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Zhao Y, Zhang L, Xia L, E H, Wang T, Lu H, Chen H, She Y, Tang H, Wu J, Zhao D, Chen C. A METTL3-NFE2L3 axis mediates tumor stemness and progression in lung adenocarcinoma. SCIENCE ADVANCES 2025; 11:eadt7682. [PMID: 40249818 PMCID: PMC12007586 DOI: 10.1126/sciadv.adt7682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 03/14/2025] [Indexed: 04/20/2025]
Abstract
The progression of lung adenocarcinoma is primarily driven by cancer stem cells (CSCs), which have self-renewal capabilities and confer resistance to therapies, including neoadjuvant treatments combining chemotherapy and immune checkpoint inhibitors. In this study, we identified that OV6+ tumor cells exhibit stem-like characteristics and are notably enriched in patients with non-major pathological response, closely associated with resistance to combination therapies. Hypoxia and HIF1α were found to drive the formation of OV6+ CSCs. METTL3, a methyltransferase, was revealed as a critical regulator of OV6+ CSCs by stabilizing NFE2L3 messenger RNA via an N6-methyladenosine-dependent manner, thereby up-regulating NFE2L3 and activating the intrinsic WNT signaling pathway essential for maintaining stemness. OV6+ tumor cells promoted M2 macrophage infiltration and the formation of an immunosuppressive tumor microenvironment (TME). Targeting METTL3 effectively eliminated OV6+ CSCs and suppressed tumor progression. Moreover, the combination of STM2457 with cisplatin overcame chemoresistance, remodeled the TME, and provided promising insights for enhancing the efficacy of neoadjuvant combination therapies.
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Affiliation(s)
- Yue Zhao
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Lei Zhang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Lang Xia
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Haoran E
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Tao Wang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Huinan Lu
- Peking University Yangtze Center of Future Health Technology, Wuxi, Jiangsu, China
| | - Hezhong Chen
- Department of Thoracic Surgery, Changhai Hospital, Navy Medical University, Shanghai, China
| | - Yunlang She
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Hao Tang
- Department of Respiratory and Critical Care Medicine, Changzheng Hospital, Navy Medical University, Shanghai, China
| | - Junqi Wu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Deping Zhao
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Chang Chen
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
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E H, Zhang L, Yang Z, Xu L, Wang T, Guo J, Xia L, Yu J, Wang H, She Y, Wu J, Zhao Y, Chen C, Zhao D. SNAI1 promotes epithelial-mesenchymal transition and maintains cancer stem cell-like properties in thymic epithelial tumors through the PIK3R2/p-EphA2 Axis. J Exp Clin Cancer Res 2024; 43:324. [PMID: 39702326 DOI: 10.1186/s13046-024-03243-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Accepted: 11/29/2024] [Indexed: 12/21/2024] Open
Abstract
BACKGROUND Thymic epithelial tumors (TETs) are infrequent malignancies that arise from the anterior mediastinum. Therapeutic options for TETs, especially thymic carcinoma (TC), remain relatively constrained. This study aims to investigate the oncogenic hub gene and its underlying mechanisms in TETs, as well as to identify potential therapeutic targets. METHODS Weighted gene co-expression network analysis (WGCNA) and differential gene expression (DEG) analysis were utilized to identify significant oncogenes using The Cancer Genome Atlas (TCGA) database. LASSO logistic regression analysis was performed to assess the association between hub genes and clinical parameters. The influence of the hub gene on promoting epithelial-mesenchymal transition (EMT), tumor progression, and regulating cancer stem cell-like properties was assessed both in vitro and in vivo. Single-cell RNA sequencing (scRNA-seq) was utilized to analyze the alterations in the tumor and its microenvironment following the administration of the hub gene's inhibitor. Multiplex immunohistochemistry (mIHC) was employed to validate the results. The potential mechanism was further elucidated through the utilization of Cleavage Under Targets and Tagmentation (CUT&Tag), RNA-sequencing, chromatin immunoprecipitation (ChIP), CUT&RUN, luciferase reporter assay, co-immunoprecipitation (Co-IP), mass spectrometry (MS) and phosphoproteomic assays. RESULTS SNAI1 was identified as a hub transcription factor for TETs, and its positive correlation with the invasiveness of the disease was confirmed. Subsequent experiments revealed that the upregulation of SNAI1 augmented the migration, invasion, and EMT of TET cell lines. Furthermore, we observed that the overexpression of SNAI1 sustained cancer stem cell-like properties. ScRNA-seq demonstrated that the use of a SNAI1 inhibitor inhibited the transition of macrophages from M1 to M2 phenotype, a finding further validated by multiplex immunohistochemistry (mIHC). Phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2) was identified as one of the downstream targets of SNAI1 through CUT&Tag and RNA-sequencing, a finding validated by ChIP-qPCR, CUT&RUN-qPCR, luciferase reporter and immunofluorescence assays. Co-IP, MS and phosphoproteomic assays further confirmed that PIK3R2 directly interacted with phosphorylated EphA2 (p-EphA2), facilitating downstream GSK3β/β-catenin signaling pathway. CONCLUSION The tumorigenic role of SNAI1 through the PIK3R2/p-EphA2 axis was preliminarily validated in TETs. A potential therapeutic strategy for TETs may involve the inhibition of SNAI1.
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Affiliation(s)
- Haoran E
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200443, China
| | - Lei Zhang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200443, China
| | - Zhenhua Yang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200443, China
- Department of Thoracic Surgery, Ningbo No.2 Hospital, Ningbo, 315000, China
| | - Long Xu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200443, China
| | - Tao Wang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200443, China
| | - Junhong Guo
- Department of Pathology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China
| | - Lang Xia
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200443, China
| | - Juemin Yu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200443, China
| | - Heyong Wang
- Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China
| | - Yunlang She
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200443, China
| | - Junqi Wu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200443, China
| | - Yue Zhao
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200443, China.
| | - Chang Chen
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200443, China.
| | - Deping Zhao
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200443, China.
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Zhao YX, Zhao HP, Zhao MY, Yu Y, Qi X, Wang JH, Lv J. Latest insights into the global epidemiological features, screening, early diagnosis and prognosis prediction of esophageal squamous cell carcinoma. World J Gastroenterol 2024; 30:2638-2656. [PMID: 38855150 PMCID: PMC11154680 DOI: 10.3748/wjg.v30.i20.2638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 04/26/2024] [Accepted: 05/13/2024] [Indexed: 05/27/2024] Open
Abstract
As a highly invasive carcinoma, esophageal cancer (EC) was the eighth most prevalent malignancy and the sixth leading cause of cancer-related death worldwide in 2020. Esophageal squamous cell carcinoma (ESCC) is the major histological subtype of EC, and its incidence and mortality rates are decreasing globally. Due to the lack of specific early symptoms, ESCC patients are usually diagnosed with advanced-stage disease with a poor prognosis, and the incidence and mortality rates are still high in many countries, especially in China. Therefore, enormous challenges still exist in the management of ESCC, and novel strategies are urgently needed to further decrease the incidence and mortality rates of ESCC. Although the key molecular mechanisms underlying ESCC pathogenesis have not been fully elucidated, certain promising biomarkers are being investigated to facilitate clinical decision-making. With the advent and advancement of high-throughput technologies, such as genomics, proteomics and metabolomics, valuable biomarkers with high sensitivity, specificity and stability could be identified for ESCC. Herein, we aimed to determine the epidemiological features of ESCC in different regions of the world, especially in China, and focused on novel molecular biomarkers associated with ESCC screening, early diagnosis and prognosis prediction.
