression of the LILRB family in tumor tissues and tumor-free liver tissues at the protein level by using immunohistochemistry. The STRING website was used to explore the interaction between the LILRB family and their related genes. The DAVID database was used to perform the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Flow cytometry was used to assess the infiltrated NK cells in liver cancer tissues. Results Our study revealed that the mRNA expression of LILRB1, LILRB2, LILRB3, and LILRB5 was downregulated, while compared with normal tissues, the mRNA expression of LILRB4 was upregulated in liver cancer tissues. Survival analysis revealed that LILRB2 and LILRB5 mRNA expression levels were significantly positively associated with overall survival (OS) and disease-free survival (DSS) and that the mRNA expression of all LILRB family members was significantly positively correlated with recurrence-free survival (RFS) and progression-free survival (PFS). Next, we further found that the mRNA expression of all LILRB family members was significantly associated with the infiltration of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells in liver cancer. Finally, GO and KEGG analyses found that the LILRB family and its related genes were involved in antigen processing and presentation and natural killer cell-mediated cytotoxicity pathways. Conclusions Our study suggested that LILRB family expression was associated with the prognosis of liver cancer patients and infiltrated immune cells. The LILRB family might be involved in antigen processing and presentation and natural killer cell-mediated cytotoxicity pathways. Supplementary Information The online version contains supplementary material available at 10.1186/s12957-022-02562-w.
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Affiliation(s)
- Jing Fan
- Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Zhong Fu Road, Gulou District, Nanjing, Jiangsu, People's Republic of China, 210003
| | - Lili Wang
- Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Zhong Fu Road, Gulou District, Nanjing, Jiangsu, People's Republic of China, 210003
| | - Miao Chen
- Nanjing University of Chinese Medicine, Han Zhong Road, Jianye District, Nanjing, Jiangsu, People's Republic of China, 210029
| | - Jiakang Zhang
- Nanjing University of Chinese Medicine, Han Zhong Road, Jianye District, Nanjing, Jiangsu, People's Republic of China, 210029
| | - Jiayan Li
- Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Zhong Fu Road, Gulou District, Nanjing, Jiangsu, People's Republic of China, 210003
| | - Fangnan Song
- Department of Hepatobiliary Surgery, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Zhong Fu Road, Gulou District, Nanjing, Jiangsu, People's Republic of China, 210003
| | - Aidong Gu
- Department of Hepatobiliary Surgery, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Zhong Fu Road, Gulou District, Nanjing, Jiangsu, People's Republic of China, 210003
| | - Dandan Yin
- Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Zhong Fu Road, Gulou District, Nanjing, Jiangsu, People's Republic of China, 210003
| | - Yongxiang Yi
- Department of Hepatobiliary Surgery, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Zhong Fu Road, Gulou District, Nanjing, Jiangsu, People's Republic of China, 210003.
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A Liver Damage Prediction Using Partial Differential Segmentation with Improved Convolutional Neural Network. JOURNAL OF HEALTHCARE ENGINEERING 2022; 2022:4055491. [PMID: 35265300 PMCID: PMC8898868 DOI: 10.1155/2022/4055491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/20/2021] [Accepted: 01/17/2022] [Indexed: 11/19/2022]
Abstract
Background The liver is one of the most significant and most essential organs in the human body. It is divided into two granular lobes, one on the right and one on the left, connected by a bile duct. The liver is essential in the removal of waste products from human food consumption, the creation of bile, the regulation of metabolic activities, the cleaning of the blood by sensitizing digestive management, and the storage of vitamins and minerals. To perform the classification of liver illnesses using computed tomography (CT scans), two critical phases must first be completed: liver segmentation and categorization. The most difficult challenge in categorizing liver disease is distinguishing the liver from the other organs near it. Methodology. Liver biopsy is a kind of invasive diagnostic procedure, widely regarded as the gold standard for accurately estimating the severity of liver disease. Noninvasive approaches for examining liver illnesses, such as blood serum markers and medical imaging (ultrasound, magnetic resonance MR, and CT) have also been developed. This approach uses the Partial Differential Technique (PDT) to separate the liver from the other organs and Level Set Methodology (LSM) for separating the cancer location from the surrounding tissue based on the projected pictures used as input. With the help of an Improved Convolutional Classifier, the categorization of different phases may be accomplished. Results Several accuracies, sensitivity, and specificity measurements are produced to assess the categorization of LSM using an Improved Convolutional classifier. Approximately, 97.5% of the performance accuracy of the liver categorization is achieved with a 94.5% continuous interval (CI) of [0.6775 1.0000] and an error rate of 2.1%. The suggested method's performance is compared to that of two existing algorithms, and the sensitivity and specificity provide an overall average of 96% and 93%, respectively, with 95% Continuous Interval of [0.7513 1.0000] and [0.7126 1.0000] for sensitivity and specificity, respectively.
