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Ruan L, Fang N, Zhao X, Chen W, Wu Z, Wu X. Key oncogenes and candidate drugs for hepatitis-B-driven hepatocellular carcinoma progression. Discov Oncol 2025; 16:116. [PMID: 39903352 PMCID: PMC11794919 DOI: 10.1007/s12672-025-01851-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Accepted: 01/24/2025] [Indexed: 02/06/2025] Open
Abstract
BACKGROUND This study aimed to uncover the key hepatitis-B (HB)-related liver cancer (LC) promoting genes, and clarity their interrelationships, enrichments, impacts on LC immune infiltration, and potential drugs targeting these genes. METHODS The LC-survival associated genes were acquired from the LIHC samples of the TCGA-database; and HB related genes from the DisGeNET database. The intersection was used to screen the key genes. Using the 8 HB-LC genes, we constructed prognostic models for survival prediction of HBV positive patients with LIHC and performed enrichment analysis, interaction analysis, immune infiltration analysis, and potential drug digging from the GTRP and GDSC databases. RESULTS In the core intersection of different sets. Based on these genes, prognostic cox regression models for OS and DFS were constructed. Overall, HB-LC genes were significantly negatively correlated with Th17, MAIT, monocytes, and CD4 Naive cells, while they were positively correlated with B cells, nTreg cells, and Tr1 cells. Among 8 genes, MKI67, EZH2, and CDCA5 were hub ones. Finally, 7 drugs target at least three HB-LC genes and can be used as novel drugs. CONCLUSIONS Together, eight key HB-LC genes play important cancer-promoting roles in LC, which may be the molecular mechanism by which HBV drives the development of LC.
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Affiliation(s)
- Liqin Ruan
- Jiuiiang City Key Laboratory of Cell Therapy, JiuJiang NO.1 People's Hospital, Jiujiang, China
| | - Ningbo Fang
- Jiuiiang City Key Laboratory of Cell Therapy, JiuJiang NO.1 People's Hospital, Jiujiang, China
| | - Xinhua Zhao
- Jiuiiang City Key Laboratory of Cell Therapy, JiuJiang NO.1 People's Hospital, Jiujiang, China
| | - Weili Chen
- Jiuiiang City Key Laboratory of Cell Therapy, JiuJiang NO.1 People's Hospital, Jiujiang, China
| | - Zhaoping Wu
- Jiuiiang City Key Laboratory of Cell Therapy, JiuJiang NO.1 People's Hospital, Jiujiang, China
| | - Xiaoyong Wu
- Jiuiiang City Key Laboratory of Cell Therapy, JiuJiang NO.1 People's Hospital, Jiujiang, China.
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2
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Abudoureyimu M, Sun N, Chen W, Lin X, Pan F, Wang R. Aurora-A promotes lenvatinib resistance experimentally through hsa-circ-0058046/miR-424-5p/FGFR1 axis in hepatocellular carcinoma. Int J Immunopathol Pharmacol 2025; 39:3946320251316692. [PMID: 39895095 PMCID: PMC11789117 DOI: 10.1177/03946320251316692] [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: 08/19/2024] [Accepted: 01/13/2025] [Indexed: 02/04/2025] Open
Abstract
OBJECTIVE This study aimed to investigate whether the dysregulation of Aurora-A is involved in lenvatinib resistance in hepatocellular carcinoma. METHODS Bioinformatics tools and drug sensitivity assays were used to investigate the association between Aurora-A expression level and lenvatinib resistance in hepatocellular carcinoma cell lines. Cell function experiments had performed after treatment with lenvatinib and/or a selective Aurora-A inhibitor (MLN-8237). CircRNA microarray, RIP, RNA pull-down, and dual-luciferace reporter assay were performed to identify the downstream molecular mechanism of Aurora-A dysregulation. RESULTS Aurora-A expression was positively correlated with lenvatinib resistance in hepatocellular carcinoma cells. The Aurora-A selective inhibitor MLN-8237, in combination with lenvatinib, synergistically inhibited hepatocellular carcinoma cell proliferation in vitro and vivo, suggesting the Aurora-A might be a potential therapeutic target for lenvatinib resistance. Mechanistically, Aurora-A induced FGFR1 expression through the hsa-circ-0058046/miR-424-5p/FGFR1 axis. Aurora-A promotes lenvatinib resistance through hsa-circ-0058046/miR-424-5p/FGFR1 axis in hepatocellular carcinoma cells. The simultaneous inhibition of FGFR1 by the Aurora-A inhibitor MLN-8237 and lenvatinib overcame lenvatinib resistance in hepatocellular carcinoma cells. CONCLUSION Collectively, our findings indicate that Aurora-A promotes lenvatinib resistance through the hsa-circ-0058046/miR-424-5p/FGFR1 axis in hepatocellular carcinoma (HCC) cells. These results suggest that Aurora-A may serve as a therapeutic target for HCC patients exhibiting lenvatinib resistance. Furthermore, the combination of lenvatinib and MLN-8237 shows potential for clinical trials aimed at overcoming lenvatinib resistance.
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MESH Headings
- Humans
- Quinolines/pharmacology
- Quinolines/therapeutic use
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/enzymology
- Liver Neoplasms/drug therapy
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Liver Neoplasms/enzymology
- Phenylurea Compounds/pharmacology
- Phenylurea Compounds/therapeutic use
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Neoplasm/genetics
- MicroRNAs/genetics
- MicroRNAs/metabolism
- RNA, Circular/genetics
- RNA, Circular/metabolism
- Aurora Kinase A/metabolism
- Aurora Kinase A/genetics
- Aurora Kinase A/antagonists & inhibitors
- Receptor, Fibroblast Growth Factor, Type 1/metabolism
- Receptor, Fibroblast Growth Factor, Type 1/genetics
- Animals
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Gene Expression Regulation, Neoplastic
- Pyrimidines/pharmacology
- Antineoplastic Agents/pharmacology
- Protein Kinase Inhibitors/pharmacology
- Azepines/pharmacology
- Mice, Nude
- Signal Transduction/drug effects
- Mice
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Affiliation(s)
- Mubalake Abudoureyimu
- Department of Medical Oncology, Affiliated Jinling Hospital, Medical School, Nanjing University, Nanjing, China
| | - Ni Sun
- Department of Medical Oncology, Affiliated Jinling Hospital, Medical School, Nanjing University, Nanjing, China
| | - Weiwei Chen
- Department of Medical Oncology, Affiliated Jinling Hospital, Nanjing Medical University, Nanjing, China
| | - Xinrong Lin
- Department of Medical Oncology, Affiliated Jinling Hospital, Medical School, Nanjing University, Nanjing, China
| | - Fan Pan
- Department of Medical Oncology, Affiliated Jinling Hospital, Medical School, Nanjing University, Nanjing, China
| | - Rui Wang
- Department of Medical Oncology, Affiliated Jinling Hospital, Medical School, Nanjing University, Nanjing, China
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3
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Heidari R, Assadollahi V, Marashi SN, Elahian F, Mirzaei SA. The miRNA-mRNA Regulatory Network in Human Hepatocellular Carcinoma by Transcriptomic Analysis From GEO. Cancer Rep (Hoboken) 2025; 8:e70098. [PMID: 39764737 PMCID: PMC11705453 DOI: 10.1002/cnr2.70098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Revised: 10/03/2024] [Accepted: 12/12/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Bioinformatics analysis of hepatocellular carcinoma (HCC) expression profiles can aid in understanding its molecular mechanisms and identifying new targets for diagnosis and treatment. AIM In this study, we analyzed expression profile datasets and miRNA expression profiles related to HCC from the GEO using R software to detect differentially expressed genes (DEGs) and differentially expressed miRNAs (DEmiRs). METHODS AND RESULTS Common DEGs were identified, and a PPI network was constructed using the STRING database and Cytoscape software to identify hub genes. The reduced levels of tumor suppressor miRNAs or down regulated DEmiRs may be increased levels of oncogenes, the oncomirs or up regulated DEmiRs may be decreased levels of tumor suppressor genes in cancerous cells. According to this strategy, increased and decreased DEGs, also increased and decreased DEmiRs were selected. The multimir package was employed to predict target genes for DEmiRs then DEmiRs-hub gene network created. We identified approximately 1000 overlapping DEGs and 60 DEmiRs. Hub genes included RRM2, MELK, KIF11, KIF23, NCAPG, DLGAP5, BUB1B, AURKB, CCNB1, KIF20A, CCNA2, TTK, PBK, TOP2A, CDK1, MAD2L1, BIRC5, ASPM, CDCA8, and CENPF, all associated with significantly worse survival in HCC. miR-224, miR-24, miR-182, miRNA-1-3p, miR-30a, miR-27a, and miR-214 were identified as important DEmiRs with targeting more than six hub genes. CONCLUSION Generally, our findings offer insight into the interaction of hub genes and miRNAs in the development of HCC by bioinformatics analysis, information that may prove useful in identifying biomarkers and therapeutic targets in HCC.
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Affiliation(s)
- Razieh Heidari
- Cancer Research Center, Basic Health Sciences InstituteShahrekord University of Medical SciencesShahrekordIran
- Department of Medical Biotechnology, School of Advanced TechnologiesShahrekord University of Medical SciencesShahrekordIran
| | - Vahideh Assadollahi
- Department of Tissue Engineering & Applied Cell Sciences, School of Advanced TechnologiesShahrekord University of Medical SciencesShahrekordIran
| | - Seyedeh Negar Marashi
- Department of Medical Biotechnology, School of Advanced TechnologiesShahrekord University of Medical SciencesShahrekordIran
| | - Fatemeh Elahian
- Department of Medical Biotechnology, School of Advanced TechnologiesShahrekord University of Medical SciencesShahrekordIran
- Advanced Technology CoresBaylor College of MedicineTexasUSA
| | - Seyed Abbas Mirzaei
- Department of Medical Biotechnology, School of Advanced TechnologiesShahrekord University of Medical SciencesShahrekordIran
- Cellular and Molecular Research Center, Basic Health Sciences InstituteShahrekord University of Medical SciencesShahrekordIran
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Chen X, Yan Y, Liu Y, Yi Q, Xu Z. Tabersonine enhances cisplatin sensitivity by modulating Aurora kinase A and suppressing epithelial-mesenchymal transition in triple-negative breast cancer. PHARMACEUTICAL BIOLOGY 2024; 62:394-403. [PMID: 38739003 PMCID: PMC11095288 DOI: 10.1080/13880209.2024.2351934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 04/25/2024] [Accepted: 04/28/2024] [Indexed: 05/14/2024]
Abstract
CONTEXT Tabersonine has been investigated for its role in modulating inflammation-associated pathways in various diseases. However, its regulatory effects on triple-negative breast cancer (TNBC) have not yet been fully elucidated. OBJECTIVE This study uncovers the anticancer properties of tabersonine in TNBC cells, elucidating its role in enhancing chemosensitivity to cisplatin (CDDP). MATERIALS AND METHODS After tabersonine (10 μM) and/or CDDP (10 μM) treatment for 48 h in BT549 and MDA-MB-231 cells, cell proliferation was evaluated using the cell counting kit-8 and colony formation assays. Quantitative proteomics, online prediction tools and molecular docking analyses were used to identify potential downstream targets of tabersonine. Transwell and wound-healing assays and Western blot analysis were used to assess epithelial-mesenchymal transition (EMT) phenotypes. RESULTS Tabersonine demonstrated inhibitory effects on TNBC cells, with IC50 values at 48 h being 18.1 μM for BT549 and 27.0 μM for MDA-MB-231. The combined treatment of CDDP and tabersonine synergistically suppressed cell proliferation in BT549 and MDA-MB-231 cells. Enrichment analysis revealed that the proteins differentially regulated by tabersonine were involved in EMT-related signalling pathways. This combination treatment also effectively restricted EMT-related phenotypes. Through the integration of online target prediction and proteomic analysis, Aurora kinase A (AURKA) was identified as a potential downstream target of tabersonine. AURKA expression was reduced in TNBC cells post-treatment with tabersonine. DISCUSSION AND CONCLUSIONS Tabersonine significantly enhances the chemosensitivity of CDDP in TNBC cells, underscoring its potential as a promising therapeutic agent for TNBC treatment.
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Affiliation(s)
- Xi Chen
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yuanliang Yan
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yuanhong Liu
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qiaoli Yi
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhijie Xu
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
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5
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Garcia CJC, Grisetti L, Tiribelli C, Pascut D. The ncRNA-AURKA Interaction in Hepatocellular Carcinoma: Insights into Oncogenic Pathways, Therapeutic Opportunities, and Future Challenges. Life (Basel) 2024; 14:1430. [PMID: 39598228 PMCID: PMC11595987 DOI: 10.3390/life14111430] [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: 08/30/2024] [Revised: 10/15/2024] [Accepted: 11/03/2024] [Indexed: 11/29/2024] Open
Abstract
Hepatocellular carcinoma (HCC) represents a major public health concern and ranks among the leading cancer-related mortalities globally. Due to the frequent late-stage diagnosis of HCC, therapeutic options remain limited. Emerging evidence highlights the critical role of non-coding RNAs (ncRNAs) in the regulation of Aurora kinase A (AURKA), one of the key hub genes involved in several key cancer pathways. Indeed, the dysregulated interaction between ncRNAs and AURKA contributes to tumor development, progression, and therapeutic resistance. This review delves into the interplay between ncRNAs and AURKA and their role in hepatocarcinogenesis. Recent findings underscore the involvement of the ncRNAs and AURKA axis in tumor development and progression. Furthermore, this review also discusses the clinical significance of targeting ncRNA-AURKA axes, offering new perspectives that could lead to innovative therapeutic strategies aimed at improving outcomes for HCC patients.
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Affiliation(s)
- Clarissa Joy C. Garcia
- Liver Cancer Unit, Fondazione Italiana Fegato—ONLUS, 34149 Trieste, Italy
- Department of Life Sciences, Università degli Studi di Trieste, 34127 Trieste, Italy
| | - Luca Grisetti
- National Institute of Gastroenterology—IRCCS “Saverio de Bellis”, 70013 Castellana Grotte, Italy
| | - Claudio Tiribelli
- Liver Cancer Unit, Fondazione Italiana Fegato—ONLUS, 34149 Trieste, Italy
| | - Devis Pascut
- Liver Cancer Unit, Fondazione Italiana Fegato—ONLUS, 34149 Trieste, Italy
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6
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Ren X, Feng N. Unveiling novel prognostic biomarkers and therapeutic targets for HBV-associated hepatocellular carcinoma through integrated bioinformatic analysis. Medicine (Baltimore) 2024; 103:e40134. [PMID: 39470543 PMCID: PMC11521037 DOI: 10.1097/md.0000000000040134] [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: 05/14/2024] [Revised: 06/15/2024] [Accepted: 09/27/2024] [Indexed: 10/30/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally, with limited treatment options. The goal of this study was to use integrated bioinformatic analysis to find possible biomarkers for prognosis and therapeutic targets for hepatitis B (HBV)-associated HCC. Three microarray datasets (GSE84402, GSE121248, and E-GEOD-19665) from patients with HBV-associated HCC were combined and analyzed. We identified differentially expressed genes (DEGs) and performed pathway enrichment analysis. We constructed protein-protein interaction networks to identify hub genes. We identified a total of 374 DEGs, which included 90 up-regulated and 284 down-regulated genes. Pathway enrichment analysis revealed associations with cell cycle, oocyte meiosis, and the p53 signaling pathway for up-regulated DEGs. Twenty hub genes were identified, and 9 of them (ZWINT, MELK, DLGAP5, BIRC5, AURKA, HMMR, CDK1, TTK, and MAD2L1) were validated using the Cancer Genome Atlas data and Kaplan-Meier survival analysis. These genes were significantly associated with a poor prognosis in HCC patients. Our research shows that ZWINT, MELK, DLGAP5, BIRC5, AURKA, HMMR, CDK1, TTK, and MAD2L1 may be useful for predicting how HBV-associated HCC will progress and for finding new ways to treat it. In addition to these further studies are needed to elucidate the functions of the remaining 11 identified hub genes (RRM2, NUSAP1, PBK, CCNB1, CCNB2, BUB1B, NEK2, CENPF, ASPM, TOP2A, and BUB1) in HCC development and progression.
