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Xue C, Dai YZ, Li GL, Zhang Y. Prediction of prognosis, efficacy of lung adenocarcinoma by machine learning model based on immune and metabolic related genes. Discov Oncol 2024; 15:778. [PMID: 39692796 DOI: 10.1007/s12672-024-01515-x] [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: 07/07/2024] [Accepted: 11/04/2024] [Indexed: 12/19/2024] Open
Abstract
BACKGROUND The aim of this study is to integrate immune and metabolism-related genes in order to construct a predictive model for predicting the prognosis and treatment response of LUAD(lung adenocarcinoma) patients, aiming to address the challenges posed by this highly lethal and heterogeneous disease. MATERIAL AND METHODS Using TCGA-LUAD as the training subset, differential gene expression analysis, batch survival analysis, Lasso regression analysis, univariate and multivariate Cox regression analysis were performed to construct prognostic related gene models. GEO queue as validation subsets, is used to validate build Riskscore. Then, we explore the Riskscore and mutation status, immune cell infiltration, the relationship between immune therapy and chemotherapy, and build the model of the nomogram. RESULTS The Riskscore has been determined to be composed of seven gene. In the high-risk group defined by this score, both early-stage and advanced-stage LUAD patients exhibit a decreased overall survival rate. The mutation status of patients as well as immune cell infiltration show associations with the Riskscore value obtained from these genes' expression levels. Furthermore, there exist variations in response to immunotherapy as well as sensitivity to commonly used chemotherapy drugs among different individuals. Lastly, when using a column line plot model based on the calculated Riskscore values, we obtain a concordance index (C-index) was 0 .716 (95% CI 0.671-0.762), and time-dependent ROC predicted probabilities of 1-, 3- and 5-year survival for LUAD patients were 0.752, 0.725 and 0.654, respectively. CONCLUSION In conclusion, we have successfully developed a predictive model incorporating immune and metabolism-related genes, encompassing gene expression levels of CAT/CCL20/GPI/INSL4 NT5E/GSTA3/GNPNAT1. This comprehensive model not only enables the prognosis prediction for LUAD patients but also facilitates the prediction of their response to first-line chemotherapy drugs and immune checkpoint inhibitors, thus demonstrating its broad potential in clinical applications. However, our study still has limitations as it is based on TCGA and GEO databases with limited pathological characteristics of patients. Therefore, more practical and valuable factors are needed to predict efficacy. The crosstalk between metabolism and immunity remains to be explored. Finally, this study lacks experimental evidence for the underlying gene expression of prognosis and further research is required.
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Affiliation(s)
- Cong Xue
- Department of Cardiothoracic Surgery, Zhangzhou Affiliated Hospital of Fujian Medical University, No. 59, Shengli Road, Zhangzhou, 363000, Fujian, China
| | - Yi-Zhi Dai
- Department of Cardiothoracic Surgery, Zhangzhou Affiliated Hospital of Fujian Medical University, No. 59, Shengli Road, Zhangzhou, 363000, Fujian, China
| | - Gui-Long Li
- Department of Cardiothoracic Surgery, Zhangzhou Affiliated Hospital of Fujian Medical University, No. 59, Shengli Road, Zhangzhou, 363000, Fujian, China
| | - Yi Zhang
- Department of Cardiothoracic Surgery, Zhangzhou Affiliated Hospital of Fujian Medical University, No. 59, Shengli Road, Zhangzhou, 363000, Fujian, China.
