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Tran PL, Kim O, Hwangbo C, Kim HJ, Kim YM, Lee JH. SDCBP/Syntenin-1 stabilizes BACH1 by disassembling the SCF FBXO22-BACH1 complex in triple-negative breast cancer. EMBO J 2025:10.1038/s44318-025-00440-1. [PMID: 40263598 DOI: 10.1038/s44318-025-00440-1] [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: 07/29/2024] [Revised: 03/20/2025] [Accepted: 03/24/2025] [Indexed: 04/24/2025] Open
Abstract
BACH1 is a redox-sensitive transcription factor facilitating tumor progression in triple-negative breast cancer (TNBC). However, the molecular mechanisms regulating BACH1 function in TNBC remain unclear. In this study, we demonstrate that SDCBP, a tandem-PDZ-domain protein, stabilizes BACH1 by disassembling the Skp1-Cullin1-FBXO22 (SCFFBXO22)-BACH1 complex via a heme/heme-oxygenase-1-independent manner in TNBC cells. Our data revealed that SDCBP and BACH1 expression show a significant positive correlation in TNBC cells and TNBC patients tumor tissues. Mechanistically, SDCBP via its PDZ1 domain disassembles the SCFFBXO22-BACH1 complex via its PDZ1 domain, thereby preventing BACH1 K48-linked polyubiquitination and proteasomal degradation. Knocking down SDCBP induces BACH1 degradation and downregulates expressions of BACH1-induced metastatic genes, thereby suppressing tumor progression in mice bearing TNBC tumors. Moreover, depleting SDCBP leads to upregulation of BACH1-repressed electron transport chain (ETC) genes, such as NDUFA4 and COX6B2, and increases mitochondrial activity, enhancing anti-tumor efficacy of metformin against TNBC both in vitro and in vivo. These data demonstrate a novel alternative mechanism for BACH1 stabilization mediated by SDCBP, implicating the SDCBP-BACH1 axis as a potential target for enhancing ETC inhibitor efficacy in TNBC combinational therapy.
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Affiliation(s)
- Phi-Long Tran
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon-si, Gangwon-do, 24341, Republic of Korea
| | - Okhwa Kim
- Kangwon Institute of Inclusive Technology, Kangwon National University, Chuncheon-si, Gangwon-do, 24341, Republic of Korea
| | - Cheol Hwangbo
- Division of Applied Life Science (BK21 Four), Division of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju-si, Gyeongsangnam-do, 52828, Republic of Korea
| | - Hyo-Jin Kim
- Division of Applied Life Science (BK21 Four), Division of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju-si, Gyeongsangnam-do, 52828, Republic of Korea
| | - Young-Myeong Kim
- Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon-si, Gangwon-do, 24341, Republic of Korea
| | - Jeong-Hyung Lee
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon-si, Gangwon-do, 24341, Republic of Korea.
- Kangwon Institute of Inclusive Technology, Kangwon National University, Chuncheon-si, Gangwon-do, 24341, Republic of Korea.
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Consoli V, Sorrenti V, Gulisano M, Spampinato M, Vanella L. Navigating heme pathways: the breach of heme oxygenase and hemin in breast cancer. Mol Cell Biochem 2025; 480:1495-1518. [PMID: 39287890 PMCID: PMC11842487 DOI: 10.1007/s11010-024-05119-5] [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: 08/06/2024] [Accepted: 09/07/2024] [Indexed: 09/19/2024]
Abstract
Breast cancer remains a significant global health challenge, with diverse subtypes and complex molecular mechanisms underlying its development and progression. This review comprehensively examines recent advances in breast cancer research, with a focus on classification, molecular pathways, and the role of heme oxygenases (HO), heme metabolism implications, and therapeutic innovations. The classification of breast cancer subtypes based on molecular profiling has significantly improved diagnosis and treatment strategies, allowing for tailored approaches to patient care. Molecular studies have elucidated key signaling pathways and biomarkers implicated in breast cancer pathogenesis, shedding light on potential targets for therapeutic intervention. Notably, emerging evidence suggests a critical role for heme oxygenases, particularly HO-1, in breast cancer progression and therapeutic resistance, highlighting the importance of understanding heme metabolism in cancer biology. Furthermore, this review highlights recent advances in breast cancer therapy, including targeted therapies, immunotherapy, and novel drug delivery systems. Understanding the complex interplay between breast cancer subtypes, molecular pathways, and innovative therapeutic approaches is essential for improving patient outcomes and developing more effective treatment strategies in the fight against breast cancer.
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Affiliation(s)
- Valeria Consoli
- Department of Drug and Health Sciences, University of Catania, 95125, Catania, Italy
- CERNUT - Research Centre on Nutraceuticals and Health Products, University of Catania, 95125, Catania, Italy
| | - Valeria Sorrenti
- Department of Drug and Health Sciences, University of Catania, 95125, Catania, Italy
- CERNUT - Research Centre on Nutraceuticals and Health Products, University of Catania, 95125, Catania, Italy
| | - Maria Gulisano
- Department of Drug and Health Sciences, University of Catania, 95125, Catania, Italy
| | - Mariarita Spampinato
- Department of Drug and Health Sciences, University of Catania, 95125, Catania, Italy
| | - Luca Vanella
- Department of Drug and Health Sciences, University of Catania, 95125, Catania, Italy.
- CERNUT - Research Centre on Nutraceuticals and Health Products, University of Catania, 95125, Catania, Italy.
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3
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Li R, Ji Y, Ye R, Tang G, Wang W, Chen C, Yang Q. Potential therapies for non-coding RNAs in breast cancer. Front Oncol 2024; 14:1452666. [PMID: 39372872 PMCID: PMC11449682 DOI: 10.3389/fonc.2024.1452666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 08/29/2024] [Indexed: 10/08/2024] Open
Abstract
Breast cancer (BC) is one of the frequent tumors that seriously endanger the physical and mental well-being in women with strong heterogeneity, and its pathogenesis involves multiple risk factors. Depending on the type of BC, hormonal therapy, targeted therapy, and immunotherapy are the current systemic treatment options along with conventional chemotherapy. Despite significant progress in understanding BC pathogenesis and therapeutic options, there is still a need to identify new therapeutic targets and develop more effective treatments. According to recent sequencing and profiling studies, non-coding (nc) RNAs genes are deregulated in human cancers via deletion, amplification, abnormal epigenetic, or transcriptional regulation, and similarly, the expression of many ncRNAs is altered in breast cancer cell lines and tissues. The ability of single ncRNAs to regulate the expression of multiple downstream gene targets and related pathways provides a theoretical basis for studying them for cancer therapeutic drug development and targeted delivery. Therefore, it is far-reaching to explore the role of ncRNAs in tumor development and their potential as therapeutic targets. Here, our review outlines the potential of two major ncRNAs, long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) as diagnostic and prognostic biomarkers as well as targets for new therapeutic strategies in breast cancer.
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Affiliation(s)
- Ruonan Li
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu Medical University, Bengbu, Anhui, China
- School of Laboratory Medicine, Bengbu Medical University, Bengbu, Anhui, China
| | - Yuxin Ji
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu Medical University, Bengbu, Anhui, China
- School of Laboratory Medicine, Bengbu Medical University, Bengbu, Anhui, China
| | - Ruyin Ye
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu Medical University, Bengbu, Anhui, China
- Department of Life Sciences, Bengbu Medical University, Bengbu, Anhui, China
| | - Guohui Tang
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu Medical University, Bengbu, Anhui, China
- Department of Life Sciences, Bengbu Medical University, Bengbu, Anhui, China
| | - Wenrui Wang
- Department of Life Sciences, Bengbu Medical University, Bengbu, Anhui, China
| | - Changjie Chen
- School of Laboratory Medicine, Bengbu Medical University, Bengbu, Anhui, China
| | - Qingling Yang
- School of Laboratory Medicine, Bengbu Medical University, Bengbu, Anhui, China
- Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, Anhui, China
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4
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Xu D, Wang W, Wang D, Ding J, Zhou Y, Zhang W. Long noncoding RNA MALAT-1: A versatile regulator in cancer progression, metastasis, immunity, and therapeutic resistance. Noncoding RNA Res 2024; 9:388-406. [PMID: 38511067 PMCID: PMC10950606 DOI: 10.1016/j.ncrna.2024.01.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 01/24/2024] [Accepted: 01/24/2024] [Indexed: 03/22/2024] Open
Abstract
Long noncoding RNAs (lncRNAs) are RNA transcripts longer than 200 nucleotides that do not code for proteins but have been linked to cancer development and metastasis. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) influences crucial cancer hallmarks through intricate molecular mechanisms, including proliferation, invasion, angiogenesis, apoptosis, and the epithelial-mesenchymal transition (EMT). The current article highlights the involvement of MALAT-1 in drug resistance, making it a potential target to overcome chemotherapy refractoriness. It discusses the impact of MALAT-1 on immunomodulatory molecules, such as major histocompatibility complex (MHC) proteins and PD-L1, leading to immune evasion and hindering anti-tumor immune responses. MALAT-1 also plays a significant role in cancer immunology by regulating diverse immune cell populations. In summary, MALAT-1 is a versatile cancer regulator, influencing tumorigenesis, chemoresistance, and immunotherapy responses. Understanding its precise molecular mechanisms is crucial for developing targeted therapies, and therapeutic strategies targeting MALAT-1 show promise for improving cancer treatment outcomes. However, further research is needed to fully uncover the role of MALAT-1 in cancer biology and translate these findings into clinical applications.
