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Mangiola S, Brown R, Zhan C, Berthelet J, Guleria S, Liyanage C, Ostrouska S, Wilcox J, Merdas M, Fuge-Larsen P, Bell C, Schröder J, Mielke LA, Mariadason JM, Tsao SCH, Chen Y, Yadav VK, Vodala S, Anderson RL, Merino D, Behren A, Yeo B, Papenfuss AT, Pal B. Circulating immune cells exhibit distinct traits linked to metastatic burden in breast cancer. Breast Cancer Res 2025; 27:73. [PMID: 40340807 PMCID: PMC12063295 DOI: 10.1186/s13058-025-01982-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Accepted: 02/14/2025] [Indexed: 05/10/2025] Open
Abstract
BACKGROUND Circulating immune cells play a crucial role in the anti-tumour immune response, yet the systemic immune system in metastatic breast cancers is not fully characterised. Investigating the cellular and molecular changes in peripheral blood mononuclear cells (PBMCs) from breast cancer patients could elucidate the role of circulating immune cells in metastasis and aid in identifying biomarkers for disease burden and progression. METHODS In this study, we characterised the systemic immune landscape associated with varying levels of metastatic burden by analysing the single-cell transcriptomes of PBMCs from breast cancer patients and healthy controls. Our research focused on identifying changes in immune cell composition, transcriptional programs, and immune-cell communication networks linked to metastatic burden. Additionally, we compared these PBMC features onto a single-cell atlas of primary breast tumours to study corresponding traits in tumour-infiltrating immune cells. RESULTS In metastatic breast cancer, PBMCs exhibit a significant downregulation of the adaptive immune system and a decreased number and activity of unconventional T cells, such as γδ T cells. Additionally, metastatic burden is associated with impaired cell communication pathways involved in immunomodulatory functions. We also identified a gene signature derived from myeloid cells shared between tumour immune infiltrates and circulating immune cells in breast cancer patients. CONCLUSIONS Our study provides a comprehensive single-cell molecular profile of the peripheral immune system in breast cancer, offering a valuable resource for understanding metastatic disease in terms of tumour burden. By identifying immune traits linked to metastasis, we have unveiled potential new biomarkers of metastatic disease.
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Affiliation(s)
- S Mangiola
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
- Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
- South Australian immunoGENomics Cancer Institute, Adelaide, SA, 5005, Australia.
| | - R Brown
- School of Cancer Medicine, La Trobe University, Bundoora, VIC, 3086, Australia
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia
| | - C Zhan
- South Australian immunoGENomics Cancer Institute, Adelaide, SA, 5005, Australia
| | - J Berthelet
- School of Cancer Medicine, La Trobe University, Bundoora, VIC, 3086, Australia
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia
| | - S Guleria
- School of Cancer Medicine, La Trobe University, Bundoora, VIC, 3086, Australia
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia
| | - C Liyanage
- School of Cancer Medicine, La Trobe University, Bundoora, VIC, 3086, Australia
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia
| | - S Ostrouska
- School of Cancer Medicine, La Trobe University, Bundoora, VIC, 3086, Australia
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia
| | - J Wilcox
- School of Cancer Medicine, La Trobe University, Bundoora, VIC, 3086, Australia
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia
| | - M Merdas
- School of Cancer Medicine, La Trobe University, Bundoora, VIC, 3086, Australia
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia
| | - P Fuge-Larsen
- School of Cancer Medicine, La Trobe University, Bundoora, VIC, 3086, Australia
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia
| | - C Bell
- School of Cancer Medicine, La Trobe University, Bundoora, VIC, 3086, Australia
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia
- Austin Health, Heidelberg, VIC, 3084, Australia
| | - J Schröder
- Peter Doherty Institute for Infection and Immunity, Parkville, VIC, 3052, Australia
- The University of Melbourne, Parkville, VIC, 3052, Australia
| | - L A Mielke
- School of Cancer Medicine, La Trobe University, Bundoora, VIC, 3086, Australia
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia
- La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, 3086, Australia
| | - J M Mariadason
- School of Cancer Medicine, La Trobe University, Bundoora, VIC, 3086, Australia
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia
| | - S Chang-Hao Tsao
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia
- Austin Health, Heidelberg, VIC, 3084, Australia
| | - Y Chen
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
| | - V K Yadav
- Rutgers New Jersey Medical School, Newark, NJ, USA
| | - S Vodala
- Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, USA
| | - R L Anderson
- School of Cancer Medicine, La Trobe University, Bundoora, VIC, 3086, Australia
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia
| | - D Merino
- School of Cancer Medicine, La Trobe University, Bundoora, VIC, 3086, Australia
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia
| | - A Behren
- School of Cancer Medicine, La Trobe University, Bundoora, VIC, 3086, Australia
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia
| | - B Yeo
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia
- Austin Health, Heidelberg, VIC, 3084, Australia
| | - A T Papenfuss
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
- Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
| | - B Pal
- School of Cancer Medicine, La Trobe University, Bundoora, VIC, 3086, Australia.
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia.
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Chen Y, Tang Z, Tang Z, Fu L, Liang G, Zhang Y, Tao C, Wang B. Identification of core immune-related genes CTSK, C3, and IFITM1 for diagnosing Helicobacter pylori infection-associated gastric cancer through transcriptomic analysis. Int J Biol Macromol 2025; 287:138645. [PMID: 39667460 DOI: 10.1016/j.ijbiomac.2024.138645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 11/28/2024] [Accepted: 12/09/2024] [Indexed: 12/14/2024]
Abstract
OBJECTIVES To identify diagnostic genes and mechanisms linking Helicobacter pylori (H. pylori) infection to gastric cancer. METHODS Gene expression profiles from GEO were analyzed using differential expression gene (DEG) analysis, weighted gene co-expression network analysis (WGCNA), and functional enrichment. A random forest (RF) model assessed immune-related diagnostic genes, examining their expression, diagnostic performance, prognostic value, and immune cell relationships. Expression patterns of core genes were evaluated with single-cell RNA sequencing (scRNA-seq), and a regulatory network involving miRNA, mRNA, and transcription factors was built. RESULTS We identified 75 genes and developed an RF model including 15 immune-related genes, notably CTSK, NR4A3, C3, and IFITM1. Except for NR4A3, these genes showed higher expression in datasets, confirmed by in vitro tests. Their diagnostic performance had an AUC > 0.7, enhancing to >0.85 in a multi-gene model. Survival analysis linked gene upregulation to poorer prognosis, and scRNA-seq and immune cell infiltration analysis underscored their roles in immune dysregulation and pathogenicity in H. pylori-related gastric cancer. CONCLUSIONS CTSK, C3, and IFITM1 are crucial in H. pylori-related gastric cancer, forming a robust diagnostic model and guiding future diagnostic and therapeutic research.
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Affiliation(s)
- Yuzuo Chen
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zhihui Tang
- Department of Microbiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610041, China
| | - Zhuoyun Tang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Lifa Fu
- Department of Microbiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610041, China
| | - Ge Liang
- Department of Microbiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610041, China
| | - Yanrong Zhang
- Department of Microbiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610041, China
| | - Chuanmin Tao
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Baoning Wang
- Department of Microbiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610041, China.
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Maxwell A, Swanson G, Thy Nguyen A, Hu A, Richards D, You Y, Stephan L, Manaloto M, Liao A, Ding J, Mor G. Hydroquinone impairs trophoblast migration and invasion via AHR-twist-IFITM1 axis. Placenta 2024; 155:88-99. [PMID: 39173312 PMCID: PMC11421844 DOI: 10.1016/j.placenta.2024.07.315] [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: 03/27/2024] [Revised: 07/21/2024] [Accepted: 07/31/2024] [Indexed: 08/24/2024]
Abstract
INTRODUCTION Embryo implantation is a tightly regulated process, critical for a successful pregnancy. After attachment of the blastocyst to the surface epithelium of the endometrium trophoblast migrate from the trophectoderm and invade into the stromal component of endometrium. Alterations on either process will lead to implantation failure or miscarriage. Volatile organic compounds (VOCs) such as benzene induce pregnancy complications, including preterm birth and miscarriages. The mechanism of this effect is unknown. The objective of this study was to elucidate the impact of benzene metabolite, Hydroquinone, on trophoblast function. We tested the hypothesis that Hydroquinone activates the Aryl hydrocarbon receptor (AhR) pathway modulating trophoblast migration and invasion. METHODS First-trimester trophoblast cells (Sw.71) were treated with hydroquinone (6 and 25 μM). Trophoblast migration and invasion was evaluated using a 3D invasion/migration model. Gene expression was quantified by q-PCR and Western blot analysis. RESULTS Hydroquinone impairs trophoblast migration and invasion. This loss is associated with the activation of the AhR pathway which reduced the expression of Twist1and IFITM1. IFITM1 overexpression can rescue impaired trophoblast migration. DISCUSSION Our study highlights that hydroquinone treatment induces the activation of the AhR pathway in trophoblast cells, which impairs trophoblast invasion and migration. We postulate that activation of the AhR pathway in trophoblast suppress Twist1 and a subsequent IFITM1. Thus, the AhR-Twist1-IFITM1 axis represent a critical pathway involved in the regulation of trophoblast migration and it is sensitive to benzene exposure. These findings provide crucial insights into the molecular mechanisms underlying pregnancy complications induced by air pollution.
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Affiliation(s)
- Anthony Maxwell
- C.S Mott Center for Human Growth and Development, Wayne State University, Detroit, MI, USA
| | - Grace Swanson
- C.S Mott Center for Human Growth and Development, Wayne State University, Detroit, MI, USA
| | - Annie Thy Nguyen
- C.S Mott Center for Human Growth and Development, Wayne State University, Detroit, MI, USA
| | - Anna Hu
- C.S Mott Center for Human Growth and Development, Wayne State University, Detroit, MI, USA
| | - Darby Richards
- C.S Mott Center for Human Growth and Development, Wayne State University, Detroit, MI, USA
| | - Yuan You
- C.S Mott Center for Human Growth and Development, Wayne State University, Detroit, MI, USA
| | - Laura Stephan
- C.S Mott Center for Human Growth and Development, Wayne State University, Detroit, MI, USA
| | - Marcia Manaloto
- C.S Mott Center for Human Growth and Development, Wayne State University, Detroit, MI, USA
| | - Aihua Liao
- Institute of Reproductive Health, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China
| | - Jiahui Ding
- C.S Mott Center for Human Growth and Development, Wayne State University, Detroit, MI, USA; Department of Obstetrics and Gynecology, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Gil Mor
- C.S Mott Center for Human Growth and Development, Wayne State University, Detroit, MI, USA; Department of Obstetrics and Gynecology, School of Medicine, Wayne State University, Detroit, MI, USA.
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Otálora-Otálora BA, Payán-Gómez C, López-Rivera JJ, Pedroza-Aconcha NB, Aristizábal-Guzmán C, Isaza-Ruget MA, Álvarez-Moreno CA. Global transcriptomic network analysis of the crosstalk between microbiota and cancer-related cells in the oral-gut-lung axis. Front Cell Infect Microbiol 2024; 14:1425388. [PMID: 39228892 PMCID: PMC11368877 DOI: 10.3389/fcimb.2024.1425388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 07/15/2024] [Indexed: 09/05/2024] Open
Abstract
Background The diagnosis and treatment of lung, colon, and gastric cancer through the histologic characteristics and genomic biomarkers have not had a strong impact on the mortality rates of the top three global causes of death by cancer. Methods Twenty-five transcriptomic analyses (10 lung cancer, 10 gastric cancer, and 5 colon cancer datasets) followed our own bioinformatic pipeline based on the utilization of specialized libraries from the R language and DAVID´s gene enrichment analyses to identify a regulatory metafirm network of transcription factors and target genes common in every type of cancer, with experimental evidence that supports its relationship with the unlocking of cell phenotypic plasticity for the acquisition of the hallmarks of cancer during the tumoral process. The network's regulatory functional and signaling pathways might depend on the constant crosstalk with the microbiome network established in the oral-gut-lung axis. Results The global transcriptomic network analysis highlighted the impact of transcription factors (SOX4, TCF3, TEAD4, ETV4, and FOXM1) that might be related to stem cell programming and cancer progression through the regulation of the expression of genes, such as cancer-cell membrane receptors, that interact with several microorganisms, including human T-cell leukemia virus 1 (HTLV-1), the human papilloma virus (HPV), the Epstein-Barr virus (EBV), and SARS-CoV-2. These interactions can trigger the MAPK, non-canonical WNT, and IFN signaling pathways, which regulate key transcription factor overexpression during the establishment and progression of lung, colon, and gastric cancer, respectively, along with the formation of the microbiome network. Conclusion The global transcriptomic network analysis highlights the important interaction between key transcription factors in lung, colon, and gastric cancer, which regulates the expression of cancer-cell membrane receptors for the interaction with the microbiome network during the tumorigenic process.
