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Tasneem M, Gupta SD, Ahmed Jony MJ, Minkara M, Dey RK, Ferdoush J. Identification of key biomarker genes in liver hepatocellular carcinoma and kidney renal clear cell carcinoma progression: A shared high-throughput screening and molecular docking method with potentials for targeted therapeutic interventions. J Genet Eng Biotechnol 2025; 23:100497. [PMID: 40390492 PMCID: PMC12049835 DOI: 10.1016/j.jgeb.2025.100497] [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: 09/20/2024] [Accepted: 04/14/2025] [Indexed: 05/21/2025]
Abstract
BACKGROUND AND OBJECTIVES Liver Hepatocellular Carcinoma (LIHC) and Kidney Renal Clear Cell Carcinoma (KIRC) are leading causes of cancer death worldwide, but their early detections remain hindered by a lack of genetic markers. Our study aims to find prospective biomarkers that could serve as prognostic indicators for efficient drug candidates for KIRC and LIHC treatment. METHODS To detect differentially expressed genes (DEGs), four datasets were used: GSE66271 and GSE213324 for KIRC, and GSE135631 and GSE202853 for LIHC. Visualization of DEGs was done using heatmaps, volcano plots, and Venn diagrams. Hub genes were identified via PPI analysis and the cytoHubba plugin in Cytoscape. Their expression was evaluated using box plots, stage plots, and survival plots for prognostic assessment via GEPIA2. Molecular docking with PyRx's AutoDock Vina identified optimal binding interactions between compounds and proteins. Pharmacokinetic and toxicity analyses reinforced the drug-likeness and safety of these compounds. RESULTS In this study, 47 DEGs were identified, with the top 10 hub genes being TOP2A, BUB1, PTTG1, CCNB2, NUSAP1, KIF20A, BIRC5, RRM2, NDC80 and CDC45, chosen for their high MCC scores. Data mining revealed a correlation between TOP2A expression and clinical survival outcomes in KIRC and LIHC patients. Docking studies of the TOP2A structure identified a promising compound from Andrographis paniculata with high binding energy and interactions with TOP2A. Pharmacokinetic and toxicity assessments support its potential as a drug candidate. CONCLUSION Our study emphasizes TOP2A's prognostic significance in KIRC and LIHC and recognizes Andrographis paniculata compound as potential therapeutics, offering prospective for enhanced treatment and patient outcomes in these cancers.
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Affiliation(s)
- Maisha Tasneem
- Department of Biotechnology and Genetic Engineering, Noakhali Science and Technology University, Noakhali 3814, Bangladesh
| | - Shipan Das Gupta
- Department of Biotechnology and Genetic Engineering, Noakhali Science and Technology University, Noakhali 3814, Bangladesh
| | - Md Jubair Ahmed Jony
- Department of Biotechnology and Genetic Engineering, Noakhali Science and Technology University, Noakhali 3814, Bangladesh
| | - Maya Minkara
- Department of Biology, Geology, and Environmental Science, University of Tennessee at Chattanooga, 615 McCallie Ave, Chattanooga, TN 37403, USA
| | | | - Jannatul Ferdoush
- Department of Biology, Geology, and Environmental Science, University of Tennessee at Chattanooga, 615 McCallie Ave, Chattanooga, TN 37403, USA.
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Hu X, Chen Y, Ying H, He C, Ren Y, Tian Y, Tan Y. Metabolic-associated fatty liver disease (MAFLD) promotes the progression of hepatocellular carcinoma by enhancing KIF20A expression. Int Immunopharmacol 2025; 154:114589. [PMID: 40168801 DOI: 10.1016/j.intimp.2025.114589] [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: 02/13/2025] [Revised: 03/27/2025] [Accepted: 03/28/2025] [Indexed: 04/03/2025]
Abstract
BACKGROUND Compared to other HCC, those related to MAFLD exhibit distinct prognostic differences. This article aims to elucidate the impact of MAFLD on HCC prognosis through the lens of KIF20A, thereby providing a theoretical foundation for targeted therapies in MAFLD-related HCC. METHODS We employed the Weighted gene co-expression network analysis (WGCNA) method alongside the Mime package to identify key genes associated with MAFLD-related HCC. Subsequently, we utilized OCLR and CytoTRACE algorithms to evaluate the relationship between these genes and HCC stemness. The R package was employed to conduct immunological analyses on both mRNA sequencing and single-cell data. We validated the effects of core genes on HCC through experimental approaches, including cell culture, Transwell assays, Western Blot, and proliferation assays. Finally, we predicted potential therapeutic drugs using the OncoPredict software package. RESULTS WGCNA identified the cyan module associated with MAFLD in GSE135251 and the blue module linked to HCC in TCGA. Further analysis identified KIF20A as the core gene in MAFLD-related HCC. Utilizing the OCLR and CytoTRACE algorithms, KIF20A was found to correlate with mRNA stemness index (mRNAsi). Analysis of public databases revealed that KIF20A promotes immune tolerance through the SPP1-CD44 pathway and drives HCC progression via the G2M checkpoint. Experimental results demonstrated that lipotoxic damage in HCC cells and small extracellular vesicles (sEVs) derived from these cells upregulate KIF20A, thereby accelerating HCC progression. Finally, OncoPredict and AutoDock were employed to predict drugs targeting KIF20A. CONCLUSION MAFLD-related HCC can elevate KIF20A levels and promote tumor proliferation and migration.
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Affiliation(s)
- Xinsong Hu
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Yifei Chen
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China; Department of Laboratory Medicine, Wujin Hospital Affiliated With Jiangsu University (The Wujin Clinical College of Xuzhou Medical University), Changzhou, Jiangsu, China
| | - Hao Ying
- Department of Neurology, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Cong He
- The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang, Jiangsu, China
| | - Yangyang Ren
- Clinical Laboratory, Xinyi People's Hospital, Xuzhou, Jiangsu, China.
| | - Yiqing Tian
- Clinical Laboratory, Xuzhou Central Hospital, The Affiliated XuZhou Hospital of Medical College of Southeast University, Xuzhou, Jiangsu, China.
| | - Youwen Tan
- The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang, Jiangsu, China.