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Cai Y, Fu Y, Liu C, Wang X, You P, Li X, Song Y, Mu X, Fang T, Yang Y, Gu Y, Zhang H, He Z. Stathmin 1 is a biomarker for diagnosis of microvascular invasion to predict prognosis of early hepatocellular carcinoma. Cell Death Dis 2022; 13:176. [PMID: 35210426 PMCID: PMC8873260 DOI: 10.1038/s41419-022-04625-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 01/26/2022] [Accepted: 02/07/2022] [Indexed: 01/27/2023]
Abstract
Microvascular invasion (MVI) is presently evaluated as a high-risk factor to be directly relative to postoperative prognosis of hepatocellular carcinoma (HCC). Up to now, diagnosis of MVI mainly depends on the postoperative pathological analyses with H&E staining assay, based on numbers and distribution characteristics of MVI to classify the risk levels of MVI. However, such pathological analyses lack the specificity to discriminate MVI in HCC specimens, especially in complicated pathological tissues. In addition, the efficiency to precisely define stages of MVI is not satisfied. Thus, any biomarker for both conforming diagnosis of MVI and staging its levels will efficiently and effectively promote the prediction of early postoperative recurrence and metastasis for HCC. Through bioinformatics analysis and clinical sample verification, we discovered that Stathmin 1 (STMN1) gene was significantly up-regulated at the locations of MVI. Combining STMN1 immunostaining with classic H&E staining assays, we established a new protocol for MVI pathological diagnosis. Next, we found that the degrees of MVI risk could be graded according to expression levels of STMN1 for prognosis prediction on recurrence rates and overall survival in early HCC patients. STMN1 affected epithelial-mesenchymal transformation (EMT) of HCC cells by regulating the dynamic balance of microtubules through signaling of “STMN1-Microtubule-EMT” axis. Inhibition of STMN1 expression in HCC cells reduced their lung metastatic ability in recipients of mouse model, suggesting that STMN1 also could be a potential therapeutic target for inhibiting HCC metastasis. Therefore, we conclude that STMN1 has potentials for clinical applications as a biomarker for both pathological diagnosis and prognostic prediction, as well as a therapeutic target for HCC.
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Affiliation(s)
- Yongchao Cai
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University School of Medicine, Shanghai, 200123, P. R. China.,Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, P. R. China.,Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, P. R. China
| | - Yong Fu
- Department of Liver Surgery V, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, P. R. China
| | - Changcheng Liu
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University School of Medicine, Shanghai, 200123, P. R. China.,Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, P. R. China.,Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, P. R. China
| | - Xicheng Wang
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University School of Medicine, Shanghai, 200123, P. R. China.,Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, P. R. China.,Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, P. R. China
| | - Pu You
- Institute of Brain-Intelligence Science and Technology, Zhangjiang Laboratory & Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai, 201210, P. R. China
| | - Xiuhua Li
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University School of Medicine, Shanghai, 200123, P. R. China.,Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, P. R. China.,Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, P. R. China
| | - Yanxiang Song
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University School of Medicine, Shanghai, 200123, P. R. China.,Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, P. R. China.,Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, P. R. China
| | - Xiaolan Mu
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University School of Medicine, Shanghai, 200123, P. R. China.,Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, P. R. China.,Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, P. R. China
| | - Ting Fang
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University School of Medicine, Shanghai, 200123, P. R. China.,Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, P. R. China.,Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, P. R. China
| | - Yang Yang
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University School of Medicine, Shanghai, 200123, P. R. China.,Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, P. R. China.,Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, P. R. China
| | - Yuying Gu
- Department of cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, P.R. China
| | - Haibin Zhang
- Department of Liver Surgery V, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, P. R. China.