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Affiliation(s)
- Yi-Xin Zhao
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - He-Ping Zhao
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Meng-Yao Zhao
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Yan Yu
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Xi Qi
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Ji-Han Wang
- Institute of Medical Research, Northwestern Polytechnical University, Xi’an 710072, Shaanxi Province, China
| | - Jing Lv
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
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Choksi Y. Autophagy Regulates Esophageal Epithelial Renewal. Cell Mol Gastroenterol Hepatol 2024; 18:155-156. [PMID: 38583484 PMCID: PMC11282409 DOI: 10.1016/j.jcmgh.2024.03.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 03/14/2024] [Indexed: 04/09/2024]
Affiliation(s)
- Yash Choksi
- Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee.
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5
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Klochkova A, Karami AL, Fuller AD, Parham LR, Panchani SR, Natarajan S, Jackson JL, Mu A, Tan Y, Cai KQ, Klein-Szanto AJ, Muir AB, Tétreault MP, Graña X, Hamilton KE, Whelan KA. Autophagy Contributes to Homeostasis in Esophageal Epithelium Where High Autophagic Vesicle Level Marks Basal Cells With Limited Proliferation and Enhanced Self-Renewal Potential. Cell Mol Gastroenterol Hepatol 2024; 18:15-40. [PMID: 38452871 PMCID: PMC11126828 DOI: 10.1016/j.jcmgh.2024.02.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 02/27/2024] [Accepted: 02/28/2024] [Indexed: 03/09/2024]
Abstract
BACKGROUND & AIMS Autophagy plays roles in esophageal pathologies both benign and malignant. Here, we aim to define the role of autophagy in esophageal epithelial homeostasis. METHODS We generated tamoxifen-inducible, squamous epithelial-specific Atg7 (autophagy related 7) conditional knockout mice to evaluate effects on esophageal homeostasis and response to the carcinogen 4-nitroquinoline 1-oxide (4NQO) using histologic and biochemical analyses. We fluorescence-activated cell sorted esophageal basal cells based on fluorescence of the autophagic vesicle (AV)-identifying dye Cyto-ID and then subjected these cells to transmission electron microscopy, image flow cytometry, three-dimensional organoid assays, RNA sequencing, and cell cycle analysis. Three-dimensional organoids were subjected to passaging, single-cell RNA sequencing, cell cycle analysis, and immunostaining. RESULTS Genetic autophagy inhibition in squamous epithelium resulted in increased proliferation of esophageal basal cells under homeostatic conditions and also was associated with significant weight loss in mice treated with 4NQO that further displayed perturbed epithelial tissue architecture. Esophageal basal cells with high AV level (Cyto-IDHigh) displayed limited organoid formation capability on initial plating but passaged more efficiently than their counterparts with low AV level (Cyto-IDLow). RNA sequencing suggested increased autophagy in Cyto-IDHigh esophageal basal cells along with decreased cell cycle progression, the latter of which was confirmed by cell cycle analysis. Single-cell RNA sequencing of three-dimensional organoids generated by Cyto-IDLow and Cyto-IDHigh cells identified expansion of 3 cell populations and enrichment of G2/M-associated genes in the Cyto-IDHigh group. Ki67 expression was also increased in organoids generated by Cyto-IDHigh cells, including in basal cells localized beyond the outermost cell layer. CONCLUSIONS Autophagy contributes to maintenance of the esophageal proliferation-differentiation gradient. Esophageal basal cells with high AV level exhibit limited proliferation and generate three-dimensional organoids with enhanced self-renewal capacity.
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Affiliation(s)
- Alena Klochkova
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
| | - Adam L Karami
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
| | - Annie D Fuller
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
| | - Louis R Parham
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Surali R Panchani
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
| | - Shruthi Natarajan
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
| | - Jazmyne L Jackson
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
| | - Anbin Mu
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
| | - Yinfei Tan
- Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | - Kathy Q Cai
- Histopathology Facility, Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | | | - Amanda B Muir
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Marie-Pier Tétreault
- Department of Medicine, Gastroenterology and Hepatology Division, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Xavier Graña
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania; Department of Cancer & Cellular Biology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
| | - Kathryn E Hamilton
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Kelly A Whelan
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania; Department of Cancer & Cellular Biology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania.
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Wang L, Liu H, Liu Y, Guo S, Yan Z, Chen G, Wu Q, Xu S, Zhou Q, Liu L, Peng M, Cheng X, Yan T. Potential markers of cancer stem-like cells in ESCC: a review of the current knowledge. Front Oncol 2024; 13:1324819. [PMID: 38239657 PMCID: PMC10795532 DOI: 10.3389/fonc.2023.1324819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 12/01/2023] [Indexed: 01/22/2024] Open
Abstract
In patients with esophageal squamous cell carcinoma (ESCC), the incidence and mortality rate of ESCC in our country are also higher than those in the rest of the world. Despite advances in the treatment department method, patient survival rates have not obviously improved, which often leads to treatment obstruction and cancer repeat. ESCC has special cells called cancer stem-like cells (CSLCs) with self-renewal and differentiation ability, which reflect the development process and prognosis of cancer. In this review, we evaluated CSLCs, which are identified from the expression of cell surface markers in ESCC. By inciting EMTs to participate in tumor migration and invasion, stem cells promote tumor redifferentiation. Some factors can inhibit the migration and invasion of ESCC via the EMT-related pathway. We here summarize the research progress on the surface markers of CSLCs, EMT pathway, and the microenvironment in the process of tumor growth. Thus, these data may be more valuable for clinical applications.