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Affiliation(s)
| | - César Payán-Gómez
- Dirección Académica, Universidad Nacional de Colombia, Sede de La Paz, La Paz, Colombia
| | - Juan Javier López-Rivera
- Grupo de Investigación INPAC, Specialized Laboratory, Clinica Universitaria Colombia, Clínica Colsanitas S.A., Bogotá, Colombia
| | | | - Claudia Aristizábal-Guzmán
- Grupo de Investigación INPAC, Unidad de Investigación, Fundación Universitaria Sanitas, Bogotá, Colombia
| | - Mario Arturo Isaza-Ruget
- Keralty, Sanitas International Organization, Grupo de Investigación INPAC, Fundación Universitaria Sanitas, Bogotá, Colombia
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Lee J, Hwang JA, Hong SH, Kim SY, Seol D, Choi IJ, Lee YS. Overexpression of heat shock protein 47 is associated with increased proliferation and metastasis in gastric cancer. Genomics Inform 2024; 22:6. [PMID: 38907287 PMCID: PMC11184955 DOI: 10.1186/s44342-024-00010-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 05/22/2024] [Indexed: 06/23/2024] Open
Abstract
Here, we investigated that the heat shock protein 47 (HSP47) plays a crucial role in the progression of gastric cancer (GC). We analyzed HSP47 gene expression in GC cell lines and patient tissues. The HSP47 mRNA and protein expression levels were significantly higher in GC cell lines and tumor tissues compared to normal gastric mucosa. Using siRNA to silence the expression of HSP47 in GC cells resulted in a significant reduction in their proliferation, wound healing, migration, and invasion capacities. Additionally, we also showed that the mRNA expression of matrix metallopeptidase-7 (MMP-7), a metastasis-promoting gene, was significantly reduced in HSP47 siRNA-transfected GC cells. We confirmed that the HSP47 promoter region was methylated in the SNU-216 GC cell line expressing low levels of HSP47 and in most non-cancerous gastric tissues. It means that the expression of HSP47 is regulated by epigenetic regulatory mechanisms. These findings suggest that targeting HSP47, potentially through its promoter methylation, could be a useful new therapeutic strategy for treating GC.
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Affiliation(s)
- Jieun Lee
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Jung-Ah Hwang
- Genomics Core Facility, Research Core Center, Research Institute, National Cancer Center, Goyang, Republic of Korea
| | - Seung-Hyun Hong
- Genomics Core Facility, Research Core Center, Research Institute, National Cancer Center, Goyang, Republic of Korea
| | | | - Donghyeok Seol
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Il Ju Choi
- Center for Gastric Cancer, National Cancer Center, Goyang, Republic of Korea
| | - Yeon-Su Lee
- Rare Cancer Branch, Research Institute, National Cancer Center, Goyang, Republic of Korea.
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Yue L, Gong T, Jiang W, Qian L, Gong W, Sun Y, Cai X, Xu H, Liu F, Wang H, Li S, Zhu Y, Zheng Z, Wu Q, Guo T. Proteomic profiling of ovarian clear cell carcinomas identifies prognostic biomarkers for chemotherapy. Proteomics 2024; 24:e2300242. [PMID: 38171885 DOI: 10.1002/pmic.202300242] [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: 06/08/2023] [Revised: 11/17/2023] [Accepted: 11/20/2023] [Indexed: 01/05/2024]
Abstract
Clear cell ovarian carcinoma (CCOC) is a relatively rare subtype of ovarian cancer (OC) with high degree of resistance to standard chemotherapy. Little is known about the underlying molecular mechanisms, and it remains a challenge to predict its prognosis after chemotherapy. Here, we first analyzed the proteome of 35 formalin-fixed paraffin-embedded (FFPE) CCOC tissue specimens from a cohort of 32 patients with CCOC (H1 cohort) and characterized 8697 proteins using data-independent acquisition mass spectrometry (DIA-MS). We then performed proteomic analysis of 28 fresh frozen (FF) CCOC tissue specimens from an independent cohort of 24 patients with CCOC (H2 cohort), leading to the identification of 9409 proteins with DIA-MS. After bioinformatics analysis, we narrowed our focus to 15 proteins significantly correlated with the recurrence free survival (RFS) in both cohorts. These proteins are mainly involved in DNA damage response, extracellular matrix (ECM), and mitochondrial metabolism. Parallel reaction monitoring (PRM)-MS was adopted to validate the prognostic potential of the 15 proteins in the H1 cohort and an independent confirmation cohort (H3 cohort). Interferon-inducible transmembrane protein 1 (IFITM1) was observed as a robust prognostic marker for CCOC in both PRM data and immunohistochemistry (IHC) data. Taken together, this study presents a CCOC proteomic data resource and a single promising protein, IFITM1, which could potentially predict the recurrence and survival of CCOC.
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Affiliation(s)
- Liang Yue
- School of Life Sciences, Fudan University, Shanghai, China
- Westlake Center for Intelligent Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang Province, China
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang Province, China
- Research Center for Industries of the Future, Westlake University, Hangzhou, Zhejiang, China
| | - Tingting Gong
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University
| | - Wenhao Jiang
- Westlake Center for Intelligent Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang Province, China
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang Province, China
- Research Center for Industries of the Future, Westlake University, Hangzhou, Zhejiang, China
| | - Liujia Qian
- Westlake Center for Intelligent Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang Province, China
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang Province, China
- Research Center for Industries of the Future, Westlake University, Hangzhou, Zhejiang, China
| | - Wangang Gong
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | - Yaoting Sun
- Westlake Center for Intelligent Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang Province, China
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang Province, China
- Research Center for Industries of the Future, Westlake University, Hangzhou, Zhejiang, China
| | - Xue Cai
- Westlake Center for Intelligent Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang Province, China
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang Province, China
- Research Center for Industries of the Future, Westlake University, Hangzhou, Zhejiang, China
| | - Heli Xu
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Fanghua Liu
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - He Wang
- Westlake Center for Intelligent Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang Province, China
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang Province, China
- Research Center for Industries of the Future, Westlake University, Hangzhou, Zhejiang, China
| | - Sainan Li
- Westlake Center for Intelligent Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang Province, China
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang Province, China
- Research Center for Industries of the Future, Westlake University, Hangzhou, Zhejiang, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
- National Health Commission Key Laboratory of Reproductive Health, Institute of Reproductive and Child Health, Peking University, Beijing, China
| | - Yi Zhu
- Westlake Center for Intelligent Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang Province, China
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang Province, China
- Research Center for Industries of the Future, Westlake University, Hangzhou, Zhejiang, China
| | - Zhiguo Zheng
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | - Qijun Wu
- Department of Clinical Epidemiology, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Tiannan Guo
- Westlake Center for Intelligent Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang Province, China
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang Province, China
- Research Center for Industries of the Future, Westlake University, Hangzhou, Zhejiang, China
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Pawar P, Gokavi J, Wakhare S, Bagul R, Ghule U, Khan I, Ganu V, Mukherjee A, Shete A, Rao A, Saxena V. MiR-155 Negatively Regulates Anti-Viral Innate Responses among HIV-Infected Progressors. Viruses 2023; 15:2206. [PMID: 38005883 PMCID: PMC10675553 DOI: 10.3390/v15112206] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 09/28/2023] [Accepted: 10/02/2023] [Indexed: 11/26/2023] Open
Abstract
HIV infection impairs host immunity, leading to progressive disease. An anti-retroviral treatment efficiently controls viremia but cannot completely restore the immune dysfunction in HIV-infected individuals. Both host and viral factors determine the rate of disease progression. Among the host factors, innate immunity plays a critical role; however, the mechanism(s) associated with dysfunctional innate responses are poorly understood among HIV disease progressors, which was investigated here. The gene expression profiles of TLRs and innate cytokines in HIV-infected (LTNPs and progressors) and HIV-uninfected individuals were examined. Since the progressors showed a dysregulated TLR-mediated innate response, we investigated the role of TLR agonists in restoring the innate functions of the progressors. The stimulation of PBMCs with TLR3 agonist-poly:(I:C), TLR7 agonist-GS-9620 and TLR9 agonist-ODN 2216 resulted in an increased expression of IFN-α, IFN-β and IL-6. Interestingly, the expression of IFITM3, BST-2, IFITM-3, IFI-16 was also increased upon stimulation with TLR3 and TLR7 agonists, respectively. To further understand the molecular mechanism involved, the role of miR-155 was explored. Increased miR-155 expression was noted among the progressors. MiR-155 inhibition upregulated the expression of TLR3, NF-κB, IRF-3, TNF-α and the APOBEC-3G, IFITM-3, IFI-16 and BST-2 genes in the PBMCs of the progressors. To conclude, miR-155 negatively regulates TLR-mediated cytokines as wel l as the expression of host restriction factors, which play an important role in mounting anti-HIV responses; hence, targeting miR-155 might be helpful in devising strategic approaches towards alleviating HIV disease progression.
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Affiliation(s)
- Puja Pawar
- Division of Immunology and Serology, ICMR-National AIDS Research Institute, Pune 411026, India; (P.P.); (J.G.); (S.W.); (V.G.); (A.S.)
| | - Jyotsna Gokavi
- Division of Immunology and Serology, ICMR-National AIDS Research Institute, Pune 411026, India; (P.P.); (J.G.); (S.W.); (V.G.); (A.S.)
| | - Shilpa Wakhare
- Division of Immunology and Serology, ICMR-National AIDS Research Institute, Pune 411026, India; (P.P.); (J.G.); (S.W.); (V.G.); (A.S.)
| | - Rajani Bagul
- Division of Clinical Sciences, ICMR-National AIDS Research Institute, Pune 411026, India; (R.B.); (U.G.); (A.R.)
| | - Ujjwala Ghule
- Division of Clinical Sciences, ICMR-National AIDS Research Institute, Pune 411026, India; (R.B.); (U.G.); (A.R.)
| | - Ishrat Khan
- Division of Virology, ICMR-National AIDS Research Institute, Pune 411026, India; (I.K.); (A.M.)
| | - Varada Ganu
- Division of Immunology and Serology, ICMR-National AIDS Research Institute, Pune 411026, India; (P.P.); (J.G.); (S.W.); (V.G.); (A.S.)
| | - Anupam Mukherjee
- Division of Virology, ICMR-National AIDS Research Institute, Pune 411026, India; (I.K.); (A.M.)
| | - Ashwini Shete
- Division of Immunology and Serology, ICMR-National AIDS Research Institute, Pune 411026, India; (P.P.); (J.G.); (S.W.); (V.G.); (A.S.)
| | - Amrita Rao
- Division of Clinical Sciences, ICMR-National AIDS Research Institute, Pune 411026, India; (R.B.); (U.G.); (A.R.)
| | - Vandana Saxena
- Division of Immunology and Serology, ICMR-National AIDS Research Institute, Pune 411026, India; (P.P.); (J.G.); (S.W.); (V.G.); (A.S.)
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São José C, Garcia-Pelaez J, Ferreira M, Arrieta O, André A, Martins N, Solís S, Martínez-Benítez B, Ordóñez-Sánchez ML, Rodríguez-Torres M, Sommer AK, Te Paske IBAW, Caldas C, Tischkowitz M, Tusié MT, Hoogerbrugge N, Demidov G, de Voer RM, Laurie S, Oliveira C. Combined loss of CDH1 and downstream regulatory sequences drive early-onset diffuse gastric cancer and increase penetrance of hereditary diffuse gastric cancer. Gastric Cancer 2023; 26:653-666. [PMID: 37249750 PMCID: PMC10361908 DOI: 10.1007/s10120-023-01395-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 04/30/2023] [Indexed: 05/31/2023]
Abstract
BACKGROUND Germline CDH1 pathogenic or likely pathogenic variants cause hereditary diffuse gastric cancer (HDGC). Once a genetic cause is identified, stomachs' and breasts' surveillance and/or prophylactic surgery is offered to asymptomatic CDH1 carriers, which is life-saving. Herein, we characterized an inherited mechanism responsible for extremely early-onset gastric cancer and atypical HDGC high penetrance. METHODS Whole-exome sequencing (WES) re-analysis was performed in an unsolved HDGC family. Accessible chromatin and CDH1 promoter interactors were evaluated in normal stomach by ATAC-seq and 4C-seq, and functional analysis was performed using CRISPR-Cas9, RNA-seq and pathway analysis. RESULTS We identified a germline heterozygous 23 Kb CDH1-TANGO6 deletion in a family with eight diffuse gastric cancers, six before age 30. Atypical HDGC high penetrance and young cancer-onset argued towards a role for the deleted region downstream of CDH1, which we proved to present accessible chromatin, and CDH1 promoter interactors in normal stomach. CRISPR-Cas9 edited cells mimicking the CDH1-TANGO6 deletion display the strongest CDH1 mRNA downregulation, more impacted adhesion-associated, type-I interferon immune-associated and oncogenic signalling pathways, compared to wild-type or CDH1-deleted cells. This finding solved an 18-year family odyssey and engaged carrier family members in a cancer prevention pathway of care. CONCLUSION In this work, we demonstrated that regulatory elements lying down-stream of CDH1 are part of a chromatin network that control CDH1 expression and influence cell transcriptome and associated signalling pathways, likely explaining high disease penetrance and very young cancer-onset. This study highlights the importance of incorporating scientific-technological updates and clinical guidelines in routine diagnosis, given their impact in timely genetic diagnosis and disease prevention.
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Affiliation(s)
- Celina São José
- i3S-Instituto de Investigação e Inovação em Saúde, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal
- IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
- Doctoral Programme in Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal
| | - José Garcia-Pelaez
- i3S-Instituto de Investigação e Inovação em Saúde, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal
- IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
- Doctoral Programme in Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Marta Ferreira
- i3S-Instituto de Investigação e Inovação em Saúde, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal
- IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
- Department Computer Science Faculty of Science, University of Porto, Porto, Portugal
| | - Oscar Arrieta
- Thoracic Oncology Unit, Department of Thoracic Oncology, Instituto Nacional de Cancerología, Mexico City, Mexico
| | - Ana André
- i3S-Instituto de Investigação e Inovação em Saúde, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal
- IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
| | - Nelson Martins
- i3S-Instituto de Investigação e Inovação em Saúde, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal
- IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
- Master Programme in Molecular Medicine and Oncology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Samantha Solís
- INCMNSZ/Instituto de Investigaciones Biomédicas, Unidad de Biología Molecular y Medicina Genómica Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, UNAM Mexico City, Mexico
| | - Braulio Martínez-Benítez
- Pathology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, INCMNSZ Mexico City, Mexico
| | - María Luisa Ordóñez-Sánchez
- INCMNSZ/Instituto de Investigaciones Biomédicas, Unidad de Biología Molecular y Medicina Genómica Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, UNAM Mexico City, Mexico
| | - Maribel Rodríguez-Torres
- INCMNSZ/Instituto de Investigaciones Biomédicas, Unidad de Biología Molecular y Medicina Genómica Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, UNAM Mexico City, Mexico
| | - Anna K Sommer
- Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany
| | - Iris B A W Te Paske
- Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
| | - Carlos Caldas
- Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK
- Department of Oncology, University of Cambridge, Cambridge, UK
- Cambridge Experimental Cancer Medicine Centre (ECMC), CRUK Cambridge Centre, NIHR Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Marc Tischkowitz
- Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK
| | - Maria Teresa Tusié
- INCMNSZ/Instituto de Investigaciones Biomédicas, Unidad de Biología Molecular y Medicina Genómica Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, UNAM Mexico City, Mexico
| | - Nicoline Hoogerbrugge
- Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
| | - German Demidov
- Institute of Medical Genetics and Applied Genomics, Tübingen, Germany
| | - Richarda M de Voer
- Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
| | - Steve Laurie
- The Barcelona Institute of Science and Technology, CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona, Spain
| | - Carla Oliveira
- i3S-Instituto de Investigação e Inovação em Saúde, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.
- IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal.
- FMUP-Faculty of Medicine of the University of Porto, Porto, Portugal.
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Ismailov ZB, Belykh ES, Chernykh AA, Udoratina AM, Kazakov DV, Rybak AV, Kerimova SN, Velegzhaninov IO. Systematic review of comparative transcriptomic studies of cellular resistance to genotoxic stress. MUTATION RESEARCH. REVIEWS IN MUTATION RESEARCH 2023; 792:108467. [PMID: 37657754 DOI: 10.1016/j.mrrev.2023.108467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 08/19/2023] [Accepted: 08/28/2023] [Indexed: 09/03/2023]
Abstract
The development of resistance by tumor cells to various types of therapy is a significant problem that decreases the effectiveness of oncology treatments. For more than two decades, comparative transcriptomic studies of tumor cells with different sensitivities to ionizing radiation and chemotherapeutic agents have been conducted in order to identify the causes and mechanisms underlying this phenomenon. However, the results of such studies have little in common and often contradict each other. We have assumed that a systematic analysis of a large number of such studies will provide new knowledge about the mechanisms of development of therapeutic resistance in tumor cells. Our comparison of 123 differentially expressed gene (DEG) lists published in 98 papers suggests a very low degree of consistency between the study results. Grouping the data by type of genotoxic agent and tumor type did not increase the similarity. The most frequently overexpressed genes were found to be those encoding the transport protein ABCB1 and the antiviral defense protein IFITM1. We put forward a hypothesis that the role played by the overexpression of the latter in the development of resistance may be associated not only with the stimulation of proliferation, but also with the limitation of exosomal communication and, as a result, with a decrease in the bystander effect. Among down regulated DEGs, BNIP3 was observed most frequently. The expression of BNIP3, together with BNIP3L, is often suppressed in cells resistant to non-platinum genotoxic chemotherapeutic agents, whereas it is increased in cells resistant to ionizing radiation. These observations are likely to be mediated by the binary effects of these gene products on survival, and regulation of apoptosis and autophagy. The combined data also show that even such obvious mechanisms as inhibition of apoptosis and increase of proliferation are not universal but show multidirectional changes.
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Affiliation(s)
- Z B Ismailov
- Institute of Biology of Komi Science Centre of the Ural Branch of the Russian Academy of Sciences, 28b Kommunisticheskaya St., Syktyvkar 167982, Russia
| | - E S Belykh
- Institute of Biology of Komi Science Centre of the Ural Branch of the Russian Academy of Sciences, 28b Kommunisticheskaya St., Syktyvkar 167982, Russia
| | - A A Chernykh
- Institute of Physiology of Komi Science Centre of the Ural Branch of the Russian Academy of Sciences, 50 Pervomaiskaya St., Syktyvkar 167982, Russia
| | - A M Udoratina
- Lobachevsky State University of Nizhny Novgorod, 23 Gagarin Avenue, Nizhny Novgorod 603022, Russia
| | - D V Kazakov
- Institute of Physics and Mathematics of Komi Science Centre of the Ural Branch of the Russian Academy of Sciences, 4 Oplesnina St., Syktyvkar 167982, Russia
| | - A V Rybak
- Institute of Biology of Komi Science Centre of the Ural Branch of the Russian Academy of Sciences, 28b Kommunisticheskaya St., Syktyvkar 167982, Russia
| | - S N Kerimova
- State Medical Institution Komi Republican Oncology Center, 46 Nyuvchimskoe highway, Syktyvkar 167904, Russia
| | - I O Velegzhaninov
- Institute of Biology of Komi Science Centre of the Ural Branch of the Russian Academy of Sciences, 28b Kommunisticheskaya St., Syktyvkar 167982, Russia.
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10
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Deng Y, Wang F, Wu X, Du K, Yang Q, Xia T. The m6A-regulation and single cell effect pattern in sunitinib resistance on clear cell renal cell carcinoma: Identification and validation of targets. Front Pharmacol 2023; 14:1131610. [PMID: 37063301 PMCID: PMC10102343 DOI: 10.3389/fphar.2023.1131610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Accepted: 03/23/2023] [Indexed: 04/03/2023] Open
Abstract
Background: Sunitinib is the main target drug for clear cell renal cell carcinoma. However, the effect of sunitinib is often limited by acquired drug resistance.Methods: The open-accessed data used in this study were obtained from different online public databases, which were analyzed using the R software. The RNA level of specific genes was detected using quantitative Real-Time PCR. Sunitinib-resistant cell lines were constructed based on protocol get from the previous study. Colony formation and Cell Counting Kit-8 assays were applied to detect cell proliferation ability.Results: In this study, through publicly available data and high-quality analysis, we deeply explored the potential biological mechanisms that affect the resistance of sunitinib. Detailed, data from GSE64052, GSE76068 and The Cancer Genome Atlas were extracted. We identified the IFITM1, IL6, MX2, PCOLCE2, RSAD2 and SLC2A3 were associated with sunitinib resistance. Single-cell analysis, prognosis analysis and m6A regulatory network were conducted to investigate their role. Moreover, the MX2 was selected for further analysis, including its biological role and effect on the ccRCC microenvironment. Interestingly, we noticed that MX2 might be an immune-related gene that could affect the response rate of immunotherapy. Then, in vitro experiments validated the overexpression of MX2 in sunitinib-resistance cells. Colony formation assay indicated that the knockdown of MX2 could remarkably inhibit the proliferation ability of 786-O-Res and Caki-1-Res when exposed to sunitinib.Conclusion: In summary, through publicly available data and high-quality analysis, we deeply explored the potential biological mechanisms that affect the resistance of sunitinib. MX2 was selected for further analysis, including its biological role and effect on the ccRCC microenvironment. Finally, in vitro experiments were used to validate its role in ccRCC.
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Affiliation(s)
- Yanxi Deng
- Clinical Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Fang Wang
- Clinical Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Xinhui Wu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Kangming Du
- Department of Cardiothoracic Surgery, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Qing Yang
- Department of Cardiothoracic Surgery, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- *Correspondence: Qing Yang, ; Ting Xia,
| | - Ting Xia
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- *Correspondence: Qing Yang, ; Ting Xia,
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11
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Xie W, Cheng J, Hong Z, Cai W, Zhuo H, Hou J, Lin L, Wei X, Wang K, Chen X, Song Y, Wang Z, Cai J. Multi-Transcriptomic Analysis Reveals the Heterogeneity and Tumor-Promoting Role of SPP1/CD44-Mediated Intratumoral Crosstalk in Gastric Cancer. Cancers (Basel) 2022; 15:cancers15010164. [PMID: 36612160 PMCID: PMC9818284 DOI: 10.3390/cancers15010164] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/20/2022] [Accepted: 12/25/2022] [Indexed: 12/29/2022] Open
Abstract
GC is a fatal disease with high heterogeneity and invasiveness. Recently, SPP1 has been reported to be involved in the tumor progression of multiple human cancers; however, the role of SPP1 in GC heterogeneity and whether it is associated with the invasiveness and mortality of GC remain unclear. Here, we combined multiple RNA sequencing approaches to evaluate the impact of SPP1 on GC. Through bulk RNA sequencing (bulk RNA-seq) and immunohistochemistry (IHC), we found that SPP1 was highly expressed in GC, and high levels of SPP1 were associated with macrophage infiltration, an advanced tumor stage, and higher mortality for advanced GC patients. Furthermore, through simultaneous single-cell and spatial analysis, we demonstrated that SPP1+ macrophages are tumor-specific macrophages unique to cancer and enriched in the deep layer of GC tissue. Cell-cell communication analysis revealed that SPP1/CD44 interactions between SPP1+ macrophages and their localized tumor epithelial cells could activate downstream target genes in epithelial cells to promote dynamic changes in intratumor heterogeneity. Moreover, these activated genes were found to be closely associated with poor clinical GC outcomes and with cancer-related pathways that promote GC progression, as shown by survival analysis and enrichment analysis, respectively. Collectively, our study reveals that tumor-specific SPP1+ macrophages drive the architecture of intratumor heterogeneity to evolve with tumor progression and that SPP1 may serve as a prognostic marker for advanced GC patients, as well as a potential therapeutic target for GC.
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Affiliation(s)
- Wen Xie
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361001, China
| | - Jia Cheng
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361001, China
| | - Zhijun Hong
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361001, China
| | - Wangyu Cai
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361001, China
| | - Huiqin Zhuo
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361001, China
| | - Jingjing Hou
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361001, China
| | - Lingyun Lin
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361001, China
| | - Xujin Wei
- The Graduate School of Fujian Medical University, Fuzhou 350004, China
| | - Kang Wang
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361001, China
| | - Xin Chen
- The Graduate School of Fujian Medical University, Fuzhou 350004, China
| | - Yucheng Song
- The Graduate School of Fujian Medical University, Fuzhou 350004, China
| | - Zhenfa Wang
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361001, China
| | - Jianchun Cai
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361001, China
- The Graduate School of Fujian Medical University, Fuzhou 350004, China
- Correspondence:
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Friedlová N, Zavadil Kokáš F, Hupp TR, Vojtěšek B, Nekulová M. IFITM protein regulation and functions: Far beyond the fight against viruses. Front Immunol 2022; 13:1042368. [PMID: 36466909 PMCID: PMC9716219 DOI: 10.3389/fimmu.2022.1042368] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 10/27/2022] [Indexed: 07/30/2023] Open
Abstract
Interferons (IFNs) are important cytokines that regulate immune responses through the activation of hundreds of genes, including interferon-induced transmembrane proteins (IFITMs). This evolutionarily conserved protein family includes five functionally active homologs in humans. Despite the high sequence homology, IFITMs vary in expression, subcellular localization and function. The initially described adhesive and antiproliferative or pro-oncogenic functions of IFITM proteins were diluted by the discovery of their antiviral properties. The large set of viruses that is inhibited by these proteins is constantly expanding, as are the possible mechanisms of action. In addition to their beneficial antiviral effects, IFITM proteins are often upregulated in a broad spectrum of cancers. IFITM proteins have been linked to most hallmarks of cancer, including tumor cell proliferation, therapeutic resistance, angiogenesis, invasion, and metastasis. Recent studies have described the involvement of IFITM proteins in antitumor immunity. This review summarizes various levels of IFITM protein regulation and the physiological and pathological functions of these proteins, with an emphasis on tumorigenesis and antitumor immunity.
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Affiliation(s)
- Nela Friedlová
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czechia
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czechia
| | - Filip Zavadil Kokáš
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czechia
| | - Ted R. Hupp
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czechia
- Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Bořivoj Vojtěšek
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czechia
| | - Marta Nekulová
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czechia
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Liu Z, Zhang W, Zhang B, Chen S, Ling C. MiR-504-3p Has Tumor-Suppressing Activity and Decreases IFITM1 Expression in Non-Small Cell Lung Cancer Cells. Genet Test Mol Biomarkers 2022; 26:351-359. [PMID: 36027039 DOI: 10.1089/gtmb.2021.0158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Objective: To analyze the impact of expression of miR-504-3p on the proliferation, migration, cell cycle transit and rate of apoptosis of NSCLC cells and explore the underlying mechanisms. Methods: The Cancer Genome Atlas (TCGA) database was used to compare the expression levels of miR-504 between NSCLC tissues and normal lung tissues. NSCLC cells were transfected with lentiviral vectors that either overexpressed or knocked down miR-504-3p to evaluate its effects on NSCLC biological behavior. Quantitative Real Time Polymerase Chain Reaction was used to measure the levels of miR-504-3p and Interferon-Induced Transmembrane Protein 1 (IFITM1). A luciferase reporter array was used to reveal whether miR-504-3p directly targets IFITM1. Results: The expression of miR-504 was significantly down-regulated in lung cancer tissues compared to normal lung tissues. Overexpression of miR-504-3p in NSCLC cell lines inhibited cell proliferation, migration and promoted cell apoptosis. Meanwhile, changes in the expression level of miR-504-3p had no significant effect on NSCLC cell cycle progression. Moreover, over-expressed miR-504-3p following its transfection significantly decreased the expression of IFITM1 in NSCLC cell lines and suppressed the activity of the luciferase reporter containing wild type but not mutant IFITM1 3' -UTR. Conclusion: miR-504-3p inhibits cell proliferation and migration and promotes cell apoptosis in NSCLC cells. MiR-504-3p decreases IFITM1 expression in NSCLC cells, which may be a potential mechanism of its tumor-suppressive functions in NSCLC.