| | - Zhiying He
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University School of Medicine, Shanghai, 200123, P. R. China. .,Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, P. R. China. .,Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, P. R. China.
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Meng X, Dong S, Yangyang L, Wang S, Xu X, Liu T, Zhuang X. Adenosine triphosphate-binding cassette subfamily C members in liver hepatocellular carcinoma: Bioinformatics-driven prognostic value. Medicine (Baltimore) 2022; 101:e28869. [PMID: 35363194 PMCID: PMC9282002 DOI: 10.1097/md.0000000000028869] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 12/16/2021] [Indexed: 01/04/2023] Open
Abstract
Aberrant expression of adenosine triphosphate-binding cassette subfamily C (ABCC), one of the largest superfamilies and transporter gene families of membrane proteins, is associated with various tumors. However, its relationship with liver hepatocellular carcinoma (LIHC) remains unclear.We used the Oncomine, UALCAN, Human Protein Atlas, GeneMANIA, GO, Kyoto Encyclopedia of Genes and Genomes (KEGG), TIMER, and Kaplan-Meier Plotter databases. On May 20, 2021, we searched these databases for the terms ABCC1, ABCC2, ABCC3, ABCC4, ABCC5, ABCC6, ABCC7, ABCC8, ABCC9, ABCC10, ABCC11, ABCC12, ABCC13, and "liver cancer." The exposure group comprised LIHC patients, and the control group comprised normal patients (those with noncancerous liver tissue). All patients shown in the retrieval language search were included. We compared the mRNA expression of these proteins in LIHC and control patients to examine the potential role of ABCC1-13 in LIHC.Relative to the normal liver tissue, mRNA expression of ABCC1/2/3/4/5/6/10 was significantly upregulated (P < .001), and that of ABCC9/11 significantly downregulated (both P < .001), in LIHC. ABCC mRNA expression varied with gender (P < .05), except for ABCC11-13; with tumor grade (P < 0.05), except for ABCC7/12/13; with tumor stage (P < .05), except for ABCC11-13; and with lymph node metastasis status (P < .05), except for ABCC7/8/11/12/13. Based on KEGG enrichment analysis, these genes were associated with the following pathways: ABC transporters, Bile secretion, Antifolate resistance, and Peroxisome (P < .05). Except for ABCC12/13, the ABCCs were significantly associated with B cell, CD8+ T cell, CD4+ T cell, macrophage, neutrophil, and dendritic cell infiltration (P < .05). High mRNA expression of ABCC1/4/5/8 (P < .05) and low expression of ABCC6/7/9/12/13 (P < .05) indicated poor prognosis. Prognostic significance was indicated for ABCC2/13 for both men and women (P < .05); for ABCC1/6/12/13 for tumor grades 1-3 (P < .05); for ABCC5/11/12/13 for all tumor stages (P < .05); for ABCC1/11/12/13 for American Joint Committee on Cancer T stages 1-3 (P < .05); and for ABCC1/5/6/13 for vascular invasion. None showed prognostic significance for microvascular invasion (P < .05).We identified ABCC1/2/3/4/5/6/9/10/11 as potential diagnostic markers, and ABCC1/4/5/6/7/8/9/12/13 as prognostic markers, of LIHC. Our future work will promote the use of ABCCs in the diagnosis and treatment of LIHC.