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Affiliation(s)
- Xue Ren
- Medical Laboratory Center, Xi’an TCM Hospital of Encephalopathy, Xi’an, China
| | - Niaoniao Feng
- Medical Laboratory Center, Xi’an TCM Hospital of Encephalopathy, Xi’an, China
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7
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Balaji N, Kukal S, Bhat A, Pradhan N, Minocha S, Kumar S. A quartet of cancer stem cell niches in hepatocellular carcinoma. Cytokine Growth Factor Rev 2024; 79:39-51. [PMID: 39217065 DOI: 10.1016/j.cytogfr.2024.08.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 08/20/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024]
Abstract
Hepatocellular Carcinoma (HCC), the most prevalent type of primary liver cancer, is known for its aggressive behavior and poor prognosis. The Cancer Stem Cell theory, which postulates the presence of a small population of self-renewing cells called Cancer Stem Cells (CSCs), provides insights into various clinical and molecular features of HCC such as tumor heterogeneity, metabolic adaptability, therapy resistance, and recurrence. These CSCs are nurtured in the tumor microenvironment (TME), where a mix of internal and external factors creates a tumor-supportive niche that is continuously evolving both spatially and temporally, thus enhancing the tumor's complexity. This review details the origins of hepatic CSCs (HCSCs) and the factors influencing their stem-like qualities. It highlights the reciprocal crosstalk between HCSCs and the TME (hypoxic, vascular, invasive, and immune niches), exploring the signaling pathways involved and how these interactions control the malignant traits of CSCs. Additionally, it discusses potential therapeutic approaches targeting the HCSC niche and their possible uses in clinical practice.
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Affiliation(s)
- Neha Balaji
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, 110016, India
| | - Samiksha Kukal
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, 110016, India
| | - Anjali Bhat
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, 110016, India
| | - Nikita Pradhan
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, 110016, India
| | - Shilpi Minocha
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, 110016, India.
| | - Saran Kumar
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, 110016, India.
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8
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Datta N, Vp S, Parvathy K, A S S, Maliekal TT. ALDH1A1 as a marker for metastasis initiating cells: A mechanistic insight. Exp Cell Res 2024; 442:114213. [PMID: 39173941 DOI: 10.1016/j.yexcr.2024.114213] [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: 06/04/2024] [Revised: 08/12/2024] [Accepted: 08/14/2024] [Indexed: 08/24/2024]
Abstract
Since metastasis accounts for the majority of cancer morbidity and mortality, attempts are focused to block metastasis and metastasis initiating cellular programs. It is generally believed that hypoxia, reactive oxygen species (ROS) and the dysregulated redox pathways regulate metastasis. Although induction of epithelial to mesenchymal transition (EMT) can initiate cell motility to different sites other than the primary site, the initiation of a secondary tumor at a distant site depends on self-renewal property of cancer stem cell (CSC) property. That subset of metastatic cells possessing CSC property are referred to as metastasis initiating cells (MICs). Among the different cellular intermediates regulating metastasis in response to hypoxia by inducing EMT and self-renewal property, ALDH1A1 is a critical molecule, which can be used as a marker for MICs in a wide variety of malignancies. The cytosolic ALDHs can irreversibly convert retinal to retinoic acid (RA), which initiates RA signaling, important for self-renewal and EMT. The metastasis permissive tumor microenvironment increases the expression of ALDH1A1, primarily through HIF1α, and leads to metabolic reprograming through OXPHOS regulation. The ALDH1A1 expression and its high activity can reprogram the cancer cells with the transcriptional upregulation of several genes, involved in EMT through RA signaling to manifest hybrid EMT or Hybrid E/M phenotype, which is important for acquiring the characteristics of MICs. Thus, the review on this topic highlights the use of ALDH1A1 as a marker for MICs, and reporters for the marker can be effectively used to trace the population in mouse models, and to screen drugs that target MICs.
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Affiliation(s)
- Nandini Datta
- Cancer Research, Rajiv Gandhi Centre for Biotechnology (BRIC-RGCB), Thiruvananthapuram, Kerala, 695014, India
| | - Snijesh Vp
- Division of Molecular Medicine, St. John's Research Institute, St John's National Academy of Health Sciences, Bangalore, 560034, India
| | - K Parvathy
- Cancer Research, Rajiv Gandhi Centre for Biotechnology (BRIC-RGCB), Thiruvananthapuram, Kerala, 695014, India
| | - Sneha A S
- Cancer Research, Rajiv Gandhi Centre for Biotechnology (BRIC-RGCB), Thiruvananthapuram, Kerala, 695014, India
| | - Tessy Thomas Maliekal
- Cancer Research, Rajiv Gandhi Centre for Biotechnology (BRIC-RGCB), Thiruvananthapuram, Kerala, 695014, India; Regional Centre for Biotechnology, Faridabad, Haryana 121001, India.
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Liu H, Cali Daylan AE, Yang J, Tanwar A, Borczuk A, Zhang D, Chau V, Li S, Ge X, Halmos B, Zang X, Cheng H. Aurora Kinase A Inhibition Potentiates Platinum and Radiation Cytotoxicity in Non-Small-Cell Lung Cancer Cells and Induces Expression of Alternative Immune Checkpoints. Cancers (Basel) 2024; 16:2805. [PMID: 39199578 PMCID: PMC11352996 DOI: 10.3390/cancers16162805] [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: 06/24/2024] [Revised: 07/22/2024] [Accepted: 08/05/2024] [Indexed: 09/01/2024] Open
Abstract
Despite major advances in non-small-cell lung cancer (NSCLC) treatment, the five-year survival rates for patients with non-oncogene-driven tumors remain low, necessitating combinatory approaches to improve outcomes. Our prior high-throughput RNAi screening identified Aurora kinase A (AURKA) as a potential key player in cisplatin resistance. In this study, we investigated AURKA's role in platinum and radiation sensitivity in multiple NSCLC cell lines and xenograft mouse models, as well as its effect on immune checkpoints, including PD-L1, B7x, B7-H3, and HHLA2. Of 94 NSCLC patient tumor specimens, 91.5% tested positive for AURKA expression, with 34% showing moderate-to-high levels. AURKA expression was upregulated following cisplatin treatment in NSCLC cell lines PC9 and A549. Both AURKA inhibition by alisertib and inducible AURKA knockdown potentiated the cytotoxic effects of cisplatin and radiation, leading to tumor regression in doxycycline-inducible xenograft mice. Co-treated cells exhibited increased DNA double-strand breaks, apoptosis, and senescence. Additionally, AURKA inhibition alone by alisertib increased PD-L1 and B7-H3 expression. In conclusion, our study demonstrates that AURKA inhibition enhances the efficacy of platinum-based chemotherapy in NSCLC cells and modulates the expression of multiple immune checkpoints. Therefore, combinatory regimens with AURKA inhibitors should be strategically designed and further studied within the evolving landscape of chemo-immunotherapy.
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Affiliation(s)
- Huijie Liu
- Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY 10461, USA; (H.L.); (J.Y.); (A.T.)
| | - Ayse Ece Cali Daylan
- Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY 10461, USA; (H.L.); (J.Y.); (A.T.)
| | - Jihua Yang
- Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY 10461, USA; (H.L.); (J.Y.); (A.T.)
| | - Ankit Tanwar
- Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY 10461, USA; (H.L.); (J.Y.); (A.T.)
| | - Alain Borczuk
- Department of Pathology, Northwell Health, Staten Island, NY 10305, USA
| | - Dongwei Zhang
- Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN 15705, USA;
| | - Vincent Chau
- Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY 10461, USA; (H.L.); (J.Y.); (A.T.)
| | - Shenduo Li
- Department of Medicine, Mayo Clinic Comprehensive Cancer Center, Jacksonville, FL 32224, USA;
| | - Xuan Ge
- Department of Hematology/Oncology, Kaiser Permanente, Modesto, CA 95356, USA
| | - Balazs Halmos
- Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY 10461, USA; (H.L.); (J.Y.); (A.T.)
| | - Xingxing Zang
- Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY 10461, USA; (H.L.); (J.Y.); (A.T.)
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Haiying Cheng
- Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY 10461, USA; (H.L.); (J.Y.); (A.T.)
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10
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Grisetti L, Garcia CJC, Saponaro AA, Tiribelli C, Pascut D. The role of Aurora kinase A in hepatocellular carcinoma: Unveiling the intriguing functions of a key but still underexplored factor in liver cancer. Cell Prolif 2024; 57:e13641. [PMID: 38590119 PMCID: PMC11294426 DOI: 10.1111/cpr.13641] [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: 01/10/2024] [Revised: 03/12/2024] [Accepted: 03/18/2024] [Indexed: 04/10/2024] Open
Abstract
Aurora Kinase A (AURKA) plays a central role as a serine/threonine kinase in regulating cell cycle progression and mitotic functions. Over the years, extensive research has revealed the multifaceted roles of AURKA in cancer development and progression. AURKA's dysregulation is frequently observed in various human cancers, including hepatocellular carcinoma (HCC). Its overexpression in HCC has been associated with aggressive phenotypes and poor clinical outcomes. This review comprehensively explores the molecular mechanisms underlying AURKA expression in HCC and its functional implications in cell migration, invasion, epithelial-to-mesenchymal transition, metastasis, stemness, and drug resistance. This work focuses on the clinical significance of AURKA as a diagnostic and prognostic biomarker for HCC. High levels of AURKA expression have been correlated with shorter overall and disease-free survival in various cohorts, highlighting its potential utility as a sensitive prognostic indicator. Recent insights into AURKA's role in modulating the tumour microenvironment, particularly immune cell recruitment, may provide valuable information for personalized treatment strategies. AURKA's critical involvement in modulating cellular pathways and its overexpression in cancer makes it an attractive target for anticancer therapies. This review discusses the evidence about novel and selective AURKA inhibitors for more effective treatments for HCC.
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Affiliation(s)
- Luca Grisetti
- Fondazione Italiana Fegato – ONLUS, Liver Cancer UnitTriesteItaly
- Department of Life SciencesUniversità degli Studi di TriesteTriesteItaly
| | - Clarissa J. C. Garcia
- Fondazione Italiana Fegato – ONLUS, Liver Cancer UnitTriesteItaly
- Department of Life SciencesUniversità degli Studi di TriesteTriesteItaly
| | - Anna A. Saponaro
- Fondazione Italiana Fegato – ONLUS, Liver Cancer UnitTriesteItaly
| | | | - Devis Pascut
- Fondazione Italiana Fegato – ONLUS, Liver Cancer UnitTriesteItaly
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Fan Z, Pan H, Qu N, Wang X, Cao L, Chen L, Liu M. LncRNA taurine upregulated gene 1 in liver disease. Clin Chim Acta 2024; 560:119752. [PMID: 38821337 DOI: 10.1016/j.cca.2024.119752] [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: 04/10/2024] [Revised: 05/24/2024] [Accepted: 05/27/2024] [Indexed: 06/02/2024]
Abstract
Long non-coding RNAs (lncRNAs) are RNA sequences exceeding 200 nucleotides in length that lack protein-coding capacity and participate in diverse biological processes in the human body, particularly exerting a pivotal role in disease surveillance, diagnosis, and progression. Taurine upregulated gene 1 (TUG1) is a versatile lncRNA, and recent studies have revealed that the aberrant expression or function of TUG1 is intricately linked to the pathogenesis of liver diseases. Consequently, we have summarized the current understanding of the mechanism of TUG1 in liver diseases such as liver fibrosis, fatty liver, cirrhosis, liver injury, hepatitis, and liver cancer. Moreover, mounting evidence suggests that interventions targeting TUG1 or its downstream pathways may hold therapeutic promise for liver diseases. This review elucidates the characteristics, mechanisms, and targets of TUG1 in liver diseases, offering a theoretical basis for the prevention, diagnosis, treatment, and prognostic biomarkers of liver diseases.
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Affiliation(s)
- Zihao Fan
- School of Pharmaceutical Sciences, Liaoning University, No. 66, Chongshan Mid Road, Shenyang 110036, China
| | - Hao Pan
- School of Pharmaceutical Sciences, Liaoning University, No. 66, Chongshan Mid Road, Shenyang 110036, China
| | - Na Qu
- School of Pharmaceutical Sciences, Liaoning University, No. 66, Chongshan Mid Road, Shenyang 110036, China
| | - Xin Wang
- School of Pharmaceutical Sciences, Liaoning University, No. 66, Chongshan Mid Road, Shenyang 110036, China
| | - Lianrui Cao
- School of Pharmaceutical Sciences, Liaoning University, No. 66, Chongshan Mid Road, Shenyang 110036, China
| | - Lijiang Chen
- School of Pharmaceutical Sciences, Liaoning University, No. 66, Chongshan Mid Road, Shenyang 110036, China.
| | - Mingxia Liu
- School of Pharmaceutical Sciences, Liaoning University, No. 66, Chongshan Mid Road, Shenyang 110036, China.
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Jin H, Wen G, Zhu J, Liu J, Li J, Yao S, Zhao Z, Dong Z, Zhang X, An J, Liu X, Tuo B. Pantoprazole suppresses carcinogenesis and growth of hepatocellular carcinoma by inhibiting glycolysis and Na +/H + exchange. Drug Dev Res 2024; 85:e22198. [PMID: 38764200 DOI: 10.1002/ddr.22198] [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: 01/17/2024] [Revised: 04/15/2024] [Accepted: 04/30/2024] [Indexed: 05/21/2024]
Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest cancers. The prevention and therapy for this deadly disease remain a global medical challenge. In this study, we investigated the effect of pantoprazole (PPZ) on the carcinogenesis and growth of HCC. Both diethylnitrosamine (DEN) plus CCl4-induced and DEN plus high fat diet (HFD)-induced HCC models in mice were established. Cytokines and cell proliferation-associated gene in the liver tissues of mice and HCC cells were analyzed. Cellular glycolysis and Na+/H+ exchange activity were measured. The preventive administration of pantoprazole (PPZ) at a clinically relevant low dose markedly suppressed HCC carcinogenesis in both DEN plus CCl4-induced and HFD-induced murine HCC models, whereas the therapeutic administration of PPZ at the dose suppressed the growth of HCC. In the liver tissues of PPZ-treated mice, inflammatory cytokines, IL1, CXCL1, CXCL5, CXCL9, CXCL10, CCL2, CCL5, CCL6, CCL7, CCL20, and CCL22, were reduced. The administration of CXCL1, CXCL5, CCL2, or CCL20 all reversed PPZ-suppressed DEN plus CCL4-induced HCC carcinogenesis in mice. PPZ inhibited the expressions of CCNA2, CCNB2, CCNE2, CDC25C, CDCA5, CDK1, CDK2, TOP2A, TTK, AURKA, and BIRC5 in HCC cells. Further results showed that PPZ reduced the production of these inflammatory cytokines and the expression of these cell proliferation-associated genes through the inhibition of glycolysis and Na+/H+ exchange. In conclusion, PPZ suppresses the carcinogenesis and growth of HCC, which is related to inhibiting the production of inflammatory cytokines and the expression of cell proliferation-associated genes in the liver through the inhibition of glycolysis and Na+/H+ exchange.