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Affiliation(s)
- Lu Wang
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology of the Ministry of Education, Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Huijuan Liu
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology of the Ministry of Education, Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yiqian Liu
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology of the Ministry of Education, Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Shixing Guo
- Clinical Laboratory Medicine Centre, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Zhenpeng Yan
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology of the Ministry of Education, Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Guohui Chen
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology of the Ministry of Education, Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Qinglu Wu
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology of the Ministry of Education, Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Songrui Xu
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology of the Ministry of Education, Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Qichao Zhou
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology of the Ministry of Education, Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Lili Liu
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology of the Ministry of Education, Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Meilan Peng
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology of the Ministry of Education, Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xiaolong Cheng
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology of the Ministry of Education, Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Ting Yan
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology of the Ministry of Education, Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, China
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7
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Klochkova A, Karami AL, Fuller AD, Parham LR, Panchani SR, Natarajan S, Jackson JL, Mu A, Tan Y, Cai KQ, Klein-Szanto AJ, Muir AB, Tétreault MP, Hamilton KE, Whelan KA. Autophagy contributes to homeostasis in esophageal epithelium where high autophagic vesicle content marks basal cells with limited proliferation and enhanced self-renewal potential. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.20.558614. [PMID: 37781581 PMCID: PMC10541137 DOI: 10.1101/2023.09.20.558614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Abstract
Background & Aims Autophagy has been demonstrated to play roles in esophageal pathologies both benign and malignant. Here, we aim to define the role of autophagy in esophageal epithelium under homeostatic conditions. Methods We generated tamoxifen-inducible, squamous epithelial-specific Atg7 (autophagy related 7) conditional knockout mice to evaluate effects on esophageal homeostasis and response to the carcinogen 4-nitroquinoline 1-oxide (4NQO) using histological and biochemical analyses. We FACS sorted esophageal basal cells based upon fluorescence of the autophagic vesicle (AV)-identifying dye Cyto-ID, then subjected these cells to transmission electron microscopy, image flow cytometry, 3D organoid assays, RNA-Sequencing (RNA-Seq), and cell cycle analysis. 3D organoids were subjected to passaging, single cell (sc) RNA-Seq, cell cycle analysis, and immunostaining. Results Genetic autophagy inhibition in squamous epithelium resulted in increased proliferation of esophageal basal cells. Esophageal basal cells with high AV level (Cyto-ID High ) displayed limited organoid formation capability upon initial plating but passaged more efficiently than their counterparts with low AV level (Cyto-ID Low ). RNA-Seq suggested increased autophagy in Cyto- ID High esophageal basal cells along with decreased cell cycle progression, the latter of which was confirmed by cell cycle analysis. scRNA-Seq of 3D organoids generated by Cyto-ID Low and Cyto- ID High cells identified expansion of 3 cell populations, enrichment of G2/M-associated genes, and aberrant localization of cell cycle-associated genes beyond basal cell populations in the Cyto- ID High group. Ki67 expression was also increased in organoids generated by Cyto-ID High cells, including in cells beyond the basal cell layer. Squamous epithelial-specific autophagy inhibition induced significant weight loss in mice treated with 4NQO that further displayed perturbed epithelial tissue architecture. Conclusions High AV level identifies esophageal epithelium with limited proliferation and enhanced self-renewal capacity that contributes to maintenance of the esophageal proliferation- differentiation gradient in vivo .
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8
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Xuan SH, Hua ML, Xiang Z, He XL, Huang L, Jiang C, Dong P, Wu J. Roles of cancer stem cells in gastrointestinal cancers. World J Stem Cells 2023; 15:209-220. [PMID: 37181004 PMCID: PMC10173810 DOI: 10.4252/wjsc.v15.i4.209] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 02/25/2023] [Accepted: 03/27/2023] [Indexed: 04/26/2023] Open
Abstract
Cancer stem cells (CSCs) are the main cause of tumor growth, invasion, metastasis and recurrence. Recently, CSCs have been extensively studied to identify CSC-specific surface markers as well as signaling pathways that play key roles in CSCs self-renewal. The involvement of CSCs in the pathogenesis of gastrointestinal (GI) cancers also highlights these cells as a priority target for therapy. The diagnosis, prognosis and treatment of GI cancer have always been a focus of attention. Therefore, the potential application of CSCs in GI cancers is receiving increasing attention. This review summarizes the role of CSCs in GI cancers, focusing on esophageal cancer, gastric cancer, liver cancer, colorectal cancer, and pancreatic cancer. In addition, we propose CSCs as potential targets and therapeutic strategies for the effective treatment of GI cancers, which may provide better guidance for clinical treatment of GI cancers.
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Affiliation(s)
- Shi-Hai Xuan
- Department of Laboratory Medicine, The People's Hospital of Dongtai City, Dongtai 224299, Jiangsu Province, China
| | - Meng-Lu Hua
- School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
| | - Ze Xiang
- School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
| | - Xiang-Lin He
- School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
| | - Lan Huang
- Department of Clinical Laboratory, Suzhou Municipal Hospital, Suzhou 215008, Jiangsu Province, China
| | - Chun Jiang
- Department of Clinical Laboratory, Suzhou Municipal Hospital, Suzhou 215008, Jiangsu Province, China
| | - Peng Dong
- Hangzhou Institute of Cardiovascular Diseases, Hangzhou Normal University, Hangzhou 310015, Zhejiang Province, China
| | - Jian Wu
- Department of Clinical Laboratory, Suzhou Municipal Hospital, Suzhou 215008, Jiangsu Province, China.
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9
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Hussen BM, Kheder RK, Abdullah ST, Hidayat HJ, Rahman HS, Salihi A, Taheri M, Ghafouri-Fard S. Functional interplay between long non-coding RNAs and Breast CSCs. Cancer Cell Int 2022; 22:233. [PMID: 35864503 PMCID: PMC9306174 DOI: 10.1186/s12935-022-02653-4] [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: 04/09/2022] [Accepted: 07/12/2022] [Indexed: 12/14/2022] Open
Abstract
Breast cancer (BC) represents aggressive cancer affecting most women’s lives globally. Metastasis and recurrence are the two most common factors in a breast cancer patient's poor prognosis. Cancer stem cells (CSCs) are tumor cells that are able to self-renew and differentiate, which is a significant factor in metastasis and recurrence of cancer. Long non-coding RNAs (lncRNAs) describe a group of RNAs that are longer than 200 nucleotides and do not have the ability to code for proteins. Some of these lncRNAs can be mainly produced in various tissues and tumor forms. In the development and spread of malignancies, lncRNAs have a significant role in influencing multiple signaling pathways positively or negatively, making them promise useful diagnostic and prognostic markers in treating the disease and guiding clinical therapy. However, it is not well known how the interaction of lncRNAs with CSCs will affect cancer development and progression. Here, in this review, we attempt to summarize recent findings that focus on lncRNAs affect cancer stem cell self-renewal and differentiation in breast cancer development and progression, as well as the strategies and challenges for overcoming lncRNA's therapeutic resistance.
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Affiliation(s)
- Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil , Kurdistan Region, Iraq.,Center of Research and Strategic Studies, Lebanese French University, Erbil, Iraq
| | - Ramiar Kamal Kheder
- Department of Medical Analysis, Faculty of Science, Tishk International University, Erbil, Iraq.,Medical Laboratory Science, College of Science, University of Raparin, Rania, KGR, Iraq
| | - Sara Tharwat Abdullah
- Department of Pharmacology and Toxicology, College of Pharmacy, Hawler Medical University, Erbil, Iraq
| | - Hazha Jamal Hidayat
- Department of Biology, College of Education, Salahaddin University-Erbil, Erbil, Kurdistan Region, Iraq
| | - Heshu Sulaiman Rahman
- Department of Physiology, College of Medicine, University of Sulaimani, Sulaimaniyah, Republic of Iraq.,Department of Medical Laboratory Sciences, Komar University of Science and Technology, Sulaimaniyah, Republic of Iraq
| | - Abbas Salihi
- Department of Biology, College of Science, Salahaddin University-Erbil, Erbil, Kurdistan Region, Iraq
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. .,Institute of Human Genetics, Jena University Hospital, Jena, Germany.