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Affiliation(s)
- Zining Liu
- Department of Respiratory Diseases, Suzhou Municipal Hospital, Suzhou, China.,Department of Gastroenterology, Xiangcheng People's Hospital, Suzhou, China.,Department of Respiratory Diseases and The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Weili Zhang
- Department of Gastroenterology, Xiangcheng People's Hospital, Suzhou, China
| | - Biao Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Shaomu Chen
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Chunhua Ling
- Department of Respiratory Diseases and The First Affiliated Hospital of Soochow University, Suzhou, China
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Co-expression of DDR2 and IFITM1 promotes breast cancer cell proliferation, migration and invasion and inhibits apoptosis. J Cancer Res Clin Oncol 2022; 148:3385-3398. [PMID: 35761108 DOI: 10.1007/s00432-022-04110-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 06/02/2022] [Indexed: 10/17/2022]
Abstract
PURPOSE To investigate the roles of DDR2 and IFITM1 in breast cancer (BC). METHODS The expression of DDR2 and IFITM1 in BC tissues and cell lines was measured. DDR2 and/or IFITM1 were knocked down in BT20 and MDA-MB-231 cells, after which the viability, mobility and apoptosis of the cells were tested. Xenograft mouse models were established through subcutaneous tumor transplantation. RESULTS DDR2 and IFITM1 were highly expressed in invasive BC tissues and cell lines. Overexpression of DDR2 and/or IFITM1 was associated with poorer clinical outcomes and patient survival. Knockdown of DDR2 or IFITM1 suppressed the viability and invasiveness of BT20 and MDA-MB-231 cells and restrained the growth of xenograft tumors in nude mice. Simultaneous knockdown of IFITM1 and DDR2 surpassed knockdown of IFITM1 alone in suppressing BC development. CONCLUSIONS DDR2 and IFITM1 are co-expressed to facilitate the malignant behaviors of BC cells and promote the development of tumors.
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Eke I, Aryankalayil MJ, Bylicky MA, Sandfort V, Vanpouille-Box C, Nandagopal S, Graves EE, Giaccia AJ, Coleman CN. Long-term expression changes of immune-related genes in prostate cancer after radiotherapy. Cancer Immunol Immunother 2022; 71:839-850. [PMID: 34435232 PMCID: PMC8873240 DOI: 10.1007/s00262-021-03036-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 08/16/2021] [Indexed: 01/14/2023]
Abstract
The expression of immune-related genes in cancer cells can alter the anti-tumor immune response and thereby impact patient outcomes. Radiotherapy has been shown to modulate immune-related genes dependent on the fractionation regimen. To identify long-term changes in gene expression after irradiation, PC3 (p53 deleted) and LNCaP (p53 wildtype) prostate cancer cells were irradiated with either a single dose (SD, 10 Gy) or a fractionated regimen (MF) of 10 fractions (1 Gy per fraction). Whole human genome arrays were used to determine gene expression at 24 h and 2 months after irradiation. Immune pathway activation was analyzed with Ingenuity Pathway Analysis software. Additionally, 3D colony formation assays and T-cell cytotoxicity assays were performed. LNCaP had a higher basal expression of immunogenic genes and was more efficiently killed by cytotoxic T-cells compared to PC3. In both cell lines, MF irradiation resulted in an increase in multiple immune-related genes immediately after irradiation, while at 2 months, SD irradiation had a more pronounced effect on radiation-induced gene expression. Both immunogenic and immunosuppressive genes were upregulated in the long term in PC3 cells by a 10 Gy SD irradiation but not in LNCaP. T-cell-mediated cytotoxicity was significantly increased in 10 Gy SD PC3 cells compared to the unirradiated control and could be further enhanced by treatment with immune checkpoint inhibitors. Irradiation impacts the expression of immune-related genes in cancer cells in a fractionation-dependent manner. Understanding and targeting these changes may be a promising strategy for primary prostate cancer and recurrent tumors.
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Affiliation(s)
- Iris Eke
- Department of Radiation Oncology, Center for Clinical Sciences Research (CCSR), Stanford University School of Medicine, 269 Campus Dr., Room 1260, Stanford, CA, 94305, USA.
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
| | - Molykutty J Aryankalayil
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Michelle A Bylicky
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Veit Sandfort
- Department of Radiology, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | | | - Saravanan Nandagopal
- Department of Radiation Oncology, Center for Clinical Sciences Research (CCSR), Stanford University School of Medicine, 269 Campus Dr., Room 1260, Stanford, CA, 94305, USA
| | - Edward E Graves
- Department of Radiation Oncology, Center for Clinical Sciences Research (CCSR), Stanford University School of Medicine, 269 Campus Dr., Room 1260, Stanford, CA, 94305, USA
| | - Amato J Giaccia
- Department of Radiation Oncology, Center for Clinical Sciences Research (CCSR), Stanford University School of Medicine, 269 Campus Dr., Room 1260, Stanford, CA, 94305, USA
- Oxford Institute of Radiation Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX37DQ, UK
| | - C Norman Coleman
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
- Radiation Research Program, National Cancer Institute, National Institutes of Health, Rockville, MD, 20850, USA
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Escher TE, Dandawate P, Sayed A, Hagan CR, Anant S, Lewis-Wambi J. Enhanced IFNα Signaling Promotes Ligand-Independent Activation of ERα to Promote Aromatase Inhibitor Resistance in Breast Cancer. Cancers (Basel) 2021; 13:5130. [PMID: 34680281 PMCID: PMC8534010 DOI: 10.3390/cancers13205130] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 10/06/2021] [Accepted: 10/11/2021] [Indexed: 01/07/2023] Open
Abstract
Aromatase inhibitors (AIs) reduce estrogen levels up to 98% as the standard practice to treat postmenopausal women with estrogen receptor-positive (ER+) breast cancer. However, approximately 30% of ER+ breast cancers develop resistance to treatment. Enhanced interferon-alpha (IFNα) signaling is upregulated in breast cancers resistant to AIs, which drives expression of a key regulator of survival, interferon-induced transmembrane protein 1 (IFITM1). However, how upregulated IFNα signaling mediates AI resistance is unknown. In this study, we utilized MCF-7:5C cells, a breast cancer cell model of AI resistance, and demonstrate that these cells exhibit enhanced IFNα signaling and ligand-independent activation of the estrogen receptor (ERα). Experiments demonstrated that STAT1, the mediator of intracellular signaling for IFNα, can interact directly with ERα. Notably, inhibition of IFNα signaling significantly reduced ERα protein expression and ER-regulated genes. In addition, loss of ERα suppressed IFITM1 expression, which was associated with cell death. Notably, chromatin immunoprecipitation experiments validated that both ERα and STAT1 associate with ERE sequences in the IFITM1 promoter. Overall, hyperactivation of IFNα signaling enhances ligand-independent activation of ERα, which promotes ER-regulated, and interferon stimulated gene expression to promote survival in AI-resistant breast cancer cells.
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Affiliation(s)
- Taylor E. Escher
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA; (T.E.E.); (P.D.); (A.S.); (C.R.H.); (S.A.)
| | - Prasad Dandawate
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA; (T.E.E.); (P.D.); (A.S.); (C.R.H.); (S.A.)
- The University of Kansas Cancer Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
| | - Afreen Sayed
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA; (T.E.E.); (P.D.); (A.S.); (C.R.H.); (S.A.)
| | - Christy R. Hagan
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA; (T.E.E.); (P.D.); (A.S.); (C.R.H.); (S.A.)
- The University of Kansas Cancer Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
- Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
| | - Shrikant Anant
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA; (T.E.E.); (P.D.); (A.S.); (C.R.H.); (S.A.)
- The University of Kansas Cancer Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
| | - Joan Lewis-Wambi
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA; (T.E.E.); (P.D.); (A.S.); (C.R.H.); (S.A.)
- The University of Kansas Cancer Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
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Provance OK, Geanes ES, Lui AJ, Roy A, Holloran SM, Gunewardena S, Hagan CR, Weir S, Lewis-Wambi J. Disrupting interferon-alpha and NF-kappaB crosstalk suppresses IFITM1 expression attenuating triple-negative breast cancer progression. Cancer Lett 2021; 514:12-29. [PMID: 34022283 PMCID: PMC8221017 DOI: 10.1016/j.canlet.2021.05.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 04/20/2021] [Accepted: 05/05/2021] [Indexed: 12/15/2022]
Abstract
Overexpression of interferon induced transmembrane protein-1 (IFITM1) enhances tumor progression in multiple cancers, but its role in triple-negative breast cancer (TNBC) is unknown. Here, we explore the functional significance and regulation of IFITM1 in TNBC and strategies to target its expression. Immunohistochemistry staining of a tissue microarray demonstrates that IFITM1 is overexpressed in TNBC samples which is confirmed by TCGA analysis. Targeting IFITM1 by siRNA or CRISPR/Cas9 in TNBC cell lines significantly inhibits proliferation, colony formation, and wound healing in vitro. Orthotopic mammary fat pad and mammary intraductal studies reveal that loss of IFITM1 reduces TNBC tumor growth and invasion in vivo. RNA-seq analysis of IFITM1/KO cells reveals significant downregulation of several genes involved in proliferation, migration, and invasion and functional studies identified NF-κB as an important downstream target of IFITM1. Notably, siRNA knockdown of p65 reduces IFITM1 expression and a drug-repurposing screen of FDA approved compounds identified parthenolide, an NFκB inhibitor, as a cytotoxic agent for TNBC and an inhibitor of IFITM1 in vitro and in vivo. Overall, our findings suggest that targeting IFITM1 by suppressing interferon-alpha/NFκB signaling represents a novel therapeutic strategy for TNBC treatment.
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Affiliation(s)
- Olivia K Provance
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Eric S Geanes
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Asona J Lui
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA; Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Anuradha Roy
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA; High Throughput Screening Laboratory, University of Kansas, Lawrence, KS, 66049, USA
| | - Sean M Holloran
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA; Department of Biochemistry, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Sumedha Gunewardena
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Christy R Hagan
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA; Department of Biochemistry, University of Kansas Medical Center, Kansas City, KS, 66160, USA; The University of Kansas Cancer Center, Kansas City, KS, 66160, USA
| | - Scott Weir
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA; The University of Kansas Cancer Center, Kansas City, KS, 66160, USA; The Institute for Advancing Medical Innovation, Kansas City, KS, 66160, USA
| | - Joan Lewis-Wambi
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA; The University of Kansas Cancer Center, Kansas City, KS, 66160, USA.
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Li X, Liang R, Yang L. Commentary: Identification of IFN-Induced Transmembrane Protein 1 With Prognostic Value in Pancreatic Cancer Using Network Module-Based Analysis. Front Oncol 2021; 11:707516. [PMID: 34354954 PMCID: PMC8329442 DOI: 10.3389/fonc.2021.707516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 07/08/2021] [Indexed: 11/13/2022] Open
Affiliation(s)
- Xinxiao Li
- Department of Oncology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Renba Liang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Liu Yang
- Department of Oncology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
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Abstract
Interferon (IFN)-induced transmembrane protein 1 (IFITM1), a member of the IFN-induced transmembrane protein family, is reported to be highly expressed in tumor tissues as well as cancer cell lines, and it is an independent prognostic biomarker for patients with certain tumor types, such as gallbladder carcinoma, esophageal adenocarcinoma, colorectal cancer, and gastric cancer. Moreover, overexpression of IFITM1 promotes tumor cell proliferation, invasion, metastasis, angiogenesis, and therapeutic resistance, including endocrine therapy, chemotherapy, and radiotherapy resistance. Due to these diverse functions of IFITM1 in tumors, targeting IFITM1 may provide a novel strategy for cancer treatment and be highly desirable to improve cancer patient outcomes. Herein, we decipher the role of IFITM1 in cancer in detail.
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20
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Wu L, Zhu X, Yan D, Tang M, Ma C, Yan S. Identification of IFN-Induced Transmembrane Protein 1 With Prognostic Value in Pancreatic Cancer Using Network Module-Based Analysis. Front Oncol 2021; 11:626883. [PMID: 33869009 PMCID: PMC8044951 DOI: 10.3389/fonc.2021.626883] [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: 11/07/2020] [Accepted: 02/08/2021] [Indexed: 12/12/2022] Open
Abstract
Despite improvements reported in diagnosis and treatments in recent decades, pancreatic cancer is still characterized by poor prognosis and low survival rate among solid tumors. Intensive interests have grown in exploring novel predictive biomarkers, aiming to enhance the efficiency in early detection and treatment prognosis. In this study, we identified the differentially expressed genes (DEGs) in pancreatic cancer by analyzing five gene expression profiles and established the functional modules according to the functional interaction (FI) network between the DEGs. A significant upregulation of the selected DEG, interferon (IFN)-induced transmembrane protein 1 (IFITM1), was evaluated in several bioinformatics online tools and verified with immunohistochemistry staining from samples of 90 patients with pancreatic cancer. Prognostic data showed that high expression of IFITM1 associated with poor survival, and multivariate Cox regression analysis showed IFITM1 was one of the independent prognostic factors for overall survival. Meanwhile, significant correlations of the expression of IFITM1 and the infiltration of immune cells were found by TIMER. Furthermore, a higher level of IFITM1 was assessed in pancreatic cancer cell lines compared to normal human pancreatic duct epithelial cells, and silencing IFITM1 in tumor cells remarkedly inhibited cancer tumorigenicity. Collectively, our findings suggested that IFITM1 might have promising utility for pancreatic cancer.
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Affiliation(s)
- Lingyun Wu
- Department of Radiation Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xinli Zhu
- Department of Radiation Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Danfang Yan
- Department of Radiation Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Mengmeng Tang
- Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chiyuan Ma
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Senxiang Yan
- Department of Radiation Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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21
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O'Brien VP, Koehne AL, Dubrulle J, Rodriguez AE, Leverich CK, Kong VP, Campbell JS, Pierce RH, Goldenring JR, Choi E, Salama NR. Sustained Helicobacter pylori infection accelerates gastric dysplasia in a mouse model. Life Sci Alliance 2021; 4:e202000967. [PMID: 33310760 PMCID: PMC7768197 DOI: 10.26508/lsa.202000967] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 11/23/2020] [Accepted: 11/24/2020] [Indexed: 12/12/2022] Open
Abstract
More than 80% of gastric cancer is attributable to stomach infection with Helicobacter pylori (Hp). Gastric preneoplastic progression involves sequential tissue changes, including loss of parietal cells, metaplasia and dysplasia. In transgenic mice, active KRAS expression recapitulates these tissue changes in the absence of Hp infection. This model provides an experimental system to investigate additional roles of Hp in preneoplastic progression, beyond its known role in initiating inflammation. Tissue histology, gene expression, the immune cell repertoire, and metaplasia and dysplasia marker expression were assessed in KRAS+ mice +/-Hp infection. Hp+/KRAS+ mice had severe T-cell infiltration and altered macrophage polarization; a different trajectory of metaplasia; more dysplastic glands; and greater proliferation of metaplastic and dysplastic glands. Eradication of Hp with antibiotics, even after onset of metaplasia, prevented or reversed these tissue phenotypes. These results suggest that gastric preneoplastic progression differs between Hp+ and Hp- cases, and that sustained Hp infection can promote the later stages of gastric preneoplastic progression.