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Chen D, Lin D, Li H, Yang J, Liu L, Zhang H, Tang D, Wang K. The glycolytic characteristics of hepatocellular carcinoma and its interaction with the microenvironment: a comprehensive omics study. J Transl Med 2025; 23:424. [PMID: 40211257 PMCID: PMC11987379 DOI: 10.1186/s12967-025-06421-6] [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: 12/01/2024] [Accepted: 03/25/2025] [Indexed: 04/12/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a common malignant tumor characterized by a high recurrence rate and poor prognosis. This study aimed to identify glycolysis-related prognostic markers and immunological abnormalities in patients with HCC. METHODS We collected samples from cancerous and adjacent non-cancerous tissues for transcriptomic, metabolomic, and 16 S rRNA sequencing analyses. Glycolysis-related prognostic markers were identified by integrating public data from The Cancer Genome Atlas, GSE14520, and GSE76427 datasets. Additionally, single-cell sequencing data (GSE202642) were used to analyze the significantly infiltrated cellular subpopulations in HCC and investigate the expression of prognostic markers across different cell types. Spatial transcriptomics and mass cytometry (CyTOF) data were used to examine the expression differences in immune cells across tumor, peritumoral, and control tissues. Key prognostic markers were validated using reverse transcription-quantitative polymerase chain reaction, western blotting, and immunohistochemistry. RESULTS Differentially expressed genes (DEGs) between HCC and control tissues were primarily clustered in cell cycle and metabolic pathways, particularly in the glycolysis pathway. Metabolomic analysis identified 175 differentially expressed metabolites that were mainly enriched in digestive and amino acid metabolism pathways. 16 S rRNA analysis revealed a significant increase in the abundance of Aenigmarchaeota and a decrease in the abundance of Proteobacteria in HCC tissues. The former was positively associated with glycolysis, whereas the latter showed a negative association. Through public data integration, 17 glycolysis-related DEGs were identified and 101 predictive models were constructed using machine learning. The StepCox[both] + random survival forest model using AGL, G6PD, GOT2, and KIF20A exhibited the best diagnostic performance among the three datasets. Single-cell RNA sequencing indicated significant infiltration of CD8 + Tex, CD8 + T, CD8 + Trm, and epithelial cells in HCC tissues. AGL, G6PD, GOT2, and KIF20A were highly expressed in CD8 + Tex cells, CD8 + Trm cells, macrophages, and monocytes, respectively. Spatial transcriptomics and CyTOF analyses showed greater infiltration of CD8 + Tex and CD8 + Trm cells in tumor tissues than in controls. Molecular assays further confirmed that G6PD and KIF20A expression levels were significantly higher, whereas AGL and GOT2 expression levels were lower, in HCC tissues than in control tissues. CONCLUSION Through integrative multi-omics analysis, we identified glycolysis-related prognostic markers with distinct expression profiles across immune cell subsets in HCC. Our findings identify potential biomarkers and therapeutic targets for the diagnosis and treatment of HCC.
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Affiliation(s)
- Dan Chen
- School of Public Health, Xinjiang Medical University, Urumqi, 830017, China
| | - Dandan Lin
- School of Public Health, Xinjiang Medical University, Urumqi, 830017, China
| | - Huling Li
- Department of Medical Engineering and Technology, Xinjiang Medical University, Urumqi, 830017, China
| | - Jiandong Yang
- School of Public Health, Xinjiang Medical University, Urumqi, 830017, China
| | - Lei Liu
- School of Public Health, Xinjiang Medical University, Urumqi, 830017, China
| | - Hanyuan Zhang
- Department of Medical Engineering and Technology, Xinjiang Medical University, Urumqi, 830017, China
| | - Dandan Tang
- Department of Medical Engineering and Technology, Xinjiang Medical University, Urumqi, 830017, China
| | - Kai Wang
- Department of Medical Engineering and Technology, Xinjiang Medical University, Urumqi, 830017, China.
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Huan Y, She P, Cai X, Qi J, Zhang C. Identification of key biomarkers in breast cancer based on bioinformatics analysis and experimental verification. J Egypt Natl Canc Inst 2025; 37:5. [PMID: 39988630 DOI: 10.1186/s43046-025-00260-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 02/01/2025] [Indexed: 02/25/2025] Open
Abstract
BACKGROUND Breast cancer (BC) is a malignant tumor characterized by a high incidence rate and is the leading cause of cancer-related deaths among women worldwide. This study aims to identify key genes and potential prognostic biomarkers using a bioinformatics approach. METHODS Three microarray datasets, GSE86374, GSE120129, and GSE29044, were downloaded from the GEO database. GEO2R and Venn diagram software were employed to identify differentially expressed genes (DEGs), while DAVID was utilized for functional enrichment analysis. Subsequently, STRING and Cytoscape were used to construct the protein-protein interaction (PPI) network among the DEGs. UALCAN, GEPIA, and the Kaplan-Meier plotter were employed for prognostic analysis. Following this, the correlations and alterations of key genes were examined using cBioPortal. Finally, immunohistochemistry (IHC) was performed to validate the expression levels of the key genes. RESULTS A total of 323 differentially expressed genes (DEGs) were identified. From the protein-protein interaction (PPI) network, 37 hub genes were selected. Validation using UALCAN, GEPIA, and Kaplan-Meier plotters revealed that three key genes-RACGAP1, SPAG5, and KIF20A-were significantly overexpressed and associated with poor prognosis in breast cancer (BC), as well as advanced tumor staging. The correlations and alterations of these key genes, as demonstrated on cBioPortal, indicated that their alterations co-occurred. Experimental verification through immunohistochemistry (IHC) confirmed that the proteins of these key genes were highly expressed in tumor tissues. CONCLUSIONS The key genes identified in this study can enhance our understanding of the molecular mechanisms underlying breast cancer (BC). Additionally, these genes may serve as potential sensitive biomarkers for patients with BC.
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Affiliation(s)
- Yu Huan
- Department of Clinical Laboratory, Jiading District Maternal and Children Health Hospital, Shanghai, 201821, People's Republic of China
| | - Ping She
- School of Computer Science and Technology, Xi'an Jiaotong University, Xi'an, Shanxi, 710049, People's Republic of China
| | - Xushan Cai
- Department of Clinical Laboratory, Jiading District Maternal and Children Health Hospital, Shanghai, 201821, People's Republic of China.
| | - Jiehua Qi
- Department of Clinical Laboratory, Jiading District Maternal and Children Health Hospital, Shanghai, 201821, People's Republic of China
| | - Chunli Zhang
- Department of Clinical Laboratory, Jiading District Maternal and Children Health Hospital, Shanghai, 201821, People's Republic of China
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Shodry S, Hasan YTN, Ahdi IR, Ulhaq ZS. Gene targets with therapeutic potential in hepatocellular carcinoma. World J Gastrointest Oncol 2024; 16:4543-4547. [PMID: 39678796 PMCID: PMC11577361 DOI: 10.4251/wjgo.v16.i12.4543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 08/03/2024] [Accepted: 08/13/2024] [Indexed: 11/12/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Major treatments include liver transplantation, resection, and chemotherapy, but the 5-year recurrence rate remains high. Late diagnosis often prevents surgical intervention, contributing to poor patient survival rates. Carcinogenesis in HCC involves genetic alterations that drive the transformation of normal cells into malignant ones. Enhancer of zeste homolog 2 (EZH2), a key regulator of cell cycle progression, is frequently upregulated in HCC and is associated with advanced stages and poor prognosis, making it a potential biomarker. Additionally, signal transducer and activator of transcription 3, which binds to EZH2, affects disease staging and outcomes. Targeting EZH2 presents a promising therapeutic strategy. On the other hand, abnormal lipid metabolism is a hallmark of HCC and impacts prognosis. Fatty acid binding protein 5 is highly expressed in HCC tissues and correlates with key oncogenes, suggesting its potential as a biomarker. Other genes such as guanine monophosphate synthase, cell division cycle associated 5, and epidermal growth factor receptor provide insights into the molecular mechanisms of HCC, offering potential as biomarkers and therapeutic targets.