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Affiliation(s)
- Hai Jin
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Guorong Wen
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Jiaxing Zhu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Jielong Liu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Jingguo Li
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Shun Yao
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Zhenglan Zhao
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Zhiqi Dong
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Xue Zhang
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Jiaxing An
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Xuemei Liu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Biguang Tuo
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
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Sun Y, Zhang S, Zhang X, Li G, Sun F, Wang M, Ren C, Jiang A, Yang T. AURKA Enhances the Glycolysis and Development of Ovarian Endometriosis Through ERβ. Endocrinology 2024; 165:bqae018. [PMID: 38340326 DOI: 10.1210/endocr/bqae018] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 01/21/2024] [Accepted: 02/07/2024] [Indexed: 02/12/2024]
Abstract
Ovarian endometriosis (EMs) is a benign, estrogen-dependent gynecological disorder. Estrogen receptor beta (ERβ), a nuclear receptor for estradiol, plays an important role in the development of ovarian EMs. Here, we investigated the biological significance of aurora kinase A (AURKA) in ovarian EMs and the mechanism by which it regulates ERβ. We used immunohistochemical assays to verify that AURKA and ERβ were highly expressed in ectopic endometrial tissues. Cell proliferation and colony formation assays were used to demonstrate that AURKA promoted the proliferation of EMs cells. Wound-healing assay, Transwell migration assay, and Matrigel invasion assay further showed that AURKA enhanced the ability of EMs cells to migrate and invade. In addition, AURKA was shown to stimulate glycolysis in EMs cells by measuring the concentration of glucose and lactate in the cell supernatants. Moreover, the AURKA inhibitor alisertib was found to inhibit the progression of ovarian EMs and glycolysis in a mouse model of EMs by measuring ectopic tissues as well as by testing the peritoneal fluid of mice. Furthermore, coimmunoprecipitation assay showed that AURKA interacted with ERβ. The rescue experiments confirmed that AURKA regulated the development and glycolysis of ovarian EMs in an ERβ-dependent manner. AURKA contributed to the development of ovarian EMs by upregulating of ERβ. AURKA may represent a new target for the treatment of ovarian EMs.
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Affiliation(s)
- Yujun Sun
- Department of Reproductive Medicine, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong Province, 261041, P.R. China
- Department of Emergency, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong Province, 261041, P.R. China
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong Province, 261053, P.R. China
| | - Shucai Zhang
- Department of Emergency, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong Province, 261041, P.R. China
| | - Xiaohui Zhang
- Department of Obstetrics and Gynecology, Zhucheng People's Hospital, Shandong Second Medical University, Weifang, Shandong Province, 262299, P.R. China
| | - Guotao Li
- Department of Reproductive Medicine, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong Province, 261041, P.R. China
- Department of Emergency, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong Province, 261041, P.R. China
| | - Fangyuan Sun
- Department of Reproductive Medicine, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong Province, 261041, P.R. China
- Department of Emergency, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong Province, 261041, P.R. China
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong Province, 261053, P.R. China
| | - Mengxue Wang
- Department of Reproductive Medicine, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong Province, 261041, P.R. China
- Department of Emergency, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong Province, 261041, P.R. China
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong Province, 261053, P.R. China
| | - Chune Ren
- Department of Reproductive Medicine, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong Province, 261041, P.R. China
- Department of Emergency, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong Province, 261041, P.R. China
| | - Aifang Jiang
- Department of Reproductive Medicine, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong Province, 261041, P.R. China
- Department of Emergency, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong Province, 261041, P.R. China
| | - Tingting Yang
- Department of Reproductive Medicine, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong Province, 261041, P.R. China
- Department of Emergency, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong Province, 261041, P.R. China
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Lu TL, Li CL, Gong YQ, Hou FT, Chen CW. Identification of tumor antigens and immune subtypes of hepatocellular carcinoma for mRNA vaccine development. World J Gastrointest Oncol 2023; 15:1717-1738. [PMID: 37969406 PMCID: PMC10631436 DOI: 10.4251/wjgo.v15.i10.1717] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 08/10/2023] [Accepted: 09/18/2023] [Indexed: 10/10/2023] Open
Abstract
BACKGROUND mRNA vaccines have been investigated in multiple tumors, but limited studies have been conducted on their use for hepatocellular carcinoma (HCC). AIM To identify candidate mRNA vaccine antigens for HCC and suitable subpopulations for mRNA vaccination. METHODS Gene expression profiles and clinical information of HCC datasets were obtained from International Cancer Genome Consortium and The Cancer Genome Atlas. Genes with somatic mutations and copy number variations were identified by cBioPortal analysis. The differentially expressed genes with significant prognostic value were identified by Gene Expression Profiling Interactive Analysis 2 website analysis. The Tumor Immune Estimation Resource database was used to assess the correlation between candidate antigens and the abundance of antigen-presenting cells (APCs). Tumor-associated antigens were overexpressed in tumors and associated with prognosis, genomic alterations, and APC infiltration. A consensus cluster analysis was performed with the Consensus Cluster Plus package to identify the immune subtypes. The weighted gene coexpression network analysis (WGCNA) was used to determine the candidate biomarker molecules for appropriate populations for mRNA vaccines. RESULTS AURKA, CCNB1, CDC25C, CDK1, TRIP13, PES1, MCM3, PPM1G, NEK2, KIF2C, PTTG1, KPNA2, and PRC1 were identified as candidate HCC antigens for mRNA vaccine development. Four immune subtypes (IS1-IS4) and five immune gene modules of HCC were identified that were consistent in both patient cohorts. The immune subtypes showed distinct cellular and clinical characteristics. The IS1 and IS3 immune subtypes were immunologically "cold". The IS2 and IS4 immune subtypes were immunologically "hot", and the immune checkpoint genes and immunogenic cell death genes were upregulated in these subtypes. IS1-related modules were identified with the WGCNA algorithm. Ultimately, five hub genes (RBP4, KNG1, METTL7A, F12, and ABAT) were identified, and they might be potential biomarkers for mRNA vaccines. CONCLUSION AURKA, CCNB1, CDC25C, CDK1, TRIP13, PES1, MCM3, PPM1G, NEK2, KIF2C, PTTG1, KPNA2, and PRC1 have been identified as candidate HCC antigens for mRNA vaccine development. The IS1 and IS3 immune subtypes are suitable populations for mRNA vaccination. RBP4, KNG1, METTL7A, F12, and ABAT are potential biomarkers for mRNA vaccines.
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Affiliation(s)
- Tai-Liang Lu
- Department of General Surgery, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410005, Hunan Province, China
| | - Cheng-Long Li
- Department of General Surgery, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410005, Hunan Province, China
| | - Yong-Qiang Gong
- Department of General Surgery, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410005, Hunan Province, China
| | - Fu-Tao Hou
- Department of General Surgery, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410005, Hunan Province, China
| | - Chao-Wu Chen
- Department of General Surgery, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410005, Hunan Province, China
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Wang Y, Zhong Y, Zheng X, Cheng N, Yang Y, Yang Y, Wang F, Zhuang Q, Huang Y, Guo W, Liao N, Yang X, Zhao B, Liu X. LncRNA TIALD contributes to hepatocellular carcinoma metastasis via inducing AURKA lysosomal degradation. Cell Death Discov 2023; 9:316. [PMID: 37773181 PMCID: PMC10541412 DOI: 10.1038/s41420-023-01620-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 08/15/2023] [Accepted: 08/18/2023] [Indexed: 10/01/2023] Open
Abstract
The N6-methyladenosine (m6A) RNA methyltransferase METTL16 is an emerging player in RNA modification landscape and responsible for the deposition of m6A in a few transcripts. AURKA (aurora kinase A) has been confirmed as an oncogene in cancer development including hepatocellular carcinoma (HCC). Nevertheless, it remains unclear whether METTL16 mediated m6A modification of lncRNAs can regulate AURKA activation in cancer progression. Here we aimed to investigate the functional links between lncRNAs and the m6A modification in AURKA signaling and HCC progression. Here we show that LncRNA TIALD (transcript that induced AURKA Lysosomal degradation) was down-regulated in HCC tissues by METTL16 mediated m6A methylation to facilitate its RNA degradation, and correlates with poor prognosis. Functional assays reveal that TIALD inhibits HCC metastasis both in vitro and in vivo. Mechanistically, TIALD directly interacts with AURKA and facilitate its degradation through the lysosomal pathway to inhibited EMT and metastasis of HCC. AURKA's specific inhibitor alisertib exerts effective therapeutic effect on liver cancer with low TIALD expression, which might provide a new insight into HCC therapy. Our study uncovers a negative functional loop of METTL16-TIALD-AURKA axis, and identifies a new mechanism for METTL16 mediated m6A-induced decay of TIALD on AURKA signaling in HCC progression, which may provide potential prognostic and therapeutic targets for HCC.
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Affiliation(s)
- Yingchao Wang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, P. R. China
- Fujian Provincial Clinical Research Center for Hepatobiliary and Pancreatic Tumors, Fuzhou, 350025, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, P. R. China
| | - Yue Zhong
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, P. R. China
- College of Life Science, Fujian Agriculture and Forestry University, Fuzhou, 350002, P. R. China
| | - Xiaoyuan Zheng
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, P. R. China
- Fujian Provincial Clinical Research Center for Hepatobiliary and Pancreatic Tumors, Fuzhou, 350025, P. R. China
| | - Niangmei Cheng
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, P. R. China
- Fujian Provincial Clinical Research Center for Hepatobiliary and Pancreatic Tumors, Fuzhou, 350025, P. R. China
| | - Yong Yang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, P. R. China
| | - Ye Yang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, P. R. China
| | - Fei Wang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, P. R. China
- Fujian Provincial Clinical Research Center for Hepatobiliary and Pancreatic Tumors, Fuzhou, 350025, P. R. China
| | - Qiuyu Zhuang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, P. R. China
- Fujian Provincial Clinical Research Center for Hepatobiliary and Pancreatic Tumors, Fuzhou, 350025, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, P. R. China
| | - Yao Huang
- Fujian Provincial Clinical Research Center for Hepatobiliary and Pancreatic Tumors, Fuzhou, 350025, P. R. China
| | - Wuhua Guo
- Fujian Provincial Clinical Research Center for Hepatobiliary and Pancreatic Tumors, Fuzhou, 350025, P. R. China
| | - Naishun Liao
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, P. R. China
- Fujian Provincial Clinical Research Center for Hepatobiliary and Pancreatic Tumors, Fuzhou, 350025, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, P. R. China
| | - Xiaoyu Yang
- Fuzhou Hospital of Traditional Chinese Medicine Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou, 350001, China
| | - Bixing Zhao
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, P. R. China.
- Fujian Provincial Clinical Research Center for Hepatobiliary and Pancreatic Tumors, Fuzhou, 350025, P. R. China.
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, P. R. China.
| | - Xiaolong Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, P. R. China.
- Fujian Provincial Clinical Research Center for Hepatobiliary and Pancreatic Tumors, Fuzhou, 350025, P. R. China.
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, P. R. China.
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Li S, Hao L, Hu X, Li L. A systematic study on the treatment of hepatitis B-related hepatocellular carcinoma with drugs based on bioinformatics and key target reverse network pharmacology and experimental verification. Infect Agent Cancer 2023; 18:41. [PMID: 37393234 DOI: 10.1186/s13027-023-00520-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: 05/20/2023] [Accepted: 06/20/2023] [Indexed: 07/03/2023] Open
Abstract
BACKGROUND Chronic hepatitis B virus (HBV) infection is the major etiology of hepatocellular carcinoma (HCC). However, the mechanism of hepatitis B-related hepatocellular carcinoma (HBV-related HCC) is still unclear. Therefore, understanding the pathogenesis and searching for drugs to treat HBV-related HCC was an effective strategy to treat this disease. PURPOSE Bioinformatics was used to predict the potential targets of HBV-related HCC. The reverse network pharmacology of key targets was used to analyze the clinical drugs, traditional Chinese medicine (TCM) and small molecules of TCM in the treatment of HBV-related HCC. METHODS In this study, three microarray datasets totally containing 330 tumoral samples and 297 normal samples were selected from the GEO database. These microarray datasets were used to screen DEGs. And the expression profile and survival of 6 key genes were analyzed. In addition, Comparative Toxicogenomics Database and Coremine Medical database were used to enrich clinical drugs and TCM of HBV-related HCC by the 6 key targets. Then the obtained TCM were classified based on the Chinese Pharmacopoeia. Among these top 6 key genes, CDK1 and CCNB1 had the most connection nodes and the highest degree and were the most significantly expressed. In general, CDK1 and CCNB1 tend to form a complex, which is conducive to cell mitosis. Hence, this study mainly studied CDK1 and CCNB1. HERB database was used to predict small molecules TCM. The inhibition effect of quercetin, celastrol and cantharidin on HepG2.2.15 cells and Hep3B cells was verified by CCK8 experiment. The effects of quercetin, celastrol and cantharidin on CDK1 and CCNB1 of HepG2.2.15 cells and Hep3B cells were determined by Western Blot. RESULTS In short, 272 DEGs (53 upregulated and 219 downregulated) were identified. Among these DEGs, 6 key genes with high degree were identified, which were AURKA, BIRC5, CCNB1, CDK1, CDKN3 and TYMS. Kaplan-Meier plotter analysis showed that higher expression levels of AURKA, BIRC5, CCNB1, CDK1, CDKN3 and TYMS were associated with poor OS. According to the first 6 key targets, a variety of drugs and TCM were identified. These results showed that clinical drugs included targeted drugs, such as sorafenib, palbociclib and Dasatinib. and chemotherapy drugs, such as cisplatin and doxorubicin. TCM, such as the TCM flavor was mainly warm and bitter, and the main meridians were liver and lung. Small molecules of TCM included flavonoids, terpenoids, alkaloids and glycosides, such as quercetin, celastrol, cantharidin, hesperidin, silymarin, casticin, berberine and ursolic acid, which have great potential in anti-HBV-related HCC. For molecular docking of chemical components, the molecules with higher scores were flavonoids, alkaloids, etc. Three representative types of TCM small molecules were verified respectively, and it was found that quercetin, celastrol and cantharidin inhibited the proliferation of HepG2.2.15 cells and Hep3B cells along concentration gradient. Quercetin, celastrol and cantharidin decreased CDK1 expression in HepG2.2.15 and Hep3B cells, but for CCNB1, only cantharidin decreased CCNB1 expression in the two strains of cells. CONCLUSION In conclusion, AURKA, BIRC5, CCNB1, CDK1, CDKN3 and TYMS could be potential targets for the diagnosis and prognosis of HBV-related HCC. Clinical drugs include chemotherapeutic and targeted drug, traditional Chinese medicine is mainly bitter and warm TCM. Small molecular of TCM including flavonoids, terpenoids and glycosides and alkaloids, which have great potential in anti-HBV-related HCC. This study provides potential therapeutic targets and novel strategies for the treatment of HBV-related HCC.