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Affiliation(s)
- Valerie P O'Brien
- Fred Hutchinson Cancer Research Center, Human Biology Division, Seattle, WA, USA
| | - Amanda L Koehne
- Fred Hutchinson Cancer Research Center, Comparative Medicine Shared Resource, Seattle, WA, USA
- Fred Hutchinson Cancer Research Center, Experimental Histopathology Shared Resource, Seattle, WA, USA
| | - Julien Dubrulle
- Fred Hutchinson Cancer Research Center, Genomics and Bioinformatics Shared Resource, Seattle, WA, USA
| | - Armando E Rodriguez
- Fred Hutchinson Cancer Research Center, Human Biology Division, Seattle, WA, USA
| | - Christina K Leverich
- Fred Hutchinson Cancer Research Center, Human Biology Division, Seattle, WA, USA
| | - V Paul Kong
- Fred Hutchinson Cancer Research Center, Experimental Histopathology Shared Resource, Seattle, WA, USA
| | - Jean S Campbell
- Fred Hutchinson Cancer Research Center, Program in Immunology, Seattle, WA, USA
| | - Robert H Pierce
- Fred Hutchinson Cancer Research Center, Program in Immunology, Seattle, WA, USA
| | - James R Goldenring
- Department of Surgery, Epithelial Biology Center, Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
- Nashville Veterans Affairs Medical Center, Nashville, TN, USA
| | - Eunyoung Choi
- Department of Surgery, Epithelial Biology Center, Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Nina R Salama
- Fred Hutchinson Cancer Research Center, Human Biology Division, Seattle, WA, USA
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22
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Lin HZ, Zhang T, Chen MY, Shen JL. Novel biomarkers for the diagnosis and prognosis of gallbladder cancer. J Dig Dis 2021; 22:62-71. [PMID: 33369216 DOI: 10.1111/1751-2980.12966] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 11/10/2020] [Accepted: 12/22/2020] [Indexed: 01/17/2023]
Abstract
Gallbladder cancer (GBC) is the most common form of biliary tract malignancy with a dismal prognosis. A poor outcome in patients with GBC is related to the aggressive nature of the tumor, delayed diagnosis, and a lack of reliable biomarkers and effective treatment. Therefore, early diagnosis and accurate disease assessment are crucial to prolonging the patient survival. Identification of novel prognostic and diagnostic biomarkers may help improve the early diagnostic rate and develop specific targeted treatments for patients with GBC. We herein review the novel biomarkers that may be associated with the diagnosis and prognosis in GBC and their potential clinical significance in the management of GBC.
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Affiliation(s)
- Hong Ze Lin
- Nanshan School, Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Tao Zhang
- Nanshan School, Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Ming Yu Chen
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Ji Liang Shen
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
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23
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Li Y, Ma X, Wu W, Chen Z, Meng G. PML Nuclear Body Biogenesis, Carcinogenesis, and Targeted Therapy. Trends Cancer 2020; 6:889-906. [PMID: 32527650 DOI: 10.1016/j.trecan.2020.05.005] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 04/20/2020] [Accepted: 05/11/2020] [Indexed: 01/16/2023]
Abstract
Targeted therapy has become increasingly important in cancer therapy. For example, targeting the promyelocytic leukemia PML protein in leukemia has proved to be an effective treatment. PML is the core component of super-assembled structures called PML nuclear bodies (NBs). Although this nuclear megaDalton complex was first observed in the 1960s, the mechanism of its assembly remains poorly understood. We review recent breakthroughs in the PML field ranging from a revised assembly mechanism to PML-driven genome organization and carcinogenesis. In addition, we highlight that oncogenic oligomerization might also represent a promising target in the treatment of leukemias and solid tumors.
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Affiliation(s)
- Yuwen Li
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Rui-Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Xiaodan Ma
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Rui-Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Wenyu Wu
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Rui-Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Zhu Chen
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Rui-Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Guoyu Meng
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Rui-Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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24
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Dai L, Chen J, Lin Z, Wang Z, Mu S, Qin Z. Targeting Sphingosine Kinase by ABC294640 against Diffuse Intrinsic Pontine Glioma (DIPG). J Cancer 2020; 11:4683-4691. [PMID: 32626514 PMCID: PMC7330698 DOI: 10.7150/jca.46269] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 05/11/2020] [Indexed: 01/29/2023] Open
Abstract
As a highly aggressive pediatric brainstem tumor, diffuse intrinsic pontine glioma (DIPG) accounts for 10% to 20% of childhood brain tumors. The survival rate for DIPG remains very low, with a median survival time as less than one year even under radiotherapy, the current standard treatment. Moreover, over than 250 clinical trials have failed when trying to improve the survival compared to radiotherapy. The sphingolipid metabolism and related signaling pathways have been found closely related to cancer cell survival; however, the sphingolipid metabolism targeted therapies have never been investigated in DIPG. In the current study, the anti-DIPG activity of ABC294640, the only first-in-class orally available Sphingosine kinase (SphK) inhibitor was explored. Treatment with ABC294640 significantly repressed DIPG cell growth by inducing intracellular pro-apoptotic ceramides production and cell apoptosis. We also profiled ABC294640-induced changes in gene expression within DIPG cells and identified many new genes tightly controlled by sphingolipid metabolism, such as IFITM1 and KAL1. These genes are required for DIPG cell survival and display clinical relevance in DIPG patients' samples. Together, our findings in this study indicate that targeting sphingolipid metabolism may represent a promising strategy to improve DIPG treatment.
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Affiliation(s)
- Lu Dai
- Departments of Pathology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR 72205, USA
| | - Jungang Chen
- Departments of Pathology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR 72205, USA
| | - Zhen Lin
- Department of Pathology, Tulane University Health Sciences Center, Tulane Cancer Center, 1700 Tulane Ave., New Orleans, LA 70112, USA
| | - Zhaoxiong Wang
- Department of Pathology, Tulane University Health Sciences Center, Tulane Cancer Center, 1700 Tulane Ave., New Orleans, LA 70112, USA
| | - Shengyu Mu
- Pharmacology & Toxicology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR 72205, USA
| | - Zhiqiang Qin
- Departments of Pathology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR 72205, USA
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25
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Zhang L, Wang Z, Kong D, Zhao X, Chen X, Chai W. Knockdown of interferon-induced transmembrane protein 1 inhibited proliferation, induced cell cycle arrest and apoptosis, and suppressed MAPK signaling pathway in pancreatic cancer cells. Biosci Biotechnol Biochem 2020; 84:1603-1613. [PMID: 32434425 DOI: 10.1080/09168451.2020.1762479] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Pancreatic cancer (PC), highly malignant, is one of the most lethal cancers. Interferon-induced transmembrane protein 1 (IFITM1) has recently been regarded as a new molecular marker in human cancers. However, the role of IFITM1 in PC remains unclear. In this study, a short hairpin RNA (shRNA) was constructed to assess the effect of IFITM1 on PANC-1 and ASPC-1 cells. The level of IFITM1 was downregulated in cells transfected with shRNA targeting IFITM1 (sh-IFITM1). Silencing of IFITM1 significantly decreased cell viability, downregulated the level of Ki-67, arrested cell at G1/S phase, reduced the number of cells in S phase, and decreased cyclinD1, cyclinE, CDK2, and CDK4 levels. Moreover, Hoechst staining and Western blotting analysis showed that cell apoptosis was induced by IFITM1. IFITM1 knockdown suppressed the MAPK signaling pathway by downregulation of p-ERK, p-P38, and p-JNK levels. These findings suggested that IFITM1 could be considered a potential therapeutic target for PC.
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Affiliation(s)
- Lei Zhang
- First Department of General Surgery, Cangzhou Central Hospital , Cangzhou, Hebei, China
| | - Zhenyong Wang
- First Department of General Surgery, Cangzhou Central Hospital , Cangzhou, Hebei, China
| | - Deshuai Kong
- First Department of General Surgery, Cangzhou Central Hospital , Cangzhou, Hebei, China
| | - Xiulei Zhao
- First Department of General Surgery, Cangzhou Central Hospital , Cangzhou, Hebei, China
| | - Xiongfei Chen
- First Department of General Surgery, Cangzhou Central Hospital , Cangzhou, Hebei, China
| | - Wei Chai
- First Department of General Surgery, Cangzhou Central Hospital , Cangzhou, Hebei, China
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26
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Chen G, Cai Z, Dong X, Zhao J, Lin S, Hu X, Liu FE, Liu X, Zhang H. Genomic and Transcriptomic Landscape of Tumor Clonal Evolution in Cholangiocarcinoma. Front Genet 2020; 11:195. [PMID: 32231683 PMCID: PMC7083074 DOI: 10.3389/fgene.2020.00195] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 02/19/2020] [Indexed: 12/15/2022] Open
Abstract
Cholangiocarcinoma remained a severe threat to human health. Deciphering the genomic and/or transcriptomic profiles of tumor has been proved to be a promising strategy for exploring the mechanism of tumorigenesis and development, which could also provide valuable insights into Cholangiocarcinoma. However, little knowledge has been obtained regarding to how the alteration among different omics levels is connected. Here, using whole exome sequencing and transcriptome sequencing, we performed a thorough evaluation for the landscape of genome and transcriptome in cholangiocarcinoma and illustrate the alteration of tumor on different biological levels. Meanwhile, we also identified the clonal structure of each included tumor sample and discovered different clonal evolution patterns related to patients' survival. Furthermore, we extracted subnetworks that were greatly influenced by tumor clonal/subclonal mutations or transcriptome change. The topology relationship between genes affected by genomic/transcriptomic changes in biological interaction networks revealed that alteration of genome and transcriptome was highly correlated, and somatic mutations located on important genes might affect the expression of numerous genes in close range.
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Affiliation(s)
- Geng Chen
- School of Life Sciences and Technology, Xi’an Jiaotong University, Xi’an, China
| | - Zhixiong Cai
- School of Life Sciences and Technology, Xi’an Jiaotong University, Xi’an, China
| | - Xiuqing Dong
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Jing Zhao
- School of Life Sciences and Technology, Xi’an Jiaotong University, Xi’an, China
| | - Song Lin
- School of Life Sciences and Technology, Xi’an Jiaotong University, Xi’an, China
| | - Xi Hu
- School of Life Sciences and Technology, Xi’an Jiaotong University, Xi’an, China
| | - Fang-E Liu
- Department of Nursing, School of Medicine, Xi’an Peihua University, Xi’an, China
| | - Xiaolong Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Huqing Zhang
- School of Life Sciences and Technology, Xi’an Jiaotong University, Xi’an, China
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27
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Kim SH, In Choi H, Choi MR, An GY, Binas B, Jung KH, Chai YG. Epigenetic regulation of IFITM1 expression in lipopolysaccharide-stimulated human mesenchymal stromal cells. Stem Cell Res Ther 2020; 11:16. [PMID: 31910882 PMCID: PMC6945778 DOI: 10.1186/s13287-019-1531-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Revised: 11/21/2019] [Accepted: 12/13/2019] [Indexed: 12/17/2022] Open
Abstract
Background Toll-like receptor 4 (TLR4) ligands such as lipopolysaccharide (LPS) activate immunomodulatory functions and the migration of human mesenchymal stromal cells (hMSCs). Here, we study the migration-related gene expression of LPS-stimulated hMSCs and the role and regulation of one of the upregulated genes, encoding the interferon-induced transmembrane protein 1 (IFITM1). Methods Gene expression profiles were determined by whole-transcriptome analysis (RNA-seq) and quantitative real-time PCR (qRT-PCR). Bioinformatics approaches were used to perform network and pathway analyses. The cell migration-related genes were identified with an in vitro wound healing assay. RNA interference (RNAi) was used to suppress the IFITM1 gene expression. The IFITM1 gene enhancer was analyzed by chromatin immunoprecipitation (ChIP) sequencing, ChIP-to-PCR, luciferase reporter assays, and qRT-PCR for enhancer RNAs (eRNAs). Results RNA-seq confirmed IFITM1 as an LPS-stimulated gene, and RNAi demonstrated its importance for the LPS-stimulated migration. LPS treatment increased the eRNA expression in enhancer region R2 (2 kb upstream) of the IFITM1 gene and enriched R2 for H3K27ac. Bioinformatics implicated the transcription factors NF-κB and IRF1, ChIP assays revealed their binding to R2, and chemical inhibition of NF-κB and RNAi directed against IRF1 prevented R2 eRNA and IFITM1 gene expression. Conclusions Increased expression of the IFITM1 gene is required for LPS-stimulated hMSC migration. We described several underlying changes in the IFITM1 gene enhancer, most notably the NF-κB-mediated activation of enhancer region R2.
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Affiliation(s)
- Sun Hwa Kim
- Department of Molecular & Life Science, Hanyang University, Ansan, 15588, Republic of Korea
| | - Hae In Choi
- Department of Bionanotechnology, Hanyang University, Seoul, 04673, Republic of Korea
| | - Mi Ran Choi
- Department of Psychiatry, The Catholic University of Korea, Seoul, 06591, Republic of Korea
| | - Ga Yeong An
- Department of Bionanotechnology, Hanyang University, Seoul, 04673, Republic of Korea
| | - Bert Binas
- Department of Molecular & Life Science, Hanyang University, Ansan, 15588, Republic of Korea.
| | - Kyoung Hwa Jung
- Convergence Technology Campus of Korea Polytechnic II, Incheon, 21417, Republic of Korea.
| | - Young Gyu Chai
- Department of Molecular & Life Science, Hanyang University, Ansan, 15588, Republic of Korea. .,Department of Bionanotechnology, Hanyang University, Seoul, 04673, Republic of Korea.