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Affiliation(s)
- Syifaus Shodry
- Faculty of Medicine and Health Sciences, Maulana Ibrahim Islamic State University of Malang, Malang 65144, Jawa Timur, Indonesia
| | - Yuliono Trika Nur Hasan
- Faculty of Medicine and Health Sciences, Maulana Ibrahim Islamic State University of Malang, Malang 65144, Jawa Timur, Indonesia
| | - Iwal Reza Ahdi
- Faculty of Medicine and Health Sciences, Maulana Ibrahim Islamic State University of Malang, Malang 65144, Jawa Timur, Indonesia
| | - Zulvikar Syambani Ulhaq
- Research Center for Preclinical and Clinical Medicine, National Research and Innovation Agency Republic of Indonesia, Cibinong 16911, Indonesia
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Su Z, Zhong Y, He Y, You L, Xin F, Wang L, Liu Z. Bulk- and single cell-RNA sequencing reveal KIF20A as a key driver of hepatocellular carcinoma progression and immune evasion. Front Immunol 2024; 15:1469827. [PMID: 39555078 PMCID: PMC11563802 DOI: 10.3389/fimmu.2024.1469827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 10/14/2024] [Indexed: 11/19/2024] Open
Abstract
Introduction Kinesin family member 20A (KIF20A) is essential for cell proliferation and is implicated in promoting tumor progression, but its role in hepatocellular carcinoma (HCC) remains poorly studied. Methods Through the analysis of bulk RNA-sequencing (bulk RNA-seq) and single-cell RNA sequencing (scRNA-seq) data, the expression of KIF20A and its relationship with diagnosis, prognosis, and the immune microenvironment were examined. The association between KIF20A and the malignant progression and metastasis of HCC was confirmed through in vitro and in vivo experiments. Furthermore, patient re-staging was performed using Recursive Partitioning Analysis (RPA) to enhance clinical benefit. Results In this study, we firstly found KIF20A was overexprerssed in HCC both by bulk RNA-seq and scRNA-seq, and then the overexpression of KIF20A significantly promoted the proliferation, invasion, and metastasis in vitro. In vivo, the overexpression of KIF20A promoted the growth and lung metastasis of HCC. Furthermore, gene set variation analysis of bulk RNA-seq and scRNA-seq revealed that KIF20A might be associated with cell cycle related signaling pathways of E2F and G2M, and overexpression of KIF20A inhibited the activity of p21 and bax, as well as shortened G2 phase. Importantly, we found that KIF20A could induce T cell exhaustion via the SPP1-CD44 axe using scRNA-seq. Additionally, KIF20A was also correlated with the expression of immune checkpoint inhibitors (ICIs), and KIF20Ahigh subgroup might be benefited from the ICIs therapy. Conclusion KIF20A emerges as a pivotal driver of HCC progression, intricately regulating cell cycle pathways and modulating immune responses, which position KIF20A as a promising target for HCC management.
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Affiliation(s)
- Zhixiong Su
- Department of Radiation Oncology, Jiangxi Clinical Research Center for Cancer, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, China
- Department of Oncology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
| | - Yaqi Zhong
- Department of Hepatopancreatobiliary Surgery, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, Fujian, China
| | - Yufang He
- Department of Oncology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
| | - Lijie You
- Department of Oncology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
| | - Fuli Xin
- Department of Hepatopancreatobiliary Surgery, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, Fujian, China
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Lei Wang
- Department of Radiation Oncology, Jiangxi Clinical Research Center for Cancer, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, China
| | - Zhihua Liu
- Department of Radiation Oncology, Jiangxi Clinical Research Center for Cancer, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, China
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Pan H, Luo Z, Lin F, Zhang J, Xiong T, Hong Y, Sun B, Yang Y. FN1, a reliable prognostic biomarker for thyroid cancer, is associated with tumor immunity and an unfavorable prognosis. Oncol Lett 2024; 28:510. [PMID: 39268167 PMCID: PMC11391506 DOI: 10.3892/ol.2024.14643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 07/10/2024] [Indexed: 09/15/2024] Open
Abstract
Thyroid cancer (THCA) is a malignant tumor that affects the endocrine system. At present, an effective treatment for THCA remains elusive, particularly for medullary carcinoma and undifferentiated carcinoma, due to the lack of suitable medications and prognostic markers. Patient RNA-sequencing and clinical data were obtained from The Cancer Genome Atlas and Genotype-Tissue Expression databases. Protein-protein interaction analyses were performed for differentially expressed genes related to THCA. Moreover, the associations between fibronectin 1 (FN1), clinical data, immune checkpoint genes and immune cell infiltration was assessed. The potential functional role of the FN1 gene was evaluated through gene set enrichment analysis. Immunohistochemistry was used to assess FN1 expression in 103 cases of THCA, comprising 32 with papillary carcinoma, 30 with follicular carcinoma, 35 with medullary carcinoma and 6 with undifferentiated carcinoma. Finally, 11 co-expression modules were constructed and the expression of five identified hub genes (FN1, mucin-1, keratin 19, intracellular adhesion molecule 1 and neural cell adhesion molecule) were evaluated. The results demonstrated that higher FN1 gene expression levels were strongly associated with a higher pathologic stage and tumor stage, and were significantly associated with immune cell infiltration in THCA. Significant increases in FN1 protein expression levels were noted among patients diagnosed with four types of THCA, comprising papillary carcinoma, follicular carcinoma, medullary carcinoma and undifferentiated carcinoma. Patients diagnosed with medullary carcinoma and undifferentiated carcinoma, and with low FN1 expression levels, exhibited a significant survival advantage compared with those with high FN1 expression levels. In conclusion, the present study identified five hub genes involved in the onset and progression of THCA. Furthermore, FN1 could serve as a candidate biomarker and a therapeutic target for THCA and may be a key gene mediating THCA immune infiltration.
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Affiliation(s)
- Huili Pan
- Department of Nursing, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Zhiyan Luo
- Department of Ultrasound in Medicine, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Feng Lin
- Department of Neurology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, Zhejiang 317000, P.R. China
| | - Jing Zhang
- Department of Pathology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Ting Xiong
- Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Yurong Hong
- Department of Ultrasound in Medicine, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Bohao Sun
- Department of Pathology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Yan Yang
- Department of Nursing, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
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Li J, Su P, Li T, Hao Y, Wang T, Fu L, Liu X. The Role and Clinical Relevance of Glycolysis-Associated Genes on Immune Infiltration in Hepatocellular Carcinoma. J Cell Biochem 2024; 125:e30620. [PMID: 38923014 DOI: 10.1002/jcb.30620] [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: 04/05/2024] [Revised: 05/31/2024] [Accepted: 06/12/2024] [Indexed: 06/28/2024]
Abstract
Hepatocellular carcinoma (HCC) poses a significant challenge with dismal survival rates, necessitating a deeper understanding of its molecular mechanisms and the development of improved therapies. Metabolic reprogramming, particularly heightened glycolysis, plays a crucial role in HCC progression. Glycolysis-associated genes (GAGs) emerge as key players in HCC pathogenesis, influencing the tumor microenvironment and immune responses. This study aims to investigate the intricate interplay between GAGs and the immune landscape within HCC, offering valuable insights into potential prognostic markers and therapeutic targets to enhance treatment strategies and patient outcomes. Through the exploration of GAGs, we have identified two distinct molecular glycolytic subtypes in HCC patients, each exhibiting significant differences in both the immune microenvironment and prognosis. A risk model comprising five key GAGs was formulated and subsequently evaluated for their predictive accuracy. Our findings underscore the diverse tumor microenvironment and immune responses associated with the varying glycolytic subtypes observed in HCC. The identified key GAGs hold promise as prognostic indicators for evaluating HCC risk levels, predicting patient outcomes, and guiding clinical treatment decisions, particularly in the context of anticipating responses to immunotherapy drugs.