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Affiliation(s)
- Shenghao Li
- Chengdu University of Traditional Chinese Medicine, No. 37 Shi-er-qiao Road, Chengdu, 610075, Sichuan, People's Republic of China
- Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu, 610072, Sichuan, People's Republic of China
| | - Liyuan Hao
- Chengdu University of Traditional Chinese Medicine, No. 37 Shi-er-qiao Road, Chengdu, 610075, Sichuan, People's Republic of China
- Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu, 610072, Sichuan, People's Republic of China
| | - Xiaoyu Hu
- Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu, 610072, Sichuan, People's Republic of China.
| | - Luya Li
- Department of Pharmacy Department, The Fourth Hospital of Hebei Medical University, NO.12, Jian Kang Road, Shijiazhuang, 050010, Hebei, People's Republic of China
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Shen HM, Zhang D, Xiao P, Qu B, Sun YF. E2F1-mediated KDM4A-AS1 up-regulation promotes EMT of hepatocellular carcinoma cells by recruiting ILF3 to stabilize AURKA mRNA. Cancer Gene Ther 2023:10.1038/s41417-023-00607-0. [PMID: 36973424 DOI: 10.1038/s41417-023-00607-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 01/11/2023] [Accepted: 03/09/2023] [Indexed: 03/29/2023]
Abstract
Hepatocellular carcinoma (HCC) is a gastrointestinal tumor with high clinical incidence. Long non-coding RNAs (lncRNAs) play vital roles in modulating the growth and epithelial-mesenchymal transition (EMT) of HCC. However, the underlying mechanism of lncRNA KDM4A antisense RNA 1 (KDM4A-AS1) in HCC remains elusive. In our study, the role of KDM4A-AS1 in HCC was systematically investigated. The levels of KDM4A-AS1, interleukin enhancer-binding factor 3 (ILF3), Aurora kinase A (AURKA), and E2F transcription factor 1 (E2F1) were determined by RT-qPCR or western blot. ChIP and dual luciferase reporter experiments were performed to detect the binding relationship between E2F1 and KDM4A-AS1 promoter sequence. RIP and RNA-pull down confirmed the interaction of ILF3 with KDM4A-AS1/AURKA. Cellular functions were analyzed by MTT, flow cytometry, wound healing and transwell assays. IHC was performed to detect Ki67 in vivo. We found that KDM4A-AS1 was increased in HCC tissues and cells. Elevated KDM4A-AS1 level was correlated to poor prognosis of HCC. Knockdown of KDM4A-AS1 inhibited the proliferation, migration, invasion and EMT of HCC cells. ILF3 bound to KDM4A-AS1 and AURKA. KDM4A-AS1 maintained the stability of AURKA mRNA by recruiting ILF3. E2F1 transcriptionally activated KDM4A-AS1. Overexpressed KDM4A-AS1 reversed the contribution of E2F1 depletion to AURKA expression and EMT in HCC cells. KDM4A-AS1 promoted tumor formation in vivo through the PI3K/AKT pathway. These results revealed that E2F1 transcriptionally activated KDM4A-AS1 to regulate HCC progression via the PI3K/AKT pathway. E2F1 and KDM4A-AS1 may serve as good prognostic targets for HCC treatment.
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Affiliation(s)
- Hao-Ming Shen
- Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Di Zhang
- Department of Clinical Laboratory, The Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, China
| | - Ping Xiao
- Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Bin Qu
- Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Yi-Fan Sun
- Department of Clinical Laboratory, The Eighth Affiliated Hospital of Guangxi Medical University, Guigang City People's Hospital, Guigang, 537100, Guangxi, China.
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18
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Identification of Prognostic Biomarkers for Suppressing Tumorigenesis and Metastasis of Hepatocellular Carcinoma through Transcriptome Analysis. Diagnostics (Basel) 2023; 13:diagnostics13050965. [PMID: 36900109 PMCID: PMC10001411 DOI: 10.3390/diagnostics13050965] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 02/16/2023] [Indexed: 03/06/2023] Open
Abstract
Cancer is one of the deadliest diseases developed through tumorigenesis and could be fatal if it reaches the metastatic phase. The novelty of the present investigation is to explore the prognostic biomarkers in hepatocellular carcinoma (HCC) that could develop glioblastoma multiforme (GBM) due to metastasis. The analysis was conducted using RNA-seq datasets for both HCC (PRJNA494560 and PRJNA347513) and GBM (PRJNA494560 and PRJNA414787) from Gene Expression Omnibus (GEO). This study identified 13 hub genes found to be overexpressed in both GBM and HCC. A promoter methylation study showed these genes to be hypomethylated. Validation through genetic alteration and missense mutations resulted in chromosomal instability, leading to improper chromosome segregation, causing aneuploidy. A 13-gene predictive model was obtained and validated using a KM plot. These hub genes could be prognostic biomarkers and potential therapeutic targets, inhibition of which could suppress tumorigenesis and metastasis.
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19
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Fatma H, Siddique HR. AURORA KINASE A and related downstream molecules: A potential network for cancer therapy. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2023; 134:115-145. [PMID: 36858732 DOI: 10.1016/bs.apcsb.2022.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Aurora-A kinase (AURKA) belongs to the serine/threonine kinase family specific to cell division. In normal cells, activation of the AURKA protein is essential for regulating chromosomal segregation and centrosome maturation. The physiological concentration of AURKA accumulation has utmost importance during cell division. AURKA starts accumulating during the S phase of the cell cycle, gets functionally activated during the G2/M phase, attaches to the microtubule, and gets degraded during mitotic exit. Overexpression of AURKA could lead to deregulated cell cycle division, which is intrinsic to numerous cancers. Moreover, dysregulated AURKA affects various downstream molecules that aid in cancer pathogenesis. AURKA phosphorylates its substrates, including oncoproteins, transcriptional factors, tumor suppressor proteins, or other kinases central to various oncogenic signaling pathways critical to cancer. Considering the central role of AURKA in cell proliferation and tumorigenesis, targeting AURKA can be a novel alternative to cancer management. Several AURKA inhibitors have shown promising responses against different cancers either as a single agent or combined with various therapies. This chapter briefly discusses the role of AURKA and its downstream molecules in cancer vis-à-vis the role of AURKA inhibitor in chemoprevention.
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Affiliation(s)
- Homa Fatma
- Molecular Cancer Genetics & Translational Research Laboratory, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - Hifzur R Siddique
- Molecular Cancer Genetics & Translational Research Laboratory, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh, Uttar Pradesh, India.
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20
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Zheng D, Li J, Yan H, Zhang G, Li W, Chu E, Wei N. Emerging roles of Aurora-A kinase in cancer therapy resistance. Acta Pharm Sin B 2023. [PMID: 37521867 PMCID: PMC10372834 DOI: 10.1016/j.apsb.2023.03.013] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/17/2023] Open
Abstract
Aurora kinase A (Aurora-A), a serine/threonine kinase, plays a pivotal role in various cellular processes, including mitotic entry, centrosome maturation and spindle formation. Overexpression or gene-amplification/mutation of Aurora-A kinase occurs in different types of cancer, including lung cancer, colorectal cancer, and breast cancer. Alteration of Aurora-A impacts multiple cancer hallmarks, especially, immortalization, energy metabolism, immune escape and cell death resistance which are involved in cancer progression and resistance. This review highlights the most recent advances in the oncogenic roles and related multiple cancer hallmarks of Aurora-A kinase-driving cancer therapy resistance, including chemoresistance (taxanes, cisplatin, cyclophosphamide), targeted therapy resistance (osimertinib, imatinib, sorafenib, etc.), endocrine therapy resistance (tamoxifen, fulvestrant) and radioresistance. Specifically, the mechanisms of Aurora-A kinase promote acquired resistance through modulating DNA damage repair, feedback activation bypass pathways, resistance to apoptosis, necroptosis and autophagy, metastasis, and stemness. Noticeably, our review also summarizes the promising synthetic lethality strategy for Aurora-A inhibitors in RB1, ARID1A and MYC gene mutation tumors, and potential synergistic strategy for mTOR, PAK1, MDM2, MEK inhibitors or PD-L1 antibodies combined with targeting Aurora-A kinase. In addition, we discuss the design and development of the novel class of Aurora-A inhibitors in precision medicine for cancer treatment.
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21
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Alwadi D, Felty Q, Yoo C, Roy D, Deoraj A. Endocrine Disrupting Chemicals Influence Hub Genes Associated with Aggressive Prostate Cancer. Int J Mol Sci 2023; 24:ijms24043191. [PMID: 36834602 PMCID: PMC9959535 DOI: 10.3390/ijms24043191] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/25/2023] [Accepted: 01/30/2023] [Indexed: 02/08/2023] Open
Abstract
Prostate cancer (PCa) is one of the most frequently diagnosed cancers among men in the world. Its prevention has been limited because of an incomplete understanding of how environmental exposures to chemicals contribute to the molecular pathogenesis of aggressive PCa. Environmental exposures to endocrine-disrupting chemicals (EDCs) may mimic hormones involved in PCa development. This research aims to identify EDCs associated with PCa hub genes and/or transcription factors (TF) of these hub genes in addition to their protein-protein interaction (PPI) network. We are expanding upon the scope of our previous work, using six PCa microarray datasets, namely, GSE46602, GSE38241, GSE69223, GSE32571, GSE55945, and GSE26126, from the NCBI/GEO, to select differentially expressed genes based on |log2FC| (fold change) ≥ 1 and an adjusted p-value < 0.05. An integrated bioinformatics analysis was used for enrichment analysis (using DAVID.6.8, GO, KEGG, STRING, MCODE, CytoHubba, and GeneMANIA). Next, we validated the association of these PCa hub genes in RNA-seq PCa cases and controls from TCGA. The influence of environmental chemical exposures, including EDCs, was extrapolated using the chemical toxicogenomic database (CTD). A total of 369 overlapping DEGs were identified associated with biological processes, such as cancer pathways, cell division, response to estradiol, peptide hormone processing, and the p53 signaling pathway. Enrichment analysis revealed five up-regulated (NCAPG, MKI67, TPX2, CCNA2, CCNB1) and seven down-regulated (CDK1, CCNB2, AURKA, UBE2C, BUB1B, CENPF, RRM2) hub gene expressions. Expression levels of these hub genes were significant in PCa tissues with high Gleason scores ≥ 7. These identified hub genes influenced disease-free survival and overall survival of patients 60-80 years of age. The CTD studies showed 17 recognized EDCs that affect TFs (NFY, CETS1P54, OLF1, SRF, COMP1) that are known to bind to our PCa hub genes, namely, NCAPG, MKI67, CCNA2, CDK1, UBE2C, and CENPF. These validated differentially expressed hub genes can be potentially developed as molecular biomarkers with a systems perspective for risk assessment of a wide-ranging list of EDCs that may play overlapping and important role(s) in the prognosis of aggressive PCa.
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Affiliation(s)
- Diaaidden Alwadi
- Department of Environmental Health Sciences, Florida International University, Miami, FL 33199, USA
| | - Quentin Felty
- Department of Environmental Health Sciences, Florida International University, Miami, FL 33199, USA
| | - Changwon Yoo
- Department of Biostatistics, Florida International University, Miami, FL 33199, USA
| | - Deodutta Roy
- Department of Environmental Health Sciences, Florida International University, Miami, FL 33199, USA
| | - Alok Deoraj
- Department of Environmental Health Sciences, Florida International University, Miami, FL 33199, USA
- Correspondence:
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22
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Sak M, Williams BJ, Zumbar CT, Teer L, Al-Kawaaz MNG, Kakar A, Hey AJ, Wilson MJ, Schier LM, Chen J, Lehman NL. The CNS-penetrating taxane drug TPI 287 potentiates antiglioma activity of the AURKA inhibitor alisertib in vivo. Cancer Chemother Pharmacol 2023; 91:191-201. [PMID: 36694044 DOI: 10.1007/s00280-023-04503-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 12/30/2022] [Indexed: 01/26/2023]
Abstract
INTRODUCTION Glioblastoma (GBM) has a very poor prognosis despite current treatment. We previously found cytotoxic synergy between the AURKA inhibitor alisertib and the CNS-penetrating taxane TPI 287 against GBM tumor cells in vitro. METHODS We used an orthotopic human GBM xenograft mouse model to test if TPI 287 potentiates alisertib in vivo. Western blotting, immunohistochemistry, siRNA knockdown, annexin V binding, and 3-dimensional Matrigel invasion assays were used to investigate potential mechanisms of alisertib and TPI 287 treatment interactions. RESULTS Alisertib + TPI 287 combination therapy significantly prolonged animal survival compared to vehicle (p = 0.011), but only marginally compared to alisertib alone. Alisertib, TPI 287, and combined alisertib + TPI 287 reduced animal tumor volume compared to vehicle-treated controls. This was statistically significant for the combination therapy at 4 weeks (p < 0.0001). Alisertib + TPI 287 treatment decreased anti-apoptotic Bcl-2 protein levels in vivo and in vitro. Expression of the pro-apoptotic protein Bak was significantly increased by combination treatment (p < 0.0001). Pro-apoptotic Bim and Bak knockdown by siRNA decreased apoptosis by alisertib + TPI 287 in GB9, GB30, and U87 cells (p = 0.0005 to 0.0381). Although alisertib and TPI 287 significantly reduced GBM cell invasion (p < 0.0001), their combination was no more effective than TPI 287 alone. CONCLUSIONS Results suggest that apoptosis is the dominant mechanism of potentiation of GBM growth inhibition by alisertib + TPI 287, in part through effects on Bcl-2 family proteins, providing a rationale for further laboratory testing of an AURKA inhibitor plus TPI 287 as a potential therapy against GBM.
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Affiliation(s)
- Müge Sak
- Biochemistry and Molecular Genetics, University of Louisville, 505 S Hancock St, KY, 40202, Louisville, USA
| | - Brian J Williams
- Neurological Surgery, University of Louisville, Louisville, KY, 40202, USA
- The Brown Cancer Center, University of Louisville, Louisville, KY, 40202, USA
| | - Cory T Zumbar
- Pathology and Laboratory Medicine, University of Louisville, Louisville, KY, 40202, USA
| | - Landon Teer
- Bioengineering, University of Louisville, Louisville, KY, 40202, USA
| | - Mustafa N G Al-Kawaaz
- Pathology and Laboratory Medicine, University of Louisville, Louisville, KY, 40202, USA
| | - Aastha Kakar
- Pathology and Laboratory Medicine, University of Louisville, Louisville, KY, 40202, USA
| | - Andrew J Hey
- Pathology and Laboratory Medicine, University of Louisville, Louisville, KY, 40202, USA
| | - Megan J Wilson
- Pathology and Laboratory Medicine, University of Louisville, Louisville, KY, 40202, USA
| | - Leslie M Schier
- Pathology and Laboratory Medicine, University of Louisville, Louisville, KY, 40202, USA
| | - Joseph Chen
- Bioengineering, University of Louisville, Louisville, KY, 40202, USA
| | - Norman L Lehman
- Biochemistry and Molecular Genetics, University of Louisville, 505 S Hancock St, KY, 40202, Louisville, USA.
- Pathology and Laboratory Medicine, University of Louisville, Louisville, KY, 40202, USA.
- The Brown Cancer Center, University of Louisville, Louisville, KY, 40202, USA.
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Comparative RNA-Sequencing Analysis Reveals High Complexity and Heterogeneity of Transcriptomic and Immune Profiles in Hepatocellular Carcinoma Tumors of Viral (HBV, HCV) and Non-Viral Etiology. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:medicina58121803. [PMID: 36557005 PMCID: PMC9785216 DOI: 10.3390/medicina58121803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/01/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022]
Abstract
Background and Objectives: Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is the leading cause of cancer-related mortality. It arises and progresses against fibrotic or cirrhotic backgrounds mainly due to infection with hepatitis viruses B (HBV) or C (HCV) or non-viral causes that lead to chronic inflammation and genomic changes. A better understanding of molecular and immune mechanisms in HCC subtypes is needed. Materials and Methods: To identify transcriptional changes in primary HCC tumors with or without hepatitis viral etiology, we analyzed the transcriptomes of 24 patients by next-generation sequencing. Results: We identified common and unique differentially expressed genes for each etiological tumor group and analyzed the expression of SLC, ATP binding cassette, cytochrome 450, cancer testis, and heat shock protein genes. Metascape functional enrichment analysis showed mainly upregulated cell-cycle pathways in HBV and HCV and upregulated cell response to stress in non-viral infection. GeneWalk analysis identified regulator, hub, and moonlighting genes and highlighted CCNB1, ACTN2, BRCA1, IGF1, CDK1, AURKA, AURKB, and TOP2A in the HCV group and HSF1, HSPA1A, HSP90AA1, HSPB1, HSPA5, PTK2, and AURKB in the group without viral infection as hub genes. Immune infiltrate analysis showed that T cell, cytotoxic, and natural killer cell markers were significantly more highly expressed in HCV than in non-viral tumors. Genes associated with monocyte activation had the highest expression levels in HBV, while high expression of genes involved in primary adaptive immune response and complement receptor activity characterized tumors without viral infection. Conclusions: Our comprehensive study underlines the high degree of complexity of immune profiles in the analyzed groups, which adds to the heterogeneous HCC genomic landscape. The biomarkers identified in each HCC group might serve as therapeutic targets.