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Affiliation(s)
- Dexin Xu
- Department of Orthopedics, Jilin Province FAW General Hospital, Changchun, 130000, China
| | - Wenhai Wang
- Department of Cardiology, Jilin Province FAW General Hospital, Changchun, 130000, China
| | - Duo Wang
- Department of Geriatrics, Jilin Province FAW General Hospital, Changchun, 130000, China
| | - Jian Ding
- Department of Electrodiagnosis, Jilin Province FAW General Hospital, Changchun, 130000, China
| | - Yunan Zhou
- Department of Orthopedics, Jilin Province FAW General Hospital, Changchun, 130000, China
| | - Wenbin Zhang
- Department of Cardiology, Jilin Province FAW General Hospital, Changchun, 130000, China
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Zhang C, Qin Y, Wu Y, Xu H, Shu Y. Long non-coding RNA MALAT1 in hematological malignancies and its clinical applications. Chin Med J (Engl) 2024; 137:1151-1159. [PMID: 38557962 PMCID: PMC11101235 DOI: 10.1097/cm9.0000000000003090] [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: 11/17/2023] [Indexed: 04/04/2024] Open
Abstract
ABSTRACT Metastasis-associated lung adenocarcinoma transcript 1 ( MALAT1 ) is a well-established oncogenic long non-coding RNA, the higher expression of which is strongly correlated with cancer events such as tumorigenesis, progression, metastasis, drug resistance, and treatment outcome in solid cancers. Recently, a series of studies has highlighted its potential role in hematological malignancies in terms of these events. Similar to solid cancers, MALAT1 can regulate various target genes via sponging and epigenetic mechanisms, but the miRNAs sponged by MALAT1 differ from those identified in solid cancers. In this review, we systematically describe the role and underlying mechanisms of MALAT1 in multiple types of hematological malignancies, including regulation of cell proliferation, metastasis, stress response, and glycolysis. Clinically, MALAT1 expression is related to poor treatment outcome and drug resistance, therefore exhibiting potential prognostic value in multiple myeloma, lymphoma, and leukemia. Finally, we discuss the evaluation of MALAT1 as a novel therapeutic target against cancer in preclinical studies.
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Affiliation(s)
- Chunlan Zhang
- Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yun Qin
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yu Wu
- Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Heng Xu
- Department of Laboratory Medicine/Research Center of Clinical Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Institute of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yang Shu
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Department of General Surgery, Gastric Cancer Center and Laboratory of Gastric Cancer, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
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Hu D, Zhang Z, Luo X, Li S, Jiang J, Zhang J, Wu Z, Wang Y, Sun M, Chen X, Zhang B, Xu X, Wang S, Xu S, Wang Y, Huang W, Xia L. Transcription factor BACH1 in cancer: roles, mechanisms, and prospects for targeted therapy. Biomark Res 2024; 12:21. [PMID: 38321558 PMCID: PMC10848553 DOI: 10.1186/s40364-024-00570-4] [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: 11/04/2023] [Accepted: 01/22/2024] [Indexed: 02/08/2024] Open
Abstract
Transcription factor BTB domain and CNC homology 1 (BACH1) belongs to the Cap 'n' Collar and basic region Leucine Zipper (CNC-bZIP) family. BACH1 is widely expressed in mammalian tissues, where it regulates epigenetic modifications, heme homeostasis, and oxidative stress. Additionally, it is involved in immune system development. More importantly, BACH1 is highly expressed in and plays a key role in numerous malignant tumors, affecting cellular metabolism, tumor invasion and metastasis, proliferation, different cell death pathways, drug resistance, and the tumor microenvironment. However, few articles systematically summarized the roles of BACH1 in cancer. This review aims to highlight the research status of BACH1 in malignant tumor behaviors, and summarize its role in immune regulation in cancer. Moreover, this review focuses on the potential of BACH1 as a novel therapeutic target and prognostic biomarker. Notably, the mechanisms underlying the roles of BACH1 in ferroptosis, oxidative stress and tumor microenvironment remain to be explored. BACH1 has a dual impact on cancer, which affects the accuracy and efficiency of targeted drug delivery. Finally, the promising directions of future BACH1 research are prospected. A systematical and clear understanding of BACH1 would undoubtedly take us one step closer to facilitating its translation from basic research into the clinic.
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Affiliation(s)
- Dian Hu
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
| | - Zerui Zhang
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
| | - Xiangyuan Luo
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
| | - Siwen Li
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
| | - Junqing Jiang
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
| | - Jiaqian Zhang
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
| | - Zhangfan Wu
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
| | - Yijun Wang
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
| | - Mengyu Sun
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
| | - Xiaoping Chen
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases; Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Clinical Medicine Research Center for Hepatic Surgery of Hubei Province; Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, 430030, Hubei, China
| | - Bixiang Zhang
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases; Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Clinical Medicine Research Center for Hepatic Surgery of Hubei Province; Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, 430030, Hubei, China
| | - Xiao Xu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Shuai Wang
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Westlake university school of medicine, Hangzhou, 310006, China
| | - Shengjun Xu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Yufei Wang
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.
| | - Wenjie Huang
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases; Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Clinical Medicine Research Center for Hepatic Surgery of Hubei Province; Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, 430030, Hubei, China.
| | - Limin Xia
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.
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Hu Y, He Y, Luo N, Li X, Guo L, Zhang K. A feedback loop between lncRNA MALAT1 and DNMT1 promotes triple-negative breast cancer stemness and tumorigenesis. Cancer Biol Ther 2023; 24:2235768. [PMID: 37548553 PMCID: PMC10408694 DOI: 10.1080/15384047.2023.2235768] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 09/23/2022] [Accepted: 06/28/2023] [Indexed: 08/08/2023] Open
Abstract
BACKGROUND The function of long non-coding RNA (lncRNA) MALAT1 in regulating triple-negative breast cancer (TNBC) stemness and tumorigenesis was investigated. METHODS Sphere formation and colony formation assays coupled with flow cytometry were employed to evaluate the percentage of CD44high/CD44low cells, and ALDH+ cells were performed to evaluate the stemness. Bisulfite sequencing PCR (BSP) was employed to detect the methylation level of MALAT1. Tumor xenograft experiment was performed to evaluate tumorigenesis in vivo. Finally, dual-luciferase reporter and RIP assays were employed to verify the binding relationship between MALAT1 and miR-137. RESULTS Our results revealed that MALAT1 and BCL11A were highly expressed in TNBC, while miR-137 and DNMT1 were lowly expressed. Our results proved that MALAT1 positively regulated BCL11A expression through targeting miR-137. Functional experiments revealed that MALAT1 inhibited DNMT1 expression through acting on the miR-137/BCL11A pathway to enhance TNBC stemness and tumorigenesis. We also found that high MALAT1 expression in TNBC was related to the DNMT1-mediated hypomethylation of MALAT1. As expected, DNMT1 overexpression could remarkably inhibit TNBC stemness and tumorigenesis, which was eliminated by MALAT1 overexpression. CONCLUSION MALAT1 downregulated DNMT1 by miR-137/BCL11A pathway to enhance TNBC stemness and tumorigenesis; meanwhile, DNMT1/MALAT1 formed a positive feedback loop to continuously promote TNBC malignant behaviors.
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Affiliation(s)
- Yu Hu
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, P.R. China
- Department of General Surgery, Xiangya Hospital, Central South University, Clinical Research Center for Breast Cancer in Hunan Province, Changsha, Hunan Province, P.R. China
| | - Yuqiong He
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, P.R. China
- Department of General Surgery, Xiangya Hospital, Central South University, Clinical Research Center for Breast Cancer in Hunan Province, Changsha, Hunan Province, P.R. China
| | - Na Luo
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, P.R. China
- Department of General Surgery, Xiangya Hospital, Central South University, Clinical Research Center for Breast Cancer in Hunan Province, Changsha, Hunan Province, P.R. China
| | - Xin Li
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, P.R. China
- Department of General Surgery, Xiangya Hospital, Central South University, Clinical Research Center for Breast Cancer in Hunan Province, Changsha, Hunan Province, P.R. China
| | - Lei Guo
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, P.R. China
- Department of General Surgery, Xiangya Hospital, Central South University, Clinical Research Center for Breast Cancer in Hunan Province, Changsha, Hunan Province, P.R. China
| | - Kejing Zhang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, P.R. China
- Department of General Surgery, Xiangya Hospital, Central South University, Clinical Research Center for Breast Cancer in Hunan Province, Changsha, Hunan Province, P.R. China
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Barnes P, Agbo E, Wang J, Amoani B, Opoku YK, Okyere P, Saahene RO. Prognostic Worth of Nrf2/BACH1/HO-1 Protein Expression in the Development of Breast Cancer. Med Princ Pract 2023; 32:369-378. [PMID: 37827129 PMCID: PMC10727515 DOI: 10.1159/000534534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Accepted: 10/08/2023] [Indexed: 10/14/2023] Open
Abstract
OBJECTIVES Nrf2/BACH1/HO-1 proteins have been implicated in the development and progression of tumors. However, their clinical relevance in breast cancer remains unclear and understudied. This study evaluated Nrf2/BACH1/HO-1 protein expression and its relationship with age, tumor grade, tumor stage, TNM, ER, PR, HER2, and histologic type. METHODS 114 female breast cancer and 30 noncancerous tissues were evaluated for Nrf2/BACH1/HO-1 protein expression using immunohistochemistry and Western blot. The relationships between the expression and clinicopathologic factors were assessed using the χ2 test. RESULTS 74% of the cancerous samples had high Nrf2 protein expression, and 26% of them had low Nrf2 protein expression. Regarding the non-cancer samples, 43% had high Nrf2 protein expression and 57% had low Nrf2 protein expression (p < 0.002). 39% of the cancerous samples had high BACH1 protein expression, and 61% had low BACH1 protein expression. For the non-cancer samples, 80% had high BACH1 protein expression and 20% had low BACH1 protein expression (p < 0.031). 67% of the cancerous samples had high HO-1 protein expression, and 33% had low HO-1 protein expression. However, for the non-cancer samples, 17% of them had high HO-1 protein expression and 83% had low HO-1 protein expression (p < 0.001). The expression of Nrf2 and HO-1 significantly correlated with tumor grade, while BACH1 was significantly associated with tumor stage (p < 0.05). CONCLUSION Nrf2, BACH1, and HO-1 could be explored as a biomarker for cancer stage, progression, and prognosis.