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Wu L, Tang Q, Yin X, Yan D, Tang M, Xin J, Pan Q, Ma C, Yan S. The Therapeutic Potential of Adipose Tissue-Derived Mesenchymal Stem Cells to Enhance Radiotherapy Effects on Hepatocellular Carcinoma. Front Cell Dev Biol 2019; 7:267. [PMID: 31781559 PMCID: PMC6861425 DOI: 10.3389/fcell.2019.00267] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 10/18/2019] [Indexed: 12/17/2022] Open
Abstract
Several studies have investigated strategies to improve the clinical efficacy of radiotherapy (RT) against hepatocellular carcinoma (HCC), yet the prognosis remains poor. Human adipose tissue-derived mesenchymal stem cells (AT-MSCs), easily accessible and abundant in quantity, have represented as an attractive therapeutic tool for the stem cell-based treatment for cancer diseases. Through direct co-culture and indirect separate culture experiments, we showed that AT-MSCs could enhance inhibitory effect of RT on reducing HCC cell growth, migration and invasion in both in vitro and in vivo experiments. RNA-sequencing analysis revealed a noticeable interferon-induced transmembrane 1 (IFITM1)-induced tumor gene signature. Gain and loss of mechanistic studies indicated that mechanism was attributed to downregulated expression of signal transducer and activator of transcription 3 (STAT3) and matrix metallopeptidases (MMPs) and upregulated expression of P53 and caspases. Collectively, our findings suggest that AT-MSCs might enhance the therapeutic effects of RT on HCC, providing a rationale for AT-MSCs and RT combination therapy as a new remedy for HCC.
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Affiliation(s)
- Lingyun Wu
- Department of Radiation Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qiuying Tang
- Department of Radiation Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xin Yin
- Department of Radiation Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - DanFang Yan
- Department of Radiation Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Mengmeng Tang
- Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiaojiao Xin
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qiaoling Pan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chiyuan Ma
- Department of Orthopaedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Senxiang Yan
- Department of Radiation Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Gan CP, Sam KK, Yee PS, Zainal NS, Lee BKB, Abdul Rahman ZA, Patel V, Tan AC, Zain RB, Cheong SC. IFITM3 knockdown reduces the expression of CCND1 and CDK4 and suppresses the growth of oral squamous cell carcinoma cells. Cell Oncol (Dordr) 2019; 42:477-490. [PMID: 30949979 PMCID: PMC7771307 DOI: 10.1007/s13402-019-00437-z] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/27/2019] [Indexed: 12/25/2022] Open
Abstract
PURPOSE Oral squamous cell carcinoma (OSCC) is a challenging disease to treat. Up to 50% of OSCC patients with advanced disease develop recurrences. Elucidation of key molecular mechanisms underlying OSCC development may provide opportunities to target specific genes and, thus, to improve patient survival. In this study, we examined the expression and functional role of interferon transmembrane protein 3 (IFITM3) in OSCC development. METHODS The expression of IFITM3 in OSCC and normal oral mucosal tissues was assessed by qRT-PCR and immunohistochemistry. The role of IFITM3 in driving OSCC cell proliferation and survival was examined using siRNA-mediated gene knockdown, and the role of IFITM3 in driving cell cycle regulators was examined using Western blotting. RESULTS We found that IFITM3 is overexpressed in more than 79% of primary OSCCs. We also found that IFITM3 knockdown led to impaired OSCC cell growth through inhibition of cell proliferation, induction of cell cycle arrest, senescence and apoptosis. In addition, we found that IFITM3 knockdown led to reduced expressions of CCND1 and CDK4 and reduced RB phosphorylation, leading to inhibition of OSCC cell growth. This information may be instrumental for the design of novel targeted therapeutic strategies. CONCLUSIONS From our data we conclude that IFITM3 is overexpressed in OSCC and may regulate the CCND1-CDK4/6-pRB axis to mediate OSCC cell growth.
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Affiliation(s)
- Chai Phei Gan
- Head and Neck Cancer Research Team, Cancer Research Malaysia, 2nd Floor, Outpatient Centre, Subang Jaya Medical Centre, 47500, Subang Jaya, Selangor, Malaysia
| | - Kin Kit Sam
- Head and Neck Cancer Research Team, Cancer Research Malaysia, 2nd Floor, Outpatient Centre, Subang Jaya Medical Centre, 47500, Subang Jaya, Selangor, Malaysia
| | - Pei San Yee
- Head and Neck Cancer Research Team, Cancer Research Malaysia, 2nd Floor, Outpatient Centre, Subang Jaya Medical Centre, 47500, Subang Jaya, Selangor, Malaysia
| | - Nur Syafinaz Zainal
- Head and Neck Cancer Research Team, Cancer Research Malaysia, 2nd Floor, Outpatient Centre, Subang Jaya Medical Centre, 47500, Subang Jaya, Selangor, Malaysia
| | - Bernard Kok Bang Lee
- Head and Neck Cancer Research Team, Cancer Research Malaysia, 2nd Floor, Outpatient Centre, Subang Jaya Medical Centre, 47500, Subang Jaya, Selangor, Malaysia
| | - Zainal Ariff Abdul Rahman
- Department of Oral & Maxillofacial Clinical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
| | - Vyomesh Patel
- Head and Neck Cancer Research Team, Cancer Research Malaysia, 2nd Floor, Outpatient Centre, Subang Jaya Medical Centre, 47500, Subang Jaya, Selangor, Malaysia
| | - Aik Choon Tan
- Division of Medical Oncology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Rosnah Binti Zain
- Oral Cancer Research & Coordinating Centre (OCRCC), Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
| | - Sok Ching Cheong
- Head and Neck Cancer Research Team, Cancer Research Malaysia, 2nd Floor, Outpatient Centre, Subang Jaya Medical Centre, 47500, Subang Jaya, Selangor, Malaysia.
- Department of Oral & Maxillofacial Clinical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.
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Yan J, Jiang Y, Lu J, Wu J, Zhang M. Inhibiting of Proliferation, Migration, and Invasion in Lung Cancer Induced by Silencing Interferon-Induced Transmembrane Protein 1 (IFITM1). BIOMED RESEARCH INTERNATIONAL 2019; 2019:9085435. [PMID: 31205947 PMCID: PMC6530206 DOI: 10.1155/2019/9085435] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 03/27/2019] [Accepted: 04/18/2019] [Indexed: 01/09/2023]
Abstract
Interferon-induced transmembrane protein 1 (IFITM1), a 17-kDa membrane protein, is generally known as a modulator in many cellular functions. Recent studies showed overexpression of IFITM1 in cancers and relationship between IFITM1 overexpression and tumor progression. However, the role of IFITM1 in lung cancer remains unclear. Here, we presented the overexpression of IFITM1 in lung cancer tissues and cell lines A549 and H460 using quantitative Real-Time RT-PCR. In vitro assay indicated IFITM1 silencing inhibited lung cancer cell proliferation, migration, and invasion. Further, in vivo assay showed that IFITM1 silencing markedly suppressed cell growth and metastasis of lung cancer in tumor-bearing BALB/c nude mice. Mechanistically, we found that IFITM1 silencing significantly alleviated the protein levels of β-catenin, cyclin D1, and c-Mycin lung cancer cells and tumor samples. Taken together, our study revealed the role of IFITM1 as a tumor promoter during lung cancer development and the possible molecular mechanism.
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Affiliation(s)
- Jun Yan
- Department of Pathology, Tianjin First Center Hospital, Tianjin 300192, China
| | - Ying Jiang
- Department of Pathology, Tianjin First Center Hospital, Tianjin 300192, China
| | - Jianfeng Lu
- Department of Pathology, Tianjin First Center Hospital, Tianjin 300192, China
| | - Jianhui Wu
- Department of Pathology, Tianjin First Center Hospital, Tianjin 300192, China
| | - Mingfang Zhang
- Department of Pathology, Tianjin First Center Hospital, Tianjin 300192, China
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Necula L, Matei L, Dragu D, Neagu AI, Mambet C, Nedeianu S, Bleotu C, Diaconu CC, Chivu-Economescu M. Recent advances in gastric cancer early diagnosis. World J Gastroenterol 2019; 25:2029-2044. [PMID: 31114131 PMCID: PMC6506585 DOI: 10.3748/wjg.v25.i17.2029] [Citation(s) in RCA: 287] [Impact Index Per Article: 47.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 04/03/2019] [Accepted: 04/19/2019] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) remains an important cause of cancer death worldwide with a high mortality rate due to the fact that the majority of GC cases are diagnosed at an advanced stage when the prognosis is poor and the treatment options are limited. Unfortunately, the existing circulating biomarkers for GC diagnosis and prognosis display low sensitivity and specificity and the GC diagnosis is based only on the invasive procedures such as upper digestive endoscopy. There is a huge need for less invasive or non-invasive tests but also highly specific biomarkers in case of GC. Body fluids such as peripheral blood, urine or saliva, stomach wash/gastric juice could be a source of specific biomarkers, providing important data for screening and diagnosis in GC. This review summarized the recently discovered circulating molecules such as microRNAs, long non-coding RNAs, circular RNAs, which hold the promise to develop new strategies for early diagnosis of GC.
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Affiliation(s)
- Laura Necula
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
- Faculty of Medicine, Titu Maiorescu University, Bucharest 040441, Romania
| | - Lilia Matei
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Denisa Dragu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Ana I Neagu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Cristina Mambet
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Saviana Nedeianu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Coralia Bleotu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Carmen C Diaconu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Mihaela Chivu-Economescu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
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Gómez-Herranz M, Nekulova M, Faktor J, Hernychova L, Kote S, Sinclair EH, Nenutil R, Vojtesek B, Ball KL, Hupp TR. The effects of IFITM1 and IFITM3 gene deletion on IFNγ stimulated protein synthesis. Cell Signal 2019; 60:39-56. [PMID: 30951861 PMCID: PMC7111284 DOI: 10.1016/j.cellsig.2019.03.024] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 03/29/2019] [Accepted: 03/29/2019] [Indexed: 02/02/2023]
Abstract
Interferon-induced transmembrane proteins IFITM1 and IFITM3 (IFITM1/3) play a role in both RNA viral restriction and in human cancer progression. Using immunohistochemical staining of FFPE tissue, we identified subgroups of cervical cancer patients where IFITM1/3 protein expression is inversely related to metastasis. Guide RNA-CAS9 methods were used to develop an isogenic IFITM1/IFITM3 double null cervical cancer model in order to define dominant pathways triggered by presence or absence of IFITM1/3 signalling. A pulse SILAC methodology identified IRF1, HLA-B, and ISG15 as the most dominating IFNγ inducible proteins whose synthesis was attenuated in the IFITM1/IFITM3 double-null cells. Conversely, SWATH-IP mass spectrometry of ectopically expressed SBP-tagged IFITM1 identified ISG15 and HLA-B as dominant co-associated proteins. ISG15ylation was attenuated in IFNγ treated IFITM1/IFITM3 double-null cells. Proximity ligation assays indicated that HLA-B can interact with IFITM1/3 proteins in parental SiHa cells. Cell surface expression of HLA-B was attenuated in IFNγ treated IFITM1/IFITM3 double-null cells. SWATH-MS proteomic screens in cells treated with IFITM1-targeted siRNA cells resulted in the attenuation of an interferon regulated protein subpopulation including MHC Class I molecules as well as IFITM3, STAT1, B2M, and ISG15. These data have implications for the function of IFITM1/3 in mediating IFNγ stimulated protein synthesis including ISG15ylation and MHC Class I production in cancer cells. The data together suggest that pro-metastatic growth associated with IFITM1/3 negative cervical cancers relates to attenuated expression of MHC Class I molecules that would support tumor immune escape.
IFITM1/3 expression in cervical cancers inversely correlates with metastases. Isogenic IFITM1 and IFITM3 null cervical cancer cells were developed. Pulse SILAC approaches were used to define IFITM1/3 dependent signalling pathways. The major IFITM1/3-interferon-γ dependent effectors are HLA-B and ISG15. IFITM1/3 loss would be predicted to reduce HLA expression and ISG15ylation in vivo.
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Affiliation(s)
- Maria Gómez-Herranz
- University of Edinburgh, Institute of Genetics and Molecular Medicine, Edinburgh EH4 2XR, United Kingdom
| | - Marta Nekulova
- Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic
| | - Jakub Faktor
- Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic
| | - Lenka Hernychova
- Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic
| | - Sachin Kote
- University of Gdansk, International Centre for Cancer Vaccine Science, Department of Chemistry, Gdansk, Poland
| | - Elizabeth H Sinclair
- University of Edinburgh, Institute of Genetics and Molecular Medicine, Edinburgh EH4 2XR, United Kingdom
| | - Rudolf Nenutil
- Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic
| | - Borivoj Vojtesek
- Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic.
| | - Kathryn L Ball
- University of Edinburgh, Institute of Genetics and Molecular Medicine, Edinburgh EH4 2XR, United Kingdom; Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic.
| | - Ted R Hupp
- University of Edinburgh, Institute of Genetics and Molecular Medicine, Edinburgh EH4 2XR, United Kingdom; Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic; University of Gdansk, International Centre for Cancer Vaccine Science, Department of Chemistry, Gdansk, Poland.