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24
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Li G, Tian Y, Gao Z. The role of AURKA/miR-199b-3p in hepatocellular carcinoma cells. J Clin Lab Anal 2022; 36:e24758. [PMID: 36377304 PMCID: PMC9756977 DOI: 10.1002/jcla.24758] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 10/14/2022] [Accepted: 10/24/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Previous studies proved that AURKA functions as an oncogene in several cancers. This article aimed to probe the miRNA-induced regulatory mechanism of AURKA in hepatocellular carcinoma (HCC). METHODS Differentially expressed genes in TCGA-LIHC dataset were screened by bioinformatics methods. Levels of miR-199b-3p and AURKA mRNA were examined by qRT-PCR. Western blot was utilized to evaluate protein levels of AURKA, p-AKT, and AKT. Dual-luciferase assay was introduced to explore their interaction. MTT, colony formation, scratch healing, transwell, and flow cytometry assays were introduced into cell proliferation, migration, invasion, and apoptosis assessment. The impact of miR-199b-3p/AURKA axis on HCC tumor growth was determined in a tumor xenograft model. RESULTS We found that AURKA was highly expressed in HCC and was coupled to poor prognosis of HCC. As manifested by cellular assays, compared to the normal cells HL-7702, AURKA presented notably high expression in HCC cell lines. Overexpressed AURKA evidently impelled the proliferation, colony formation, migration, and invasion of HCC cells while suppressing apoptosis. The regulatory gene upstream of AURKA was predicted to be miR-199b-3p by bioinformatics method, and there was a markedly negative correlation between the two. Overexpressed miR-199b-3p constrained HCC cell proliferation, migration, and invasion while fostering apoptosis, which could be counteracted by upregulating AURKA. MiR-199b-3p repressed the tumor growth in vivo by targeting AURKA and affected PI3K/AKT signaling pathway. CONCLUSION To summarize, this study implied the regulatory mechanism of miR-199b-3p/AURKA axis in HCC, and supplied optional therapeutic targets for HCC patients.
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Affiliation(s)
- Guogang Li
- Department of Hepatobiliary and Pancreatic SurgeryThe Second Affiliated Hospital Zhejiang University School of MedicineHangzhouZhejiang ProvinceChina
| | - Yang Tian
- Department of Hepatobiliary and Pancreatic SurgeryThe Second Affiliated Hospital Zhejiang University School of MedicineHangzhouZhejiang ProvinceChina
| | - Zhenzhen Gao
- Department of Hepatobiliary and Pancreatic SurgeryThe Second Affiliated Hospital Zhejiang University School of MedicineHangzhouZhejiang ProvinceChina
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25
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Urh K, Zidar N, Boštjančič E. Bioinformatics Analysis of RNA-seq Data Reveals Genes Related to Cancer Stem Cells in Colorectal Cancerogenesis. Int J Mol Sci 2022; 23:ijms232113252. [PMID: 36362041 PMCID: PMC9654446 DOI: 10.3390/ijms232113252] [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: 09/27/2022] [Revised: 10/26/2022] [Accepted: 10/28/2022] [Indexed: 11/06/2022] Open
Abstract
Cancer stem cells (CSC) play one of the crucial roles in the pathogenesis of various cancers, including colorectal cancer (CRC). Although great efforts have been made regarding our understanding of the cancerogenesis of CRC, CSC involvement in CRC development is still poorly understood. Using bioinformatics and RNA-seq data of normal mucosa, colorectal adenoma, and carcinoma (n = 106) from GEO and TCGA, we identified candidate CSC genes and analyzed pathway enrichment analysis (PEI) and protein–protein interaction analysis (PPI). Identified CSC-related genes were validated using qPCR and tissue samples from 47 patients with adenoma, adenoma with early carcinoma, and carcinoma without and with lymph node metastasis and were compared to normal mucosa. Six CSC-related genes were identified: ANLN, CDK1, ECT2, PDGFD, TNC, and TNXB. ANLN, CDK1, ECT2, and TNC were differentially expressed between adenoma and adenoma with early carcinoma. TNC was differentially expressed in CRC without lymph node metastases whereas ANLN, CDK1, and PDGFD were differentially expressed in CRC with lymph node metastases compared to normal mucosa. ANLN and PDGFD were differentially expressed between carcinoma without and with lymph node metastasis. Our study identified and validated CSC-related genes that might be involved in early stages of CRC development (ANLN, CDK1, ECT2, TNC) and in development of metastasis (ANLN, PDGFD).
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Chen Q, Bao L, Huang Y, Lv L, Zhang G, Chen Y. Clinical significance and immunogenomic landscape analysis of glycolysis-associated prognostic model to guide clinical therapy in hepatocellular carcinoma. J Gastrointest Oncol 2022; 13:1351-1366. [PMID: 35837198 DOI: 10.21037/jgo-22-503] [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: 05/05/2022] [Accepted: 06/16/2022] [Indexed: 11/06/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is a common malignant tumor with a poor prognosis and high mortality rate worldwide. Glucose metabolism disorder is one of the most important characteristics of HCC. However, as the primary risk factors for the prognosis of HCC patients are unclear, the survival prognosis and therapy response of patients cannot be accurately predicted. Methods First, gene sets of 29 cancer hallmarks were collected from public databases. The z-score of various cancer hallmarks were quantitively analyzed by a single-sample gene set enrichment analysis (ssGSEA) of HCC patients. Next, a glycolysis-related gene signature (GRS) was constructed using a series of bioinformatics methods, which were used to predict the survival prognosis of HCC patients and the immunotherapy benefits. The prediction accuracy of the GRS was validated in different HCC cohorts and clinical subgroups. Additionally, a decision tree and nomogram were also established based on the GRS and other clinical variables. Finally, the genomic alterations and tumor immune microenvironment of the HCC patients were examined. Results Among the 29 cancer hallmarks, glycolysis was the most predominant risk factor for a poor prognosis in HCC. We subsequently constructed a novel GRS comprising 12 glycolysis-related genes. The high-GRS patients had a poorer survival prognosis than the low-GRS patients. The GRS exhibited a powerful ability to predict survival prognosis in different HCC cohorts and clinical feature subgroups. Additionally, the decision tree and nomogram aided in the risk stratification and prognosis evaluations of HCC patients. Further, we found that a high GRS was characterized by a severe tumor stage, pathological grade, and other clinical features. There were significant differences in the genomic alterations, immune cells, and immune checkpoints between the low- and high-GRS patients, especially in relation to the tumor protein p53 mutation and immunosuppressive cells. Notably, we also found that the GRS could be used to identify HCC patients who are more sensitive to chemotherapy and immunotherapy. Conclusions In summary, the GRS may be a useful tool for predicting the prognosis and guiding the clinical therapy of HCC patients.
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Affiliation(s)
- Qingshan Chen
- Department of Pharmacy, Third Affiliated Hospital of Naval Military Medical University, Shanghai, China
| | - Leilei Bao
- Department of Pharmacy, Third Affiliated Hospital of Naval Military Medical University, Shanghai, China
| | - Yueying Huang
- Department of Pharmacy, Third Affiliated Hospital of Naval Military Medical University, Shanghai, China
| | - Lei Lv
- Department of Pharmacy, Third Affiliated Hospital of Naval Military Medical University, Shanghai, China
| | - Guoqing Zhang
- Department of Pharmacy, Third Affiliated Hospital of Naval Military Medical University, Shanghai, China
| | - Yi Chen
- Department of Hepatobiliary Surgery, Shanghai Public Health Clinical Center of Fudan University, Shanghai, China
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27
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Targeting protein kinases in cancer stem cells. Essays Biochem 2022; 66:399-412. [PMID: 35607921 DOI: 10.1042/ebc20220002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 05/01/2022] [Accepted: 05/11/2022] [Indexed: 12/12/2022]
Abstract
Cancer stem cells (CSCs) are subpopulations of cancer cells within the tumor bulk that have emerged as an attractive therapeutic target for cancer therapy. Accumulating evidence has shown the critical involvement of protein kinase signaling pathways in driving tumor development, cancer relapse, metastasis, and therapeutic resistance. Given that protein kinases are druggable targets for cancer therapy, tremendous efforts are being made to target CSCs with kinase inhibitors. In this review, we summarize the current knowledge and overview of the roles of protein kinases in various signaling pathways in CSC regulation and drug resistance. Furthermore, we provide an update on the preclinical and clinical studies for the use of kinase inhibitors alone or in combination with current therapies for effective cancer therapy. Despite great premises for the use of kinase inhibitors against CSCs, further investigations are needed to evaluate their efficiencies without any adverse effects on normal stem cells.
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Miligy IM, Toss MS, Gorringe KL, Ellis IO, Green AR, Rakha EA. Aurora Kinase A Is an Independent Predictor of Invasive Recurrence in Breast Ductal Carcinoma in situ. Pathobiology 2022; 89:382-392. [PMID: 35533650 DOI: 10.1159/000522244] [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: 10/01/2021] [Accepted: 01/24/2022] [Indexed: 01/07/2023] Open
Abstract
INTRODUCTION Aurora Kinase A (AURKA/STK15) has a role in centrosome duplication and is a regulator of mitotic cell proliferation. It is over-expressed in breast cancer and other cancers, however; its role in ductal carcinoma in situ (DCIS) remains to be defined. This study aims to characterize AURKA protein expression in DCIS and evaluate its prognostic significance. METHODS AURKA was assessed immunohistochemically in a large well-characterized cohort of DCIS (n = 776 pure DCIS and 239 DCIS associated with invasive breast cancer [DCIS-mixed]) with long-term follow-up data (median = 105 months) and basic molecular characterization. RESULTS High AURKA expression was observed in 15% of DCIS cases and was associated with features of aggressiveness including larger tumour size, high nuclear grade, hormone receptor negativity, HER2 positivity, and high Ki67 proliferation index. AURKA expression was higher in DCIS associated with invasive breast cancer than in pure DCIS (p < 0.0001). In the DCIS-mixed cohort, the invasive component showed higher AURKA expression than the DCIS component (p < 0.0001). Outcome analysis revealed that AURKA was a predictor of invasive recurrence (p = 0.002). CONCLUSION High AURKA expression is associated with poor prognosis in DCIS and might be a potential marker to predict DCIS progression to invasive disease.
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Affiliation(s)
- Islam M Miligy
- Division of Cancer and Stem Cells, Nottingham Breast Cancer Research Centre, School of Medicine, Nottingham City Hospital, The University of Nottingham, Nottingham, UK, .,Histopathology Department, Faculty of Medicine, Menoufia University, Shebeen El-Kom, Egypt,
| | - Michael S Toss
- Division of Cancer and Stem Cells, Nottingham Breast Cancer Research Centre, School of Medicine, Nottingham City Hospital, The University of Nottingham, Nottingham, UK
| | - Kylie L Gorringe
- Cancer Genomics Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
| | - Ian O Ellis
- Division of Cancer and Stem Cells, Nottingham Breast Cancer Research Centre, School of Medicine, Nottingham City Hospital, The University of Nottingham, Nottingham, UK
| | - Andrew R Green
- Division of Cancer and Stem Cells, Nottingham Breast Cancer Research Centre, School of Medicine, Nottingham City Hospital, The University of Nottingham, Nottingham, UK
| | - Emad A Rakha
- Division of Cancer and Stem Cells, Nottingham Breast Cancer Research Centre, School of Medicine, Nottingham City Hospital, The University of Nottingham, Nottingham, UK
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Chen X, Liu C, Zhang Z, Wang M, Guo S, Li T, Sun H, Zhang P. ZNF655 Promotes the Progression of Glioma Through Transcriptional Regulation of AURKA. Front Oncol 2022; 12:770013. [PMID: 35280721 PMCID: PMC8907887 DOI: 10.3389/fonc.2022.770013] [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: 09/03/2021] [Accepted: 01/10/2022] [Indexed: 12/21/2022] Open
Abstract
OBJECTIVES Glioma has a high degree of malignancy, strong invasiveness, and poor prognosis, which is always a serious threat to human health. Previous studies have reported that C2H2 zinc finger (ZNF) protein is involved in the progression of various cancers. In this study, the clinical significance, biological behavior, and molecule mechanism of ZNF655 in glioma were explored. METHODS The expression of ZNF655 in glioma and its correlation with prognosis were analyzed through public datasets and immunohistochemical (IHC) staining. The shRNA-mediated ZNF655 knockdown was used to explore the effects of ZNF655 alteration on the phenotypes and tumorigenesis of human glioma cell lines. Chromatin immunoprecipitation (ChIP)-qPCR and luciferase reporter assays were performed to determine the potential mechanism of ZNF655 regulating Aurora kinase A (AURKA). RESULTS ZNF655 was abundantly expressed in glioma tissue and cell lines SHG-44 and U251. Knockdown of suppressed the progression of glioma cells, which was characterized by reduced proliferation, enhanced apoptosis, cycle repression in G2, inhibition of migration, and weakened tumorigenesis. Mechanistically, transcription factor ZNF655 activated the expression of AURKA by directly binding to the promoter of AURKA. In addition, downregulation of AURKA partially reversed the promoting effects of overexpression of ZNF655 on glioma cells. CONCLUSIONS ZNF655 promoted the progression of glioma by binding to the promoter of AURKA, which may be a promising target for molecular therapy.
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Affiliation(s)
- Xu Chen
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, China
| | - Chao Liu
- Department of Neurosurgery of the First Affiliated Hospital of Zhengzhou University, Zhengzhou City, China
| | - Zhenyu Zhang
- Department of Neurosurgery of the First Affiliated Hospital of Zhengzhou University, Zhengzhou City, China
| | - Meng Wang
- Department of Neurosurgery of the First Affiliated Hospital of Zhengzhou University, Zhengzhou City, China
| | - Shewei Guo
- Department of Neurosurgery of the First Affiliated Hospital of Zhengzhou University, Zhengzhou City, China
| | - Tianhao Li
- Department of Neurosurgery of the First Affiliated Hospital of Zhengzhou University, Zhengzhou City, China
| | - Hongwei Sun
- Department of Neurosurgery of the First Affiliated Hospital of Zhengzhou University, Zhengzhou City, China
| | - Peng Zhang
- Department of Neurosurgery of the First Affiliated Hospital of Zhengzhou University, Zhengzhou City, China
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30
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Oxethazaine inhibits esophageal squamous cell carcinoma proliferation and metastasis by targeting aurora kinase A. Cell Death Dis 2022; 13:189. [PMID: 35217647 PMCID: PMC8881465 DOI: 10.1038/s41419-022-04642-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 01/28/2022] [Accepted: 02/07/2022] [Indexed: 11/09/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC), a malignant neoplasm with high incidence, is a severe global public health threat. The current modalities used for treating ESCC include surgery, chemotherapy, and radiotherapy. Although ESCC management and treatment strategies have improved over the last decade, the overall 5-year survival rate remains <20%. Therefore, the identification of novel therapeutic strategies that can increase ESCC patient survival rates is urgently needed. Oxethazaine, an amino-amide anesthetic agent, is mainly prescribed in combination with antacids to relieve esophagitis, dyspepsia, and other gastric disorders. In the present study, we found that oxethazaine inhibited the proliferation and migration of esophageal cancer cells. According to the results of in vitro screening and binding assays, oxethazaine binds directly to AURKA, suppresses AURKA activity, and inhibits the downstream effectors of AURKA. Notably, we found that oxethazaine suppressed tumor growth in three patient-derived esophageal xenograft mouse models and tumor metastasis in vivo. Our findings suggest that oxethazaine can inhibit ESCC proliferation and metastasis in vitro and in vivo by targeting AURKA.