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Xu H, Ma H, Zha L, Li Q, Pan H, Zhang L. Engineered exosomes transporting the lncRNA, SVIL-AS1, inhibit the progression of lung cancer via targeting miR-21-5p. Am J Cancer Res 2024; 14:3335-3347. [PMID: 39113865 PMCID: PMC11301303 DOI: 10.62347/yrjk5888] [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: 04/18/2024] [Accepted: 06/20/2024] [Indexed: 08/10/2024] Open
Abstract
In this study, we constructed engineered exosomes carrying the long non-coding RNA (lncRNA) SVIL-AS1 (SVIL-AS1 Exos), and explored its role and mechanism in lung cancer. After the construction of SVIL-AS1 Exos, their physicochemical characteristics were identified. Then, their function and effect in three different cell lines, A549, HeLa, and HepG2, were detected using western blot, the quantitative reverse transcriptase polymerase chain reaction, flow cytometry, 5-ethynyl-2'-deoxyuridine, and Cell Counting Kit-8 experiments. Finally, a mouse xenograft model was constructed to analyze tumor growth and explore the in vivo utility of SVIL-AS1 Exos using hematoxylin and eosin staining, immunohistochemistry, and the TdT-mediated dUTP nick end labeling assay. The results demonstrated that SVIL-AS1 Exos preferentially targeted A549 lung cancer cells over HeLa and HepG2 cells. SVIL-AS1 Exos promoted apoptosis and inhibited A549 cell proliferation by elevating expression of the lncRNA, SVIL-AS1. In vivo, SVIL-AS1 Exos effectively inhibited the growth of lung cancer A549 cells. Furthermore, SVIL-AS1 Exos suppressed the expression of miR-21-5p and upregulated the expression of caspase-9, indicating that SVIL-AS1 may regulate the development of lung cancer through the miR-21-5p/caspase-9 pathway. In conclusion, the engineered SVIL-AS1 Exos targeted lung cancer cells to inhibit the expression of miR-21-5p, upregulate the expression of caspase-9, and inhibit the development of lung cancer.
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Affiliation(s)
- Hao Xu
- Department of Respiratory, The People's Hospital of Danyang, Affiliated Danyang Hospital of Nantong University Danyang 212300, Jiangsu, China
| | - Hongda Ma
- Department of Respiratory, The People's Hospital of Danyang, Affiliated Danyang Hospital of Nantong University Danyang 212300, Jiangsu, China
| | - Lifen Zha
- Department of Respiratory, The People's Hospital of Danyang, Affiliated Danyang Hospital of Nantong University Danyang 212300, Jiangsu, China
| | - Qian Li
- Department of Respiratory, The People's Hospital of Danyang, Affiliated Danyang Hospital of Nantong University Danyang 212300, Jiangsu, China
| | - Huiming Pan
- Department of Respiratory, The People's Hospital of Danyang, Affiliated Danyang Hospital of Nantong University Danyang 212300, Jiangsu, China
| | - Ladi Zhang
- Department of Respiratory, The People's Hospital of Danyang, Affiliated Danyang Hospital of Nantong University Danyang 212300, Jiangsu, China
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Azhar NA, Abu Bakar SA, Citartan M, Ahmad NH. mRNA transcriptome profiling of human hepatocellular carcinoma cells HepG2 treated with Catharanthus roseus-silver nanoparticles. World J Hepatol 2023; 15:393-409. [PMID: 37034237 PMCID: PMC10075008 DOI: 10.4254/wjh.v15.i3.393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 01/17/2023] [Accepted: 03/03/2023] [Indexed: 04/11/2023] Open
Abstract
BACKGROUND The demand for the development of cancer nanomedicine has increased due to its great therapeutic value that can overcome the limitations of conventional cancer therapy. However, the presence of various bioactive compounds in crude plant extracts used for the synthesis of silver nanoparticles (AgNPs) makes its precise mechanisms of action unclear. AIM To assessed the mRNA transcriptome profiling of human HepG2 cells exposed to Catharanthus roseus G. Don (C. roseus)-AgNPs. METHODS The proliferative activity of hepatocellular carcinoma (HepG2) and normal human liver (THLE3) cells treated with C. roseusAgNPs were measured using MTT assay. The RNA samples were extracted and sequenced using BGIseq500 platform. This is followed by data filtering, mapping, gene expression analysis, differentially expression genes analysis, Gene Ontology analysis, and pathway analysis. RESULTS The mean IC50 values of C. roseusAgNPs on HepG2 was 4.38 ± 1.59 μg/mL while on THLE3 cells was 800 ± 1.55 μg/mL. Transcriptome profiling revealed an alteration of 296 genes. C. roseusAgNPs induced the expression of stress-associated genes such as MT, HSP and HMOX-1. Cellular signalling pathways were potentially activated through MAPK, TNF and TGF pathways that are responsible for apoptosis and cell cycle arrest. The alteration of ARF6, EHD2, FGFR3, RhoA, EEA1, VPS28, VPS25, and TSG101 indicated the uptake of C. roseus-AgNPs via both clathrin-dependent and clathrin-independent endocytosis. CONCLUSION This study provides new insights into gene expression study of biosynthesised AgNPs on cancer cells. The cytotoxicity effect is mediated by the aberrant gene alteration, and more interestingly the unique selective antiproliferative properties indicate the C. roseusAgNPs as an ideal anticancer candidate.