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Affiliation(s)
- Jing Li
- Wisdom Lake Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Peng Su
- Wisdom Lake Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York, USA
| | - Ting Li
- Wisdom Lake Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Yang Hao
- Wisdom Lake Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Tianjun Wang
- Wisdom Lake Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Lei Fu
- Wisdom Lake Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Xin Liu
- Wisdom Lake Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou, China
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Zhao K, Li X, Feng Y, Wang J, Yao W. The role of kinesin family members in hepatobiliary carcinomas: from bench to bedside. Biomark Res 2024; 12:30. [PMID: 38433242 PMCID: PMC10910842 DOI: 10.1186/s40364-024-00559-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 01/03/2024] [Indexed: 03/05/2024] Open
Abstract
As a major component of the digestive system malignancies, tumors originating from the hepatic and biliary ducts seriously endanger public health. The kinesins (KIFs) are molecular motors that enable the microtubule-dependent intracellular trafficking necessary for mitosis and meiosis. Normally, the stability of KIFs is essential to maintain cell proliferation and genetic homeostasis. However, aberrant KIFs activity may destroy this dynamic stability, leading to uncontrolled cell division and tumor initiation. In this work, we have made an integral summarization of the specific roles of KIFs in hepatocellular and biliary duct carcinogenesis, referring to aberrant signal transduction and the potential for prognostic evaluation. Additionally, current clinical applications of KIFs-targeted inhibitors have also been discussed, including their efficacy advantages, relationship with drug sensitivity or resistance, the feasibility of combination chemotherapy or other targeted agents, as well as the corresponding clinical trials. In conclusion, the abnormally activated KIFs participate in the regulation of tumor progression via a diverse range of mechanisms and are closely associated with tumor prognosis. Meanwhile, KIFs-aimed inhibitors also carry out a promising tumor-targeted therapeutic strategy that deserves to be further investigated in hepatobiliary carcinoma (HBC).
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Affiliation(s)
- Kai Zhao
- Department of Biliary and Pancreatic Surgery, Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China
| | - Xiangyu Li
- Department of Thoracic Surgery Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China
| | - Yunxiang Feng
- Department of Biliary and Pancreatic Surgery, Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China
| | - Jianming Wang
- Department of Biliary and Pancreatic Surgery, Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China.
- Affiliated Tianyou Hospital, Wuhan University of Science & Technology, 430064, Wuhan, China.
| | - Wei Yao
- Department of Oncology Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China.
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Wu M, Wu X, Han J. KIF20A Promotes CRC Progression and the Warburg Effect through the C-Myc/HIF-1α Axis. Protein Pept Lett 2024; 31:107-115. [PMID: 38037834 DOI: 10.2174/0109298665256238231120093150] [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: 05/15/2023] [Revised: 09/01/2023] [Accepted: 10/24/2023] [Indexed: 12/02/2023]
Abstract
BACKGROUND Colorectal cancer (CRC) is a prevalent form of cancer globally, characterized by a high mortality rate. Therefore, discovering effective therapeutic approaches for CRC treatment is critical. METHODS The levels of KIF20A in CRC clinical samples were determined using Western Blot and immunofluorescence assay. SW480 cells were transfected with siRNA targeting KIF20A, while HT-29 cells were transfected with a KIF20A overexpression vector. Cell viability and apoptosis of CRC cells were assessed using CCK-8 and TUNEL analysis. Migration ability was investigated using Transwell. The levels of pyruvate, lactate and ATP were determined through corresponding assay kits. Western Blot was applied to confirm the level of proteins associated with glycolysis, c- Myc, HIF-1α, PKM2 and LDHA. Subsequently, functional rescue experiments were conducted to investigate further the regulatory relationship between KIF20A, c-Myc, and HIF-1α in colorectal cancer (CRC), employing the c-Myc inhibitor 10058-F4 and c-Myc overexpression plasmids. RESULTS KIF20A was up-regulated in vivo and in vitro in CRC. KIF20A knockdown inhibited cell viability and migration while promoting cell apoptosis in SW480 cells. Conversely, overexpression of KIF20A yielded contrasting effects in HT-29 cells. Moreover, inhibition of KIF20A restrained the pyruvate, lactate production and ATP level, whereas overexpression of KIF20A enhanced the Warburg effect. Western Blot indicated that knockdown KIF20A attenuated the levels of c-Myc, HIF-1α, PKM2 and LDHA. In addition, rescue experiments further verified that KIF20A enhanced the Warburg effect by the KIF20A/c-Myc/HIF-1α axis in CRC. CONCLUSION KIF20A, being a crucial regulator in the progression of CRC, has the potential to be a promising therapeutic target for the treatment of CRC.
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Affiliation(s)
- Min Wu
- Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Gaotanyan Zhengjie No. 30, Shapingba District, ChongQing, 400038, China
| | - Xianqiang Wu
- Haisco Pharmaceutical Group Company Ltd., 136 Baili Road, Wenjiang District, Chengdu, 611130, China
| | - Jie Han
- Department of General Surgery, The Third Affiliated Hospital of Chongqing Medical University, Shuanghu Branch Road No. 1, Yubei District, Chongqing, 401120, China
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11
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Shi Y, Feng Y, Qiu P, Zhao K, Li X, Deng Z, Wang J. Identifying the programmed cell death index of hepatocellular carcinoma for prognosis and therapy response improvement by machine learning: a bioinformatics analysis and experimental validation. Front Immunol 2023; 14:1298290. [PMID: 38170006 PMCID: PMC10759150 DOI: 10.3389/fimmu.2023.1298290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 11/24/2023] [Indexed: 01/05/2024] Open
Abstract
Background Despite advancements in hepatocellular carcinoma (HCC) treatments, the prognosis for patients remains suboptimal. Cumulative evidence suggests that programmed cell death (PCD) exerts crucial functions in HCC. PCD-related genes are potential predictors for prognosis and therapeutic responses. Methods A systematic analysis of 14 PCD modes was conducted to determine the correlation between PCD and HCC. A novel machine learning-based integrative framework was utilized to construct the PCD Index (PCDI) for prognosis and therapeutic response prediction. A comprehensive analysis of PCDI genes was performed, leveraging data including single-cell sequencing and proteomics. GBA was selected, and its functions were investigated in HCC cell lines by in vitro experiments. Results Two PCD clusters with different clinical and biological characteristics were identified in HCC. With the computational framework, the PCDI was constructed, demonstrating superior prognostic predictive efficacy and surpassing previously published prognostic models. An efficient clinical nomogram based on PCDI and clinicopathological factors was then developed. PCDI was intimately associated with immunological attributes, and PCDI could efficaciously predict immunotherapy response. Additionally, the PCDI could predict the chemotherapy sensitivity of HCC patients. A multilevel panorama of PCDI genes confirmed its stability and credibility. Finally, the knockdown of GBA could suppress both the proliferative and invasive capacities of HCC cells. Conclusion This study systematically elucidated the association between PCD and HCC. A robust PCDI was constructed for prognosis and therapy response prediction, which would facilitate clinical management and personalized therapy for HCC.