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Affiliation(s)
- Precious Barnes
- Department of Physician Assistant Studies, School of Allied Health Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Elvis Agbo
- Department of Human Anatomy, Histology and Embryology, College of Medicine, Jinggangshan University, Ji’an City, China
| | - Jianjie Wang
- Department of Immunology, College of Basic Medicine, Jiamusi University, Jiamusi, China
| | - Benjamin Amoani
- Department of Biomedical Sciences, School of Allied Health Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Yeboah Kwaku Opoku
- Department of Biology Education, University of Education, Winneba, Ghana
| | - Perditer Okyere
- Department of Medicine, School of Medicine and Dentistry, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Roland Osei Saahene
- Department of Microbiology and Immunology, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
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Elanany MM, Mostafa D, Hamdy NM. Remodeled tumor immune microenvironment (TIME) parade via natural killer cells reprogramming in breast cancer. Life Sci 2023; 330:121997. [PMID: 37536617 DOI: 10.1016/j.lfs.2023.121997] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 07/20/2023] [Accepted: 07/31/2023] [Indexed: 08/05/2023]
Abstract
Breast cancer (BC) is the main cause of cancer-related mortality among women globally. Despite substantial advances in the identification and management of primary tumors, traditional therapies including surgery, chemotherapy, and radiation cannot completely eliminate the danger of relapse and metastatic illness. Metastasis is controlled by microenvironmental and systemic mechanisms, including immunosurveillance. This led to the evolvement of immunotherapies that has gained much attention in the recent years for cancer treatment directed to the innate immune system. The long forgotten innate immune cells known as natural killer (NK) cells have emerged as novel targets for more effective therapeutics for BC. Normally, NK cells has the capacity to identify and eradicate tumor cells either directly or by releasing cytotoxic granules, chemokines and proinflammatory cytokines. Yet, NK cells are exposed to inhibitory signals by cancer cells, which causes them to become dysfunctional in the immunosuppressive tumor microenvironment (TME) in BC, supporting tumor escape and spread. Potential mechanisms of NK cell dysfunction in BC metastasis have been recently identified. Understanding these immunologic pathways driving BC metastasis will lead to improvements in the current immunotherapeutic strategies. In the current review, we highlight how BC evades immunosurveillance by rendering NK cells dysfunctional and we shed the light on novel NK cell- directed therapies.
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Affiliation(s)
- Mona M Elanany
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Ain Shams University, Abassia, 11566 Cairo, Egypt
| | - Dina Mostafa
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Ain Shams University, Abassia, 11566 Cairo, Egypt.
| | - Nadia M Hamdy
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Ain Shams University, Abassia, 11566 Cairo, Egypt.
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Lampropoulou DI, Papadimitriou M, Papadimitriou C, Filippou D, Kourlaba G, Aravantinos G, Gazouli M. The Role of EMT-Related lncRNAs in Ovarian Cancer. Int J Mol Sci 2023; 24:10079. [PMID: 37373222 PMCID: PMC10298523 DOI: 10.3390/ijms241210079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 06/09/2023] [Accepted: 06/10/2023] [Indexed: 06/29/2023] Open
Abstract
Ovarian cancer (OC) is one of the deadliest cancers worldwide; late diagnosis and drug resistance are two major factors often responsible for high morbidity and treatment failure. Epithelial-to-mesenchymal transition (EMT) is a dynamic process that has been closely linked with cancer. Long non-coding RNAs (lncRNAs) have been also associated with several cancer-related mechanisms, including EMT. We conducted a literature search in the PubMed database in order to sum up and discuss the role of lncRNAs in regulating OC-related EMT and their underlying mechanisms. Seventy (70) original research articles were identified, as of 23 April 2023. Our review concluded that the dysregulation of lncRNAs is highly associated with EMT-mediated OC progression. A comprehensive understanding of lncRNAs' mechanisms in OC will help in identifying novel and sensitive biomarkers and therapeutic targets for this malignancy.
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Affiliation(s)
| | - Marios Papadimitriou
- Myeloma Division, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA;
- Second Department of Surgery, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Christos Papadimitriou
- Second Department of Surgery, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Dimitrios Filippou
- Department of Anatomy and Surgical Anatomy, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
- National Organization for Medicines (EOF), 15562 Athens, Greece
| | - Georgia Kourlaba
- Department of Nursing, University of Peloponnese, 22100 Tripoli, Greece;
| | | | - Maria Gazouli
- Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
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11
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Mekky RY, Ragab MF, Manie T, Attia AA, Youness RA. MALAT-1: Immunomodulatory lncRNA hampering the innate and the adaptive immune arms in triple negative breast cancer. Transl Oncol 2023; 31:101653. [PMID: 36907052 PMCID: PMC10025146 DOI: 10.1016/j.tranon.2023.101653] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 02/05/2023] [Accepted: 03/05/2023] [Indexed: 03/13/2023] Open
Abstract
BACKGROUND Triple negative breast cancer (TNBC) is known as hot immunogenic tumor. Yet, it is one of the most aggressive BC subtypes. TNBC evolve several tactics to evade the immune surveillance phenomena, one of which is shedding of natural killer (NK) cells activating immune ligands such as MICA/B and/or by inducing the expression of the immune checkpoints such as PD-L1 and B7-H4. MALAT-1 is an oncogenic lncRNA. MALAT-1 immunogenic profile is not well investigated. AIM The study aims at exploring the immunogenic role of MALAT-1 in TNBC patients and cell lines and to identify its molecular mechanism in altering both innate and adaptive immune cells present at the tumor microenvironment of TNBC METHODS: BC patients (n = 35) were recruited. Primary NK cells and cytotoxic T lymphocytes were isolated from normal individuals using the negative selection method. MDA-MB-231 cells were cultured and transfected by several oligonucleotides by lipofection technique. Screening of ncRNAs was performed using q-RT-PCR. Immunological functional analysis experiments were performed upon co-culturing primary natural killer cells and cytotoxic T lymphocytes using LDH assay. Bioinformatics analysis was performed to identify potential microRNAs targeted by MALAT-1. RESULTS MALAT-1 expression was significantly upregulated in BC patinets with a profound expression in TNBC patients compared to their normal counterparts. Correlation analysis revealed a positive correlation between MALAT-1, tumor size and lymph node metastasis. Knocking down of MALAT-1 in MDA-MB-231 cells resulted in a significant induction of MICA/B, repression of PD-L1 and B7-H4 expression levels. Enhancement of cytotoxic activity of co-cultured NK and CD8+ cells with MALAT-1 siRNAs transfected MDA-MB-231 cells. In silico analysis revealed that miR-34a and miR-17-5p are potential targets to MALAT-1; accordingly, they were found to be downregulated in BC patients. Forcing the expression of miR-34a in MDA-MB-231 cells resulted in a significant induction in MICA/B levels. Ectopic expression of miR-17-5p in MDA-MB-231 cells significantly repressed the expression of PD-L1 and B7-H4 checkpoints. Validations of MALAT-1/miR-34a" and "MALAT-1/miR-17-5p axes were performed by a series of co-transfections and functional assessment of cytotoxic profile of primary immune cells. CONCLUSION This study proposes a novel epigenetic alteration exerted by TNBC cells mainly by inducing the expression of MALAT-1 lncRNA. MALAT-1 mediates innate and adaptive immune suppression events partially via targeting miR-34a/MICA/B and miR-175p/PD-L1/B7-H4 axes in TNBC patients and cell lines.
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Affiliation(s)
- Radwa Y Mekky
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA University), Cairo 12622, Egypt
| | - Mai F Ragab
- Pharmacology Department, School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, Cairo 11835, Egypt
| | - Tamer Manie
- Department of Breast Surgery, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Abdelrahman A Attia
- General Surgery Department, Ain Shams University, Demerdash Hospital, Cairo, Egypt
| | - Rana A Youness
- Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, Cairo 11835, Egypt.
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12
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Aprile M, Costa V, Cimmino A, Calin GA. Emerging role of oncogenic long noncoding RNA as cancer biomarkers. Int J Cancer 2023; 152:822-834. [PMID: 36082440 DOI: 10.1002/ijc.34282] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 08/19/2022] [Accepted: 08/22/2022] [Indexed: 02/05/2023]
Abstract
The view of long noncoding RNAs as nonfunctional "garbage" has been definitely outdated by the large body of evidence indicating this class of ncRNAs as "golden junk", especially in precision oncology. Indeed, in light of their oncogenic role and the higher expression in multiple cancer types compared with paired adjacent tissues, the clinical interest for lncRNAs as diagnostic and/or prognostic biomarkers has been rapidly increasing. The emergence of large-scale sequencing technologies, their subsequent diffusion even in small research and clinical centers, the technological advances for the detection of low-copy lncRNAs in body fluids, coupled to the huge reduction of operating costs, have nowadays made possible to rapidly and comprehensively profile them in multiple tumors and large cohorts. In this review, we first summarize some relevant data about the oncogenic role of well-studied lncRNAs having a clinical relevance. Then, we focus on the description of their potential use as diagnostic/prognostic biomarkers, including an updated overview about licensed patents or clinical trials on lncRNAs in oncology.