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Affiliation(s)
- Xiangtong Meng
- Changchun University of Chinese Medicine, 1035 Bo Shuo Road, Changchun City, Jilin Province, China
| | - Shen Dong
- Changchun University of Chinese Medicine, 1035 Bo Shuo Road, Changchun City, Jilin Province, China
| | - Liu Yangyang
- Changchun University of Chinese Medicine, 1035 Bo Shuo Road, Changchun City, Jilin Province, China
- Endocrinology, First Affiliated Hospital to Changchun University of Chinese Medicine, 1478 Gongnong Road, Changchun City, Jilin Province, China
| | - Song Wang
- Changchun University of Chinese Medicine, 1035 Bo Shuo Road, Changchun City, Jilin Province, China
| | - Xiaohao Xu
- Changchun University of Chinese Medicine, 1035 Bo Shuo Road, Changchun City, Jilin Province, China
- Research Center of Traditional Chinese Medicine, First Affiliated Hospital to Changchun University of Chinese Medicine, Changchun City, Jilin Province, China
| | - Tiejun Liu
- Changchun University of Chinese Medicine, 1035 Bo Shuo Road, Changchun City, Jilin Province, China
- Department of Hepatology, First Affiliated Hospital to Changchun University of Chinese Medicine, 1478 Gongnong Road, Changchun City, Jilin Province, China
| | - Xiong Zhuang
- Changchun University of Chinese Medicine, 1035 Bo Shuo Road, Changchun City, Jilin Province, China
- Department of Hepatology, First Affiliated Hospital to Changchun University of Chinese Medicine, 1478 Gongnong Road, Changchun City, Jilin Province, China
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Wu L, Yin X, Jiang K, Yin J, Yu H, Yang L, Ma C, Yan S. Comprehensive profiling of the TRIpartite motif family to identify pivot genes in hepatocellular carcinoma. Cancer Med 2022; 11:1712-1731. [PMID: 35142083 PMCID: PMC8986146 DOI: 10.1002/cam4.4552] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 11/27/2021] [Accepted: 12/13/2021] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION TRIpartite motif (TRIM) proteins are important members of the Really Interesting New Gene-finger-containing E3 ubiquitin-conjugating enzyme and are involved in the progression of hepatocellular carcinoma (HCC). However, the diverse expression patterns of TRIMs and their roles in prognosis and immune infiltrates in HCC have yet to be analyzed. MATERIALS Combined with previous research, we used an Oncomine database and the Human Protein Atlas to compare TRIM family genes' transcriptional levels between tumor samples and normal liver tissues, as verified by the Gene Expression Profiling Interactive Analysis database. We investigated the patient survival data of TRIMs from the Kaplan-Meier plotter database. Clinicopathologic characteristics associations and potential diagnostic and prognostic values were validated with clinical and expressional data collected from the cancer genome atlas. RESULTS We identified TRIM28, TRIM37, TRIM45, and TRIM59 as high-priority members of the TRIMs family that modulates HCC. Low expression of TRIM28 was associated with shorter overall survival (OS) than high expression (log-rank p = 0.009). The same trend was identified for TRIM37 (p = 0.001), TRIM45 (p = 0.013), and TRIM59 (p = 0.011). Multivariate analysis indicated that the level of TRIM37 was a significant independent prognostic factor for both OS (p = 0.043) and progression-free interval (p = 0.044). We performed expression and mutation analysis and functional pathways and tumor immune infiltration analysis of the changes in TRIM factors. CONCLUSION These data suggested that TRIM28, TRIM37, TRIM45, and TRIM59 could serve as efficient prognostic biomarkers and therapeutic targets in HCC.