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Affiliation(s)
- Yuanxin Shi
- Department of Biliary and Pancreatic Surgery/Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yunxiang Feng
- Department of Biliary and Pancreatic Surgery/Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Peng Qiu
- Department of Biliary and Pancreatic Surgery/Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kai Zhao
- Department of Biliary and Pancreatic Surgery/Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiangyu Li
- Department of Biliary and Pancreatic Surgery/Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhengdong Deng
- Department of Pediatric Surgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jianming Wang
- Department of Biliary and Pancreatic Surgery/Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Affiliated Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
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12
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Qiu C, Wu H, Shi W. Characterization of stem cell subtypes and prognostic signature in hepatocellular carcinoma. J Cancer Res Clin Oncol 2023; 149:14081-14100. [PMID: 37548770 DOI: 10.1007/s00432-023-05239-3] [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: 05/29/2023] [Accepted: 07/31/2023] [Indexed: 08/08/2023]
Abstract
BACKGROUND Cancer stem cells (CSCs) were linked to cancer aggressiveness and poor prognosis in patients with hepatocellular carcinoma (HCC). METHODS We integrated two external HCC cohorts to develop the stem cell subtypes according to unsupervised clustering with 26 stem cell gene sets. Between the subtypes, differences in prognosis, clinical characteristics, recognized HCC subtypes, metabolic profile, immune-related features, somatic mutation, and drug sensitivity were examined. The prognostic signature was created, and validated by numerous cohorts, and used to assess the efficacy of immunotherapy and transcatheter arterial chemoembolization (TACE) treatment. The nomogram was developed based on the signature and clinical features. We further examined the function of KIF20A in HCC and proved that KIF20A had the potential to regulate the stemness of HCC cells through western blot. RESULTS Low stem cell patterns, a good prognosis, positive clinical features, specific molecular subtypes, low metastatic characteristics, and an abundance of metabolic and immunological aspects were associated with Cluster 1, whereas Cluster 2 was the reverse. Chemotherapy and immunotherapy were more effective in Cluster 1. Cluster 1 and CTNNB1 and ALB mutation were more closely. Additionally, the prognosis, immunotherapeutic, and TACE therapy responses were all worse in the high-risk group. The nomogram could predict the survival probability of HCC patients. KIF20A was discovered to be overexpressed in HCC and was revealed to be connected to the stemness of the HepG2 cell line. CONCLUSIONS Two stem cell subgroups with different prognoses, metabolic, and immunological characteristics in HCC patients were identified. We also created a 7-gene prognostic signature and a nomogram to estimate the survival probability. The function of KIF20A in HCC stemness was initially examined.
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Affiliation(s)
- Chenjie Qiu
- Department of General Surgery, Changzhou Hospital of Traditional Chinese Medicine, Changzhou, China.
| | - Huili Wu
- Department of Endodontics, Changzhou Hospital of Traditional Chinese Medicine, Changzhou, China
| | - Wenxiang Shi
- Department of Pediatric Cardiology, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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13
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Luo K, Zhong Y, Guo Y, Nie J, Xu Y, Zhou H. Integrated bioinformatics analysis and experimental validation reveals hub genes of rheumatoid arthritis. Exp Ther Med 2023; 26:480. [PMID: 37745040 PMCID: PMC10515114 DOI: 10.3892/etm.2023.12179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 08/01/2023] [Indexed: 09/26/2023] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by systemic inflammation, especially synovitis, leading to joint damage. It is important to explore potential biomarkers and therapeutic targets to improve the clinical treatment of RA. However, the potential underlying mechanisms of action of available treatments for RA have not yet been fully elucidated. The present study investigated the potential biomarkers of RA and identified specific targets for therapeutic intervention. A comprehensive analysis was performed using mRNA files downloaded from the Gene Expression Omnibus. Differences in gene expression were analyzed and compared between the normal and RA groups. In addition, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed on differentially expressed genes (DEGs). A protein-protein interaction network, Molecular Complex Detection and cytoHubba network were evaluated to identify hub genes. Finally, using an experimental RA rat model induced by Freund's complete adjuvant (FCA), the expression of potential biomarkers or target genes in RA were verified through reverse transcription-quantitative PCR. The results of the mRNA dataset processing revealed 195 DEGs in patients with RA when compared with the healthy controls. Moreover, 10 hub genes were identified in patients with RA and four candidate mRNAs were identified, as follows: Discs large homolog-associated protein 5 (DLGAP5), kinesin family member 20A (KIF20A), maternal embryonic leucine zipper kinase (MELK) and nuclear division cycle 80 (NDC80). Finally, the bioinformatics analysis results were validated by quantifying the expression of the DLGAP5, KIF20A, MELK and NDC80 genes in the FCA-induced experimental RA rat model. The findings of the present study suggested that the treatment of RA may be successful through the inhibition of DLGAP5, KIF20A, MELK and NDC80 expression. Therefore, the targeting of these genes may result in more effective treatments for patients with RA.
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Affiliation(s)
- Kun Luo
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610075, P.R. China
| | - Yumei Zhong
- Department of Painology, Chengdu Integrated TCM & Western Medicine Hospital/Chengdu First People's Hospital, Chengdu, Sichuan 610095, P.R. China
| | - Yanding Guo
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610075, P.R. China
| | - Jingwei Nie
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610075, P.R. China
| | - Yimei Xu
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610075, P.R. China
| | - Haiyan Zhou
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610075, P.R. China
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14
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Zhang GX, Ding XS, Wang YL. Prognostic model of hepatocellular carcinoma based on cancer grade. World J Clin Cases 2023; 11:6383-6397. [PMID: 37900243 PMCID: PMC10600993 DOI: 10.12998/wjcc.v11.i27.6383] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 08/02/2023] [Accepted: 08/23/2023] [Indexed: 09/20/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. With highly invasive biological characteristics and a lack of obvious clinical manifestations, HCC usually has a poor prognosis and ranks fourth in cancer mortality. The aetiology and exact molecular mechanism of primary HCC are still unclear. AIM To select the characteristic genes that are significantly associated with the prognosis of HCC patients and construct a prognosis model of this malignancy. METHODS By comparing the gene expression levels of patients with different cancer grades of HCC, we screened out differentially expressed genes associated with tumour grade. By protein-protein interaction (PPI) network analysis, we obtained the top 2 PPI networks and hub genes from these differentially expressed genes. By using least absolute shrinkage and selection operator Cox regression, 13 prognostic genes were selected for feature extraction, and a prognostic risk model of HCC was established. RESULTS The model had significant prognostic ability in HCC. We also analysed the biological functions of these prognostic genes. CONCLUSION By comparing the gene profiles of patients with different stages of HCC, We have constructed a prognosis model consisting of 13 genes that have important prognostic value. This model has good application value and can be explained clinically.
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Affiliation(s)
- Guo-Xin Zhang
- Department of General Surgery, Aviation General Hospital, Beijing 100010, China
| | - Xiao-Sheng Ding
- Department of Oncology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - You-Li Wang
- Department of General Surgery, Aviation General Hospital, Beijing 100010, China
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15
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Yao Y, Lv J, Wang G, Hong X. Multi-omics analysis and validation of the tumor microenvironment of hepatocellular carcinoma under RNA modification patterns. MATHEMATICAL BIOSCIENCES AND ENGINEERING : MBE 2023; 20:18318-18344. [PMID: 38052560 DOI: 10.3934/mbe.2023814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/07/2023]
Abstract
BACKGROUND Multiple types of RNA modifications are associated with the prognosis of hepatocellular carcinoma (HCC) patients. However, the overall mediating effect of RNA modifications on the tumor microenvironment (TME) and the prognosis of patients with HCC is unclear. METHODS Thoroughly analyze the TME, biological processes, immune infiltration and patient prognosis based on RNA modification patterns and gene patterns. Construct a prognostic model (RNA modification score, RNAM-S) to predict the overall survival (OS) in HCC patients. Analyze the immune status, cancer stem cell (CSC), mutations and drug sensitivity of HCC patients in both the high and low RNAM-S groups. Verify the expression levels of the four characteristic genes of the prognostic RNAM-S using in vitro cell experiments. RESULTS Two modification patterns and two gene patterns were identified in this study. Both the high-expression modification pattern and the gene pattern exhibited worse OS. A prognostic RNAM-S model was constructed based on four featured genes (KIF20A, NR1I2, NR2F1 and PLOD2). Cellular experiments suggested significant dysregulation of the expression levels of these four genes. In addition, validation of the RNAM-S model using each data set showed good predictive performance of the model. The two groups of HCC patients (high and low RNAM-S groups) exhibited significant differences in immune status, CSC, mutation and drug sensitivity. CONCLUSION The findings of the study demonstrate the clinical value of RNA modifications, which provide new insights into the individualized treatment for patients with HCC.