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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10
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Cheng X, Lou K, Ding L, Zou X, Huang R, Xu G, Zou J, Zhang G. Clinical potential of the Hippo-YAP pathway in bladder cancer. Front Oncol 2022; 12:925278. [PMID: 35912245 PMCID: PMC9336529 DOI: 10.3389/fonc.2022.925278] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 06/27/2022] [Indexed: 11/13/2022] Open
Abstract
Bladder cancer (BC) is one of the world’s most frequent cancers. Surgery coupled with adjuvant platinum-based chemotherapy is the current standard of therapy for BC. However, a high proportion of patients progressed to chemotherapy-resistant or even neoplasm recurrence. Hence, identifying novel treatment targets is critical for clinical treatment. Current studies indicated that the Hippo-YAP pathway plays a crucial in regulating the survival of cancer stem cells (CSCs), which is related to the progression and reoccurrence of a variety of cancers. In this review, we summarize the evidence that Hippo-YAP mediates the occurrence, progression and chemotherapy resistance in BC, as well as the role of the Hippo-YAP pathway in regulating bladder cancer stem-like cells (BCSCs). Finally, the clinical potential of Hippo-YAP in the treatment of BC was prospected.
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Affiliation(s)
- Xin Cheng
- First Clinical College, Gannan Medical University, Ganzhou, China
- Department of Urology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Institute of Urology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Kecheng Lou
- First Clinical College, Gannan Medical University, Ganzhou, China
- Department of Urology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Institute of Urology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Liang Ding
- First Clinical College, Gannan Medical University, Ganzhou, China
- Department of Urology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Institute of Urology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Xiaofeng Zou
- Department of Urology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Institute of Urology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Department of Jiangxi Engineering Technology Research Center of Calculi Prevention, Gannan Medical University, Ganzhou, China
| | - Ruohui Huang
- Department of Urology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Institute of Urology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Department of Jiangxi Engineering Technology Research Center of Calculi Prevention, Gannan Medical University, Ganzhou, China
| | - Gang Xu
- Department of Urology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Institute of Urology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Department of Jiangxi Engineering Technology Research Center of Calculi Prevention, Gannan Medical University, Ganzhou, China
| | - Junrong Zou
- Department of Urology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Institute of Urology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Department of Jiangxi Engineering Technology Research Center of Calculi Prevention, Gannan Medical University, Ganzhou, China
| | - Guoxi Zhang
- Department of Urology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Institute of Urology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Department of Jiangxi Engineering Technology Research Center of Calculi Prevention, Gannan Medical University, Ganzhou, China
- *Correspondence: Guoxi Zhang,
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11
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Zhou S, Sun X, Jin Z, Yang H, Ye W. The role of autophagy in initiation, progression, TME modification, diagnosis, and treatment of esophageal cancers. Crit Rev Oncol Hematol 2022; 175:103702. [PMID: 35577254 DOI: 10.1016/j.critrevonc.2022.103702] [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: 01/26/2022] [Revised: 04/14/2022] [Accepted: 05/02/2022] [Indexed: 10/18/2022] Open
Abstract
Autophagy is a highly conserved metabolic process with a cytoprotective function. Autophagy is involved in cancer, infection, immunity, and inflammation and may be a potential therapeutic target. Increasing evidence has revealed that autophagy has primary implications for esophageal cancer, including its initiation, progression, tumor microenvironment (TME) modification, diagnosis, and treatment. Notably, autophagy displayed excellent application potential in radiotherapy combined with immunotherapy. Radiotherapy combined with immunotherapy is a new potential therapeutic strategy for cancers, including esophageal cancer. Autophagy modulators can work as adjuvant enhancers in radiotherapy or immunotherapy of cancers. This review highlights the most recent data related to the role of autophagy regulation in esophageal cancer.
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Affiliation(s)
- Suna Zhou
- Department of Radiation Oncology, Xi'an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi 710018, P.R. China; Laboratory of Cellular and Molecular Radiation Oncology, The Affiliated Taizhou Hospital, Wenzhou Medical University, Taizhou 317000, Zhejiang, P.R. China; Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou, P.R. China
| | - Xuefeng Sun
- Laboratory of Cellular and Molecular Radiation Oncology, The Affiliated Taizhou Hospital, Wenzhou Medical University, Taizhou 317000, Zhejiang, P.R. China; Department of Radiation Oncology, The Affiliated Taizhou Hospital, Wenzhou Medical University, Taizhou, P.R. China
| | - Zhicheng Jin
- Laboratory of Cellular and Molecular Radiation Oncology, The Affiliated Taizhou Hospital, Wenzhou Medical University, Taizhou 317000, Zhejiang, P.R. China; Department of Radiation Oncology, The Affiliated Taizhou Hospital, Wenzhou Medical University, Taizhou, P.R. China
| | - Haihua Yang
- Laboratory of Cellular and Molecular Radiation Oncology, The Affiliated Taizhou Hospital, Wenzhou Medical University, Taizhou 317000, Zhejiang, P.R. China; Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou, P.R. China; Department of Radiation Oncology, The Affiliated Taizhou Hospital, Wenzhou Medical University, Taizhou, P.R. China
| | - Wenguang Ye
- Department of Gastroenterology, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou, P.R. China.
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12
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Luan S, Zeng X, Zhang C, Qiu J, Yang Y, Mao C, Xiao X, Zhou J, Zhang Y, Yuan Y. Advances in Drug Resistance of Esophageal Cancer: From the Perspective of Tumor Microenvironment. Front Cell Dev Biol 2021; 9:664816. [PMID: 33816512 PMCID: PMC8017339 DOI: 10.3389/fcell.2021.664816] [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] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Accepted: 02/28/2021] [Indexed: 02/05/2023] Open
Abstract
Drug resistance represents the major obstacle to get the maximum therapeutic benefit for patients with esophageal cancer since numerous patients are inherently or adaptively resistant to therapeutic agents. Notably, increasing evidence has demonstrated that drug resistance is closely related to the crosstalk between tumor cells and the tumor microenvironment (TME). TME is a dynamic and ever-changing complex biological network whose diverse cellular and non-cellular components influence hallmarks and fates of tumor cells from the outside, and this is responsible for the development of resistance to conventional therapeutic agents to some extent. Indeed, the formation of drug resistance in esophageal cancer should be considered as a multifactorial process involving not only cancer cells themselves but cancer stem cells, tumor-associated stromal cells, hypoxia, soluble factors, extracellular vesicles, etc. Accordingly, combination therapy targeting tumor cells and tumor-favorable microenvironment represents a promising strategy to address drug resistance and get better therapeutic responses for patients with esophageal cancer. In this review, we mainly focus our discussion on molecular mechanisms that underlie the role of TME in drug resistance in esophageal cancer. We also discuss the opportunities and challenges for therapeutically targeting tumor-favorable microenvironment, such as membrane proteins, pivotal signaling pathways, and cytokines, to attenuate drug resistance in esophageal cancer.