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Affiliation(s)
- Nur Asna Azhar
- Department of Biomedical Science, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas 13200, Pulau Pinang, Malaysia
- Liver Malignancies Research Program, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas 13200, Pulau Pinang, Malaysia
| | - Siti Aishah Abu Bakar
- Department of Biomedical Science, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas 13200, Pulau Pinang, Malaysia
- Faculty of Bioresources and Food Industry, Universiti Sultan Zainal Abidin, Besut Campus, Besut 22200, Terengganu, Malaysia
| | - Marimuthu Citartan
- Department of Biomedical Science, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas 13200, Pulau Pinang, Malaysia
| | - Nor Hazwani Ahmad
- Department of Biomedical Science, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas 13200, Pulau Pinang, Malaysia
- Liver Malignancies Research Program, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas 13200, Pulau Pinang, Malaysia
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Sun K, Zhang Z, Wang D, Huang Y, Zhang J, Lian C. B cell-related tertiary lymphoid structure may exert inhibitory effects on lung adenocarcinoma and SARS-COV-2. Heliyon 2023; 9:e14334. [PMID: 36942234 PMCID: PMC10008815 DOI: 10.1016/j.heliyon.2023.e14334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/26/2023] [Accepted: 02/28/2023] [Indexed: 03/14/2023] Open
Abstract
Background The prognosis of lung adenocarcinoma (LUAD) is poor. Infection with coronavirus disease 2019 (COVID-19) may further worsen the outcome of LUAD. This study utilized the immune model and the COVID-19 receptor signal to identify the potential immune structure affecting the prognosis of COVID-19 and LUAD. Methods A prognostic model was established and verified. The correlation between immune cells and risk score was examined through a variety of immune calculation methods. Gene set variation analysis (GSVA) was used to explore the correlation between the immune signaling pathway, risk model, COVID-19 binding receptor (CO19ORS) signal, and different clinicopathological factors. Results The analysis showed that the prognosis of patients was better in the low-risk group versus the high-risk group. The tertiary lymphoid structure dominated by T and B cells (TLS1) can improve the prognosis of patients in the low-risk group. Interestingly, the CO19ORS was enriched only in females and aged >65 years. The age group >65 years is closely related to the tertiary lymphatic structure of the newborn (TLS2), while the female sex is closely related to the TLS2 and TLS1 signature. The two groups exhibited a high level of inflammation-related signal distribution. In the near future, I will collect LUAD and COVID-19 related organizations to verify the changes of 8 risk protein. Conclusion TLS1 structure may improve the prognosis of patients with LUAD and SARS-COV-2 (Severe acute respiratory syndrome coronavirus 2). This unexpected discovery provides new insight into the comprehensive treatment of patients with LUAD and SARS-COV-2.