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IFITM1 Outperforms CD10 in Differentiating Low-grade Endometrial Stromal Sarcomas From Smooth Muscle Neoplasms of the Uterus. Int J Gynecol Pathol 2018; 37:372-378. [PMID: 28700435 DOI: 10.1097/pgp.0000000000000424] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Distinguishing between uterine neoplasms of smooth muscle and endometrial stromal origin is a frequent diagnostic challenge. We investigated the staining pattern of interferon-induced transmembrane protein-1 (IFITM1), a novel endometrial stromal marker, in endometrial and smooth muscle uterine neoplasms and compared it with CD10 in its ability to differentiate between these two groups. Immunohistochemistry for IFITM1 and CD10 was performed in 20 cases of smooth muscle neoplasms (10 cases leiomyoma, 10 cases leiomyosarcoma), 14 cases of endometrial stromal sarcoma (ESS) (12 cases of low grade and 2 cases of high grade) and 12 cases of carcinosarcoma. Staining was scored in terms of intensity and distribution (0=absent, 1=weak/<50%, 2=moderate/50%-75%, 3=strong/>75%). A total score was obtained by adding intensity and distribution scores and classified as positive (score 3-6) or negative (score 0-2). IFITM1 was positive in 10 of 12 (83%) low-grade ESSs, 6 of 20 (30%) smooth muscle tumors (leiomyomas and leiomyosarcomas) and 11 of 12 carcinosarcomas (91.6%). The 2 cases of high-grade ESS were IFITM1 negative. While both IFITM1 (83%) and CD10 (91%) had high sensitivity in differentiating low-grade ESSs from smooth muscle neoplasms, IFITM1 (70%) had higher specificity compared with CD10 (45%). In this study IFITM1 appears to be a more specific marker of endometrial stromal differentiation compared with CD10 in differentiating low-grade ESSs from smooth muscle neoplasms. Thus, IFITM1 may be a valuable tool as part of an immunohistochemical evaluation panel in this diagnostic scenario.
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Shao Q, Lin Z, Wu X, Tang J, Lu S, Feng D, Cheng C, Qing L, Yao K, Chen Y. Transcriptome sequencing of neurologic diseases associated genes in HHV-6A infected human astrocyte. Oncotarget 2018; 7:48070-48080. [PMID: 27344170 PMCID: PMC5217001 DOI: 10.18632/oncotarget.10127] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2015] [Accepted: 06/01/2016] [Indexed: 01/21/2023] Open
Abstract
Human Herpesvirus 6 (HHV-6) has been involved in the development of several central nervous system (CNS) diseases, such as Alzheimer's disease, multiple sclerosis and glioma. In order to identify the pathogenic mechanism of HHV-6A infection, we carried out mRNA-seq study of human astrocyte HA1800 cell with HHV-6A GS infection. Using mRNA-seq analysis of HA1800-control cells with HA1800-HHV-6A GS cells, we identified 249 differentially expressed genes. After investigating these candidate genes, we found seven genes associated with two or more CNS diseases: CTSS, PTX3, CHI3L1, Mx1, CXCL16, BIRC3, and BST2. This is the first transcriptome sequencing study which showed the significant association of these genes between HHV-6A infection and neurologic diseases. We believe that our findings can provide a new perspective to understand the pathogenic mechanism of HHV-6A infection and neurologic diseases.
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Affiliation(s)
- Qing Shao
- Department of Immunology, Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China.,Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Zhe Lin
- Department of Immunology, Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Xiaohui Wu
- Genetic Data Analysis Group, Shanghai Biotechnology Corporation, Shanghai, People's Republic of China
| | - Junwei Tang
- Liver Transplantation Center of The First Affiliated Hospital and Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Shuai Lu
- Department of Immunology, Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Dongju Feng
- Department of Immunology, Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Ci Cheng
- Department of Immunology, Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Lanqun Qing
- Department of Immunology, Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Kun Yao
- Department of Immunology, Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Yun Chen
- Department of Immunology, Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
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Li D, Yang Z, Liu Z, Zou Q, Yuan Y. DDR2 and IFITM1 Are Prognostic Markers in Gallbladder Squamous Cell/Adenosquamous Carcinomas and Adenocarcinomas. Pathol Oncol Res 2017; 25:157-167. [PMID: 29043607 DOI: 10.1007/s12253-017-0314-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 09/18/2017] [Indexed: 12/16/2022]
Abstract
This study was conducted to investigate the expressions of DDR2 and IFITM1 and their clinical and pathological significances in the rare type squamous cell/adenosquamous carcinomas (SC/ASC) and ordinary adenocarcinomas (AC) of gallbladder cancers. DDR2 and IFITM1 expression was examined in 69 SC/ASCs and 146 ACs using EnVision immunohistochemistry. Results showed that the percentage of positive DDR2 and IFITM1 expression was significantly higher in SC/ASC patients with high TNM stage, lymph node metastasis, invasion, and no resection surgery compared to patients with low TNM stages, no lymph node metastasis, no invasion, and resection surgery (P < 0.05 or P < 0.01). The positive rate of DDR2 was significantly higher in SC/ASC patients with large tumor sizes than patients with small tumor sizes (p < 0.05). The percentage of positive DDR2 and IFITM1 expressions was significantly higher in AC patients with high TNM stages that didn't receive resection surgery compared to patients with low TNM stages that did receive resection surgery (P < 0.05 or P < 0.01). The positive rate of IFITM1 was significantly higher in AC patients with lymph node metastasis and invasion than in patients without metastasis and invasion (p < 0.05). Positive DDR2 and IFITM1 expression was closely associated with a decreased overall survival in SC/ASC and AC patients (P < 0.05 or P < 0.01). AUC analysis showed that DDR2 and IFITM1 was sensitive and specific for the diagnosis of SC/ASC (AUC = 0.740 and AUC =0.733, respectively) and AC (AUC = 0.710 and AUC =0.741, respectively). In conclusion, positive DDR2 and IFITM1 expression is a marker for the clinical severity, poor prognosis, and diagnosis of gallbladder SC/ASC and AC.
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Affiliation(s)
- Daiqiang Li
- Department of Pathology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhulin Yang
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
| | - Ziru Liu
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Qiong Zou
- Department of Pathology, Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yuan Yuan
- Department of Pathology, Third Xiangya Hospital, Central South University, Changsha, Hunan, China
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Lui AJ, Geanes ES, Ogony J, Behbod F, Marquess J, Valdez K, Jewell W, Tawfik O, Lewis-Wambi J. IFITM1 suppression blocks proliferation and invasion of aromatase inhibitor-resistant breast cancer in vivo by JAK/STAT-mediated induction of p21. Cancer Lett 2017; 399:29-43. [PMID: 28411130 DOI: 10.1016/j.canlet.2017.04.005] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Revised: 03/23/2017] [Accepted: 04/04/2017] [Indexed: 12/19/2022]
Abstract
Interferon induced transmembrane protein 1 (IFITM1) belongs to a family of interferon stimulated genes (ISGs) that is associated with tumor progression and DNA damage resistance; however, its role in endocrine resistance is not known. Here, we correlate IFITM1 expression with clinical stage and poor response to endocrine therapy in a tissue microarray consisting of 94 estrogen receptor (ER)-positive breast tumors. IFITM1 overexpression is confirmed in the AI-resistant MCF-7:5C cell line and not found in AI-sensitive MCF-7 cells. In this study, the orthotopic (mammary fat pad) and mouse mammary intraductal (MIND) models of breast cancer are used to assess tumor growth and invasion in vivo. Lentivirus-mediated shRNA knockdown of IFITM1 in AI-resistant MCF-7:5C cells diminished tumor growth and invasion and induced cell death, whereas overexpression of IFITM1 in wild-type MCF-7 cells promoted estrogen-independent growth and enhanced their aggressive phenotype. Mechanistic studies indicated that loss of IFITM1 in MCF-7:5C cells markedly increased p21 transcription, expression and nuclear localization which was mediated by JAK/STAT activation. These findings suggest IFITM1 overexpression contributes to breast cancer progression and that targeting IFITM1 may be therapeutically beneficial to patients with endocrine-resistant disease.
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Affiliation(s)
- Asona J Lui
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, USA; The University of Kansas Cancer Center, Kansas City, KS 66160, USA.
| | - Eric S Geanes
- Department of Cancer Biology, University of Kansas Medical Center, USA; The University of Kansas Cancer Center, Kansas City, KS 66160, USA.
| | - Joshua Ogony
- Department of Cancer Biology, University of Kansas Medical Center, USA; The University of Kansas Cancer Center, Kansas City, KS 66160, USA.
| | - Fariba Behbod
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, USA; The University of Kansas Cancer Center, Kansas City, KS 66160, USA.
| | - Jordan Marquess
- University of Kansas Medical Center School of Medicine, USA.
| | - Kelli Valdez
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, USA; The University of Kansas Cancer Center, Kansas City, KS 66160, USA.
| | - William Jewell
- The University of Kansas Cancer Center, Kansas City, KS 66160, USA.
| | - Ossama Tawfik
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, USA.
| | - Joan Lewis-Wambi
- Department of Cancer Biology, University of Kansas Medical Center, USA; The University of Kansas Cancer Center, Kansas City, KS 66160, USA.
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Ramanathan A, Ramanathan A. Interferon Induced Transmembrane Protein-1 Gene Expression as a Biomarker for Early Detection of Invasive Potential of Oral Squamous Cell Carcinomas. Asian Pac J Cancer Prev 2017; 17:2297-9. [PMID: 27221933 DOI: 10.7314/apjcp.2016.17.4.2297] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Early detection of malignant transformation with expression biomarkers has significant potential to improve the survival rate of patients as such biomarkers enable prediction of progression and assess sensitivity to chemotherapy. The expression of interferon inducible transmembrane protein 1 (IFITM1) has been associated with early invasion events in several carcinomas, including head and neck cancers, and hence has been proposed as a novel candidate biomarker. As the incidence of oral squamous cell carcinoma (OSCC) is highest in the Indian population, we sought to investigate: 1) the expression pattern of IFITM1 in OSCC tissue samples obtained from Indian patients of Dravidian origin; and 2) the possibility of using IFITM1 expression as a potential biomarker. MATERIALS AND METHODS Total RNA extracted from thirty eight OSCC biopsy samples was subjected to semi-quantitative RT-PCR with IFITM1 and GAPDH specific primers. RESULTS Of the thirty eight OSCC samples that were analyzed, IFITM1 overexpression was identified in fifteen (39%). Seven expressed a low level, while the remainder expressed high level of IFITM1. CONCLUSIONS The overexpression of IFITM1 in OSCC samples indicates that IFITM1 may be explored for the possibility of use as a high confidence diagnostic biomarker in oral cancers. To the best of our knowledge, this is the first time that IFITM1 overexpression is being reported in Indian OSCC samples.
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Affiliation(s)
- Arvind Ramanathan
- Human Genetics Laboratory, Sree Balaji Medical and Dental College and Hospital, Bharath University, Narayanapuram, Pallikaranai, Chennai, Tamil Nadu, India E-mail :
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Borg D, Hedner C, Gaber A, Nodin B, Fristedt R, Jirström K, Eberhard J, Johnsson A. Expression of IFITM1 as a prognostic biomarker in resected gastric and esophageal adenocarcinoma. Biomark Res 2016; 4:10. [PMID: 27186374 PMCID: PMC4867989 DOI: 10.1186/s40364-016-0064-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Accepted: 05/04/2016] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND There is an increasing amount of reports on IFITM1 (interferon-inducible transmembrane protein 1) in various malignancies. The aim of this study was to examine the expression of IFITM1 and its prognostic significance in gastroesophageal adenocarcinoma. METHODS Tissue samples were obtained from a consecutive cohort of 174 patients surgically treated between 2006 and 2010 for gastroesophageal (gastric, gastroesophageal junction and esophageal) adenocarcinoma, not subjected to neoadjuvant therapy. Expression of IFITM1 was examined using immunohistochemistry on tissue microarrays of primary tumors and paired samples of adjacent normal epithelium, intestinal metaplasia and lymph node metastases. RESULTS Expression of IFITM1 was significantly elevated in primary tumors and lymph node metastases compared to adjacent normal epithelium and intestinal metaplasia, regardless of tumor location. Overexpression of IFITM1 was associated with M0-disease (no distant metastases). In gastric cancer IFITM1 expression was significantly associated with improved TTR (time to recurrence) in Kaplan-Meier analysis and Cox regression, both in the unadjusted analysis (HR 0.33, 95 % CI 0.12-0.88) and in the adjusted analysis (HR 0.32, 95 % CI 0.12-0.87) but there was no significant impact on OS (overall survival). In esophageal adenocarcinoma expression of IFITM1 had no impact on TTR or OS in Kaplan-Meier-analyses, but in the adjusted Cox regression IFITM1 expression had a negative impact on both TTR (HR 3.05, 95 % CI 1.09-8.53) and OS (HR 2.71, 95 % CI 1.11-6.67). CONCLUSIONS IFITM1 was overexpressed in gastroesophageal adenocarcinoma and associated with M0-disease. In gastric cancer IFITM1 expression had a positive impact on TTR but in esophageal cancer it seemed to have an adverse impact on survival. The reason for the diverging prognostic impact of IFITM1 in esophageal and gastric cancer is unclear and warrants further studies.