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Affiliation(s)
- Siyuan Luan
- Department of Thoracic Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoxi Zeng
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China
| | - Chao Zhang
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China
| | - Jiajun Qiu
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yushang Yang
- Department of Thoracic Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Chengyi Mao
- Department of Thoracic Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Xin Xiao
- Department of Thoracic Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Jianfeng Zhou
- Department of Thoracic Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Yonggang Zhang
- Department of Periodical Press, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
- Nursing Key Laboratory of Sichuan Province, Chengdu, China
| | - Yong Yuan
- Department of Thoracic Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
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13
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He Z, Chen J, Chen X, Wang H, Tang L, Han C. microRNA-377 acts as a suppressor in esophageal squamous cell carcinoma through CBX3-dependent P53/P21 pathway. J Cell Physiol 2020; 236:107-120. [PMID: 33459391 DOI: 10.1002/jcp.29631] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Accepted: 01/30/2020] [Indexed: 12/19/2022]
Abstract
Stem cells play pivotal roles in esophageal squamous cell carcinoma (ESCC) recurrence and metastasis. The self-renewal ability of stem cells was associated with specific microRNAs (miRs). Herein, we identified the effects of miR-377 on ESCC stem cell activities. First, the expression of miR-377 in ESCC and adjacent normal tissues was determined. The relationship between miR-377 and chromobox protein homolog 3 (CBX3) was assessed by a dual-luciferase reporter gene assay. miR-377 was overexpressed or inhibited in ESCC stem cells to explore its role in ESCC. To further investigate the mechanism of miR-377 in ESCC, cells were introduced with short hairpin RNA against CBX3 or pifithrin-α (inhibitor of P53 pathway). Besides, the expression of P21, P53, CD133, CD13, Nanog, sex determining region Y-Box 2 (Sox2), and octamer-binding transcription factor 4 (Oct4), cell sphere formation, colony formation, and proliferation were evaluated respectively. Finally, limiting dilution assay in vivo and tumor xenograft in nude mice were conducted to confirm the roles of miR-377 in vivo. miR-377 was poorly expressed in ESCC. Overexpression of miR-377 could suppress the stem-like trait of ESCC as well as the tumor growth in vivo. miR-377 targeted CBX3 to activate the P53/P21 pathway. Besides, the expression of stem-like markers including CD133, CD13, Oct4, Sox2, and Nanog was decreased, and the abilities of cell sphere formation, colony formation, proliferation, and tumorigenicity were significantly reduced by overexpressing miR-377 or silencing CBX3. The results were reversed after inactivating the P53/P21 pathway. In summary, upregulation of miR-377 inhibits the self-renewal of ESCC stem cells by inhibiting CBX3 expression and promoting activation of the P53/P21 pathway.
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Affiliation(s)
- Zhisheng He
- Department of Thoracic Surgery Oncology, Jiangxi Cancer Hospital, Nanchang, China
| | - Junjing Chen
- Department of Radiation Oncology, Jiangxi Cancer Hospital, Nanchang, China
| | - Xiaoliang Chen
- Department of Thoracic Surgery Oncology, Jiangxi Cancer Hospital, Nanchang, China
| | - Huanyuan Wang
- Department of Thoracic Surgery Oncology, Jiangxi Cancer Hospital, Nanchang, China
| | - Lang Tang
- Department of Thoracic Surgery Oncology, Jiangxi Cancer Hospital, Nanchang, China
| | - Chunbin Han
- Department of Thoracic Surgery Oncology, Jiangxi Cancer Hospital, Nanchang, China
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14
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Chen Y, Lu Y, Ren Y, Yuan J, Zhang N, Kimball H, Zhou L, Yang M. Starvation-induced suppression of DAZAP1 by miR-10b integrates splicing control into TSC2-regulated oncogenic autophagy in esophageal squamous cell carcinoma. Theranostics 2020; 10:4983-4996. [PMID: 32308763 PMCID: PMC7163442 DOI: 10.7150/thno.43046] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Accepted: 03/21/2020] [Indexed: 12/14/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) accounts for about 90% of all incident esophageal cancers, with a 5-year survival rate of < 20%. Autophagy is of particular importance in cancers; however, the detailed regulatory mechanisms of oncogenic autophagy in ESCC have not been fully elucidated. In the present study, we address how splicing control of TSC2 is involved in mTOR-regulated oncogenic autophagy. Methods: Alternative splicing events controlled by DAZAP1 in ESCC cells were identified via RNAseq. Differential phosphorylation of short or long TSC2 splicing variants by AKT and their impacts on mTOR signaling were also examined. Results: We found that starvation-induced miR-10b could enhance autophagy via silencing DAZAP1, a key regulator of pre-mRNA alternative splicing. Intriguingly, we observed a large number of significantly changed alternative splicing events, especially exon skipping, upon RNAi of DAZAP1. TSC2 was verified as one of the crucial target genes of DAZAP1. Silencing of DAZAP1 led to the exclusion of TSC2 exon 26 (from Leu947 to Arg988), producing a short TSC2 isoform. The short TSC2 isoform cannot be phosphorylated at Ser981 by AKT, which resulted in continuous activation of TSC2 in ESCC. The active TSC2 inhibited mTOR via RHEB, leading to continually stimulated oncogenic autophagy of ESCC cells. Conclusions: Our data revealed an important physiological function of tumor suppressor DAZAP1 in autophagy regulation and highlighted the potential of controlling mRNA alternative splicing as an effective therapeutic application for cancers.
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15
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Wang C, Hong T, Wang Y, Gan S, Wang Q, Li J, Zuo L, Cui X. Integration of intratumoral RASSF10 expression and tumor-associated macrophages into the established clinical indicators better predicts the prognosis of clear cell renal cell carcinoma patients. Oncoimmunology 2020; 9:1736793. [PMID: 32313718 PMCID: PMC7153841 DOI: 10.1080/2162402x.2020.1736793] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 12/16/2019] [Accepted: 01/13/2020] [Indexed: 12/18/2022] Open
Abstract
A helpful evaluation system is crucial for the postoperative prognosis prediction of clear cell renal cell carcinoma (ccRCC) patients. This study determined the prognostic value of combining intratumoral RASSF10 expression and tumor-associated macrophages (TAMs) with the established clinicopathological indicators in ccRCC patients. RASSF10 expression was analyzed in ccRCC patient data from online databases and ccRCC cell lines. Two independent ccRCC patient cohorts were employed to examine the prognostic value of RASSF10 and other markers by immunohistochemistry (IHC) and statistical analyses. We found that RASSF10 expression was downregulated in ccRCC specimens from the TCGA datasets and three independent institutions. RASSF10 expression was negatively correlated with disease progression and TAM infiltration in ccRCC. In addition, low RASSF10 expression and high TAM infiltration predicted a high TNM stage, SSIGN score, WHO/ISUP grading, and a poor prognosis in two independent ccRCC patient cohorts. Moreover, RASSF10, CD68 or CD163, TNM stage, and SSIGN score were identified as independent risk factors in predicting ccRCC patients' prognosis. Time-dependent c-index analyses revealed that the combination of RASSF10 and TAMs resulted in a higher index than that resulting from each alone in the postoperative prognosis of ccRCC patients, and the integration of RASSF10 and TAMs with the TNM stage or SSIGN score achieved the best accuracy in assessing the prognosis of ccRCC patients. These findings were validated in the randomized training, validation, and combined cohorts. Taken together, the combination of the RASSF10-TAM classifier and current clinical parameters yields superior accuracy in predicting the ccRCC patients' postoperative outcome.