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Yang T, Chen Y, Xu J, Li J, Liu H, Liu N. Bioinformatics screening the novel and promising targets of curcumin in hepatocellular carcinoma chemotherapy and prognosis. BMC Complement Med Ther 2022; 22:21. [PMID: 35078445 PMCID: PMC8788085 DOI: 10.1186/s12906-021-03487-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 12/06/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The aim of present study was to screen the novel and promising targets of curcumin in hepatocellular carcinoma diagnosis and chemotherapy. METHODS Potential targets of curcumin were screened from SwissTargetPrediction, ParmMapper and drugbank databases. Potential aberrant genes of hepatocellular carcinoma were screened from Genecards databases. Fifty paired hepatocellular carcinoma patients' gene expression profiles from the GEO database were used to test potential targets of curcumin. Besides, GO analysis, KEGG pathway enrichment analysis and PPI network construction were used to explore the underlying mechanism of candidate hub genes. ROC analysis and Kaplan-Meier analysis were used to evaluate the diagnostic and prognostic value of candidate hub genes, respectively. Real-time PCR was used to verify the results of bioinformatics analysis. RESULTS Bioinformatics analysis results suggested that AURKA, CDK1, CCNB1, TOP2A, CYP2B6, CYP2C9, and CYP3A4 genes served as candidate hub genes. AURKA, CDK1, CCNB1 and TOP2A were significantly upregulated and correlated with poor prognosis in hepatocellular carcinoma, AUC values of which were 95.7, 96.9, 98.1 and 96.1% respectively. There was not significant correlation between the expression of CYP2B6 and prognosis of hepatocellular carcinoma, while CYP2C9 and CYP3A4 genes were significantly downregulated and correlated with poor prognosis in hepatocellular carcinoma. AUC values of CYP2B6, CYP2C9, and CYP3A4 were 96.0, 97.0 and 88.0% respectively. In vitro, we further confirmed that curcumin significantly downregulated the expression of AURKA, CDK1, and TOP2A genes, while significantly upregulated the expression of CYP2B6, CYP2C9, and CYP3A4 genes. CONCLUSIONS Our results provided a novel panel of AURKA, CDK1, TOP2A, CYP2C9, and CYP3A4 candidate genes for curcumin related chemotherapy of hepatocellular carcinoma.
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Affiliation(s)
- Tingting Yang
- Scientific Research Center, The First Affiliated Hospital of Guangdong Pharmaceutical University, Gonghexiheng Street 1, Guangzhou, Guangdong, 510080, P.R. China
| | - Yibiao Chen
- Department of Head and Neck Radiotherapy, Meizhou City People's Hospital, No.6 Building, Huangtang Road 63, Meijiang District, Meizhou, Guangdong, 514031, P.R. China
| | - Jiexuan Xu
- Scientific Research Center, The First Affiliated Hospital of Guangdong Pharmaceutical University, Gonghexiheng Street 1, Guangzhou, Guangdong, 510080, P.R. China
| | - Jinyuan Li
- Department of Head and Neck Radiotherapy, Meizhou City People's Hospital, No.6 Building, Huangtang Road 63, Meijiang District, Meizhou, Guangdong, 514031, P.R. China
| | - Hong Liu
- Scientific Research Center, The First Affiliated Hospital of Guangdong Pharmaceutical University, Gonghexiheng Street 1, Guangzhou, Guangdong, 510080, P.R. China.
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangdong Pharmaceutical University, Gonghexiheng Street 1, Guangzhou, Guangdong, 510080, P.R. China.
| | - Naihua Liu
- Scientific Research Center, The First Affiliated Hospital of Guangdong Pharmaceutical University, Gonghexiheng Street 1, Guangzhou, Guangdong, 510080, P.R. China.
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangdong Pharmaceutical University, Gonghexiheng Street 1, Guangzhou, Guangdong, 510080, P.R. China.
- Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Nonglin Down Street 19, Guangzhou, Guangdong, 510080, P.R. China.
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Yang Z, Wu X, Li J, Zheng Q, Niu J, Li S. CCNB2, CDC20, AURKA, TOP2A, MELK, NCAPG, KIF20A, UBE2C, PRC1, and ASPM May Be Potential Therapeutic Targets for Hepatocellular Carcinoma Using Integrated Bioinformatic Analysis. Int J Gen Med 2022; 14:10185-10194. [PMID: 34992437 PMCID: PMC8710976 DOI: 10.2147/ijgm.s341379] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 12/09/2021] [Indexed: 01/14/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC) is a highly malignant, recurrent and drug-resistant tumor, and patients often lose the opportunity for surgery when they are diagnosed. Abnormal gene expression is closely related to the occurrence of HCC. The aim of the present study was to identify the differentially expressed genes (DEGs) between tumor tissue and non-tumor tissue of HCC samples in order to investigate the mechanisms of liver cancer. Methods The gene expression profile (GSE62232, GSE89377, and GSE112790) was downloaded from the Gene Expression Omnibus (GEO) and analyzed using the online tool GEO2R to identify differentially expressed genes (DEGs). Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed using the Database for Annotation, Visualization and Integrated Discovery. Protein–protein interaction (PPI) of these DEGs was analyzed based on the Search Tool for the Retrieval of Interacting Genes database and visualized by Cytoscape software. In addition, we used the online Kaplan–Meier plotter survival analysis tool to evaluate the prognostic value of hub genes expression. HPA database was used to reveal the differences in protein level of hub genes. Results A total of 50 upregulated DEGs and 122 downregulated DEGs were identified. Among them, ten hub genes with a high degree of connectivity were picked out. Overexpression of these hub genes was associated with unfavorable prognosis of HCC. Conclusion Our study suggests that CCNB2, CDC20, AURKA, TOP2A, MELK, NCAPG, KIF20A, UBE2C, PRC1, and ASPM were overexpressed in HCC compared with normal liver tissue. Overexpression of these genes was an unfavorable prognostic factor of HCC patients. Further study is needed to explore the value of them in the diagnosis and treatment of HCC. ![]()
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Affiliation(s)
- Zhiqiang Yang
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Xinglang Wu
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Junbo Li
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Qiang Zheng
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Junwei Niu
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Shengwei Li
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
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Albaradei S, Uludag M, Thafar MA, Gojobori T, Essack M, Gao X. Predicting Bone Metastasis Using Gene Expression-Based Machine Learning Models. Front Genet 2021; 12:771092. [PMID: 34858485 PMCID: PMC8631472 DOI: 10.3389/fgene.2021.771092] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 10/20/2021] [Indexed: 11/13/2022] Open
Abstract
Bone is the most common site of distant metastasis from malignant tumors, with the highest prevalence observed in breast and prostate cancers. Such bone metastases (BM) cause many painful skeletal-related events, such as severe bone pain, pathological fractures, spinal cord compression, and hypercalcemia, with adverse effects on life quality. Many bone-targeting agents developed based on the current understanding of BM onset's molecular mechanisms dull these adverse effects. However, only a few studies investigated potential predictors of high risk for developing BM, despite such knowledge being critical for early interventions to prevent or delay BM. This work proposes a computational network-based pipeline that incorporates a ML/DL component to predict BM development. Based on the proposed pipeline we constructed several machine learning models. The deep neural network (DNN) model exhibited the highest prediction accuracy (AUC of 92.11%) using the top 34 featured genes ranked by betweenness centrality scores. We further used an entirely separate, "external" TCGA dataset to evaluate the robustness of this DNN model and achieved sensitivity of 85%, specificity of 80%, positive predictive value of 78.10%, negative predictive value of 80%, and AUC of 85.78%. The result shows the models' way of learning allowed it to zoom in on the featured genes that provide the added benefit of the model displaying generic capabilities, that is, to predict BM for samples from different primary sites. Furthermore, existing experimental evidence provides confidence that about 50% of the 34 hub genes have BM-related functionality, which suggests that these common genetic markers provide vital insight about BM drivers. These findings may prompt the transformation of such a method into an artificial intelligence (AI) diagnostic tool and direct us towards mechanisms that underlie metastasis to bone events.
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Affiliation(s)
- Somayah Albaradei
- Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.,Faculty of Computing and Information Technology, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mahmut Uludag
- Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Maha A Thafar
- Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.,College of Computers and Information Technology, Taif University, Taif, Saudi Arabia
| | - Takashi Gojobori
- Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Magbubah Essack
- Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Xin Gao
- Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
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Liu R, Jiang Z, Kong W, Zheng S, Dai T, Wang G. A Novel Nine-Gene Signature Associated With Immune Infiltration for Predicting Prognosis in Hepatocellular Carcinoma. Front Genet 2021; 12:730732. [PMID: 34917126 PMCID: PMC8669621 DOI: 10.3389/fgene.2021.730732] [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: 06/25/2021] [Accepted: 11/08/2021] [Indexed: 01/10/2023] Open
Abstract
Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, and its prognosis remains unsatisfactory. The identification of new and effective markers is helpful for better predicting the prognosis of patients with HCC and for conducting individualized management. The oncogene Aurora kinase A (AURKA) is involved in a variety of tumors; however, its role in liver cancer is poorly understood. The aim of this study was to establish AURKA-related gene signatures for predicting the prognosis of patients with HCC. Methods: We first analyzed the expression of AURKA in liver cancer and its prognostic significance in different data sets. Subsequently, we selected genes with prognostic value related to AURKA and constructed a gene signature based on them. The predictive ability of the gene signature was tested using the HCC cohort development and verification data sets. A nomogram was constructed by integrating the risk score and clinicopathological characteristics. Finally, the influence of the gene signature on the immune microenvironment in HCC was comprehensively analyzed. Results: We found that AURKA was highly expressed in HCC, and it exhibited prognostic value. We selected eight AURKA-related genes with prognostic value through the protein-protein interaction network and successfully constructed a gene signature. The nine-gene signature could effectively stratify the risk of patients with HCC and demonstrated a good ability in predicting survival. The nomogram showed good discrimination and consistency of risk scores. In addition, the high-risk group showed a higher percentage of immune cell infiltration (i.e., macrophages, myeloid dendritic cells, neutrophils, and CD4+T cells). Moreover, the immune checkpoints SIGLEC15, TIGIT, CD274, HAVCR2, and PDCD1LG2 were also higher in the high-risk group versus the low-risk group. Conclusions: This gene signature may be useful prognostic markers and therapeutic targets in patients with HCC.
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Affiliation(s)
- Rongqiang Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - ZeKun Jiang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Weihao Kong
- Department of Emergency Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Shiyang Zheng
- Department of Breast Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Tianxing Dai
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Guoying Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Chen X, Xia Z, Wan Y, Huang P. Identification of hub genes and candidate drugs in hepatocellular carcinoma by integrated bioinformatics analysis. Medicine (Baltimore) 2021; 100:e27117. [PMID: 34596112 PMCID: PMC8483840 DOI: 10.1097/md.0000000000027117] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 08/14/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the third cancer-related cause of death in the world. Until now, the involved mechanisms during the development of HCC are largely unknown. This study aims to explore the driven genes and potential drugs in HCC. METHODS Three mRNA expression datasets were used to analyze the differentially expressed genes (DEGs) in HCC. The bioinformatics approaches include identification of DEGs and hub genes, Gene Ontology terms analysis and Kyoto encyclopedia of genes and genomes enrichment analysis, construction of protein-protein interaction network. The expression levels of hub genes were validated based on The Cancer Genome Atlas, Gene Expression Profiling Interactive Analysis, and the Human Protein Atlas. Moreover, overall survival and disease-free survival analysis of HCC patients were further conducted by Kaplan-Meier plotter and Gene Expression Profiling Interactive Analysis. DGIdb database was performed to search the candidate drugs for HCC. RESULTS A total of 197 DEGs were identified. The protein-protein interaction network was constructed using Search Tool for the Retrieval of Interacting Genes software, 10 genes were selected by Cytoscape plugin cytoHubba and served as hub genes. These 10 genes were all closely related to the survival of HCC patients. DGIdb database predicted 29 small molecules as the possible drugs for treating HCC. CONCLUSION Our study provides some new insights into HCC pathogenesis and treatments. The candidate drugs may improve the efficiency of HCC therapy in the future.
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Affiliation(s)
- Xiaolong Chen
- National Key Clinical Department, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhixiong Xia
- Department of Pathology, The Center Hospital of Wuhan, Hubei, China
| | - Yafeng Wan
- Department of Hepatobiliary Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Ping Huang
- National Key Clinical Department, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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36
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Wu C, Qi X, Qiu Z, Deng G, Zhong L. Low expression of KIF20A suppresses cell proliferation, promotes chemosensitivity and is associated with better prognosis in HCC. Aging (Albany NY) 2021; 13:22148-22163. [PMID: 34491228 PMCID: PMC8507281 DOI: 10.18632/aging.203494] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 06/18/2021] [Indexed: 12/29/2022]
Abstract
This study analysed the microarray datasets from Gene Expression Omnibus (GEO) database, and aimed to identify novel potential hub genes associated with the progression of HCC via bioinformatics analysis and experimental validation. The common differentially expressed genes (DEGs) from five GEO datasets were screened using GEO2R tool. The expression and survival analysis of hub genes in HCC were performed using Gene Expression Profiling Interactive Analysis, UALCAN and Kaplan-Meier plotter tools. In vitro functional assays were used to determine the caspase-3, -9, cell proliferation and chemo-sensitivity of HCC cells. A total of 177 common DEGs were identified between normal liver and HCC tissues among these datasets. Functional enrichment and PPI network analysis identified 22 hub genes from the common DEGs. The mRNA expression of 22 hub genes was all significantly up-regulated in HCC tissues compared to that in normal liver tissues. Further survival analysis showed that 10 hub genes predicted poor prognosis of patients with HCC. More importantly, the in vitro functional studies demonstrated that KIF20A knockdown suppressed the HCC cell proliferation and promoted the chemosensitivity of HCC cells to cisplatin and sorafenib. In conclusion, the present study identified a total of 177 common DEGs among 5 GEO microarray datasets and found that 10 hub genes could predict the poor prognosis of patients with HCC using the comprehensive bioinformatics analysis. Furthermore, KIF20A silence suppressed cell proliferation and enhanced chemosensitivity in HCC cells. Further studies may be required to determine the mechanistic role of these hub genes in HCC progression.