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Affiliation(s)
- Marianna Aprile
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council (CNR), Naples, Italy
| | - Valerio Costa
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council (CNR), Naples, Italy
| | - Amelia Cimmino
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council (CNR), Naples, Italy
| | - George Adrian Calin
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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13
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Yin Z, Wang J, Li T, Ma L, Kang J, Liu G. miR-188-5p and Host MALAT1 Regulate RBE Cell Migration, Invasion, and Apoptosis via Up-regulating PSMD10 in Cholangiocarcinoma. Appl Biochem Biotechnol 2023; 195:655-671. [PMID: 36121635 DOI: 10.1007/s12010-022-04136-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/28/2022] [Indexed: 02/08/2023]
Abstract
The study is designed to explore the regulatory network that MALAT1 competitively binds with miR-188-5p to up-regulate PSMD10 to facilitate cholangiocarcinoma cell migration and invasion and suppress apoptosis. qRT-PCR and fluorescence in situ hybridization (FISH) were used to examine the expression and positive signal of MALAT1 and miR-188-5p in cholangiocarcinoma tissues and HIBEC, HCCC-9810, RBE, and QBC939 cells. Western blot, qRT-PCR, and immunohistochemistry were selected to detect PSMD10 expression in cholangiocarcinoma tissues and cell lines. Dual luciferase reporter gene assay was adopted to verify that miR-188-5p targeted MALAT1 and PSMD10. qRT-PCR, pull down, and western blot were used to examine the regulation of MALAT1-miR-188-5p-PSMD10 axis. Transwell, wound healing assay, and Tunel cell apoptosis were adopted to respectively detect the regulatory abilities of MALAT1-miR-188-5p-PSMD10 axis on cell invasion, migration, and apoptosis. Western blot was used to detect the regulation mechanism of MALAT1 on Bax, Bcl-2, and caspase-3 proteins. Nude mice subcutaneous xenograft model of cholangiocarcinoma was established to examine the impacts of MALAT1 on subcutaneous tumor growth. Immunohistochemistry was adopted to examine the positive indicator of Ki67 antibodies and SMD10 antibodies in each group. MALAT1 and PSMD10 were highly expressed in cholangiocarcinoma tissues and cell lines, while miR-188-5p was lowly expressed. MALAT1 could competitively bind to miR-188-5p, and miR-188-5p could negatively regulate PSMD10. MALAT1, In-miR-188-5p, and PSMD10 could facilitate cell invasion and migration and inhibit apoptosis, while siMALAT1, miR-188-5p, and siPSMD10 produced an opposite result. MALAT1-miR-188-5p-PSMD10 axis could promote RBE cell invasion and migration and inhibit apoptosis, whereas siMALAT1-In-miR-188-5p-siPSMD10 axis showed an opposite result. On the other hand, it was verified that up-regulation/down-regulation of MALAT1 can inhibit/promote Bax and caspase-3 proteins and promote/inhibit the expression of Bcl-2 protein. MALAT1 could facilitate subcutaneous tumor growth and enhance cell proliferation and positive signal of PSMD10, while miR-188-5p worked in an opposite direction. MALAT1 competitively binds to miR-188-5p to up-regulate mRNA translation and protein expression of PSMD10, thereby facilitating cholangiocarcinoma cell invasion and migration and inhibiting its apoptosis. However, interfering MALAT1-miR-188-5p-PSMD10 axis could inhibit the occurrence and development of cholangiocarcinoma.
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Affiliation(s)
- Zhaoqiang Yin
- Department of Minimally Invasive and Biliary Surgery, The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang, 050000, Hebei, China
| | - Jianlong Wang
- Department of Minimally Invasive and Biliary Surgery, The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang, 050000, Hebei, China
| | - Tao Li
- Department of Minimally Invasive and Biliary Surgery, The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang, 050000, Hebei, China
| | - Lifeng Ma
- Department of Minimally Invasive and Biliary Surgery, The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang, 050000, Hebei, China
| | - Jiansheng Kang
- Department of Minimally Invasive and Biliary Surgery, The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang, 050000, Hebei, China
| | - Guochao Liu
- Department of Minimally Invasive and Biliary Surgery, The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang, 050000, Hebei, China.
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14
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Exosomes Derived from Tumor Cells Initiate Breast Cancer Cell Metastasis and Chemoresistance through a MALAT1-Dependent Mechanism. JOURNAL OF ONCOLOGY 2022; 2022:5483523. [PMID: 35813865 PMCID: PMC9262507 DOI: 10.1155/2022/5483523] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 05/16/2022] [Indexed: 11/17/2022]
Abstract
Background. Chemoresistance poses a great hindrance in the treatment of breast cancer (BC). Interestingly, exosome (Exo)-mediated transfer of long noncoding RNAs (lncRNAs) has been reported to regulate chemoresistance in diverse diseases. We herein investigate the potential role of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) transferred by BC cell-derived Exo in chemoresistance of BC cells. Methods. BC-related lncRNAs were identified. Exosomes were isolated and verified from BC cells. The expression patterns of MALAT1 were then examined in the adriamycin (ADR)-sensitive and resistant cells and the isolated Exo, followed by the analysis of the downstream microRNA (miRNA) of MALAT1. The role and mechanism of MALAT1 transmitted by BC cell-derived Exo in BC cell metastasis and chemoresistance were assessed. Results. MALAT1 was highly expressed in BC cells and their Exo. In addition, MALAT1 delivered by BC cell-derived Exo augmented the malignant properties and chemoresistance of BC cells. Mechanistically, MALAT1 bound to miR-1-3p and limited the miR-1-3p expression, which sequentially targeted the vasodilator-stimulated phosphoprotein (VASP) protein. Moreover, silencing of VASP inhibited the activation of the RAP1 member of RAS oncogene family (Rap1) signaling pathway, which led to the attenuation of BC cell malignant properties and chemoresistance. In vivo assay further validated the tumor-promoting effect of Exo-MALAT1 via regulation of the miR-1-3p/VASP/Rap1 axis. Conclusion. Collectively, MALAT1 loaded by BC cell-derived Exo can accelerate BC cell metastasis and chemoresistance via disruption of miR-1-3p-mediated inhibition of the VASP/Rap1 signaling axis.
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15
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Ye L, Pan K, Fang S, Wu SN, Chen S, Tang S, Wang N, Zhang H, Tong X, Shi X, Feng S, Xiang D, Zou R, Hu Y, Xue X, Guo G. Four Types of RNA Modification Writer-Related lncRNAs Are Effective Predictors of Prognosis and Immunotherapy Response in Serous Ovarian Carcinoma. Front Immunol 2022; 13:863484. [PMID: 35585970 PMCID: PMC9108167 DOI: 10.3389/fimmu.2022.863484] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 03/31/2022] [Indexed: 12/26/2022] Open
Abstract
Serous ovarian carcinoma (SOC) is a gynecological malignancy with high mortality rates. Currently, there is a lack of reliable biomarkers for accurate SOC patient prognosis. Here, we analyzed SOC RNA-Seq data from The Cancer Genome Atlas (TCGA) to identify prognostic biomarkers. Through the pearson correlation analysis, univariate Cox regression analysis, and LASSO-penalized Cox regression analysis, we identified nine lncRNAs significantly associated with four types of RNA modification writers (m6A, m1A, APA, and A-I) and with the prognosis of SOC patients (P <0.05). Six writer-related lncRNAs were ultimately selected following multivariate Cox analysis. We established a risk prediction model based on these six lncRNAs and evaluated its prognostic value in multiple groups (training set, testing set, and entire set). Our risk prediction model could effectively predict the prognosis of SOC patients with different clinical characteristics and their responses to immunotherapy. Lastly, we validated the predictive reliability and sensitivity of the lncRNA-based model via a nomogram. This study explored the association between RNA modification writer-related lncRNAs and SOC prognosis, providing a potential complement for the clinical management of SOC patients.
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Affiliation(s)
- Lele Ye
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
- Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Kan Pan
- First Clinical College, Wenzhou Medical University, Wenzhou, China
| | - Su Fang
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Su-Ni Wu
- Department of Gynecologic Oncology, Wenzhou Central Hospital, Wenzhou, China
| | - Su Chen
- Department of Gynecologic Oncology, Wenzhou Central Hospital, Wenzhou, China
| | - Sangsang Tang
- Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Nan Wang
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Haoke Zhang
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Xinya Tong
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Xinyu Shi
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Shiyu Feng
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Dan Xiang
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Ruanmin Zou
- Department of Obstetrics and Gynecology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Yingying Hu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiangyang Xue
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Gangqiang Guo
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
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Prognostic Implications of MALAT1 and BACH1 Expression and Their Correlation with CTCs and Mo-MDSCs in Triple Negative Breast Cancer and Surgical Management Options. Int J Breast Cancer 2022; 2022:8096764. [PMID: 35096427 PMCID: PMC8791720 DOI: 10.1155/2022/8096764] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 12/28/2021] [Indexed: 02/06/2023] Open
Abstract
Background. Triple negative breast cancer (TNBC) is a biologically separate entity of breast cancer that cannot get benefits from targeted or endocrine therapy. Objective. To assess the expression of MALAT1 and BACH1, as well as monocyte-myeloid-derived suppressor cell (Mo-MDSC) levels and circulating tumor cell (CTC) count in TNBC to correlate these markers with the clinic-pathological criteria of TNCB patients and to evaluate their roles as predictive markers for selection of the patients that can be operated by oncoplastic conserving breast surgery. Methods. Eighty-eight TNBC were managed by modified doughnut breast oncoplastic surgery in early stages and by modified radical mastectomy for patients with late stages unsuitable for breast-conserving. All were examined for MALAT1 and BACH1 expression by immunohistochemistry and RT-PCR as well as Mo-MDSC levels and CTCs. Results. MALAT1 and BACH1 expressions are correlated with the larger size, lymph node, distance metastasis, and TNM staging (
).
and high MO-MDSCs were significantly more in TNBC with MALAT1 and BACH1 overexpression. The survival study proved that DFS for patients with both positive expression of MALAT1 and BACH1 was shorter than that of one positive expression, and both negative expression
,
, and high Mo-MDSCs are associated with poor outcomes. No significant difference between modified round block and modified radical mastectomy techniques as regards recurrence. However, all postoperative management outcomes were significantly better in patients operated by oncoplastic conserving breast surgery. Conclusion. BACH1 and MALAT1 expressions are significantly upregulated in TNBC. They are correlated with CTCs and Mo-MDCs, and all are associated with poor outcomes. Not all TNBC patients have a bad prognosis, patients negative for one of MALAT1 and BACH1 or both, have a slightly good prognosis, and so can be managed by breast oncoplastic conserving surgery.