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Affiliation(s)
- Chao Wang
- Department of Urinary Surgery, Gongli Hospital, Second Military Medical University (Naval Medical University), Shanghai, China.,Department of Urology, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Tianyu Hong
- Department of Urinary Surgery, Gongli Hospital, Second Military Medical University (Naval Medical University), Shanghai, China.,Department of Urinary Surgery, Postgraduate Training Base in Shanghai Gongli Hospital, Ningxia Medical University, Yinchuan, Ningxia, China
| | - Yuning Wang
- Department of Urinary Surgery, Gongli Hospital, Second Military Medical University (Naval Medical University), Shanghai, China.,Department of Urinary Surgery, Postgraduate Training Base in Shanghai Gongli Hospital, Ningxia Medical University, Yinchuan, Ningxia, China
| | - Sishun Gan
- Department of Urinary Surgery, The Third Affiliated Hospital of Second Military, Medical University (Eastern Hepatobiliary Surgery Hospital), Shanghai, China
| | - Qifeng Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Jian Li
- Department of Urinary Surgery, Gongli Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Li Zuo
- Department of Urology, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Xingang Cui
- Department of Urinary Surgery, Gongli Hospital, Second Military Medical University (Naval Medical University), Shanghai, China.,Department of Urinary Surgery, The Third Affiliated Hospital of Second Military, Medical University (Eastern Hepatobiliary Surgery Hospital), Shanghai, China
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16
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Roles for Autophagy in Esophageal Carcinogenesis: Implications for Improving Patient Outcomes. Cancers (Basel) 2019; 11:cancers11111697. [PMID: 31683722 PMCID: PMC6895837 DOI: 10.3390/cancers11111697] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 10/25/2019] [Accepted: 10/26/2019] [Indexed: 02/07/2023] Open
Abstract
Esophageal cancer is among the most aggressive forms of human malignancy with five-year survival rates of <20%. Autophagy is an evolutionarily conserved catabolic process that degrades and recycles damaged organelles and misfolded proteins to maintain cellular homeostasis. While alterations in autophagy have been associated with carcinogenesis across tissues, cell type- and context-dependent roles for autophagy have been reported. Herein, we review the current knowledge related to autophagy in esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), the two most common subtypes of esophageal malignancy. We explore roles for autophagy in the development and progression of ESCC and EAC. We then continue to discuss molecular markers of autophagy as they relate to esophageal patient outcomes. Finally, we summarize current literature examining roles for autophagy in ESCC and EAC response to therapy and discuss considerations for the potential use of autophagy inhibitors as experimental therapeutics that may improve patient outcomes in esophageal cancer.
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17
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Zhao Y, Zhu J, Shi B, Wang X, Lu Q, Li C, Chen H. The transcription factor LEF1 promotes tumorigenicity and activates the TGF-β signaling pathway in esophageal squamous cell carcinoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:304. [PMID: 31296250 PMCID: PMC6625065 DOI: 10.1186/s13046-019-1296-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 06/25/2019] [Indexed: 12/28/2022]
Abstract
Background Esophageal squamous cell carcinoma (ESCC) is the most difficult subtype of esophageal cancer to treat due to the paucity of effective targeted therapy. ESCC is believed to arise from cancer stem cells (CSCs) that contribute to metastasis and chemoresistance. Despite advances in diagnosis and treatment, the prognosis of ESCC patients remains poor. Methods In this study, we applied western blot, quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry, RNA-Seq analysis, luciferase reporter assay, Chip-qPCR, bioinformatics analysis, and a series of functional assays to show the potential role of LEF1 in regulating esophageal CSCs. Results We found that the overexpression of LEF1 was associated with aberrant clinicopathological characteristics and the poor prognosis of ESCC patients. In addition, the elevated expression of LEF1 and OV6 was significantly associated with aberrant clinicopathological features, and poor patient prognosis. Moreover, the overexpression of LEF1 was observed in esophageal CSCs purified by the magnetic sorting of adherent and spheroidal ESCC cells. The increased level of LEF1 in CSCs facilitated the expression of CSC markers, stem cell-like properties, resistance to chemotherapy, and tumorigenicity and increased the percentage of CSCs in ESCC samples. Conversely, the knockdown of LEF1 significantly diminished the self-renewal properties of ESCC. We showed that LEF1 played an important mechanical role in activating the TGF-β signaling pathway by directly binding to the ID1 gene promoter. A positive association between LEF1 and ID1 expression was also observed in clinical ESCC samples. Conclusion Our results indicate that the overexpression of LEF1 promotes a CSC-like phenotype in and the tumorigenicity of ESCC by activating the TGF-β signaling pathway. The inhibition of LEF1 might therefore be a novel therapeutic target to inactivate CSCs and inhibit tumor progression. Electronic supplementary material The online version of this article (10.1186/s13046-019-1296-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yue Zhao
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China
| | - Ji Zhu
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China
| | - Bowen Shi
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China
| | - Xinyu Wang
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China
| | - Qijue Lu
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China
| | - Chunguang Li
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.
| | - Hezhong Chen
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.
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18
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Zhao Y, Lu Q, Li C, Wang X, Jiang L, Huang L, Wang C, Chen H. PRMT1 regulates the tumour-initiating properties of esophageal squamous cell carcinoma through histone H4 arginine methylation coupled with transcriptional activation. Cell Death Dis 2019; 10:359. [PMID: 31043582 PMCID: PMC6494844 DOI: 10.1038/s41419-019-1595-0] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 04/09/2019] [Accepted: 04/12/2019] [Indexed: 12/15/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC) is the most difficult subtype of esophageal cancer to treat due to a paucity of effective targeted therapy. ESCC is believed to arise from tumour initiating cells (TICs), which contribute to metastasis and chemoresistance. In this study, we found that Protein arginine methyltransferase 1(PRMT1) was highly expressed in ESCCs and associated with aberrant clinicopathological characteristics of ESCC patients. In ESCC specimens, the elevated expression of PRMT1 and OV6 was significantly associated with histologic grade, TNM stage and poor patient prognosis. Moreover, overexpression of PRMT1 was observed in esophageal TICs purified by magnetic sorting of adherent and spheroid ECA109/TE1 cells. The increased level of PRMT1 in TICs facilitated the expression of TIC markers, stem cell-like properties, resistance to chemotherapy, tumorigenicity and increased their percentages in ECSS samples. Conversely, knockdown of PRMT1 significantly diminished the self-renewal properties of ESCC. Moreover, we show that PRMT1 can catalyse histone H4R3 asymmetric dimethylation and promote transcription activation of down-stream genes. Further RNA-Seq transcriptome analysis reveals that overexpression of PRMT1 in ESCC cell lines activates Wnt/β-catenin and Notch signaling pathway. Together, our studies highlight that PRMT1 activates and maintains esophageal TICs by mediating transcription alteration through histone H4 arginine methylation.
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Affiliation(s)
- Yue Zhao
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, 200433, Shanghai, China
| | - Qijue Lu
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, 200433, Shanghai, China
| | - Chunguang Li
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, 200433, Shanghai, China
| | - Xinyu Wang
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, 200433, Shanghai, China
| | - Long Jiang
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, 200433, Shanghai, China
| | - Lei Huang
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, 200433, Shanghai, China
| | - Chao Wang
- Department of Urology, Changhai Hospital, Second Military Medical University, 200433, Shanghai, China.
| | - Hezhong Chen
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, 200433, Shanghai, China.