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Affiliation(s)
- Kang Sun
- Research Center of Clinical Laboratory Science, Bengbu Medical College, Bengbu, 233030, China
| | - Zhiqiang Zhang
- Research Center of Clinical Laboratory Science, Bengbu Medical College, Bengbu, 233030, China
| | - Dongqin Wang
- Research Center of Clinical Laboratory Science, Bengbu Medical College, Bengbu, 233030, China
| | - Yinlong Huang
- Department of Genetics, School of Life Sciences, Bengbu Medical College, Bengbu, 233030, China
| | - Jing Zhang
- Department of Genetics, School of Life Sciences, Bengbu Medical College, Bengbu, 233030, China
| | - Chaoqun Lian
- Research Center of Clinical Laboratory Science, Bengbu Medical College, Bengbu, 233030, China
- Department of Biochemistry and Molecular Biology, School of Laboratory Medicine, Bengbu Medical College, Bengbu, 233030, China
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Tian C, Su J, Ma Z, Wu Y, Ma H. lncRNA NBAT1 Inhibits Cell Metastasis and Promotes Apoptosis in Endometrial Cancer by Sponging miR-21-5p to Regulate PTEN. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:9304392. [PMID: 35912140 PMCID: PMC9328976 DOI: 10.1155/2022/9304392] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 07/09/2022] [Indexed: 11/18/2022]
Abstract
Objective Long noncoding RNA neuroblastoma-associated transcript 1 (NBAT1) is implicated in the progression of various cancers. Nevertheless, its biological function in endometrial cancer (EC) remains unknown. Methods The levels of NBAT1, miR-21-5p, and PTEN in EC cells and EC tissues were examined by RT-qPCR. Western blot was carried out to assess the protein expression of PTEN. The dual-luciferase reporter assay was conducted to explore the interactions among NBAT1, miR-21-5p, and PTEN. The effect of NBAT1 on EC proliferation, metastasis, and apoptosis was evaluated by CCK-8, transwell assays, wound healing, and flow cytometry. miR-21-5p mimics or NBAT1+miR-21-5p were transfected into HEC-1A and Ishikawa cells to investigate whether NBAT1 regulated EC tumorigenesis via sponging miR-21-5p. Results NBAT1 is downregulated, and miR-21-5p is upregulated in EC cells and tumor tissues. Overexpression of NBAT1 inhibits the proliferation, migration, and invasion abilities of EC cells and facilitated apoptosis. NBAT1 directly binds and negatively regulates miR-21-5p in EC. miR-21-5p mimics reverses the effect of lncRNA NBAT1 overexpression on the proliferation and migration of EC cells. PTEN is a downstream gene of miR-21-5p. lncRNA NBTA1 elevates PTEN expression via sponging miR-21-5p. Conclusions lncRNA NBAT1 acts as a tumor suppressor in EC via regulating PTEN through sponging miR-21-5p.
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Affiliation(s)
- Chunhua Tian
- Department of Obstetrics and Gynecology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, 750002 Ningxia, China
| | - Jing Su
- Department of Obstetrics and Gynecology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, 750002 Ningxia, China
| | - Zhao Ma
- Department of Obstetrics and Gynecology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, 750002 Ningxia, China
| | - Yang Wu
- Department of Obstetrics and Gynecology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, 750002 Ningxia, China
| | - Hongyun Ma
- Department of Obstetrics and Gynecology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, 750002 Ningxia, China
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Zheng P, Zhang H, Jiang W, Wang L, Liu L, Zhou Y, Zhou L, Liu H. Establishment of a Prognostic Model of Lung Adenocarcinoma Based on Tumor Heterogeneity. Front Mol Biosci 2022; 9:807497. [PMID: 35480896 PMCID: PMC9035852 DOI: 10.3389/fmolb.2022.807497] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 03/15/2022] [Indexed: 12/12/2022] Open
Abstract
Lung cancer is one of the main cancer types due to its persistently high incidence and mortality, yet a simple and effective prognostic model is still lacking. This study aimed to identify independent prognostic genes related to the heterogeneity of lung adenocarcinoma (LUAD), generate a prognostic risk score model, and construct a nomogram in combination with other pathological characteristics to predict patients’ overall survival (OS). A significant amount of data pertaining to single-cell RNA sequencing (scRNA-seq), RNA sequencing (RNA-seq), and somatic mutation were used for data mining. After statistical analyses, a risk scoring model was established based on eight independent prognostic genes, and the OS of high-risk patients was significantly lower than that of low-risk patients. Interestingly, high-risk patients were more sensitive and effective to immune checkpoint blocking therapy. In addition, it was noteworthy that CCL20 not only affected prognosis and differentiation of LUAD but also led to poor histologic grade of tumor cells. Ultimately, combining risk score, clinicopathological information, and CCL20 mutation status, a nomogram with good predictive performance and high accuracy was established. In short, our research established a prognostic model that could be used to guide clinical practice based on the constantly updated big multi-omics data. Finally, this analysis revealed that CCL20 may become a potential therapeutic target for LUAD.