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Igarashi K, Nishizawa H, Matsumoto M. Iron in Cancer Progression: Does BACH1 Promote Metastasis by Altering Iron Homeostasis? Subcell Biochem 2022; 100:67-80. [PMID: 36301491 DOI: 10.1007/978-3-031-07634-3_2] [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] [Indexed: 06/16/2023]
Abstract
The transcription factor BACH1, which is regulated by direct binding of prosthetic group heme, promotes epithelial-mesenchymal transition (EMT) and drives metastasis of diverse types of cancer cells. De-regulated target genes of BACH1 in cancer cells include those for glycolysis, oxidative phosphorylation, epithelial cell adhesion, and mesodermal cell motility. In addition, the canonical target genes of BACH1 include genes for the regulation of iron homeostasis. Importantly, cancer cells are addicted to iron. We summarize known functions of BACH1 in cancer and discuss how BACH1 may affect iron homeostasis in cancer cells to support their progression by increasing mobile iron within cells. The dependency on BACH1 for cancer progression may also confer upon cancer cells susceptibility to iron-dependent cell death ferroptosis. Finally, we discuss that the human transcription factors provide research opportunities for better understanding of cancer cell properties.
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Affiliation(s)
- Kazuhiko Igarashi
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
| | - Hironari Nishizawa
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Mitsuyo Matsumoto
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
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18
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Kanugo A, Gautam RK, Kamal MA. Recent advances of nanotechnology in the diagnosis and therapy of triple-negative breast cancer (TNBC). Curr Pharm Biotechnol 2021; 23:1581-1595. [PMID: 34967294 DOI: 10.2174/1389201023666211230113658] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 11/03/2021] [Accepted: 11/19/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND The development of advanced treatment of triple-negative breast cancer (TNBC) is the utmost need of an era. TNBC is recognized as the most aggressive, metastatic cancer and the leading cause of mortality in females worldwide. The lack of expression of triple receptors namely, estrogen, progesterone, and human epidermal receptor2 defined TNBC. OBJECTIVE The current review introduced the novel biomarkers such as miRNA and family, PD1, EGFR, VEGF, TILs, P53, AR and PI3K, etc. contributed significantly to the prognosis and diagnosis of TNBC. Once diagnosed the utilization advanced approaches available for TNBC because of the limitations of chemotherapy. Novel approaches include lipid-based (liposomes, SLN, NLC, and SNEDDS), polymer-based (micelle, nanoparticles, dendrimers, and quantum dots), advanced nanocarriers such as (exosomes, antibody and peptide-drug conjugates), carbon-based nanocarriers (Carbon nanotubes, and graphene oxide). Lipid-based delivery is used for excellent carriers for hydrophobic drugs, biocompatibility, and lesser systemic toxicities than chemotherapeutic agents. Polymer-based approaches are preferred over lipids for providing longer circulation time, nanosize, high loading efficiency, high linking; avoiding the expulsion of drugs, targeted action, diagnostic and biosensing abilities. Advanced approaches like exosomes, conjugated moieties are preferred over polymeric for possessing potency, high penetrability, biomarkers, and avoiding the toxicity of tissues. Carbon-based gained wide applicability for their unique properties like a versatile carrier, prognostic, diagnostic, sensing, photodynamic, and photothermal characteristics. CONCLUSION The survival rate can be increased by utilizing several kinds of biomarkers. The advanced approaches can also be significantly useful in the prognosis and theranostic of triple-negative breast cancer. One of the biggest successes in treating with nanotechnology-based approaches is the marked reduction of systemic toxicity with high therapeutic effectiveness compared with chemotherapy, surgery, etc. The requirements such as prompt diagnosis, longer circulation time, high efficiency, and high potency, can be fulfilled with these nanocarriers.
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Affiliation(s)
- Abhishek Kanugo
- Department of Pharmaceutics, SVKM NMIMS School of Pharmacy and Technology Management, Shirpur, Dhule, India
| | - Rupesh K Gautam
- Department of Pharmacology, MM School of Pharmacy, Maharishi Markandeshwar University, Sadopur-Ambala (Haryana) India
| | - Mohammad Amjad Kamal
- West China School of Nursing / Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
- King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia
- Enzymoics, 7 Peterlee Place, Hebersham, NSW 2770; Novel Global Community Educational Foundation, Australia
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Li K, Xu K, He Y, Lu L, Mao Y, Gao P, Liu G, Wu J, Zhang Y, Xiang Y, Luo Z, Cai K. Functionalized Tumor-Targeting Nanosheets Exhibiting Fe(II) Overloading and GSH Consumption for Ferroptosis Activation in Liver Tumor. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2021; 17:e2102046. [PMID: 34448349 DOI: 10.1002/smll.202102046] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 06/12/2021] [Indexed: 06/13/2023]
Abstract
Liver tumor is difficult to cure for its high degree of malignancy and rapid progression characteristics. Ferroptosis as a new model of inducing cell death is expected to break the treatment bottleneck of liver tumors. Here, a strategy to induce ferroptosis in HepG2 cells with acid-degradable tumor targeted nanosheets Cu-Hemin-PEG-Lactose acid (Cu-Hemin-PEG-LA) is proposed. After highly ingested by HepG2 cells, Cu-Hemin-PEG-LA nanosheets are degraded by weak acid and release Cu(II) and hemin, which consuming intracellular glutathione (GSH) content and increasing the expression of heme oxygenase 1 (HMOX1) protein, respectively. Furthermore, the expression of glutathione peroxidase 4 protein (GPX4) is down-regulated by consumption intracellular GSH content via converting GSH into glutathione oxidized (GSSG), which is named the classical mode. The intracellular Fe2+ content is overloaded by the significant up-regulation of HMOX1 expression, which is denoted as nonclassical mode. The synergistic effect of classical and nonclassical mode increased the intracellular lipid reactive oxide species, induced the occurrence of ferroptosis and up-regulated the expression of BH3 interacting domain death agonist (BID), apoptosis-inducing factor (AIF), and endonuclease G proteins (EndoG). The synergistic strategy demonstrate the excellent ferroptosis induction ability and antitumor efficacy in vivo, which provides great potential for the clinical transformation of ferroptosis.
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Affiliation(s)
- Ke Li
- Key Laboratory of Biorheological Science and Technology, Ministry of Education College of Bioengineering, Chongqing University, Chongqing, 400044, P. R. China
| | - Kun Xu
- Key Laboratory of Biorheological Science and Technology, Ministry of Education College of Bioengineering, Chongqing University, Chongqing, 400044, P. R. China
| | - Ye He
- Key Laboratory of Biorheological Science and Technology, Ministry of Education College of Bioengineering, Chongqing University, Chongqing, 400044, P. R. China
| | - Lu Lu
- Key Laboratory of Biorheological Science and Technology, Ministry of Education College of Bioengineering, Chongqing University, Chongqing, 400044, P. R. China
| | - Yulan Mao
- Key Laboratory of Biorheological Science and Technology, Ministry of Education College of Bioengineering, Chongqing University, Chongqing, 400044, P. R. China
| | - Pengfei Gao
- Key Laboratory of Biorheological Science and Technology, Ministry of Education College of Bioengineering, Chongqing University, Chongqing, 400044, P. R. China
| | - Genhua Liu
- Key Laboratory of Biorheological Science and Technology, Ministry of Education College of Bioengineering, Chongqing University, Chongqing, 400044, P. R. China
| | - Jing Wu
- Key Laboratory of Biorheological Science and Technology, Ministry of Education College of Bioengineering, Chongqing University, Chongqing, 400044, P. R. China
| | - Yuchen Zhang
- School of Life Science, Chongqing University, Chongqing, 400044, P. R. China
| | - Yang Xiang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education College of Bioengineering, Chongqing University, Chongqing, 400044, P. R. China
| | - Zhong Luo
- School of Life Science, Chongqing University, Chongqing, 400044, P. R. China
| | - Kaiyong Cai
- Key Laboratory of Biorheological Science and Technology, Ministry of Education College of Bioengineering, Chongqing University, Chongqing, 400044, P. R. China
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20
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Lu L, Liu G, Lin C, Li K, He T, Zhang J, Luo Z, Cai K. Mitochondrial Metabolism Targeted Nanoplatform for Efficient Triple-Negative Breast Cancer Combination Therapy. Adv Healthc Mater 2021; 10:e2100978. [PMID: 34387391 DOI: 10.1002/adhm.202100978] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 08/02/2021] [Indexed: 12/17/2022]
Abstract
Tumor reprogram pathway of mitochondrial metabolism is an emerging approach for malignant tumor treatment, such as triple-negative breast cancer. In this study, a tumor/mitochondria cascaded targeting, adenosine-triphosphate (ATP) responsive nanocarrier of zeolitic imidazolate framework-90 (ZIF-90) for breast cancer combination therapy is reported. Atovaquone (AVO) and hemin are loaded into ZIF-90, then a peptide iRGD with tumor-targeting ability is modified on the ZIF-90 nanoplatform. Hemin can specifically degrade BTB and CNC homology1 (BACH1), resulting in the changes of mitochondrial metabolism, and AVO acts as the inhibitor of the electron transport chain (ETC). The degradation of BACH1 using hemin can effectively improve the anti-tumor efficiency of mitochondrial metabolism inhibitor AVO, by increasing dependency on mitochondrial respiration. This nanoplatform displays both tumor-targeting and mitochondria-targeting capacity with high level of ATP responsive drug release behavior. The specific characteristic of mitochondria-targeting ability of this nanoplatform can increase the accumulation of AVO in the mitochondria, and in turn, can effectively improve the inhibition of the ETC. Both in vitro and in vivo results reveal that this composite nanocarrier has excellent tumor inhibition ability with limited side effects. Accordingly, this study provides an attractive strategy in the mitochondrial metabolism for cancer targeted therapy.