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Affiliation(s)
- Yuanqian Yao
- Guangxi University of Chinese medicine, NanNing 530000, China
| | - Jianlin Lv
- The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530000, China
| | - Guangyao Wang
- The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530000, China
| | - Xiaohua Hong
- Guangxi University of Chinese medicine, NanNing 530000, China
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16
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Li R, Liu X, Deng K, Wang X. M7G methylated core genes (METTL1 and WDR4) and associated RNA risk signatures are associated with prognosis and immune escape in HCC. BMC Med Genomics 2023; 16:179. [PMID: 37528384 PMCID: PMC10394781 DOI: 10.1186/s12920-023-01614-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 07/21/2023] [Indexed: 08/03/2023] Open
Abstract
N7 methylguanosine (m7G) has a crucial role the development of hepatocellular carcinoma (HCC). This study aimed to investigate the impact of the m7G methylation core genes (METTL1 and WDR4) and associated RNA risk signatures on HCC. we found m7G methylation core genes (METTL1 and WDR4) were upregulated in four HCC cell lines, and downregulation of METTL1 and WDR4 attenuated HCC cell proliferation, migration, and invasion. Moreover, METTL1 and WDR4 are upregulated in HCC tissues, and that there is a significant positive correlation between them. METTL1 and WDR4 were identified as independent prognostic markers for HCC by employing overall survival (OS), disease-specific survival (DSS), Progression Free Interval survival (PFI), and univariate/multivariate Cox analyses. We identified 1479 coding RNAs (mRNAs) and 232 long non-coding RNAs (lncRNAs) associated with METTL1 / WDR4 by using weighted coexpression network analysis (WGCNA) and co-clustering analysis. The least absolute shrinkage and selection operator (lasso) were used to constructing mRNA and lncRNA risk signatures associated with the METTL1 / WDR4. These risk were independent poor prognostic factors in HCC. Furthermore, we found that METTL1 / WDR4 expression and mRNA / lncRNA risk scores were closely associated with TP53 mutations. Clinicopathological features correlation results showed that METTL1 / WDR4 expression and mRNA / lncRNA risk score were associated with the stage and invasion depth (T) of HCC. To predict the overall survival of HCC individuals, we constructed a nomogram with METTL1/WDR4 expression, mRNA/lncRNA risk score, and clinicopathological features. In addition, we combined single-cell sequencing datasets and immune escape-related checkpoints to construct an immune escape-related protein-protein interaction(PPI) network. In conclusion, M7G methylated core genes (METTL1 and WDR4) and associated RNA risk signatures are associated with prognosis and immune escape in HCC.
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Affiliation(s)
- Rui Li
- Jiangnan University Medical Center, WuXi, China
- Wuxi No.2 People's Hospital, WuXi, China
- The Affiliated Wuxi No.2 People's Hospital of Clinical College of Nantong University, WuXi, China
| | | | - Kaiyuan Deng
- Jiangnan University Medical Center, WuXi, China
- Wuxi No.2 People's Hospital, WuXi, China
- The Affiliated Wuxi No.2 People's Hospital of Clinical College of Nantong University, WuXi, China
| | - Xin Wang
- Jiangnan University Medical Center, WuXi, China.
- Wuxi No.2 People's Hospital, WuXi, China.
- The Affiliated Wuxi No.2 People's Hospital of Clinical College of Nantong University, WuXi, China.
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17
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Xiong Z, Yang Y, Li W, Lin Y, Huang W, Zhang S. Exploring Key Biomarkers and Common Pathogenesis of Seven Digestive System Cancers and Their Correlation with COVID-19. Curr Issues Mol Biol 2023; 45:5515-5533. [PMID: 37504265 PMCID: PMC10378662 DOI: 10.3390/cimb45070349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 06/26/2023] [Accepted: 06/27/2023] [Indexed: 07/29/2023] Open
Abstract
Digestive system cancer and COVID-19 significantly affect the digestive system, but the mechanism of interaction between COVID-19 and the digestive system cancers has not been fully elucidated. We downloaded the gene expression of COVID-19 and seven digestive system cancers (oral, esophageal, gastric, colorectal, hepatocellular, bile duct, pancreatic) from GEO and identified hub differentially expressed genes. Multiple verifications, diagnostic efficacy, prognostic analysis, functional enrichment and related transcription factors of hub genes were explored. We identified 23 common DEGs for subsequent analysis. CytoHubba identified nine hub genes (CCNA2, CCNB1, CDKN3, ECT2, KIF14, KIF20A, KIF4A, NEK2, TTK). TCGA and GEO data validated the expression and excellent diagnostic and prognostic ability of hub genes. Functional analysis revealed that the processes of cell division and the cell cycle were essential in COVID-19 and digestive system cancers. Furthermore, six related transcription factors (E2F1, E2F3, E2F4, MYC, TP53, YBX1) were involved in hub gene regulation. Via in vitro experiments, CCNA2, CCNB1, and MYC expression was verified in 25 colorectal cancer tissue pairs. Our study revealed the key biomarks and common pathogenesis of digestive system cancers and COVID-19. These may provide new ideas for further mechanistic research.
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Affiliation(s)
- Zuming Xiong
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Yongjun Yang
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Wenxin Li
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Yirong Lin
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Wei Huang
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Sen Zhang
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
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18
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He F, Zeng P, Ma S, Yang X, Liu H, Liu Q, Zhou Y, Zhu H. Identification and validation of a novel cuproptosis-related genes signature associated with prognosis, clinical implications and immunotherapy of hepatocellular carcinoma. Front Pharmacol 2023; 14:1088993. [PMID: 36843949 PMCID: PMC9947158 DOI: 10.3389/fphar.2023.1088993] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 01/31/2023] [Indexed: 02/11/2023] Open
Abstract
Background: Cuproptosis is a novel type of regulated cell death and is reported to promote tumor occurrence and progression. However, whether a cuproptosis-related signature has an impact on hepatocellular carcinoma (HCC) is still unclear. Materials and methods: We analyzed the transcriptome data of HCC from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) database, and searched for tumor types with different cuproptosis patterns through consistent clustering of cuproptosis genes. We then constructed a Cuproptosis-Related Genes (CRGs)-based risk signature through LASSO COX regression, and further analyzed its impact on the prognosis, clinical characteristics, immune cell infiltration, and drug sensitivity of HCC. Results: We identified the expression changes of 10 cuproptosis-related genes in HCC, and all the patients can be divided into two subtypes with different prognosis by applying the consensus clustering algorithm. We then constructed a cuproptosis-related risk signature and identified five CRGs, which were highly correlated with prognosis and representative of this gene set, namely G6PD, PRR11, KIF20A, EZH2, and CDCA8. Patients in the low CRGs signature group had a favorable prognosis. We further validated the CRGs signature in ICGC cohorts and got consistent results. Besides, we also discovered that the CRGs signature was significantly associated with a variety of clinical characteristics, different immune landscapes and drug sensitivity. Moreover, we explored that the high CRGs signature group was more sensitive to immunotherapy. Conclusion: Our integrative analysis demonstrated the potential molecular signature and clinical applications of CRGs in HCC. The model based on CRGs can precisely predict the survival outcomes of HCC, and help better guide risk stratification and treatment strategy for HCC patients.