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Affiliation(s)
- Chuanxing Wu
- Department of General Surgery, Shanghai General Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China
| | - Xiaosheng Qi
- Department of General Surgery, Shanghai General Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China
| | - Zhengjun Qiu
- Department of General Surgery, Shanghai General Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China
| | - Guilong Deng
- Department of General Surgery, Shanghai General Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China
| | - Lin Zhong
- Department of General Surgery, Shanghai General Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China
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Miralaei N, Majd A, Ghaedi K, Peymani M, Safaei M. Integrated pan-cancer of AURKA expression and drug sensitivity analysis reveals increased expression of AURKA is responsible for drug resistance. Cancer Med 2021; 10:6428-6441. [PMID: 34337875 PMCID: PMC8446408 DOI: 10.1002/cam4.4161] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 07/11/2021] [Accepted: 07/12/2021] [Indexed: 12/11/2022] Open
Abstract
Introduction The AURKA gene encodes a protein kinase involved in cell cycle regulation and plays an oncogenic role in many cancers. The main objective of this study is to analyze AURKA expression in 13 common cancers and its role in prognostic and drug resistance. Method Using the cancer genome atlas (TCGA) as well as CCLE and GDSC data, the level of AURKA gene expression and its role in prognosis and its association with drug resistance were evaluated, respectively. In addition, the expression level of AURKA was assessed in colorectal cancer (CRC) and gastric cancer (GC) samples. Besides, using Gene Expression Omnibus (GEO) data, drugs that could affect the expression level of this gene were also identified. Results The results indicated that the expression level of AURKA gene in 13 common cancers increased significantly compared to normal samples or it survived poorly (HR >1, p < 0.01) in lung, prostate, kidney, bladder, and uterine cancers. Also, the gene expression data showed increased expression in CRC and GC samples compared to normal ones. The level of AURKA was significantly associated with the resistance to SB 505124, NU‐7441, and irinotecan drugs (p < 0.01). Eventually, GEO data showed that JQ1, actinomycin D1, and camptothecin could reduce the expression of AURKA gene in different cancer cell lines (logFC < 1, p < 0.01). Conclusion Increased expression of AURKA is observed in prevalent cancers and associated with poor prognostic and the development of drug resistance. In addition, some chemotherapy drugs can reduce the expression of this gene.
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Affiliation(s)
- Noushin Miralaei
- Department of Biology, Tehran North Branch, Islamic Azad University, Tehran, Iran
| | - Ahmad Majd
- Department of Biology, Tehran North Branch, Islamic Azad University, Tehran, Iran
| | - Kamran Ghaedi
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Maryam Peymani
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Masoomeh Safaei
- Department of Pathology, Cancer Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
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Lv D, Chen L, Du L, Zhou L, Tang H. Emerging Regulatory Mechanisms Involved in Liver Cancer Stem Cell Properties in Hepatocellular Carcinoma. Front Cell Dev Biol 2021; 9:691410. [PMID: 34368140 PMCID: PMC8339910 DOI: 10.3389/fcell.2021.691410] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 07/01/2021] [Indexed: 02/05/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer and one of the leading causes of cancer-related deaths worldwide. A growing body of evidence supports the hypothesis that HCC is driven by a population of cells called liver cancer stem cells (LCSCs). LCSCs have been proposed to contribute to malignant HCC progression, including promoting tumor occurrence and growth, mediating tumor metastasis, and treatment resistance, but the regulatory mechanism of LCSCs in HCC remains unclear. Understanding the signaling pathways responsible for LCSC maintenance and survival may provide opportunities to improve patient outcomes. Here, we review the current literature about the origin of LCSCs and the niche composition, describe the current evidence of signaling pathways that mediate LCSC stemness, then highlight several mechanisms that modulate LCSC properties in HCC progression, and finally, summarize the new developments in therapeutic strategies targeting LCSCs markers and regulatory pathways.
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Affiliation(s)
- Duoduo Lv
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Liyu Chen
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Lingyao Du
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Lingyun Zhou
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China.,State Key Laboratory of Biotherapy and Center of Infectious Diseases, Division of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
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ISL1 promoted tumorigenesis and EMT via Aurora kinase A-induced activation of PI3K/AKT signaling pathway in neuroblastoma. Cell Death Dis 2021; 12:620. [PMID: 34131100 PMCID: PMC8206128 DOI: 10.1038/s41419-021-03894-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 05/24/2021] [Accepted: 05/31/2021] [Indexed: 11/21/2022]
Abstract
Neuroblastoma (NB) is the most common extracranial solid malignancy in children and its mortality rate is relatively high. However, driver genes of NB are not clearly identified. Using bioinformatics analysis, we determined the top 8 differentially expressed genes (DEGs) in NB, including GFAP, PAX6, FOXG1, GAD1, PTPRC, ISL1, GRM5, and GATA3. Insulin gene enhancer binding protein 1 (ISL1) is a LIM homeodomain transcription factor which has been found to be highly expressed in a variety of malignant tumors, but the function of ISL1 in NB has not been fully elucidated. We identified ISL1 as an oncogene in NB. ISL1 is preferentially upregulated in NB tissues compared with normal tissues. High ISL1 expression is significantly associated with poor outcome of NB patients. Knockdown of ISL1 markedly represses proliferation and induces cell apoptosis in vitro, and suppresses tumorigenicity in vivo, while overexpression of ISL1 has the opposite effects. Mechanistically, we demonstrate that ISL1 promotes cell proliferation and EMT transformation through PI3K/AKT signaling pathway by upregulating Aurora kinase A (AURKA), a serine-threonine kinase that is essential for the survival of NB cells. The blockade of AURKA attenuates the function of ISL1 overexpression in the regulation of cell proliferation and migration, Conclusively, this study showed that ISL1 targeted AURKA to facilitate the development of NB, which provided new insights into the tumorigenesis of NB. Thus, ISL1 may be a promising therapeutic target in the future.
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Feng G, Xue F, He Y, Wang T, Yuan H. The Identification of Stemness-Related Genes in the Risk of Head and Neck Squamous Cell Carcinoma. Front Oncol 2021; 11:688545. [PMID: 34178686 PMCID: PMC8226229 DOI: 10.3389/fonc.2021.688545] [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: 03/31/2021] [Accepted: 05/19/2021] [Indexed: 01/04/2023] Open
Abstract
Objectives This study aimed to identify genes regulating cancer stemness of head and neck squamous cell carcinoma (HNSCC) and evaluate the ability of these genes to predict clinical outcomes. Materials and Methods The stemness index (mRNAsi) was obtained using a one-class logistic regression machine learning algorithm based on sequencing data of HNSCC patients. Stemness-related genes were identified by weighted gene co-expression network analysis and least absolute shrinkage and selection operator analysis (LASSO). The coefficient of LASSO was applied to construct a diagnostic risk score model. The Cancer Genome Atlas database, the Gene Expression Omnibus database, Oncomine database and the Human Protein Atlas database were used to validate the expression of key genes. Interaction network analysis was performed using String database and DisNor database. The Connectivity Map database was used to screen potential compounds. The expressions of stemness-related genes were validated using quantitative real‐time polymerase chain reaction (qRT‐PCR). Results TTK, KIF14, KIF18A and DLGAP5 were identified. Stemness-related genes were upregulated in HNSCC samples. The risk score model had a significant predictive ability. CDK inhibitor was the top hit of potential compounds. Conclusion Stemness-related gene expression profiles may be a potential biomarker for HNSCC.
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Affiliation(s)
- Guanying Feng
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.,Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Feifei Xue
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China
| | - Yingzheng He
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China
| | - Tianxiao Wang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China
| | - Hua Yuan
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.,Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
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Tian W, Li J, Wang Z, Zhang T, Han Y, Liu Y, Chu W, Liu Y, Yang B. HYD-PEP06 suppresses hepatocellular carcinoma metastasis, epithelial-mesenchymal transition and cancer stem cell-like properties by inhibiting PI3K/AKT and WNT/ β-catenin signaling activation. Acta Pharm Sin B 2021; 11:1592-1606. [PMID: 34221870 PMCID: PMC8245914 DOI: 10.1016/j.apsb.2021.03.040] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 02/27/2021] [Accepted: 03/12/2021] [Indexed: 02/07/2023] Open
Abstract
HYD-PEP06, an endostatin-modified polypeptide, has been shown to produce effective anti-colorectal carcinoma effects through inhibiting epithelial-mesenchymal transition (EMT). However, whether HYD-PEP06 has similar suppressive effect on hepatocellular carcinoma (HCC) remained unknown. In this study, HYD-PEP06 inhibited metastasis and EMT but not proliferation in vitro. Cignal finder pathway reporter array and Western blot analysis revealed that HYD-PEP06 suppressed HCCLM3 cell metastasis and EMT by inhibiting the PI3K/AKT pathway. Moreover, HYD-PEP06 exerted anti-metastasis effects in HepG2 cancer stem-like cells (CSCs) via suppressing the WNT/β-catenin signaling pathway. Finally, in HCCLM3 tumor-bearing BALB/c nu/nu nude mice, HYD-PEP06 substantially suppressed tumor growth, lung metastasis and HCC progress. Our results suggest that HYD-PEP06 inhibits the metastasis and EMT of HCC and CSCs as well, and thus has the potential as an agent for HCC treatment.
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Affiliation(s)
- Wei Tian
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Jiatong Li
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Zhuo Wang
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Tong Zhang
- The First Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Ying Han
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Yanyan Liu
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin 150081, China
| | - Wenfeng Chu
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Yu Liu
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Baofeng Yang
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
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Wang W, Xu S, Di Y, Zhang Z, Li Q, Guo K, Lv Y, Wang B. Novel role of LINC01013/miR-6795-5p/FMNL3 axis in the regulation of hepatocellular carcinoma stem cell features. Acta Biochim Biophys Sin (Shanghai) 2021; 53:652-662. [PMID: 33847733 DOI: 10.1093/abbs/gmab040] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Indexed: 12/30/2022] Open
Abstract
Cancer stem cells (CSCs) are major contributors to tumor initiation, recurrence, and metastasis of hepatocellular carcinoma (HCC). Some long non-coding RNAs have been reported as modulators of stem-like properties in cancer cells. However, the role of LINC01013 in liver CSCs has not yet been clarified. In this study, we aimed to elucidate the expression pattern and functions of LINC01013 in HCC. HCC tissues and normal controls were collected, and the expression pattern of LINC01013 and miR-6795-5p was identified by quick real-time polymerase chain reaction. Cell counting kit-8 assay, colony formation, and spheroid formation were performed to measure cell viability, proliferation, and self-renewal of HCC cell lines. The expression of stem markers was detected by western blot analysis. The effect of LINC01013 on viability, proliferation, and stem-like properties was detected through gain-of-function and loss-of-function experiments. The direct interaction among LINC01013, miR-6795-5p, and FMNL3 was testified by dual-luciferase reporter gene assay. Tumor-bearing mice were constructed to ascertain the functions of LINC01013 in vivo. HCC tissues showed increased LINC01013 and FMNL3 expression, while it showed a decreased miR-6795-5p expression as compared to the relative controls. Moreover, the high level of LINC01013 was closely related to the poor prognosis of HCC patients. LINC01013 directly binds to miR-6795-5p and subsequently relieves FMNL3. Silencing LINC01013, FMNL3, or overexpression of miR-6795-5p could suppress spheroid and colony formation, proliferation, as well as expression of stemness markers in HepG2 and SNU-182 cells. LINC01013 knockdown suppressed growth and stem-like traits of HCC cells in vivo by reducing FMNL3 expression. LINC01013/miR-6795-5p/FMNL3 axis may be a novel therapeutic target for HCC.
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Affiliation(s)
- Wanli Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
- Department of General Surgery, Bazhong Central Hospital, Bazhong 636000, China
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
| | - Shicheng Xu
- Department of General Surgery, Bazhong Central Hospital, Bazhong 636000, China
| | - Ying Di
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
| | - Zhiyong Zhang
- Department of General Surgery, Bazhong Central Hospital, Bazhong 636000, China
| | - Qingshan Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
| | - Kun Guo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
| | - Yi Lv
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
| | - Bo Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
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CloneSeq: A highly sensitive analysis platform for the characterization of 3D-cultured single-cell-derived clones. Dev Cell 2021; 56:1804-1817.e7. [PMID: 34010629 DOI: 10.1016/j.devcel.2021.04.026] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 03/07/2021] [Accepted: 04/23/2021] [Indexed: 12/12/2022]
Abstract
Single-cell assays have revealed the importance of heterogeneity in many biological systems. However, limited sensitivity is a major hurdle for uncovering cellular variation. To overcome it, we developed CloneSeq, combining clonal expansion inside 3D hydrogel spheres and droplet-based RNA sequencing (RNA-seq). We show that clonal cells maintain similar transcriptional profiles and cell states. CloneSeq of lung cancer cells revealed cancer-specific subpopulations, including cancer stem-like cells, that were not revealed by scRNA-seq. Clonal expansion within 3D soft microenvironments supported cellular stemness of embryonic stem cells (ESCs) even without pluripotent media, and it improved epigenetic reprogramming efficiency of mouse embryonic fibroblasts. CloneSeq of ESCs revealed that the differentiation decision is made early during Oct4 downregulation and is maintained during early clonal expansion. Together, we show CloneSeq can be adapted to different biological systems to discover rare subpopulations by leveraging the enhanced sensitivity within clones.
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Meng Z, Wu J, Liu X, Zhou W, Ni M, Liu S, Guo S, Jia S, Zhang J. Identification of potential hub genes associated with the pathogenesis and prognosis of hepatocellular carcinoma via integrated bioinformatics analysis. J Int Med Res 2021; 48:300060520910019. [PMID: 32722976 PMCID: PMC7391448 DOI: 10.1177/0300060520910019] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Objective The objective was to identify potential hub genes associated with the pathogenesis and prognosis of hepatocellular carcinoma (HCC). Methods Gene expression profile datasets were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between HCC and normal samples were identified via an integrated analysis. A protein–protein interaction network was constructed and analyzed using the STRING database and Cytoscape software, and enrichment analyses were carried out through DAVID. Gene Expression Profiling Interactive Analysis and Kaplan–Meier plotter were used to determine expression and prognostic values of hub genes. Results We identified 11 hub genes (CDK1, CCNB2, CDC20, CCNB1, TOP2A, CCNA2, MELK, PBK, TPX2, KIF20A, and AURKA) that might be closely related to the pathogenesis and prognosis of HCC. Enrichment analyses indicated that the DEGs were significantly enriched in metabolism-associated pathways, and hub genes and module 1 were highly associated with cell cycle pathway. Conclusions In this study, we identified key genes of HCC, which indicated directions for further research into diagnostic and prognostic biomarkers that could facilitate targeted molecular therapy for HCC.
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Affiliation(s)
- Ziqi Meng
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jiarui Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Xinkui Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Wei Zhou
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Mengwei Ni
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Shuyu Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Siyu Guo
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Shanshan Jia
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jingyuan Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
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Zhang P, Feng J, Wu X, Chu W, Zhang Y, Li P. Bioinformatics Analysis of Candidate Genes and Pathways Related to Hepatocellular Carcinoma in China: A Study Based on Public Databases. Pathol Oncol Res 2021; 27:588532. [PMID: 34257537 PMCID: PMC8262246 DOI: 10.3389/pore.2021.588532] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 02/01/2021] [Indexed: 12/30/2022]
Abstract
Background and Objective: Hepatocellular carcinoma (HCC) is a highly aggressive malignant tumor of the digestive system worldwide. Chronic hepatitis B virus (HBV) infection and aflatoxin exposure are predominant causes of HCC in China, whereas hepatitis C virus (HCV) infection and alcohol intake are likely the main risk factors in other countries. It is an unmet need to recognize the underlying molecular mechanisms of HCC in China. Methods: In this study, microarray datasets (GSE84005, GSE84402, GSE101685, and GSE115018) derived from Gene Expression Omnibus (GEO) database were analyzed to obtain the common differentially expressed genes (DEGs) by R software. Moreover, the gene ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed by using Database for Annotation, Visualization and Integrated Discovery (DAVID). Furthermore, the protein-protein interaction (PPI) network was constructed, and hub genes were identified by the Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape, respectively. The hub genes were verified using Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, and Kaplan-Meier Plotter online databases were performed on the TCGA HCC dataset. Moreover, the Human Protein Atlas (HPA) database was used to verify candidate genes’ protein expression levels. Results: A total of 293 common DEGs were screened, including 103 up-regulated genes and 190 down-regulated genes. Moreover, GO analysis implied that common DEGs were mainly involved in the oxidation-reduction process, cytosol, and protein binding. KEGG pathway enrichment analysis presented that common DEGs were mainly enriched in metabolic pathways, complement and coagulation cascades, cell cycle, p53 signaling pathway, and tryptophan metabolism. In the PPI network, three subnetworks with high scores were detected using the Molecular Complex Detection (MCODE) plugin. The top 10 hub genes identified were CDK1, CCNB1, AURKA, CCNA2, KIF11, BUB1B, TOP2A, TPX2, HMMR and CDC45. The other public databases confirmed that high expression of the aforementioned genes related to poor overall survival among patients with HCC. Conclusion: This study primarily identified candidate genes and pathways involved in the underlying mechanisms of Chinese HCC, which is supposed to provide new targets for the diagnosis and treatment of HCC in China.