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Affiliation(s)
- Lu Lu
- Key Laboratory of Biorheological Science and Technology Ministry of Education College of Bioengineering Chongqing University Chongqing 400044 P. R. China
| | - Genhua Liu
- Key Laboratory of Biorheological Science and Technology Ministry of Education College of Bioengineering Chongqing University Chongqing 400044 P. R. China
| | - Chuanchuan Lin
- Key Laboratory of Biorheological Science and Technology Ministry of Education College of Bioengineering Chongqing University Chongqing 400044 P. R. China
| | - Ke Li
- Key Laboratory of Biorheological Science and Technology Ministry of Education College of Bioengineering Chongqing University Chongqing 400044 P. R. China
| | - Tingting He
- Key Laboratory of Biorheological Science and Technology Ministry of Education College of Bioengineering Chongqing University Chongqing 400044 P. R. China
| | - Jixi Zhang
- Key Laboratory of Biorheological Science and Technology Ministry of Education College of Bioengineering Chongqing University Chongqing 400044 P. R. China
| | - Zhong Luo
- School of Life Science Chongqing University Chongqing 400044 P. R. China
| | - Kaiyong Cai
- Key Laboratory of Biorheological Science and Technology Ministry of Education College of Bioengineering Chongqing University Chongqing 400044 P. R. China
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21
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Pinkney HR, Black MA, Diermeier SD. Single-Cell RNA-Seq Reveals Heterogeneous lncRNA Expression in Xenografted Triple-Negative Breast Cancer Cells. BIOLOGY 2021; 10:987. [PMID: 34681087 PMCID: PMC8533545 DOI: 10.3390/biology10100987] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 09/23/2021] [Accepted: 09/26/2021] [Indexed: 12/03/2022]
Abstract
Breast cancer is the most commonly diagnosed cancer in the world, with triple-negative breast cancer (TNBC) making up 12% of these diagnoses. TNBC tumours are highly heterogeneous in both inter-tumour and intra-tumour gene expression profiles, where they form subclonal populations of varying levels of aggressiveness. These aspects make it difficult to study and treat TNBC, requiring further research into tumour heterogeneity as well as potential therapeutic targets and biomarkers. Recently, it was discovered that the majority of the transcribed genome comprises non-coding RNAs, in particular long non-coding RNAs (lncRNAs). LncRNAs are transcripts of >200 nucleotides in length that do not encode a protein. They have been characterised as regulatory molecules and their expression can be associated with a malignant phenotype. We set out to explore TNBC tumour heterogeneity in vivo at a single cell level to investigate whether lncRNA expression varies across different cells within the tumour, even if cells are coming from the same cell line, and whether lncRNA expression is sufficient to define cellular subpopulations. We applied single-cell expression profiling due to its ability to capture expression signals of lncRNAs expressed in small subpopulations of cells. Overall, we observed most lncRNAs to be expressed at low, but detectable levels in TNBC xenografts, with a median of 25 lncRNAs detected per cell. LncRNA expression alone was insufficient to define a subpopulation of cells, and lncRNAs showed highly heterogeneous expression patterns, including ubiquitous expression, subpopulation-specific expression, and a hybrid pattern of lncRNAs expressed in several, but not all subpopulations. These findings reinforce that transcriptionally defined tumour cell subpopulations can be identified in cell-line derived xenografts, and uses single-cell RNA-seq (scRNA-seq) to detect and characterise lncRNA expression across these subpopulations in xenografted tumours. Future studies will aim to investigate the spatial distribution of lncRNAs within xenografts and patient tissues, and study the potential of subclone-specific lncRNAs as new therapeutic targets and/or biomarkers.
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Affiliation(s)
- Holly R. Pinkney
- Department of Biochemistry, University of Otago, Dunedin 9016, New Zealand; (H.R.P.); (M.A.B.)
| | - Michael A. Black
- Department of Biochemistry, University of Otago, Dunedin 9016, New Zealand; (H.R.P.); (M.A.B.)
| | - Sarah D. Diermeier
- Department of Biochemistry, University of Otago, Dunedin 9016, New Zealand; (H.R.P.); (M.A.B.)
- Amaroq Therapeutics Ltd., Dunedin 9016, New Zealand
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22
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Qian J, Lei X, Sun Y, Zheng L, Li J, Zhang S, Zhang L, Li W, Shi J, Jia W, Tang T. Long non-coding RNA SNHG8 enhances triple-negative breast cancer cell proliferation and migration by regulating the miR-335-5p/PYGO2 axis. Biol Direct 2021; 16:13. [PMID: 34362407 PMCID: PMC8349079 DOI: 10.1186/s13062-021-00295-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 06/28/2021] [Indexed: 12/30/2022] Open
Abstract
Background Growing evidence has demonstrated that long non-coding RNAs (lncRNAs) can function as modulators in the development of triple-negative breast cancer (TNBC). However, the function of lncRNA small nucleolar RNA host gene 8 (SNHG8) in TNBC remains unclear. Therefore, our study aimed at investigating the role of SNHG8 in the proliferation and migration of TNBC cells. Methods SNHG8 expression was evaluated using RT-qPCR assay. Cell proliferation and migration were assessed by EdU, colony formation and Transwell assays. The levels of proteins related to EMT process were examined by western blot assay. The interaction among SNHG8, miR-335-5p and pygopus family PHD finger 2 (PYGO2) was detected by RIP assay, RNA pull down assay and luciferase reporter assay. Results SNHG8 expression was significantly up-regulated in TNBC cells. SNHG8 silencing obviously inhibited TNBC cell proliferation, migration and EMT process. Moreover, SNHG8 acted as a sponge to sequester miR-335-5p in TNBC cells. Besides, PYGO2 was proven as a target gene of miR-335-5p, and SNHG8 promoted TNBC cell proliferation, migration and EMT process through regulating miR-335-5p and PYGO2. Conclusions Totally, our study indicated that SNHG8 promoted TNBC cell proliferation and migration by regulating the miR-335-5p/PYGO2 axis.
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Affiliation(s)
- Jintao Qian
- Department of General Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, China
| | - Xinhan Lei
- Department of General Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, China
| | - Yue Sun
- Department of General Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, China
| | - Lu Zheng
- Department of General Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, China
| | - Jia Li
- Department of General Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, China
| | - Shuai Zhang
- Department of General Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, China
| | - Lei Zhang
- Department of General Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, China
| | - Wanwan Li
- Department of General Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, China
| | - Jianing Shi
- Department of General Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, China
| | - Wenjun Jia
- Department of General Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, China.
| | - Tong Tang
- Department of General Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, China.
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23
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Huang SL, Huang ZC, Zhang CJ, Xie J, Lei SS, Wu YQ, Fan PZ. LncRNA SNHG5 promotes the glycolysis and proliferation of breast cancer cell through regulating BACH1 via targeting miR-299. Breast Cancer 2021; 29:65-76. [PMID: 34351577 PMCID: PMC8732815 DOI: 10.1007/s12282-021-01281-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Accepted: 08/01/2021] [Indexed: 12/24/2022]
Abstract
Background Breast cancer (BC) is one of the most common malignant tumors in women. Accumulating studies have been reported that long non-coding RNA (lncRNA) SNHG5 is highly expressed in BC. However, the specific molecular mechanism of SNHG5 in BC is unclear. Methods Gene and protein expressions in BC cell were detected by qRT-PCR and western blotting. The proliferation and cell cycle were measured using colony formation assay and flow cytometry analysis, separately. The glucose consumption and lactate production were determined by using the glucose assay kit and lactate assay kit. A dual-luciferase reporter assay was performed to measure the interaction between miR-299 and SNHG5 or BACH1. Results SNHG5 and BACH1 expressions were increased in BC cell while miR-299 level was decreased. SNHG5 increased BACH1 expression by directly targeting miR-299. SNHG5 silencing or miR-299 overexpression suppressed the proliferation of BC cell, arrested the cell cycle in the G1 cell phase, and decreased the glucose consumption and lactate production of BC cell. However, inhibition of miR-299 or overexpression of BACH1 could reverse the inhibitory effects of sh-SNHG5 on cell proliferation and glycolysis in BC. Conclusion SNHG5 promoted the BC cell growth and glycolysis through up-regulating BACH1 expression via targeting miR-299. These findings may improve the diagnostic and therapeutic approaches to BC.