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Wang KJ, Wang C, Dai LH, Yang J, Huang H, Ma XJ, Zhou Z, Yang ZY, Xu WD, Hua MM, Lu X, Zeng SX, Wang HQ, Zhang ZS, Cheng YQ, Liu D, Tian QQ, Sun YH, Xu CL. Targeting an Autocrine Regulatory Loop in Cancer Stem-like Cells Impairs the Progression and Chemotherapy Resistance of Bladder Cancer. Clin Cancer Res 2018; 25:1070-1086. [PMID: 30397177 DOI: 10.1158/1078-0432.ccr-18-0586] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Revised: 06/15/2018] [Accepted: 11/01/2018] [Indexed: 11/16/2022]
Abstract
PURPOSE Cancer stem-like cells (CSCs) contribute to bladder cancer chemotherapy resistance and progression, but the associated mechanisms have not been elucidated. This study determined whether blocking an autocrine signaling loop in CSCs improves the therapeutic effects of cis-platinum on bladder cancer. EXPERIMENTAL DESIGN The expression of the epithelial marker OV6 and other markers in human bladder cancer specimens was examined by IHC. The CSC properties of magnetic-activated cell sorting (MACS)-isolated OV6+ and OV6- bladder cancer cells were examined. Molecular mechanisms were assessed through RNA-Seq, cytokine antibody arrays, co-immunoprecipitation (co-IP), chromatin immunoprecipitation (ChIP) and other assays. An orthotopic bladder cancer mouse model was established to evaluate the in vivo effects of a YAP inhibitor (verteporfin) and a PDGFR inhibitor (CP-673451) on the cis-platinum resistance of OV6+ CSCs in bladder cancer. RESULTS Upregulated OV6 expression positively associated with disease progression and poor prognosis for bladder cancer patients. Compared with OV6- cells, OV6+ bladder cancer cells exhibited strong CSC characteristics, including self-renewal, tumor initiation in NOD/SCID mice, and chemotherapy resistance. YAP, which maintains the stemness of OV6+ CSCs, triggered PDGFB transcription by recruiting TEAD1. Autocrine PDGF-BB signaling through its receptor PDGFR stabilized YAP and facilitated YAP nuclear translocation. Furthermore, blocking the YAP/TEAD1/PDGF-BB/PDGFR loop with verteporfin or CP-673451 inhibited the cis-platinum resistance of OV6+ bladder cancer CSCs in an orthotopic bladder cancer model. CONCLUSIONS OV6 could be a helpful indicator of disease progression and prognosis for patients with bladder cancer, and targeting the autocrine YAP/TEAD1/PDGF-BB/PDGFR loop might serve as a remedy for cis-platinum resistance in patients with advanced bladder cancer.
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Affiliation(s)
- Kai-Jian Wang
- Department of Urology, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Chao Wang
- Department of Urology, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Li-He Dai
- Department of Urology, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Jun Yang
- Department of Urology, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Hai Huang
- Department of Urology, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Xiao-Jing Ma
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York
| | - Zhe Zhou
- Department of Urology, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Ze-Yu Yang
- Department of Urology, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Wei-Dong Xu
- Department of Urology, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Mei-Mian Hua
- Department of Urology, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Xin Lu
- Department of Urology, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Shu-Xiong Zeng
- Department of Urology, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Hui-Qing Wang
- Department of Urology, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Zhen-Sheng Zhang
- Department of Urology, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Yan-Qiong Cheng
- Department of Urology, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Dan Liu
- Department of Urology, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Qin-Qin Tian
- Department of Urology, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Ying-Hao Sun
- Department of Urology, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China.
| | - Chuan-Liang Xu
- Department of Urology, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China.
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20
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Tu Y, Tan F, Zhou J, Pan J. Pristimerin targeting NF-κB pathway inhibits proliferation, migration, and invasion in esophageal squamous cell carcinoma cells. Cell Biochem Funct 2018; 36:228-240. [PMID: 29781107 DOI: 10.1002/cbf.3335] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Accepted: 04/23/2018] [Indexed: 12/20/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the leading causes of cancer-related death with poor prognosis in China. Identifying novel targeted therapies in ESCC is urgently needed. The aberrant activation of NF-κB signalling pathway is critical for prognosis and recurrence of ESCC, which make it a potential target in the treatment of ESCC. Here, we found that pristimerin inhibited ESCC cell proliferation, migration, invasion, induced cell apoptosis, and eliminated cancer stem-like cells (CSCs). It also showed a synergistic effect on ESCC when combined with 5-fluorouracil (5-FU). Moreover, pristimerin potently inhibited the growth of ESCC xenograft in nude mice. The anti-ESCC effects of pristimerin were demonstrated to be associated with the inhibition of NF-κB pathway by suppressing tumour necrosis factor α (TNFα)-induced IκBα phosphorylation, p65 translocation, and NF-κB-dependent gene expression. This study provides an evidence for the development of pristimerin to be a new therapeutic agent for ESCC. SIGNIFICANCE OF THE STUDY Although several approaches including surgery, chemotherapy, and radiotherapy had been applied in the treatment of ESCC, more effective targeted chemotherapies are required to increase the survival rates of patients. This study suggested that inhibiting NF-κB signalling pathway could be an effective approach for the treatment of ESCC. Pristimerin, a potent NF-κB inhibitor, exerted potent anti-ESCC effects both in vitro and in vivo, which may be a promising therapeutic agent for ESCC.
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Affiliation(s)
- Yuanqing Tu
- Jinan University Institute of Tumor Pharmacology, College of Pharmacy, Jinan University, Guangzhou, China
| | - Fuxing Tan
- Jinan University Institute of Tumor Pharmacology, College of Pharmacy, Jinan University, Guangzhou, China
| | - Jingfeng Zhou
- Jinan University Institute of Tumor Pharmacology, College of Pharmacy, Jinan University, Guangzhou, China
| | - Jingxuan Pan
- Jinan University Institute of Tumor Pharmacology, College of Pharmacy, Jinan University, Guangzhou, China
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21
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Huang H, Wang C, Liu F, Li HZ, Peng G, Gao X, Dong KQ, Wang HR, Kong DP, Qu M, Dai LH, Wang KJ, Zhou Z, Yang J, Yang ZY, Cheng YQ, Tian QQ, Liu D, Xu CL, Xu DF, Cui XG, Sun YH. Reciprocal Network between Cancer Stem-Like Cells and Macrophages Facilitates the Progression and Androgen Deprivation Therapy Resistance of Prostate Cancer. Clin Cancer Res 2018; 24:4612-4626. [PMID: 29691294 DOI: 10.1158/1078-0432.ccr-18-0461] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 04/03/2018] [Accepted: 04/20/2018] [Indexed: 11/16/2022]
Abstract
Purpose: Cancer stem-like cells (CSC) contribute to the progression and androgen deprivation therapy (ADT) resistance of prostate cancer. As CSCs depend on their specific niche, including tumor-associated macrophages (TAM), elucidating the network between CSCs and TAMs may help to effectively inhibit the progression and ADT resistance of prostate cancer.Experimental Design: The underlying intracellular mechanism that sustains the stem-like characteristics of CSCs in prostate cancer was assessed via RNA sequencing, co-immunoprecipitation, chromatin immunoprecipitation, and other assays. A coculture system and cytokine antibody arrays were used to examine the interaction network between CSCs and TAMs. In addition, an orthotopic prostate cancer model was established to evaluate the in vivo effects of the combined targeting of CSCs and their interaction with TAMs on ADT resistance.Results: Autophagy-related gene 7 (ATG7) facilitated the transcription of OCT4 via β-catenin, which binds to the OCT4 promoter, promoting CSC characteristics in prostate cancer, including self-renewal, tumor initiation, and drug resistance. In addition, CSCs remodeled their specific niche by educating monocytes/macrophages toward TAMs, and the CSC-educated TAMs reciprocally promoted the stem-like properties of CSCs, progression and ADT resistance of prostate cancer via IL6/STAT3. Furthermore, the combined targeting of CSCs and their interaction with TAMs by inhibiting ATG7/OCT4 and IL6 receptor effectively ameliorated ADT resistance in an orthotopic prostate cancer model.Conclusions: Targeting CSCs and their niche may prove to be a more powerful strategy than targeting CSCs alone, providing a rational approach to ameliorating ADT resistance in prostate cancer. Clin Cancer Res; 24(18); 4612-26. ©2018 AACR.