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Affiliation(s)
- Lingyun Wu
- Department of Radiation Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xin Yin
- Department of Radiation Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Kan Jiang
- Department of Radiation Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jie Yin
- Department of Radiation Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hao Yu
- Department of Radiation Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lingling Yang
- Department of Gastroenterology, the Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Chiyuan Ma
- Department of Orthopaedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Senxiang Yan
- Department of Radiation Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Wan Z, Wang X. Role of SLC39A6 in the development and progression of liver cancer. Oncol Lett 2022; 23:77. [PMID: 35111246 PMCID: PMC8771636 DOI: 10.3892/ol.2022.13197] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 12/21/2021] [Indexed: 12/11/2022] Open
Abstract
Liver cancer is one of the most common malignant solid tumor types worldwide. The solute carrier (SLC)39A family is a main member of the SLC group of membrane transport proteins, which transfer zinc to the cytoplasm when cells are depleted of zinc; thus, it may provide a novel therapeutic target for human cancer. However, the prognostic value of SLC39A genes in patients with liver cancer has remained elusive. Therefore, the present study aimed to explore whether SLC39A family genes are associated with the survival rate of patients with liver cancer and to investigate the role of key genes of the SLC39A family in liver cancer. The mRNA expression of the SLC39A family in liver cancer was obtained from the UALCAN database. Survival curve analysis was performed to investigate the prognostic value of SLC39A family genes in the overall survival of patients with liver cancer. In addition to the bioinformatics analysis, SLC39A6 was knocked down in HepG2 and Hep3B cells to examine the effect on the proliferation, migration and invasion of liver cancer cells. The results suggested that SLC39A6 was significantly upregulated in liver cancer tissues compared with normal liver tissues. High expression of SLC39A6 was significantly associated with poor overall survival of patients with liver cancer. Furthermore, knockdown of SLC39A6 inhibited the proliferation, migration and invasion of liver cancer cells in vitro and in vivo. Collectively, the results of the present study suggested that SLC39A6 may be a promising prognostic biomarker for liver cancer and is associated with the proliferation, migration and invasion of liver cancer.
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Affiliation(s)
- Zhen Wan
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Xuzhen Wang
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Su H, Tang Y, Nie K, Wang Z, Wang H, Dong H, Chen G. Identification Prognostic Value and Correlation with Tumor-Infiltrating Immune Cells of Tripartite-Motif Family Genes in Hepatocellular Carcinoma. Int J Gen Med 2022; 15:1349-1363. [PMID: 35173473 PMCID: PMC8841487 DOI: 10.2147/ijgm.s341018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 01/19/2022] [Indexed: 12/30/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is one of the most common and mortality types of malignant tumors in the world. The Tripartite-Motif (TRIM) protein family consists of more than 80 proteins with E3 ubiquitin ligase activity. Increasing studies have found that TRIM family proteins play an extremely important role in the occurrence and development of tumors. However, the expression and prognostic values of TRIMs in HCC have not been clarified. Methods We used bioinformatic methods to explore the potential function of TRIM family genes in the HCC. Web servers ONCOMINE, UALCAN, GEPIA, cBioPortal, STRING, DAVID 6.8 and TIMER were used in this research. Results We screened TRIM1-76 and found the expressions of TRIM6, TRIM11, TRIM16, TRIM18(MID1), TRIM24, TRIM28, TRIM31, TRIM37, TRIM45, TRIM52, TRIM59, TRIM66 were significantly changed in HCC. Among them, TRIM24, TRIM28, TRIM37, TRIM45 and TRIM59 had significant effects on pathological stages, overall survival and disease free survival. Functions of these genes are primarily related to transcriptional misregulation in cancer, p53 signaling pathway, alcoholism and viral carcinogenesis, FoxO signal pathway, PI3K-AKT pathway, cell cycle, microRNAs in cancer. Our results showed the significant correlation between TRIMs expression and infiltration of innate immune cells (macrophages, neutrophils, and dendritic cells). Conclusion Our result provides novel insights into the function of TRIM family genes, which may be used as potential references for drug targets and accurate survival predictions in patients with HCC.