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Affiliation(s)
- Shu-Lin Huang
- Department of Breast and Thyroid Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, No. 61, Jiefang West Road, Changsha, 410005, Hunan Province, People's Republic of China
| | - Zhong-Cheng Huang
- Department of General Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, Hunan Province, People's Republic of China
| | - Chao-Jie Zhang
- Department of Breast and Thyroid Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, No. 61, Jiefang West Road, Changsha, 410005, Hunan Province, People's Republic of China
| | - Jing Xie
- Department of Breast and Thyroid Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, No. 61, Jiefang West Road, Changsha, 410005, Hunan Province, People's Republic of China
| | - Shan-Shan Lei
- Department of Breast and Thyroid Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, No. 61, Jiefang West Road, Changsha, 410005, Hunan Province, People's Republic of China
| | - Ya-Qin Wu
- Department of Breast and Thyroid Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, No. 61, Jiefang West Road, Changsha, 410005, Hunan Province, People's Republic of China
| | - Pei-Zhi Fan
- Department of Breast and Thyroid Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, No. 61, Jiefang West Road, Changsha, 410005, Hunan Province, People's Republic of China.
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24
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Samir A, Tawab RA, El Tayebi HM. Long non-coding RNAs XIST and MALAT1 hijack the PD-L1 regulatory signaling pathway in breast cancer subtypes. Oncol Lett 2021; 22:593. [PMID: 34149904 PMCID: PMC8200942 DOI: 10.3892/ol.2021.12854] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Accepted: 01/14/2021] [Indexed: 02/06/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) have attracted widespread attention as potential biological and pathological regulators. lncRNAs are involved in several biological processes in cancer. Triple negative breast cancer (TNBC) is characterized by strong heterogeneity and aggressiveness. At present, the implication of microRNAs (miRs) and lncRNAs in immunotherapy has been poorly studied. Nevertheless, the blockade of immune checkpoints, particularly that of the programmed cell-death protein-1/programmed cell-death ligand-1 (PD-L1) axis, is considered as a principle approach in breast cancer (BC) therapy. The present study aimed to investigate the interaction between immune-modulatory upstream signaling pathways of the PD-L1 transcript that could enhance personalized targeted therapy. MDA-MB-231 cells were transfected with miR-182-5p mimics followed by RNA extraction and cDNA synthesis using a reverse transcription kit, and the expression levels of the target genes were assessed by reverse transcription-quantitative PCR. Furthermore, the expression levels of target genes were measured in tissues derived from 41 patients with BC, including patients with luminal BC and TNBC, as well as their adjacent lymph nodes. The results revealed that the expression levels of miR-182-5p, PD-L1 and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) were upregulated in MDA-MB-231 cells and BC tissues. However, X-inactive specific transcript (XIST) expression was downregulated in cancer tissues and TNBC cells. Following co-transfection of cells with small interfering RNAs specific for each target gene and miR-182-5p antagomirs, the effect of miR-182-5p was abolished in the presence of lncRNAs. Therefore, the results of the present study indicated that although miR-182-5p exhibited an oncogenic effect, XIST exerted a dominant effect on the regulation of the PD-L1 signaling pathway via the inhibition of the oncogenic function of MALAT1.
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Affiliation(s)
- Amany Samir
- Molecular Pharmacology Research Group, Department of Pharmacology and Toxicology, German University in Cairo, Cairo 11835, Egypt
| | - Reda Abdel Tawab
- Department of General Surgery, Ain Shams University, Cairo 11772, Egypt
| | - Hend M. El Tayebi
- Molecular Pharmacology Research Group, Department of Pharmacology and Toxicology, German University in Cairo, Cairo 11835, Egypt
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25
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Igarashi K, Nishizawa H, Saiki Y, Matsumoto M. The transcription factor BACH1 at the crossroads of cancer biology: From epithelial-mesenchymal transition to ferroptosis. J Biol Chem 2021; 297:101032. [PMID: 34339740 PMCID: PMC8387770 DOI: 10.1016/j.jbc.2021.101032] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 07/27/2021] [Accepted: 07/29/2021] [Indexed: 02/07/2023] Open
Abstract
The progression of cancer involves not only the gradual evolution of cells by mutations in DNA but also alterations in the gene expression induced by those mutations and input from the surrounding microenvironment. Such alterations contribute to cancer cells' abilities to reprogram metabolic pathways and undergo epithelial-to-mesenchymal transition (EMT), which facilitate the survival of cancer cells and their metastasis to other organs. Recently, BTB and CNC homology 1 (BACH1), a heme-regulated transcription factor that represses genes involved in iron and heme metabolism in normal cells, was shown to shape the metabolism and metastatic potential of cancer cells. The growing list of BACH1 target genes in cancer cells reveals that BACH1 promotes metastasis by regulating various sets of genes beyond iron metabolism. BACH1 represses the expression of genes that mediate cell–cell adhesion and oxidative phosphorylation but activates the expression of genes required for glycolysis, cell motility, and matrix protein degradation. Furthermore, BACH1 represses FOXA1 gene encoding an activator of epithelial genes and activates SNAI2 encoding a repressor of epithelial genes, forming a feedforward loop of EMT. By synthesizing these observations, we propose a “two-faced BACH1 model”, which accounts for the dynamic switching between metastasis and stress resistance along with cancer progression. We discuss here the possibility that BACH1-mediated promotion of cancer also brings increased sensitivity to iron-dependent cell death (ferroptosis) through crosstalk of BACH1 target genes, imposing programmed vulnerability upon cancer cells. We also discuss the future directions of this field, including the dynamics and plasticity of EMT.
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Affiliation(s)
- Kazuhiko Igarashi
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan; Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan.
| | - Hironari Nishizawa
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yuriko Saiki
- Department of Investigative Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Mitsuyo Matsumoto
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan; Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan
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26
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Guo L, Zhang X, Pan H, Li Y, Wang J, Li L, Dong Y, Du X, Chen J, Guo F. Prognostic and immunological significance of metastasis associated lung adenocarcinoma transcript 1 among different kinds of cancers. Bioengineered 2021; 12:4247-4258. [PMID: 34308750 PMCID: PMC8806457 DOI: 10.1080/21655979.2021.1955511] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
LncRNAs belong to the type of noncoding RNA transcripts, which exceed 200 nucleotides in size. MALAT1 as one of the earlier identified lncRNAs in cancer is investigated by more and more scientific researchers. Expression, clinical significance and function of MALAT1 in pan-cancer exist as big difference. To detect the expression and clinical significance of MALAT1 gene precisely and comprehensively among different kinds of cancers, some classical databases such as GEPIA, TIMER, KM Plotter, and PrognoScan were fully applied. An immunological role of MALAT1 among different kinds of cancers was also determined in TIMER database. Our results showed that MALAT1 was differently expressed in different kinds of cancers using GEPIA, Oncomine, and TIMER databases to analyze. Especially, MALAT1 high RNA level was related to the early stage in lung and gastric cancer patients. MALAT1 expression was closely related to prognosis among different cancer patients. Furthermore, expression of MALAT1 was related to tumor immune cell infiltrating. Expression level of MALAT1 was also related to immune makers such as macrophage, T cell, NK cells, and so on. These findings indicate that MALAT1 could be a potential prognostic biomarker of some kinds of cancer and was significantly correlated with tumor-infiltrating immune cells in a wide variety of cancers.
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Affiliation(s)
- Lili Guo
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, People's Republic of China.,Precision Medicine Center, The Affiliated People's Hospital of Shanxi Medical University, Taiyuan, People's Republic of China
| | - Xiuwen Zhang
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, People's Republic of China
| | - Hongli Pan
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, People's Republic of China
| | - Yang Li
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, People's Republic of China
| | - Jing Wang
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, People's Republic of China
| | - Lin Li
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, People's Republic of China
| | - Yafang Dong
- Precision Medicine Center, The Affiliated People's Hospital of Shanxi Medical University, Taiyuan, People's Republic of China
| | - Xinxin Du
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, People's Republic of China
| | - Jun Chen
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, People's Republic of China
| | - Fengjie Guo
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, People's Republic of China.,School of Medicine, South China University of Technology, Guangzhou, People's Republic of China
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27
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Thakur KK, Kumar A, Banik K, Verma E, Khatoon E, Harsha C, Sethi G, Gupta SC, Kunnumakkara AB. Long noncoding RNAs in triple-negative breast cancer: A new frontier in the regulation of tumorigenesis. J Cell Physiol 2021; 236:7938-7965. [PMID: 34105151 DOI: 10.1002/jcp.30463] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 05/11/2021] [Accepted: 05/20/2021] [Indexed: 12/16/2022]
Abstract
In recent years, triple-negative breast cancer (TNBC) has emerged as the most aggressive subtype of breast cancer and is usually associated with increased mortality worldwide. The severity of TNBC is primarily observed in younger women, with cases ranging from approximately 12%-24% of all breast cancer cases. The existing hormonal therapies offer limited clinical solutions in completely circumventing the TNBC, with chemoresistance and tumor recurrences being the common hurdles in the path of TNBC treatment. Accumulating evidence has correlated the dysregulation of long noncoding RNAs (lncRNAs) with increased cell proliferation, invasion, migration, tumor growth, chemoresistance, and decreased apoptosis in TNBC. Various clinical studies have revealed that aberrant expression of lncRNAs in TNBC tissues is associated with poor prognosis, lower overall survival, and disease-free survival. Due to these specific characteristics, lncRNAs have emerged as novel diagnostic and prognostic biomarkers for TNBC treatment. However, the underlying mechanism through which lncRNAs perform their actions remains unclear, and extensive research is being carried out to reveal it. Therefore, understanding of mechanisms regulating the modulation of lncRNAs will be a substantial breakthrough in effective treatment therapies for TNBC. This review highlights the association of several lncRNAs in TNBC progression and treatment, along with their possible functions and mechanisms.