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Affiliation(s)
- Fengjiao He
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China,Hunan Academy of Traditional Chinese Medicine Affiliated Hospital, Changsha, China
| | - Puhua Zeng
- Hunan Academy of Traditional Chinese Medicine Affiliated Hospital, Changsha, China
| | - Sijing Ma
- Hunan Academy of Traditional Chinese Medicine Affiliated Hospital, Changsha, China
| | - Ximing Yang
- Medical School, Hunan University of Chinese Medicine, Changsha, China
| | - Huan Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Qiong Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Yangying Zhou
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China,*Correspondence: Yangying Zhou, ; Hong Zhu,
| | - Hong Zhu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China,*Correspondence: Yangying Zhou, ; Hong Zhu,
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19
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Liu B, Su J, Fan B, Ni X, Jin T. High expression of KIF20A in bladder cancer as a potential prognostic target for poor survival of renal cell carcinoma. Medicine (Baltimore) 2023; 102:e32667. [PMID: 36637953 PMCID: PMC9839245 DOI: 10.1097/md.0000000000032667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 12/27/2022] [Indexed: 01/14/2023] Open
Abstract
Urinary system tumors are malignant tumors, including renal cancer and bladder cancer. however, molecular target of them remains unclear. GSE14762 and GSE53757 were downloaded from GEO database to screen differentially expressed genes (DEGs). Weighted gene co-expression network analysis was performed. Gene Ontology (GO) and Kyoto encyclopedia of genes and genomes were used for enrichment analysis. Gene ontology and Kyoto encyclopedia of genes and genomes analyses were performed on whole genome, as formulated by gene set enrichment analysis. Survival analysis was also performed. Comparative toxicogenomics database was used to identify diseases most associated with hub genes. A total of 1517 DEGs were identified. DEGs were mainly enriched in cancer pathway, HIF-1 signaling pathway, organic acid metabolism, glyoxylate and dicarboxylate metabolism, and protein homodimerization activity. Ten hub genes (TPX2, ASPM, NUSAP1, RAD51AP1, CCNA2, TTK, PBK, MELK, DTL, kinesin family member 20A [KIF20A]) were obtained, which were up-regulated in tumor tissue. The expression of KIF20A was related with the overall survival of renal and bladder cancer. KIF20A was up-regulated in the tumor tissue, and might worsen the overall survival of bladder and kidney cancer. KIF20A could be a novel biomarker of bladder and kidney cancer.
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Affiliation(s)
- Bin Liu
- Department of Urology Surgery, The Fourth Hospital of Hebei Medical University, Hebei, PR China
| | - Jianzhi Su
- Department of Urology Surgery, The Fourth Hospital of Hebei Medical University, Hebei, PR China
| | - Bo Fan
- Department of Urology Surgery, The Fourth Hospital of Hebei Medical University, Hebei, PR China
| | - Xiaochen Ni
- Department of Urology Surgery, The Fourth Hospital of Hebei Medical University, Hebei, PR China
| | - Tingting Jin
- Department of Urology Surgery, The Fourth Hospital of Hebei Medical University, Hebei, PR China
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Chen B, Mao T, Qin X, Zhang W, Watanabe N, Li J. Role of estrogen receptor signaling pathway-related genes in diffuse large B-cell lymphoma and identification of key targets via integrated bioinformatics analysis and experimental validation. Front Oncol 2022; 12:1029998. [PMID: 36531013 PMCID: PMC9749266 DOI: 10.3389/fonc.2022.1029998] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 11/07/2022] [Indexed: 11/17/2023] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous malignancy. Epidemiologically, the incidence of DLBCL is higher in men, and the female sex is a favorable prognostic factor, which can be explained by estrogen. This study aimed to explore the potential targets of the estrogen receptor (ER) signaling pathway and provide a meaningful way to treat DLBCL patients. Datasets were obtained from the Gene Expression Omnibus (GEO) to identify differentially expressed genes (DEGs). Representative gene sets estrogen receptor pathways, and growth regulatory pathways were identified based on Gene Set Enrichment Analysis (GSEA) analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used for function and pathway analysis. STRING and Cytoscape were used to construct the interaction network, and the MCODE plug-in performed the module analysis. GEPIA, TCGA, and LOGpc databases were used for expression and predictive analysis. The Human Protein Atlas (HPA) database was used to analyze the protein expression levels, cBioPortal was used to explore genetic alterations, and ROC analysis and prognostic assessment were used to predict the diagnostic value of genes. Finally, BJAB cells were treated with ER inhibitor fulvestrant and specific shRNA, and the expression of hub genes was verified by RT-qPCR. We identified 81 overlapping DEGs and CDC6, CDC20, KIF20A, STIL, and TOP2A as novel biomarkers affecting the prognosis of DLBCL. In addition, the STAT and KRAS pathways are considered potential growth regulatory pathways. These results hold promise for new avenues for the treatment of DLBCL patients.
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Affiliation(s)
- Bo Chen
- Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Tianjiao Mao
- Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Xiuni Qin
- Guangzhou Concord Cancer Center, Guangzhou, Guangdong, China
| | - Wenqi Zhang
- School of Basic Medicine, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Nobumoto Watanabe
- Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan
- Bio-Active Compounds Discovery Unit, RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan
| | - Jiang Li
- Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
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Zhou Y, Gu H, Shao B, Zhang S, Pall H, Peixoto RD, Mok SRS, Zhu G. Glycolysis-related gene dihydrolipoamide acetyltransferase promotes poor prognosis in hepatocellular carcinoma through the Wnt/β-catenin and PI3K/Akt signaling pathways. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:1240. [PMID: 36544660 PMCID: PMC9761179 DOI: 10.21037/atm-22-5272] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 11/17/2022] [Indexed: 11/30/2022]
Abstract
Background Recent research suggests that dihydrolipoamide acetyltransferase (DLAT), which is a copper-induced cell death-related gene, is involved in multiple biological events in tumors. This study sought to investigate the relationship between DLAT and hepatocellular carcinoma (HCC). Methods In the Cancer Genome Atlas (TCGA) database, we first identified the differentially expressed gene (i.e., DLAT), then confirmed DLAT expression, and found a link between it and the prognosis of HCC patients. An internal validation nomogram was built based on a multivariate Cox regression analysis. Data from the Tumor Immune Estimation Resource (TIMER) database was used to examine the association between DLT and immunological cells. A gene set enrichment analysis (GSEA) was conducted to investigate the probable mechanism of action. Finally, in vitro cytological research was conducted to further examin the involvement of DLAT in HCC-related unfavorable biological events. Results The database screenings showed that DLAT was a differentially expressed molecule; that is, DLAT was more highly expressed in the cancer tissues than normal tissues. TCGA results and Kaplan-Meier-plotter data sets showed that HCC patients with reduced DLAT expression had greater disease-specific survival (DSS), overall survival (OS), and progression-free interval (PFI). The prediction model had a concordance index of 0.659 (0.614-0.704), which indicates high accuracy. According to the TIMER database, tumor cells in the HCC microenvironment may be able to bypass the immune system due to the expression of DLAT. The in vitro cytological tests showed that DLAT knockdown significantly decreased the proliferation and invasion of the HCC cells. It also inhibited the activity of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (Akt) and Wnt/β-catenin signaling pathways. Conclusions Decreased DLAT expression significantly prolongs the OS, PFI, and DSS of HCC patients. DLAT may be employed as a new predictive biomarker for HCC, and may be linked to the immune system in HCC patients. The tumor microenvironment (TME) may have a significant effect on the ability of tumor cells to evade the immune system. The PI3K/Akt and Wnt/β-catenin signaling pathways may affect the prognosis of HCC by interfering with DLAT. Given these findings, HCC may be an ideal target for the development of anti-cancer therapies.