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Affiliation(s)
- Hai Huang
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Chao Wang
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Fei Liu
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Hui-Zhen Li
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Guang Peng
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Xu Gao
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Ke-Qin Dong
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Hong-Ru Wang
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - De-Pei Kong
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Min Qu
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Li-He Dai
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Kai-Jian Wang
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Zhe Zhou
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Jun Yang
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Ze-Yu Yang
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Yan-Qiong Cheng
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Qin-Qin Tian
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Dan Liu
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Chuan-Liang Xu
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Dan-Feng Xu
- Department of Urinary Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xin-Gang Cui
- Department of Urinary Surgery, The Third Affiliated Hospital of Second Military Medical University (Eastern Hepatobiliary Surgery Hospital), Shanghai, China.
- Department of Urinary Surgery, Gongli Hospital, Second Military Medical University, Shanghai, China
| | - Ying-Hao Sun
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China.
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22
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Hall TM, Tétreault MP, Hamilton KE, Whelan KA. Autophagy as a cytoprotective mechanism in esophageal squamous cell carcinoma. Curr Opin Pharmacol 2018; 41:12-19. [PMID: 29677645 DOI: 10.1016/j.coph.2018.04.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 04/02/2018] [Indexed: 12/19/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC) is amongst the most aggressive human malignancies, representing a significant health burden worldwide. Autophagy is an evolutionarily conserved catabolic process that degrades and recycles damaged organelles and misfolded proteins to maintain cellular homeostasis. Alterations in autophagy are associated with cancer pathogenesis, including ESCC; however, the functional role of autophagy in ESCC remains elusive. Here, we discuss the clinical relevance of autophagy effectors in ESCC and review current knowledge regarding the molecular mechanisms through which autophagy contributes to ESCC. We highlight the cytoprotective role of autophagy in ESCC and discuss autophagy inhibitors as novel experimental therapeutics to potentiate the effects of anti-cancer therapies and/or to overcome therapeutic resistance in ESCC.
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Affiliation(s)
- Timothy M Hall
- Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
| | - Marie-Pier Tétreault
- Department of Medicine, Gastroenterology and Hepatology Division, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Kathryn E Hamilton
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Kelly A Whelan
- Department of Pathology & Laboratory Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Fels Institute for Cancer Research & Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
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23
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Wang C, Peng G, Huang H, Liu F, Kong DP, Dong KQ, Dai LH, Zhou Z, Wang KJ, Yang J, Cheng YQ, Gao X, Qu M, Wang HR, Zhu F, Tian QQ, Liu D, Cao L, Cui XG, Xu CL, Xu DF, Sun YH. Blocking the Feedback Loop between Neuroendocrine Differentiation and Macrophages Improves the Therapeutic Effects of Enzalutamide (MDV3100) on Prostate Cancer. Clin Cancer Res 2017; 24:708-723. [PMID: 29191973 DOI: 10.1158/1078-0432.ccr-17-2446] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Revised: 10/22/2017] [Accepted: 11/20/2017] [Indexed: 11/16/2022]
Affiliation(s)
- Chao Wang
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Guang Peng
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Hai Huang
- Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Fei Liu
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - De-Pei Kong
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Ke-Qin Dong
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Li-He Dai
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Zhe Zhou
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Kai-Jian Wang
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Jun Yang
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Yan-Qiong Cheng
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Xu Gao
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Min Qu
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Hong-Ru Wang
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Feng Zhu
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Qin-Qin Tian
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Dan Liu
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Li Cao
- Institute of Neuroscience and Key Laboratory of Molecular Neurobiology of the Ministry of Education, Second Military Medical University, Shanghai, China
| | - Xin-Gang Cui
- Department of Urinary Surgery, Third Affiliated Hospital, Second Military Medical University, Shanghai, China
| | - Chuan-Liang Xu
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Dan-Feng Xu
- Department of Urinary Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
| | - Ying-Hao Sun
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China.
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24
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Huang X, Xiao R, Pan S, Yang X, Yuan W, Tu Z, Xu M, Zhu Y, Yin Q, Wu Y, Hu W, Shao L, Xiong J, Zhang Q. Uncovering the roles of long non-coding RNAs in cancer stem cells. J Hematol Oncol 2017; 10:62. [PMID: 28245841 PMCID: PMC5331729 DOI: 10.1186/s13045-017-0428-9] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2016] [Accepted: 02/23/2017] [Indexed: 12/21/2022] Open
Abstract
Cancer has been a major public health problem that has threatened human life worldwide throughout history. The main causes that contribute to the poor prognosis of cancer are metastasis and recurrence. Cancer stem cells are a group of tumor cells that possess self-renewal and differentiation ability, which is a vital cause of cancer metastasis and recurrence. Long non-coding RNAs refer to a class of RNAs that are longer than 200 nt and have no potential to code proteins, some of which can be specifically expressed in different tissues and different tumors. Long non-coding RNAs have great biological significance in the occurrence and progression of cancers. However, how long non-coding RNAs interact with cancer stem cells and then affect cancer metastasis and recurrence is not yet clear. Therefore, this review aims to summarize recent studies that focus on how long non-coding RNAs impact tumor occurrence and progression by affecting cancer stem cell self-renewal and differentiation in liver cancer, prostate cancer, breast cancer, and glioma.
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Affiliation(s)
- Xiaoxing Huang
- Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, 430071, China
| | - Ruijing Xiao
- Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, 430071, China
| | - Shan Pan
- Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, 430071, China
| | - Xiangyong Yang
- Hubei University of Technology Engineering and Technology College, Wuhan, 430000, China
| | - Wen Yuan
- Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, 430071, China
| | - Zhenbo Tu
- Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, 430071, China
| | - Ming Xu
- Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, 430071, China
| | - Yufan Zhu
- Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, 430071, China
| | - Qian Yin
- Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, 430071, China
| | - Yingjie Wu
- Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, 430071, China
| | - Weidong Hu
- Department of Oncology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Liang Shao
- Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Jie Xiong
- Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, 430071, China
| | - Qiuping Zhang
- Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, 430071, China.
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