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Affiliation(s)
- Krishan K Thakur
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, India
| | - Aviral Kumar
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, India
| | - Kishore Banik
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, India
| | - Elika Verma
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, India
| | - Elina Khatoon
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, India
| | - Choudhary Harsha
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Subash C Gupta
- Department of Biochemistry, Laboratory for Translational Cancer Research, Banaras Hindu University (BHU), Varanasi, Uttar Pradesh, India
| | - Ajaikumar B Kunnumakkara
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, India
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28
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Goyal B, Yadav SRM, Awasthee N, Gupta S, Kunnumakkara AB, Gupta SC. Diagnostic, prognostic, and therapeutic significance of long non-coding RNA MALAT1 in cancer. Biochim Biophys Acta Rev Cancer 2021; 1875:188502. [PMID: 33428963 DOI: 10.1016/j.bbcan.2021.188502] [Citation(s) in RCA: 202] [Impact Index Per Article: 50.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 12/30/2020] [Accepted: 01/02/2021] [Indexed: 12/20/2022]
Abstract
Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) is a widely studied lncRNA in cancer. Although dispensable for normal physiology, MALAT1 is important for cancer-related pathways regulation. It is localized in the nuclear speckles periphery along with centrally located pre-RNA splicing factors. MALAT1 associated cancer signaling pathways include MAPK/ERK, PI3K/AKT, β-catenin/Wnt, Hippo, VEGF, YAP, etc. Molecular tools such as immunoprecipitation, RNA pull-down, reporter assay, Northern blotting, microarray, and q-RT-PCR has been used to elucidate MALAT1's function in cancer pathogenesis. MALAT1 can regulate multiple steps in the development of tumours. The diagnostic and prognostic significance of MALAT1 has been demonstrated in cancers of the breast, cervix, colorectum, gallbladder, lung, ovary, pancreas, prostate, glioma, hepatocellular carcinoma, and multiple myeloma. MALAT1 has also emerged as a novel therapeutic target for solid as well as hematological malignancies. In experimental models, siRNA and antisense oligonucleotide (ASO) based strategy has been used for targeting MALAT1. The lncRNA has also been targeted for the chemosensitization and radiosensitization of cancer cells. However, most studies have been performed in preclinical models. How the cross-talk of MALAT1 with other signaling pathways affect cancer pathogenesis is the focus of this article. The diagnostic, prognostic, and therapeutic significance of MALAT1 in multiple cancer types are discussed.
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Affiliation(s)
- Bela Goyal
- Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Shashi Ranjan Mani Yadav
- Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Nikee Awasthee
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India
| | - Sweety Gupta
- Department of Radiation Oncology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Ajaikumar B Kunnumakkara
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, 781039, India
| | - Subash Chandra Gupta
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India.
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Malla RR, Farran B, Nagaraju GP. Understanding the function of the tumor microenvironment, and compounds from marine organisms for breast cancer therapy. World J Biol Chem 2021; 12:15-37. [PMID: 33815682 PMCID: PMC8006057 DOI: 10.4331/wjbc.v12.i2.15] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/13/2021] [Accepted: 02/20/2021] [Indexed: 02/06/2023] Open
Abstract
The pathology and physiology of breast cancer (BC), including metastasis, and drug resistance, is driven by multiple signaling pathways in the tumor microenvironment (TME), which hamper antitumor immunity. Recently, long non-coding RNAs have been reported to mediate pathophysiological develop-ments such as metastasis as well as immune suppression within the TME. Given the complex biology of BC, novel personalized therapeutic strategies that address its diverse pathophysiologies are needed to improve clinical outcomes. In this review, we describe the advances in the biology of breast neoplasia, including cellular and molecular biology, heterogeneity, and TME. We review the role of novel molecules such as long non-coding RNAs in the pathophysiology of BC. Finally, we provide an up-to-date overview of anticancer compounds extracted from marine microorganisms, crustaceans, and fishes and their synergistic effects in combination with other anticancer drugs. Marine compounds are a new discipline of research in BC and offer a wide range of anti-cancer effects that could be harnessed to target the various pathways involved in BC development, thus assisting current therapeutic regimens.
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Affiliation(s)
- Rama Rao Malla
- Department of Biochemistry and Bioinformatics, GITAM (Deemed to be University), Visakhapatnam 530045, AP, India
| | - Batoul Farran
- Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, United States
| | - Ganji Purnachandra Nagaraju
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, United States
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Ghafouri-Fard S, Tamizkar KH, Hussen BM, Taheri M. An update on the role of long non-coding RNAs in the pathogenesis of breast cancer. Pathol Res Pract 2021; 219:153373. [DOI: 10.1016/j.prp.2021.153373] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 01/31/2021] [Accepted: 02/03/2021] [Indexed: 12/18/2022]
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Fang D, Lu G. Expression and role of nuclear receptor-interacting protein 1 (NRIP1) in stomach adenocarcinoma. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1293. [PMID: 33209873 PMCID: PMC7661897 DOI: 10.21037/atm-20-6197] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Background Nuclear receptor-interacting protein 1 (NRIP1), also named NR140, has been observed differentially express in multiple cancers, but the expression levels and the prognostic role of NRIP1 in stomach adenocarcinoma (STAD) remain unclear. Methods We used the Gene Expression Profiling Interactive Analysis (GEPIA) to analyze the NRIP1 expression levels in STAD, subgroups analysis of expression of NRIP1 via the UALCAN dataset. Further, cBioPortal was used to investigate the aberration type, co-mutations status, and located mutation of NRIP1. Correlated genes, and kinases, microRNA (miRNA), and transcription factor (TF) targets were identified using LinkedOmics. The Kaplan-Meier (K-M) plotter was used to analyze the prognosis of NRIP1 and the significantly correlated genes in STAD. Then, the tumor immune estimation resource (Timer) was used to explore the relation between NRIP1 and the immune cell infiltration, and the role of immune cells in STAD. The Human Protein Atlas (HPA) was used to confirm the NRIP1 protein express in STAD stomach tissue and normal stomach tissue. Results NRIP1 significantly overexpress in STAD, and the NRIP1 expression levels were impacted by clinical features. Overexpression of NRIP1 indicated the poor prognosis of STAD. Functional enrichment analysis showed the NRIP1 mainly enriched in immune response-regulating signaling pathway, cell-substrate adhesion, mRNA processing, and pathway in cancer. Overexpression USP25, SNYJ1 indicated the poor outcome of STAD, but the overexpression of BACH1 indicated protective biomarker. MIR-331 and MIR-132 have important role in STAD. Further, NRIP1 had a significant relation with immune infiltrates and other defined genes that significantly impact immune infiltrates. Immunohistochemical showed NRIP1 protein was higher in STAD than normal sample. Conclusions In this study, we revealed that overexpression of NRIP1 in the STAD sample compared to normal samples, NRIP1 significantly associated with macrophage. The high expression levels of NRIP1 and more macrophage infiltration led to poor prognosis of STAD.
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Affiliation(s)
- Dalang Fang
- Department of Glandular Surgery, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Guanming Lu
- Department of Glandular Surgery, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
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Wu Y, Sarkissyan M, Ogah O, Kim J, Vadgama JV. Expression of MALAT1 Promotes Trastuzumab Resistance in HER2 Overexpressing Breast Cancers. Cancers (Basel) 2020; 12:E1918. [PMID: 32708561 PMCID: PMC7409266 DOI: 10.3390/cancers12071918] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Revised: 07/12/2020] [Accepted: 07/14/2020] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is associated with cancer progression. Our study examined the role of MALAT1 in breast cancer and the mechanisms involved in the regulation of MALAT1. METHODS In vitro cell and in vivo animal models were used to examine the role of MALAT1 in breast cancer. The interaction of FOXO1 (Forkhead Box O1) at the promoter region of MALAT1 was investigated by chromatin immunoprecipitation (ChIP) assay. RESULTS The data shows an elevated expression of MALAT1 in breast cancer tissues and cells compared to non-cancer tissues and cells. The highest level of MALAT1 was observed in metastatic triple-negative breast cancer and trastuzumab-resistant HER2 (human epidermal growth factor receptor 2) overexpressing (HER2+) cells. Knockdown of MALAT1 in trastuzumab-resistant HER2+ cells reversed epithelial to mesenchymal transition-like phenotype and cell invasiveness. It improved the sensitivity of the cell's response to trastuzumab. Furthermore, activation of Akt by phosphorylation was associated with the upregulation of MALAT1. The transcription factor FOXO1 regulates the expression of MALAT1 via the PI3/Akt pathway. CONCLUSIONS We show that MALAT1 contributes to HER2+ cell resistance to trastuzumab. Targeting the PI3/Akt pathway and stabilizing FOXO1 translocation could inhibit the upregulation of MALAT1.
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Affiliation(s)
- Yanyuan Wu
- Division of Cancer Research and Training, Department of Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th Street, Los Angeles, CA 90059, USA; (M.S.); (O.O.); (J.K.)
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
| | - Marianna Sarkissyan
- Division of Cancer Research and Training, Department of Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th Street, Los Angeles, CA 90059, USA; (M.S.); (O.O.); (J.K.)
| | - Ochanya Ogah
- Division of Cancer Research and Training, Department of Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th Street, Los Angeles, CA 90059, USA; (M.S.); (O.O.); (J.K.)
| | - Juri Kim
- Division of Cancer Research and Training, Department of Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th Street, Los Angeles, CA 90059, USA; (M.S.); (O.O.); (J.K.)
| | - Jaydutt V. Vadgama
- Division of Cancer Research and Training, Department of Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th Street, Los Angeles, CA 90059, USA; (M.S.); (O.O.); (J.K.)
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
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