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Affiliation(s)
| | | | | | | | | | | | - Ling Zhou
- *Correspondence: Ling Zhou, ; Huiguo Liu,
| | - Huiguo Liu
- *Correspondence: Ling Zhou, ; Huiguo Liu,
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He Y, Xu Y, Yu X, Sun Z, Guo W. The Vital Roles of LINC00662 in Human Cancers. Front Cell Dev Biol 2021; 9:711352. [PMID: 34354995 PMCID: PMC8329443 DOI: 10.3389/fcell.2021.711352] [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: 05/18/2021] [Accepted: 06/29/2021] [Indexed: 12/17/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) play crucial roles in many human diseases, particularly in tumorigenicity and progression. Although lncRNA research studies are increasing rapidly, our understanding of lncRNA mechanisms is still incomplete. The long intergenic non-protein coding RNA 662 (LINC00662) is a novel lncRNA, and accumulating evidence suggests that it is related to a variety of tumors in multiple systems, including the respiratory, reproductive, nervous, and digestive systems. LINC00662 has been shown to be upregulated in malignant tumors and has been confirmed to promote the development of malignant tumors. LINC00662 has also been reported to facilitate a variety of cellular events, such as tumor-cell proliferation, invasion, and migration, and its expression has been correlated to clinicopathological characteristics in patients with tumors. In terms of mechanisms, LINC00662 regulates gene expression by interacting with both proteins and with RNAs, so it may be a potential biomarker for cancer diagnosis, prognosis, and treatment. This article reviews the expression patterns, biological functions, and underlying molecular mechanisms of LINC00662 in tumors.
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Affiliation(s)
- Yuting He
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ, Transplantation at Henan Universities, Zhengzhou, China.,Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
| | - Yating Xu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ, Transplantation at Henan Universities, Zhengzhou, China.,Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
| | - Xiao Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ, Transplantation at Henan Universities, Zhengzhou, China.,Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
| | - Zongzong Sun
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Wenzhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ, Transplantation at Henan Universities, Zhengzhou, China.,Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
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Shigeoka M, Koma YI, Kodama T, Nishio M, Akashi M, Yokozaki H. Tongue Cancer Cell-Derived CCL20 Induced by Interaction With Macrophages Promotes CD163 Expression on Macrophages. Front Oncol 2021; 11:667174. [PMID: 34178651 PMCID: PMC8219974 DOI: 10.3389/fonc.2021.667174] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 05/10/2021] [Indexed: 01/05/2023] Open
Abstract
Background CD163-positive macrophages contribute to the aggressiveness of oral squamous cell carcinoma. We showed in a previous report that CD163-positive macrophages infiltrated not only to the cancer nest but also to its surrounding epithelium, depending on the presence of stromal invasion in tongue carcinogenesis. However, the role of intraepithelial macrophages in tongue carcinogenesis remains unclear. In this study, we assessed the biological behavior of intraepithelial macrophages on their interaction with cancer cells. Materials and Methods We established the indirect coculture system (intraepithelial neoplasia model) and direct coculture system (invasive cancer model) of human monocytic leukemia cell line THP-1-derived CD163-positive macrophages with SCC25, a tongue squamous cell carcinoma (TSCC) cell line. Conditioned media (CM) harvested from these systems were analyzed using cytokine array and enzyme-linked immunosorbent assay and extracted a specific upregulated cytokine in CM from the direct coculture system (direct CM). The correlation of both this cytokine and its receptor with various clinicopathological factors were evaluated based on immunohistochemistry using clinical samples from 59 patients with TSCC. Moreover, the effect of this cytokine in direct CM on the phenotypic alterations of THP-1 was confirmed by real-time polymerase chain reaction, western blotting, immunofluorescence, and transwell migration assay. Results It was shown that CCL20 was induced in the direct CM specifically. Interestingly, CCL20 was produced primarily in SCC25. The expression level of CCR6, which is a sole receptor of CCL20, was higher than the expression level of SCC25. Our immunohistochemical investigation showed that CCL20 and CCR6 expression was associated with lymphatic vessel invasion and the number of CD163-positive macrophages. Recombinant human CCL20 induced the CD163 expression and promoted migration of THP-1. We also confirmed that a neutralizing anti-CCL20 antibody blocked the induction of CD163 expression by direct CM in THP-1. Moreover, ERK1/2 phosphorylation was associated with the CCL20-driven induction of CD163 expression in THP-1. Conclusions Tongue cancer cell-derived CCL20 that was induced by interaction with macrophages promotes CD163 expression on macrophages.
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Affiliation(s)
- Manabu Shigeoka
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yu-Ichiro Koma
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Takayuki Kodama
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Mari Nishio
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Masaya Akashi
- Division of Oral and Maxillofacial Surgery, Department of Surgery Related, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hiroshi Yokozaki
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
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Wang H, Shi H, He X, Liao A. Downregulation of Chemokine CCL20 Involved in Myeloma Cells Resistant to Elotuzumab and Lenalidomide. Onco Targets Ther 2021; 14:2789-2795. [PMID: 33907421 PMCID: PMC8071208 DOI: 10.2147/ott.s300328] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 04/06/2021] [Indexed: 11/23/2022] Open
Abstract
Objective Few studies have focused on investigating resistance mechanisms in myeloma immunotherapy. This study aimed to explore the relevant factor involved in the resistance of Elotuzumab and lenalidomide. Methods Cell models which are resistant to Elotuzumab and lenalidomide were constructed; different expression genes in U266/WT (UW) and resistant UR, UE, and URE cells were detected by using gene expression microarray. RT-qPCR validated CCL20 mRNA expression of four cell lines and patient samples; bioinformatics analysis of CCL20 expressions in NDMM and RRMM; ELISA detected the presence of CCL20 in the plasma of MM patients; constructed UR mouse xenograft model to explore whether or not CCL20 reverse lenalidomide treatment in vivo. Results Cell models which are resistant to Elotuzumab and lenalidomide (UR, UE, URE) were successfully constructed. CCL20 gene expression decreased in resistant myeloma cell lines and RRMM patients. Furthermore, RRMM patients were found to have lower levels of CCL20 protein in their plasma compared to NDMM. CCL20 increase the sensitivity of drug-resistant myeloma cells to immunomodulatory drugs both in vivo and in vitro. Conclusion The expression of CCL20 was decreased in lenalidomide and Elotuzumab resistant U266 cells and in RRMM patients. CCL20 could therefore possibly increase the sensitivity of lenalidomide and Elotuzumab.