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Affiliation(s)
- Peng Zhang
- School of Graduates, Tianjin Medical University, Tianjin, China.,Department of Hepatology, Tianjin Second People's Hospital, Tianjin, China
| | - Jing Feng
- School of Graduates, Tianjin Medical University, Tianjin, China.,Department of Hepatology, Tianjin Second People's Hospital, Tianjin, China
| | - Xue Wu
- School of Graduates, Tianjin Medical University, Tianjin, China.,Department of Hepatology, Tianjin Second People's Hospital, Tianjin, China
| | - Weike Chu
- School of Graduates, Tianjin Medical University, Tianjin, China.,Department of Hepatology, Tianjin Second People's Hospital, Tianjin, China
| | - Yilian Zhang
- School of Graduates, Tianjin Medical University, Tianjin, China.,Department of Hepatology, Tianjin Second People's Hospital, Tianjin, China
| | - Ping Li
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin, China.,Tianjin Research Institute of Liver Diseases, Tianjin, China
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Zhang Y, Lin Z, Lin X, Zhang X, Zhao Q, Sun Y. A gene module identification algorithm and its applications to identify gene modules and key genes of hepatocellular carcinoma. Sci Rep 2021; 11:5517. [PMID: 33750838 PMCID: PMC7943822 DOI: 10.1038/s41598-021-84837-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 02/18/2021] [Indexed: 12/19/2022] Open
Abstract
To further improve the effect of gene modules identification, combining the Newman algorithm in community detection and K-means algorithm framework, a new method of gene module identification, GCNA-Kpca algorithm, was proposed. The core idea of the algorithm was to build a gene co-expression network (GCN) based on gene expression data firstly; Then the Newman algorithm was used to initially identify gene modules based on the topology of GCN, and the number of clusters and clustering centers were determined; Finally the number of clusters and clustering centers were input into the K-means algorithm framework, and the secondary clustering was performed based on the gene expression profile to obtain the final gene modules. The algorithm took into account the role of modularity in the clustering process, and could find the optimal membership module for each gene through multiple iterations. Experimental results showed that the algorithm proposed in this paper had the best performance in error rate, biological significance and CNN classification indicators (Precision, Recall and F-score). The gene module obtained by GCNA-Kpca was used for the task of key gene identification, and these key genes had the highest prognostic significance. Moreover, GCNA-Kpca algorithm was used to identify 10 key genes in hepatocellular carcinoma (HCC): CDC20, CCNB1, EIF4A3, H2AFX, NOP56, RFC4, NOP58, AURKA, PCNA, and FEN1. According to the validation, it was reasonable to speculate that these 10 key genes could be biomarkers for HCC. And NOP56 and NOP58 are key genes for HCC that we discovered for the first time.
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Affiliation(s)
- Yan Zhang
- College of Environmental Science and Engineering, Dalian Martime University, Linghai Road, Dalian, 116026, Liaoning, China
| | - Zhengkui Lin
- College of Information Science and Technology, Dalian Maritime University, Linghai Road, Dalian, 116026, Liaoning, China
| | - Xiaofeng Lin
- College of Information Science and Technology, Dalian Maritime University, Linghai Road, Dalian, 116026, Liaoning, China
| | - Xue Zhang
- College of Information Science and Technology, Dalian Maritime University, Linghai Road, Dalian, 116026, Liaoning, China
| | - Qian Zhao
- College of Information Science and Technology, Dalian Maritime University, Linghai Road, Dalian, 116026, Liaoning, China.
| | - Yeqing Sun
- College of Environmental Science and Engineering, Dalian Martime University, Linghai Road, Dalian, 116026, Liaoning, China.
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Deng J, Zhong F, Gu W, Qiu F. Exploration of Prognostic Biomarkers among Replication Factor C Family in the Hepatocellular Carcinoma. Evol Bioinform Online 2021; 17:1176934321994109. [PMID: 33628006 PMCID: PMC7885030 DOI: 10.1177/1176934321994109] [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: 10/08/2020] [Accepted: 01/19/2021] [Indexed: 01/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the common cancers with a high incidence and mortality. The human replication factor C (RFC) family contains 5 subunits that play an important role in DNA replication and DNA damage repair. RFCs are abnormally expressed in a variety of cancers; some of them are differentially expressed in HCC tissues and related to tumor growth. However, the expression, prognostic value, and effect targets of the whole RFC family in HCC are still unclear. To address these issues, we performed a multidimensional analysis of RFCs in HCC patients by Oncomine, UALCAN, GEPIA, Human protein atlas, Kaplan-Meier plotter, cBioPortal, GeneMANIA, String, and LinkedOmics. mRNA expression of RFCs was significantly increased in HCC tissues. There was a significant correlation between the expression of RFC2/3/4/5 and tumor stage of HCC patients. Besides, high mRNA expression of RFC2/4 was associated with worse overall survival (OS). Moreover, genetic alterations of RFCs were associated with worse OS in HCC patients. We found that genes co-expressed with RFC2/4 were mainly involved in biological processes, such as chromosome segregation, mitotic cell cycle phase transition, and telomere organization and they activated the cell cycle and spliceosome pathways. The gene set is mainly enriched in cancer-related kinases AURKA, ATR, CDK1, PLK1, and CHEK1. E2F family members were the key transcription factors for RFCs. Our results suggest that differentially expressed RFC2 and RFC4 are potential prognostic biomarkers in HCC and may act on E2F transcription factors and some kinase targets to dysregulate the cell cycle pathway. These efforts may provide new research directions for prognostic biomarkers and therapeutic targets in HCC.
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Affiliation(s)
- Jianxiong Deng
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, P.R. China
| | - Fangyan Zhong
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, P.R. China
| | - Weiguo Gu
- Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, P.R. China
| | - Feng Qiu
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, P.R. China
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Zhao Q, Zhang Y, Shao S, Sun Y, Lin Z. Identification of hub genes and biological pathways in hepatocellular carcinoma by integrated bioinformatics analysis. PeerJ 2021; 9:e10594. [PMID: 33552715 PMCID: PMC7821758 DOI: 10.7717/peerj.10594] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 11/26/2020] [Indexed: 12/18/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC), the main type of liver cancer in human, is one of the most prevalent and deadly malignancies in the world. The present study aimed to identify hub genes and key biological pathways by integrated bioinformatics analysis. Methods A bioinformatics pipeline based on gene co-expression network (GCN) analysis was built to analyze the gene expression profile of HCC. Firstly, differentially expressed genes (DEGs) were identified and a GCN was constructed with Pearson correlation analysis. Then, the gene modules were identified with 3 different community detection algorithms, and the correlation analysis between gene modules and clinical indicators was performed. Moreover, we used the Search Tool for the Retrieval of Interacting Genes (STRING) database to construct a protein protein interaction (PPI) network of the key gene module, and we identified the hub genes using nine topology analysis algorithms based on this PPI network. Further, we used the Oncomine analysis, survival analysis, GEO data set and random forest algorithm to verify the important roles of hub genes in HCC. Lastly, we explored the methylation changes of hub genes using another GEO data (GSE73003). Results Firstly, among the expression profiles, 4,130 up-regulated genes and 471 down-regulated genes were identified. Next, the multi-level algorithm which had the highest modularity divided the GCN into nine gene modules. Also, a key gene module (m1) was identified. The biological processes of GO enrichment of m1 mainly included the processes of mitosis and meiosis and the functions of catalytic and exodeoxyribonuclease activity. Besides, these genes were enriched in the cell cycle and mitotic pathway. Furthermore, we identified 11 hub genes, MCM3, TRMT6, AURKA, CDC20, TOP2A, ECT2, TK1, MCM2, FEN1, NCAPD2 and KPNA2 which played key roles in HCC. The results of multiple verification methods indicated that the 11 hub genes had highly diagnostic efficiencies to distinguish tumors from normal tissues. Lastly, the methylation changes of gene CDC20, TOP2A, TK1, FEN1 in HCC samples had statistical significance (P-value < 0.05). Conclusion MCM3, TRMT6, AURKA, CDC20, TOP2A, ECT2, TK1, MCM2, FEN1, NCAPD2 and KPNA2 could be potential biomarkers or therapeutic targets for HCC. Meanwhile, the metabolic pathway, the cell cycle and mitotic pathway might played vital roles in the progression of HCC.
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Affiliation(s)
- Qian Zhao
- College of Information Science and Technology, Dalian Martime University, Dalian, Liaoning, China
| | - Yan Zhang
- College of Information Science and Technology, Dalian Martime University, Dalian, Liaoning, China
| | - Shichun Shao
- College of Environmental Science and Engineering, Dalian Martime University, Dalian, Liaoning, China
| | - Yeqing Sun
- College of Environmental Science and Engineering, Dalian Martime University, Dalian, Liaoning, China
| | - Zhengkui Lin
- College of Information Science and Technology, Dalian Martime University, Dalian, Liaoning, China
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Chen H, Wu J, Lu L, Hu Z, Li X, Huang L, Zhang X, Chen M, Qin X, Xie L. Identification of Hub Genes Associated With Immune Infiltration and Predict Prognosis in Hepatocellular Carcinoma via Bioinformatics Approaches. Front Genet 2021; 11:575762. [PMID: 33505422 PMCID: PMC7831279 DOI: 10.3389/fgene.2020.575762] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 12/07/2020] [Indexed: 12/18/2022] Open
Abstract
Aims In the cancer-related research field, there is currently a major need for a greater number of valuable biomarkers to predict the prognosis of hepatocellular carcinoma (HCC). In this study, we aimed to screen hub genes related to immune cell infiltration and explore their prognostic value for HCC. Methods We analyzed five datasets (GSE46408, GSE57957, GSE74656, GSE76427, and GSE87630) from the Gene Expression Omnibus database to screen the differentially expressed genes (DEGs). A protein-protein interaction network of the DEGs was constructed using the Search Tool for the Retrieval of Interacting Genes; then, the hub genes were identified. Functional enrichment of the genes was performed on the Metascape website. Next, the expression of these hub genes was validated in several databases, including Oncomine, Gene Expression Profiling Interactive Analysis 2 (GEPIA2), and Human Protein Atlas. We explored the correlations between the hub genes and infiltrated immune cells in the TIMER2.0 database. The survival curves were generated in GEPIA2, and the univariate and multivariate Cox regression analyses were performed using TIMER2.0. Results The top ten hub genes [DNA topoisomerase II alpha (TOP2A), cyclin B2 (CCNB2), protein regulator of cytokinesis 1 (PRC1), Rac GTPase-activating protein 1 (RACGAP1), aurora kinase A (AURKA), cyclin-dependent kinase inhibitor 3 (CDKN3), nucleolar and spindle-associated protein 1 (NUSAP1), cell division cycle-associated 5 (CDCA5), abnormal spindle microtubule assembly (ASPM), and non-SMC condensin I complex subunit G (NCAPG)] were identified in subsequent analysis. These genes are most markedly enriched in cell division, suggesting their close association with tumorigenesis. Multi-database analyses validated that the hub genes were upregulated in HCC tissues. All hub genes positively correlated with several types of immune infiltration, including B cells, CD4+ T cells, macrophages, and dendritic cells. Furthermore, these hub genes served as independent prognostic factors, and the expression of these hub genes combing with the macrophage levels could help predict an unfavorable prognosis of HCC. Conclusion In sum, these hub genes (TOP2A, CCNB2, PRC1, RACGAP1, AURKA, CDKN3, NUSAP1, CDCA5, ASPM, and NCAPG) may be pivotal markers for prognostic prediction as well as potentially work as targets for immune-based intervention strategies in HCC.
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Affiliation(s)
- Huaping Chen
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Junrong Wu
- Department of Clinical Laboratory, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Liuyi Lu
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zuojian Hu
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xi Li
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Li Huang
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xiaolian Zhang
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Mingxing Chen
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xue Qin
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Li Xie
- Department of Clinical Laboratory, Second Affiliated Hospital of Guangxi Medical University, Nanning, China
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50
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Berglund A, Amankwah EK, Kim YC, Spiess PE, Sexton WJ, Manley B, Park HY, Wang L, Chahoud J, Chakrabarti R, Yeo CD, Luu HN, Pietro GD, Parker A, Park JY. Influence of gene expression on survival of clear cell renal cell carcinoma. Cancer Med 2020; 9:8662-8675. [PMID: 32986937 PMCID: PMC7666730 DOI: 10.1002/cam4.3475] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 09/03/2020] [Accepted: 09/05/2020] [Indexed: 12/14/2022] Open
Abstract
Approximately 10%‐20% of patients with clinically localized clear cell renal cell carcinoma (ccRCC) at time of surgery will subsequently experience metastatic progression. Although considerable progression was seen in the systemic treatment of metastatic ccRCC in last 20 years, once ccRCC spreads beyond the confines of the kidney, 5‐year survival is less than 10%. Therefore, significant clinical advances are urgently needed to improve overall survival and patient care to manage the growing number of patients with localized ccRCC. We comprehensively evaluated expression of 388 candidate genes related with survival of ccRCC by using TCGA RNAseq (n = 515), Total Cancer Care (TCC) expression array data (n = 298), and a well characterized Moffitt RCC cohort (n = 248). We initially evaluated all 388 genes for association with overall survival using TCGA and TCC data. Eighty‐one genes were selected for further analysis and tested on Moffitt RCC cohort using NanoString expression analysis. Expression of nine genes (AURKA, AURKB, BIRC5, CCNE1, MK167, MMP9, PLOD2, SAA1, and TOP2A) was validated as being associated with poor survival. Survival prognostic models showed that expression of the nine genes and clinical factors predicted the survival in ccRCC patients with AUC value: 0.776, 0.821 and 0.873 for TCGA, TCC and Moffitt data set, respectively. Some of these genes have not been previously implicated in ccRCC survival and thus potentially offer insight into novel therapeutic targets. Future studies are warranted to validate these identified genes, determine their biological mechanisms and evaluate their therapeutic potential in preclinical studies.
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Affiliation(s)
- Anders Berglund
- Department of Biostatistics and Bioinformatics, Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Ernest K Amankwah
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Cancer and Blood Disorders Institute, Johns Hopkins All Children's Hospital, Saint Petersburg, FL, USA
| | - Young-Chul Kim
- Department of Biostatistics, Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Philippe E Spiess
- Department of Genitourinary Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Wade J Sexton
- Department of Genitourinary Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Brandon Manley
- Department of Genitourinary Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.,Department of Integrated Mathematical Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Hyun Y Park
- Department of Cancer Epidemiology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Liang Wang
- Department of Tumor Biology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Jad Chahoud
- Department of Genitourinary Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Ratna Chakrabarti
- Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL, USA
| | - Chang D Yeo
- Division of Pulmonology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hung N Luu
- Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.,Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | - Giuliano D Pietro
- Department of Pharmacy, Universidade Federal de Sergipe, Sao Cristovao, Brazil
| | - Alexander Parker
- University of Florida College of Medicine, Jacksonville, FL, USA
| | - Jong Y Park
- Department of Cancer Epidemiology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA
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