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Affiliation(s)
- Hao Su
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China
| | - Yueheng Tang
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China
| | - Kexin Nie
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China
| | - Zhi Wang
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China
| | - Hongzhan Wang
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China
| | - Hui Dong
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China
| | - Gang Chen
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China
- Correspondence: Gang Chen, Department of Integration Traditional Chinese Medicine and Western Medicine, TongJi Hospital, Huazhong University of Science and Technology, 1095Jiefang Avenue, Wuhan, Hubei Province, 430030, People’s Republic of China, Email
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Tian F, Cai D. Overexpressed GNAZ predicts poor outcome and promotes G0/G1 cell cycle progression in hepatocellular carcinoma. Gene 2022; 807:145964. [PMID: 34530087 DOI: 10.1016/j.gene.2021.145964] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 08/19/2021] [Accepted: 09/09/2021] [Indexed: 01/11/2023]
Abstract
AIMS We aimed to investigate the role of G protein subunit alpha Z(GNAZ) in the progression and prognosis of patients with hepatocellular carcinoma (HCC). METHODS Oncomine, GEO, TCGA, GEPIA2, Kaplan-Meier Plotter, TIMER2, Metascape, CCLE, LinkedOmics, and UALCAN databases were used to analyze the differential expression of GNAZ in HCC and normal liver tissues, relationship between GNAZ expression and prognosis of patients with HCC, and expression of GNAZ in common human HCC cell lines. Western blotting was performed to analyze GNAZ expression, while the Cell Counting Kit 8 assay was used to determine cell proliferation, and flow cytometry was used to evaluate the cell cycle and apoptosis. Wound healing and transwell invasion assays were used to investigate cell metastasis and invasion. RESULTS Using Oncomine, Gene Expression Omnibus (GEO), and GEPIA2 databases, GNAZ was found to be overexpressed in HCC tissues compared with that in adjacent normal liver tissues, and western blotting analysis showed GNAZ overexpression in seven patients with HCC who underwent surgical resection of HCC and para-cancerous tissues (p < 0.01). Survival analysis revealed that high GNAZ expression was negatively associated with overall survival (OS), recurrence-free survival, progression-free survival, and disease-specific survival in patients with HCC (p < 0.05). GNAZ overexpression was associated with worse 4- month, 6- month, 12- month, 24- month, 36- month, 48- month, and 60-month OS, as well as with different clinicopathological characteristics of patients with HCC, including hepatitis virus infection state; alcohol consumption state; male; female; Asian; microvascular invasion, Stage I-II, Stage II-III, and Stage III-IV; and grade II (Cox regression, p < 0.05). KEGG/GO biological process enrichment indicated that the genes similar to GNAZ in HCC were mainly enriched in the cell cycle, cell cycle phase transition, DNA replication checkpoint, and regulation of G0 to G1 transition. siRNA-GNAZ significantly reduced the viability of JHH-2 and SNU-761 cells from 12 to 96 h; increased the percentage of cells in the G0/G1 phase and decreased that of cells in the S and G2/M phases (p < 0.05); and markedly downregulated the expression of cyclin D, cyclin E, and CDK2 protein. siRNA-GNAZ also significantly increased the percentage of JHH-2 and SNU-761 cell apoptosis at late stages, while the number of surviving cells decreased (p < 0.05), and upregulated the expression of apoptosis-related proteins Bax and caspase 3 protein. Furthermore, siRNA-GNAZ remarkably reduced the healing of scratch wounds in JHH-2 and SNU-761 cells and the number of invasive cells compared with that in the control group (p < 0.001). CONCLUSION Our study demonstrated that GNAZ plays a pivotal role as a potential oncogene and predicts poor prognosis in patients with HCC. It promotes tumor proliferation via cell cycle arrest, apoptosis, migration, and invasion. Thus, GNAZ may be a potential candidate biomarker providing useful insight into hepatocarcinogenesis and aggressiveness.
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Affiliation(s)
- Feng Tian
- Department of General Surgery, Lishui People's Hospital, the Six Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China
| | - Daxia Cai
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Research, Lishui Central Hospital, Zhejiang University Lishui Hospital, The Fifth Affiliated Hospital of Wenzhou Medical College, Lishui, Zhejiang, China.