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Affiliation(s)
- Huihan Wang
- Haematology Department of Shengjing Hospital, China Medical University, Shenyang, People's Republic of China
| | - Hua Shi
- Haematology Department of Shengjing Hospital, China Medical University, Shenyang, People's Republic of China
| | - Xiaowei He
- Haematology Department of Shengjing Hospital, China Medical University, Shenyang, People's Republic of China
| | - Aijun Liao
- Haematology Department of Shengjing Hospital, China Medical University, Shenyang, People's Republic of China
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Wang N, Wang S, Wang X, Zheng Y, Yang B, Zhang J, Pan B, Gao J, Wang Z. Research trends in pharmacological modulation of tumor-associated macrophages. Clin Transl Med 2021; 11:e288. [PMID: 33463063 PMCID: PMC7805405 DOI: 10.1002/ctm2.288] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 12/27/2020] [Accepted: 12/29/2020] [Indexed: 02/06/2023] Open
Abstract
As one of the most abundant immune cell populations in the tumor microenvironment (TME), tumor-associated macrophages (TAMs) play important roles in multiple solid malignancies, including breast cancer, prostate cancer, liver cancer, lung cancer, ovarian cancer, gastric cancer, pancreatic cancer, and colorectal cancer. TAMs could contribute to carcinogenesis, neoangiogenesis, immune-suppressive TME remodeling, cancer chemoresistance, recurrence, and metastasis. Therefore, reprogramming of the immune-suppressive TAMs by pharmacological approaches has attracted considerable research attention in recent years. In this review, the promising pharmaceutical targets, as well as the existing modulatory strategies of TAMs were summarized. The chemokine-chemokine receptor signaling, tyrosine kinase receptor signaling, metabolic signaling, and exosomal signaling have been highlighted in determining the biological functions of TAMs. Besides, both preclinical research and clinical trials have suggested the chemokine-chemokine receptor blockers, tyrosine kinase inhibitors, bisphosphonates, as well as the exosomal or nanoparticle-based targeting delivery systems as the promising pharmacological approaches for TAMs deletion or reprogramming. Lastly, the combined therapies of TAMs-targeting strategies with traditional treatments or immunotherapies as well as the exosome-like nanovesicles for cancer therapy are prospected.
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Affiliation(s)
- Neng Wang
- The Research Center for Integrative MedicineSchool of Basic Medical SciencesGuangzhou University of Chinese MedicineGuangzhouGuangdongChina
- The Research Center of Integrative Cancer MedicineDiscipline of Integrated Chinese and Western MedicineThe Second Clinical College of Guangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong‐Hong Kong‐Macau Joint Lab on Chinese Medicine and Immune Disease ResearchGuangzhou University of Chinese MedicineGuangzhouGuangdongChina
| | - Shengqi Wang
- The Research Center of Integrative Cancer MedicineDiscipline of Integrated Chinese and Western MedicineThe Second Clinical College of Guangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong‐Hong Kong‐Macau Joint Lab on Chinese Medicine and Immune Disease ResearchGuangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine SyndromeGuangdong Provincial Hospital of Chinese MedicineGuangdong Provincial Academy of Chinese Medical SciencesGuangzhouGuangdongChina
| | - Xuan Wang
- The Research Center of Integrative Cancer MedicineDiscipline of Integrated Chinese and Western MedicineThe Second Clinical College of Guangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong‐Hong Kong‐Macau Joint Lab on Chinese Medicine and Immune Disease ResearchGuangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine SyndromeGuangdong Provincial Hospital of Chinese MedicineGuangdong Provincial Academy of Chinese Medical SciencesGuangzhouGuangdongChina
| | - Yifeng Zheng
- The Research Center of Integrative Cancer MedicineDiscipline of Integrated Chinese and Western MedicineThe Second Clinical College of Guangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong‐Hong Kong‐Macau Joint Lab on Chinese Medicine and Immune Disease ResearchGuangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine SyndromeGuangdong Provincial Hospital of Chinese MedicineGuangdong Provincial Academy of Chinese Medical SciencesGuangzhouGuangdongChina