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Affiliation(s)
- Yuan Zhou
- Department of Hepatobiliary Surgery, Tumor Hospital Affiliated to Nantong University, Nantong Tumor Hospital, Nantong, China;,Southeast University School of Medicine, Nanjing, China
| | - Haijuan Gu
- Department of Pharmacy, Tumor Hospital Affiliated to Nantong University, Nantong Tumor Hospital, Nantong, China
| | - Bingfeng Shao
- Department of Hepatobiliary Surgery, Tumor Hospital Affiliated to Nantong University, Nantong Tumor Hospital, Nantong, China
| | - Suqing Zhang
- Department of Hepatobiliary Surgery, Tumor Hospital Affiliated to Nantong University, Nantong Tumor Hospital, Nantong, China
| | - Harpreet Pall
- Department of Pediatrics, Hackensack Meridian School of Medicine, Hackensack Meridian K. Hovnanian Children’s Hospital, Jersey Shore University Medical Center, Neptune, NJ, USA
| | | | - Shaffer R. S. Mok
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | - Guodong Zhu
- Department of Hepatobiliary Surgery, Affiliated Nantong Hospital 3 of Nantong University, Nantong, China
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22
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He H, Liang L, Huang J, Jiang S, Liu Y, Sun X, Li Y, Cong L, Jiang Y. KIF20A is associated with clinical prognosis and synergistic effect of gemcitabine combined with ferroptosis inducer in lung adenocarcinoma. Front Pharmacol 2022; 13:1007429. [PMID: 36225575 PMCID: PMC9549118 DOI: 10.3389/fphar.2022.1007429] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 09/06/2022] [Indexed: 11/20/2022] Open
Abstract
Gemcitabine (GEM), an antimetabolite that terminates DNA synthesis, is commonly used in the treatment of cancers including lung adenocarcinoma (LUAD). However, downregulation of sensitivity limits the therapeutic effect. Ferroptosis as the new form of regulated cell death has been shown to have great potential for cancer treatment with chemoresistance. Here, three genes with both ferroptosis and GEM-response-associated features were screened from RNA sequencing and public data for constructing an independent risk model. LUAD patients with different risk scores had differences in mutational landscape, gene enrichment pathways, and drug sensitivity. By Cell Counting Kit-8 assay, flow cytometry, and colony forming assay, we demonstrate that GEM and ferroptosis inducer (FIN) imidazole Ketone Erastin had a synergistic combined anti-proliferative effect on LUAD cells and knockdown of KIF20A (the core gene of our model) further enhanced cell death in vitro by inducing ferroptosis. In conclusion, we identified a link between ferroptosis and GEM response in LUAD cells and developed a robust signature that can effectively classify LUAD patients into subgroups with different overall survival. For LUAD, the combined treatment modality of GEM and FIN is potentially effective and KIF20A may be a new therapeutic target.
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Affiliation(s)
- Hua He
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, Hunan, China
- School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Lu Liang
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, Hunan, China
- School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Jingjing Huang
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, Hunan, China
- School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Shiyao Jiang
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, Hunan, China
- School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Yueying Liu
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, Hunan, China
- School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Xiaoyan Sun
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, Hunan, China
- School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Yi Li
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, Hunan, China
- School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Li Cong
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, Hunan, China
- School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Yiqun Jiang
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, Hunan, China
- School of Medicine, Hunan Normal University, Changsha, Hunan, China
- *Correspondence: Yiqun Jiang,
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23
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Lei M, Du X, Li X, Wang F, Gu L, Guo F. LINC00665 regulates hepatocellular carcinoma by modulating mRNA via the m6A enzyme. Open Life Sci 2022; 17:71-80. [PMID: 35233461 PMCID: PMC8847717 DOI: 10.1515/biol-2022-0003] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 11/05/2021] [Accepted: 12/12/2021] [Indexed: 12/13/2022] Open
Abstract
This study aimed to reveal the mechanism by which long noncoding RNAs (lncRNAs) modulate hepatocellular carcinoma (HCC) by regulating mRNA via the N6-methyladenosine (m6A) enzyme. The expression and clinical data of 365 HCC patients and 50 healthy control samples were downloaded from the the Cancer Genome Atlas (TCGA) database. Differentially expressed lncRNAs (DElncRNAs) and differentially expressed mRNAs (DEmRNAs) screened using limma packages from the R. m6A2Target database were used to predict the relationship between m6A enzyme-lncRNA and m6A enzyme-mRNA. The mRNAs in the lncRNA-m6A enzyme-mRNA network were subjected to enrichment analysis. Cox regression analysis was used to screen for RNAs significantly related to HCC prognosis. The expression of differentially expressed RNAs (DERs) was verified using the TCGA dataset and GSE55092. Eighty-five DElncRNAs and 747 DEmRNAs were identified. The mRNAs in the lncRNA-m6A enzyme-mRNA network were primarily involved in mitotic cell division, the p53 signaling pathway, and the cell cycle. Three lncRNAs and 14 mRNAs were significantly associated with HCC prognosis. Furthermore, the expression of 12 DERs differed significantly between patients in the early and advanced stages. LINC00665 was predicted to regulate 11 mRNAs by modulating IGF2BP1, IGF2BP2, and YTHDF1. Thus, this study provides new insights into the roles of lncRNA and m6A enzymes in HCC.
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Affiliation(s)
- Ming Lei
- Nursing Health Sciences College, Yunnan Open University , Kunming , Yunnan, 650500 , China
| | - Xinghua Du
- Laboratory Medicine Department, The Integrated Traditional Chinese and Western Medicine Hospital of Yunnan Province , Kunming , Yunnan, 650224 , China
| | - Xiaokai Li
- Hepatobiliary Surgery Department, The First Affiliated Hospital of Kunming Medical University , Kunming , Yunnan, 650032 , China
| | - Fuke Wang
- Sport Medicine Department, The First Affiliated Hospital of Kunming Medical University , Kunming , Yunnan, 650032 , China
| | - Ling Gu
- Pain Department, The First Affiliated Hospital of Kunming Medical University , Kunming , Yunnan, 650032 , China
| | - Feng Guo
- The Clinical Skills Training Center, Kunming Medical University, No. 1168 Chunrongxi Road Chenggong District , Kunming , Yunnan, 650500 , China
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