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Affiliation(s)
- David Borg
- Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Skåne University Hospital, 221 85 Lund, Sweden
| | - Charlotta Hedner
- Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Skåne University Hospital, 221 85 Lund, Sweden
| | - Alexander Gaber
- Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Skåne University Hospital, 221 85 Lund, Sweden
| | - Björn Nodin
- Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Skåne University Hospital, 221 85 Lund, Sweden
| | - Richard Fristedt
- Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Skåne University Hospital, 221 85 Lund, Sweden
| | - Karin Jirström
- Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Skåne University Hospital, 221 85 Lund, Sweden
| | - Jakob Eberhard
- Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Skåne University Hospital, 221 85 Lund, Sweden
| | - Anders Johnsson
- Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Skåne University Hospital, 221 85 Lund, Sweden
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Ogony J, Choi HJ, Lui A, Cristofanilli M, Lewis-Wambi J. Interferon-induced transmembrane protein 1 (IFITM1) overexpression enhances the aggressive phenotype of SUM149 inflammatory breast cancer cells in a signal transducer and activator of transcription 2 (STAT2)-dependent manner. Breast Cancer Res 2016; 18:25. [PMID: 26897526 PMCID: PMC4761146 DOI: 10.1186/s13058-016-0683-7] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Accepted: 02/03/2016] [Indexed: 12/31/2022] Open
Abstract
Background Inflammatory breast cancer (IBC) is a very aggressive and lethal subtype of breast cancer that accounts for about 4 % of all breast cancers diagnosed in the United States. Despite the efforts of several investigators to identify the molecular factors driving the aggressive phenotype of IBC, a great deal is still unknown about the molecular underpinnings of the disease. In the present study, we investigated the role of interferon-induced transmembrane protein 1 (IFITM1), a well-known interferon-stimulated gene (ISG), in promoting the aggressiveness of SUM149 IBC cells. Methods Western blot and real-time polymerase chain reaction analyses were performed to assess the protein and messenger RNA (mRNA) levels of IFITM1 and other ISGs in three IBC cell lines: SUM149, MDA-IBC-3, and SUM190. IFITM1 expression and cellular localization were assessed by using immunofluorescence, while the tumorigenic potential was assessed by performing cell migration, invasion, and colony formation assays. Small interfering RNA and short hairpin RNA knockdowns, enzyme-linked immunosorbent assays, and luciferase assays were performed to determine the functional significance of IFITM1 and signal transducers and activators of transcription 1 and 2 (STAT1/2) in SUM149 cells. Results We found that IFITM1 was constitutively overexpressed at the mRNA and protein levels in triple-negative SUM149 IBC cells, but that it was not expressed in SUM190 and MDA-IBC-3 IBC cells, and that suppression of IFITM1 or blockade of the IFNα signaling pathway significantly reduced the aggressive phenotype of SUM149 cells. Additionally, we found that knockdown of STAT2 abolished IFITM1 expression and IFITM1 promoter activity in SUM149 cells and that loss of STAT2 significantly inhibited the ability of SUM149 cells to proliferate, migrate, invade, and form 2-D colonies. Notably, we found that STAT2-mediated activation of IFITM1 was particularly dependent on the chromatin remodeler brahma-related gene 1 (BRG1), which was significantly elevated in SUM149 cells compared with SUM190 and MDA-IBC-3 cells. Conclusions These findings indicate that overexpression of IFITM1 enhances the aggressive phenotype of triple-negative SUM149 IBC cells and that this effect is dependent on STAT2/BRG1 interaction. Further studies are necessary to explore the potential of IFITM1 as a novel therapeutic target and prognostic marker for some subtypes of IBCs. Electronic supplementary material The online version of this article (doi:10.1186/s13058-016-0683-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Joshua Ogony
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.
| | - Hye Joung Choi
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.
| | - Asona Lui
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA. .,Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA.
| | | | - Joan Lewis-Wambi
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.
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Kanda M, Kodera Y. Recent advances in the molecular diagnostics of gastric cancer. World J Gastroenterol 2015; 21:9838-9852. [PMID: 26379391 PMCID: PMC4566379 DOI: 10.3748/wjg.v21.i34.9838] [Citation(s) in RCA: 92] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2015] [Revised: 06/15/2015] [Accepted: 08/25/2015] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is the third most common cause of cancer-related death in the world, representing a major global health issue. Although the incidence of GC is declining, the outcomes for GC patients remain dismal because of the lack of effective biomarkers to detect early GC and predict both recurrence and chemosensitivity. Current tumor markers for GC, including serum carcinoembryonic antigen and carbohydrate antigen 19-9, are not ideal due to their relatively low sensitivity and specificity. Recent improvements in molecular techniques are better able to identify aberrant expression of GC-related molecules, including oncogenes, tumor suppressor genes, microRNAs and long non-coding RNAs, and DNA methylation, as novel molecular markers, although the molecular pathogenesis of GC is complicated by tumor heterogeneity. Detection of genetic and epigenetic alterations from gastric tissue or blood samples has diagnostic value in the management of GC. There are high expectations for molecular markers that can be used as new screening tools for early detection of GC as well as for patient stratification towards personalized treatment of GC through prediction of prognosis and drug-sensitivity. In this review, the studies of potential molecular biomarkers for GC that have been reported in the publicly available literature between 2012 and 2015 are reviewed and summarized, and certain highlighted papers are examined.
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Global analysis of DNA methylation in hepatocellular carcinoma by a liquid hybridization capture-based bisulfite sequencing approach. Clin Epigenetics 2015; 7:86. [PMID: 26300991 PMCID: PMC4546208 DOI: 10.1186/s13148-015-0121-1] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Accepted: 08/03/2015] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Epigenetic alterations, such as aberrant DNA methylation of promoter and enhancer regions, which lead to atypical gene expression, have been associated with carcinogenesis. In hepatocellular carcinoma (HCC), genome-wide analysis of methylation has only recently been used. For a better understanding of hepatocarcinogenesis, we applied an even higher resolution analysis of the promoter methylome to identify previously unknown regions and genes differentially methylated in HCC. RESULTS Optimized liquid hybridization capture-based bisulfite sequencing (LHC-BS) was developed to quantitatively analyze 1.86 million CpG sites in individual samples from eight pairs of HCC and adjacent tissues. By linking the differentially methylated regions (DMRs) in promoters to the differentially expressed genes (DEGs), we identified 12 DMR-associated genes. We further utilized Illumina MiSeq combining the bisulfite sequencing PCR approach to validate the 12 candidate genes. Analysis of an additional 78 HCC pairs on the Illumina MiSeq platform confirmed that 7 genes showed either promoter hyper-methylation (SMAD6, IFITM1, LRRC4, CHST4, and TBX15) or hypo-methylation (CCL20 and NQO1) in HCC. CONCLUSIONS Novel methylome profiling provides a cost-efficient approach to identifying candidate genes in human HCC that may contribute to hepatocarcinogenesis. Our work provides further information critical for understanding the epigenetic processes underlying tumorigenesis and development of HCC.
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Kim SJ, Hwang JA, Ro JY, Lee YS, Chun KH. Galectin-7 is epigenetically-regulated tumor suppressor in gastric cancer. Oncotarget 2014; 4:1461-71. [PMID: 23985992 PMCID: PMC3824540 DOI: 10.18632/oncotarget.1219] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Gastric cancer is the second leading cause of cancer death and remains a major clinical challenge due to poor prognosis and limited treatment options. Therefore, the basic mechanisms underlying gastric tumorigenesis deserve investigation. Although regulation of the galactoside-binding lectin galectin-7 in cancer has been studied, its role in tumor formation and progression remains controversial. In this study, we investigated galectin-7 expression and its role in gastric cancer. Immunohistochemical staining using a tissue microarray of gastric cancer patients revealed significantly low expression levels of galectin-7 in malignant tissues compared with matched normal tissues, and decreased expression of galectin-7 in malignant tissues was associated with advanced TMN stage disease (p =0.034). Importantly, low expression of galectin-7 in normal tissues was associated with a poor survival rate (p =0.0561). Over-expression of galectin-7 in AGS gastric adenocarcinoma cells suppressed cell proliferation, migration, and invasion, whereas ablation of galectin-7 in KATO III gastric carcinoma cells reversed these properties. AGS cells that overexpressed galectin-7 could not form gastric tumors in xenografted mice. More than 70% hypermethylation was observed in 7 of 9 gastric cancer cell lines tested and 5-aza-cytidine treatment lowered galectin-7 expression by reducing methylation in 24 cancer cell lines from five different organ origins. We analyzed CpG islands in the galectin-7 genomic region and detected hypermethylation at +1566bp of exon 2, the predicted p53 binding region. DNA hypermethylation of this region was also detected in gastric cancer tissues from 20 patients. Taken together, our data indicate that galectin-7 has a tumor suppressive function, and that the gene is epigenetically modified by DNA methylation and significantly down-regulated in gastric cancer. Further study of galectin-7 regulation may lead to improved gastric cancer diagnosis and therapy.
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Affiliation(s)
- Seok-Jun Kim
- Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea
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Kim NH, Sung HY, Choi EN, Lyu D, Choi HJ, Ju W, Ahn JH. Aberrant DNA methylation in the IFITM1 promoter enhances the metastatic phenotype in an intraperitoneal xenograft model of human ovarian cancer. Oncol Rep 2014; 31:2139-46. [PMID: 24676393 DOI: 10.3892/or.2014.3110] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2014] [Accepted: 02/26/2014] [Indexed: 11/06/2022] Open
Abstract
A lack of reliable biomarkers for the early detection and risk of metastatic recurrences makes ovarian cancer the most lethal gynecological cancer. To understand the molecular mechanisms involved in ovarian cancer metastasis in vivo, we analyzed the transcriptional expression pattern in metastatic implants of human ovarian carcinoma xenografts in mice. The expression of 937 genes was significantly different, by at least 2-fold, in the xenografts compared with that in SK-OV-3 cells. We investigated the mechanisms that regulate the expression of one of the profoundly upregulated genes, interferon-induced transmembrane protein 1 (IFITM1), in the metastatic implants. Specific CpG sites within the IFITM1 promoter were hypomethylated in the metastatic implants relative to those in the wild-type SK-OV-3 cells. Treating wild-type SK-OV-3 cells with the demethylating agent 5-aza-2'-deoxycytidine enhanced IFITM1 expression in a dose-dependent manner, implying transcriptional regulation by promoter methylation. We also found that IFITM1 overexpression caused increased migration and invasiveness in SK-OV-3 cells. Our results demonstrate that IFITM1 could be a novel metastasis-promoting gene that enhances the metastatic phenotype in ovarian cancer via epigenetic transcriptional regulation. Our findings also suggest that the status of DNA methylation within the IFITM1 promoter region could be a biomarker indicating metastatic progression in ovarian cancer.
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Affiliation(s)
- Nam Hee Kim
- Department of Obstetrics and Gynecology, School of Medicine, Ewha Womans University, Yangcheon‑ku, Seoul 158-710, Republic of Korea
| | - Hye Youn Sung
- Department of Biochemistry, School of Medicine, Ewha Womans University, Yangcheon‑ku, Seoul 158-710, Republic of Korea
| | - Eun Nam Choi
- Department of Biochemistry, School of Medicine, Ewha Womans University, Yangcheon‑ku, Seoul 158-710, Republic of Korea
| | - Dahyun Lyu
- Department of Biochemistry, School of Medicine, Ewha Womans University, Yangcheon‑ku, Seoul 158-710, Republic of Korea
| | - Hyuck Jae Choi
- Department of Radiology and Research, Institute of Radiology, University of Ulsan, College of Medicine, Asan Medical Center, Songpa-ku, Seoul 138-736, Republic of Korea
| | - Woong Ju
- Department of Obstetrics and Gynecology, School of Medicine, Ewha Womans University, Yangcheon‑ku, Seoul 158-710, Republic of Korea
| | - Jung-Hyuck Ahn
- Department of Biochemistry, School of Medicine, Ewha Womans University, Yangcheon‑ku, Seoul 158-710, Republic of Korea
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Forbes NE, Abdelbary H, Lupien M, Bell JC, Diallo JS. Exploiting tumor epigenetics to improve oncolytic virotherapy. Front Genet 2013; 4:184. [PMID: 24062768 PMCID: PMC3778850 DOI: 10.3389/fgene.2013.00184] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Accepted: 08/29/2013] [Indexed: 12/20/2022] Open
Abstract
Oncolytic viruses (OVs) comprise a versatile and multi-mechanistic therapeutic platform in the growing arsenal of anticancer biologics. These replicating therapeutics find favorable conditions in the tumor niche, characterized among others by increased metabolism, reduced anti-tumor/antiviral immunity, and disorganized vasculature. Through a self-amplification that is dependent on multiple cancer-specific defects, these agents exhibit remarkable tumor selectivity. With several OVs completing or entering Phase III clinical evaluation, their therapeutic potential as well as the challenges ahead are increasingly clear. One key hurdle is tumor heterogeneity, which results in variations in the ability of tumors to support productive infection by OVs and to induce adaptive anti-tumor immunity. To this end, mounting evidence suggests tumor epigenetics may play a key role. This review will focus on the epigenetic landscape of tumors and how it relates to OV infection. Therapeutic strategies aiming to exploit the epigenetic identity of tumors in order to improve OV therapy are also discussed.
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Affiliation(s)
- Nicole E. Forbes
- Center for Innovative Cancer Research, Ottawa Hospital Research InstituteOttawa, ON, Canada
- Faculty of Medicine, University of OttawaOttawa, ON, Canada
| | - Hesham Abdelbary
- Center for Innovative Cancer Research, Ottawa Hospital Research InstituteOttawa, ON, Canada
- Faculty of Medicine, University of OttawaOttawa, ON, Canada
| | - Mathieu Lupien
- Ontario Cancer Institute, Princess Margaret Cancer Center/University Health NetworkToronto, ON, Canada
- Ontario Institute for Cancer ResearchToronto, ON, Canada
- Department of Medical Biophysics, University of TorontoToronto, ON, Canada
| | - John C. Bell
- Center for Innovative Cancer Research, Ottawa Hospital Research InstituteOttawa, ON, Canada
- Faculty of Medicine, University of OttawaOttawa, ON, Canada
| | - Jean-Simon Diallo
- Center for Innovative Cancer Research, Ottawa Hospital Research InstituteOttawa, ON, Canada
- Faculty of Medicine, University of OttawaOttawa, ON, Canada
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Ezell SA, Tsichlis PN. Akt1, EMSY, BRCA2 and type I IFN signaling: a novel arm of the IFN response. Transcription 2012; 3:305-9. [PMID: 23117821 DOI: 10.4161/trns.21904] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Interferon-stimulated transcription is thought to occur mainly through the action of the JAK/STAT pathway. However, recent findings revealed an additional PI3K/Akt-dependent pathway, which contributes to the induction of a set of interferon-stimulated genes (ISGs) through the regulation of the transcriptional repressor EMSY.
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Affiliation(s)
- Scott A Ezell
- Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, USA
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