| | - Bowen Yang
- The Research Center of Integrative Cancer MedicineDiscipline of Integrated Chinese and Western MedicineThe Second Clinical College of Guangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong‐Hong Kong‐Macau Joint Lab on Chinese Medicine and Immune Disease ResearchGuangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine SyndromeGuangdong Provincial Hospital of Chinese MedicineGuangdong Provincial Academy of Chinese Medical SciencesGuangzhouGuangdongChina
| | - Juping Zhang
- The Research Center of Integrative Cancer MedicineDiscipline of Integrated Chinese and Western MedicineThe Second Clinical College of Guangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong‐Hong Kong‐Macau Joint Lab on Chinese Medicine and Immune Disease ResearchGuangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine SyndromeGuangdong Provincial Hospital of Chinese MedicineGuangdong Provincial Academy of Chinese Medical SciencesGuangzhouGuangdongChina
| | - Bo Pan
- The Research Center of Integrative Cancer MedicineDiscipline of Integrated Chinese and Western MedicineThe Second Clinical College of Guangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong‐Hong Kong‐Macau Joint Lab on Chinese Medicine and Immune Disease ResearchGuangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine SyndromeGuangdong Provincial Hospital of Chinese MedicineGuangdong Provincial Academy of Chinese Medical SciencesGuangzhouGuangdongChina
| | - Jianli Gao
- Academy of Traditional Chinese MedicineZhejiang Chinese Medical UniversityHangzhouZhejiangChina
| | - Zhiyu Wang
- The Research Center for Integrative MedicineSchool of Basic Medical SciencesGuangzhou University of Chinese MedicineGuangzhouGuangdongChina
- The Research Center of Integrative Cancer MedicineDiscipline of Integrated Chinese and Western MedicineThe Second Clinical College of Guangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong‐Hong Kong‐Macau Joint Lab on Chinese Medicine and Immune Disease ResearchGuangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine SyndromeGuangdong Provincial Hospital of Chinese MedicineGuangdong Provincial Academy of Chinese Medical SciencesGuangzhouGuangdongChina
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Kadomoto S, Izumi K, Mizokami A. The CCL20-CCR6 Axis in Cancer Progression. Int J Mol Sci 2020; 21:ijms21155186. [PMID: 32707869 PMCID: PMC7432448 DOI: 10.3390/ijms21155186] [Citation(s) in RCA: 163] [Impact Index Per Article: 32.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/15/2020] [Accepted: 07/16/2020] [Indexed: 12/14/2022] Open
Abstract
Chemokines, which are basic proteins that exert their effects via G protein-coupled receptors and a subset of the cytokine family, are mediators deeply involved in leukocyte migration during an inflammatory reaction. Chemokine (C-C motif) ligand 20 (CCL20), also known as macrophage inflammatory protein (MIP)-3α, liver activation regulated chemokine (LARC), and Exodus-1, is a small protein that is physiologically expressed in the liver, colon, and skin, is involved in tissue inflammation and homeostasis, and has a specific receptor C-C chemokine receptor 6 (CCR6). The CCL20-CCR6 axis has long been known to be involved in inflammatory and infectious diseases, such as rheumatoid arthritis and human immunodeficiency virus infections. Recently, however, reports have shown that the CCL20-CCR6 axis is associated with several cancers, including hepatocellular carcinoma, colorectal cancer, breast cancer, pancreatic cancer, cervical cancer, and kidney cancer. The CCL20-CCR6 axis promotes cancer progression directly by enhancing migration and proliferation of cancer cells and indirectly by remodeling the tumor microenvironment through immune cell control. The present article reviewed the role of the CCL20-CCR6 axis in cancer progression and its potential as a therapeutic target.
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Affiliation(s)
| | - Kouji Izumi
- Correspondence: ; Tel.: +81-76-265-2393; Fax: +81-76-234-4263
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