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Li L, Su Q, Yang H. Preoperative prediction of microvascular invasion in hepatocellular carcinoma: a radiomic nomogram based on MRI. Clin Radiol 2021; 77:e269-e279. [PMID: 34980458 DOI: 10.1016/j.crad.2021.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 12/08/2021] [Indexed: 11/18/2022]
Abstract
AIM To develop a reliable model to predict microvascular invasion (MVI) in patients with hepatocellular carcinoma (HCC) by combining a large number of clinical and imaging examinations, especially the radiomic features of magnetic resonance imaging (MRI). MATERIALS AND METHODS Three hundred and one consecutive patients from two centres were enrolled. Least absolute shrinkage and selection operator (LASSO) regression was used to shrink the feature size, and logistic regression was used to construct a predictive radiomic signature. The ability of the nomogram to discriminate MVI in patients with HCC was evaluated using area under the curve (AUC) of receiver operating characteristics (ROC), accuracy, and calibration curves. RESULTS The radiomic signature showed a significant association with MVI (p<0.001 for all data sets). Other useful predictors of MVI included non-smooth tumour margin, internal arteries, and the alpha-fetoprotein (AFP) level. The nomogram demonstrated a strong prognostic capability in the training set and both validation sets, providing AUCs of 0.914 (95% confidence interval [CI] 0.853-0.956), 0.872 (95% CI: 0.757-0.946), and 0.881 (95% CI: 0.806-0.934), respectively. CONCLUSIONS The preoperative radiomic nomogram, incorporating clinical risk factors and a radiomic signature, could predict MVI in patients with HCC. The MRI-based radiomic-clinical model predicted the MVI of HCC effectively and was more efficient compared with the radiomic model or clinical model alone.
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Affiliation(s)
- L Li
- Department of Hepatobiliary Surgery, The People's Hospital of Qijiang, Chongqing, China
| | - Q Su
- Department of Hepatopancreatobiliary Surgery, The Affiliated Calmette Hospital of Kunming Medical University, The First People's Hospital of Kunming, Calmette Hospital Kunming, Yunnan Province, China.
| | - H Yang
- Department of Hepatobiliary Surgery, The People's Hospital of Qijiang, Chongqing, China.
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FTH promotes the proliferation and renders the HCC cells specifically resist to ferroptosis by maintaining iron homeostasis. Cancer Cell Int 2021; 21:709. [PMID: 34965856 PMCID: PMC8717654 DOI: 10.1186/s12935-021-02420-x] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 12/19/2021] [Indexed: 02/06/2023] Open
Abstract
Background Ferroptosis is a newly identified type of programmed cell death, which preferentially targets iron-rich cancer cells such as hepatocellular carcinoma (HCC). Ferritin heavy chain (FTH) is a major iron storing nanocage to store redox-inactive iron, and harbors ferroxidase activity to prevent the iron-mediated production of ROS. Our previous studies have demonstrated that FTH acts as a protective role to increase the cellular resistance to ferroptosis. However, the specific role of FTH in the development of HCC and ferroptosis resistance remains unclear. Methods The indicated databases were used for bioinformatics analysis. The abilities of cell proliferation, migration were measured by cell proliferation assay, transwell assay and wound healing assay. The levels of reactive oxygen species (ROS), lipid peroxide, free iron, mitochondrial superoxide, mitochondrial morphology and mitochondrial membrane potential (MMP) were determined by DCF-DA, C11-BODIPY, mitoSOX, mitoTracker, JC-10 and TMRM staining, respectively. The mitochondrial oxygen consumption rate was monitored by the Seahorse XF24 Analyzer. Results The pan-cancer analysis was performed and showed that FTH expression is upregulated in multiple cancers, such as LIHC, CHOL, HNSC, compared to corresponding normal tissues. In addition, the level of serum ferritin is positively associated with the progression of hepatitis, cirrhosis liver and hepatocellular carcinoma. Further investigation shed light on the strong correlation between FTH expression and tumor grades, cancer stages and prognosis of HCC. Importantly, the proteins interaction network elucidated that FTH is involved in iron homeostasis maintenance and lysosomal-dependent degradation. Enforced expression of FTH accelerates proliferation, migration and endows HCC cells specifically resistant to ferroptosis, but does not protect against cell death caused by cytotoxic compounds like oxaliplatin, irinotecan, and adriamycin. Mechanically, FTH reconstituted cells exhibit diminished peroxides accumulation, reduce mitochondrial ROS level, attenuate the impaired mitochondrial respiratory and rescue the mitochondrial homeostasis. Notably, FTH expression boosts tumorigenic potential in vivo with increased PCNA staining and lesser lipid peroxides generation. Conclusion These results provide new insights that FTH acts as an oncogene in the carcinogenesis and progression of HCC, and is hopeful to be a potential target for therapeutic intervention through ferroptosis. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-02420-x.
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Jiang Z, Xing C, Wang P, Liu X, Zhong L. Identification of Therapeutic Targets and Prognostic Biomarkers Among Chemokine (C-C Motif) Ligands in the Liver Hepatocellular Carcinoma Microenvironment. Front Cell Dev Biol 2021; 9:748269. [PMID: 34938730 PMCID: PMC8685337 DOI: 10.3389/fcell.2021.748269] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 11/17/2021] [Indexed: 12/23/2022] Open
Abstract
Background: Liver hepatocellular carcinoma (LIHC) is the third leading cause of cancer-related death and the sixth most common solid tumor worldwide. In the tumor microenvironment, the cross-talk between cancer cells, immune cells, and stromal cells exerts significant effects on neoplasia and tumor development and is modulated in part by chemokines. Chemokine (C-C motif) ligands (CCL) can directly target tumor cells and stromal cells, and they have been shown to regulate tumor cell proliferation, cancer stem-like cell properties, cancer invasiveness and metastasis, which directly and indirectly affect tumor immunity and influence cancer progression, therapy and patient outcomes. However, the prognostic values of chemokines CCL in LIHC have not been clarified. Methods: In this study, we comprehensively analyzed the relationship between transcriptional chemokines CCL and disease progression of LIHC using the ONCOMINE dataset, GEPIA, UALCAN, STRING, WebGestalt, GeneMANIA, TRRUST, DAVID 6.8, LinkedOmics, TIMER, GSCALite, and Open Targets. We validated the protein levels of chemokines CCL through western blot and immunohistochemistry. Results: The transcriptional levels of CCL5/8/11/13/15/18/20/21/25/26/27/28 in LIHC tissues were significantly elevated while CCL2/3/4/14/23/24 were significantly reduced. A significant correlation was found between the expression of CCL14/25 and the pathological stage of LIHC patients. LIHC patients with low transcriptional levels of CCL14/21 were associated with a significantly poor prognosis. The functions of differentially expressed chemokines CCL were primarily related to the chemokine signaling pathway, cytokine–cytokine receptor interactions, and TNF-α signaling pathway. Our data suggested that RELA/REL, NFKB1, STAT1/3/6, IRF3, SPI1, and JUN were key transcription factors for chemokines CCL. We found significant correlations among the expression of chemokines CCL and the infiltration of six types of immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells) and immune checkpoints (PD-1. PD-L1, and CTLA-4). The western blot and immunohistochemistry results showed that protein expression levels of CCL5 and CCL20 were upregulated in LIHC. CCL5 and CCL20 were significantly correlated with the clinical outcome of patients with LIHC, and could be negatively regulated by some drugs or small molecules. Conclusions: Our results may provide novel insights for the potential suitable targets of immunological therapy and prognostic biomarkers for LIHC.
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Affiliation(s)
- Zhongyi Jiang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Changchang Xing
- Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Pusen Wang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xueni Liu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lin Zhong
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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