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Dey M, Skipar P, Bartnik E, Piątkowski J, Sulejczak D, Czarnecka AM. MicroRNA signatures in osteosarcoma: diagnostic insights and therapeutic prospects. Mol Cell Biochem 2025; 480:2065-2075. [PMID: 39419925 PMCID: PMC11961547 DOI: 10.1007/s11010-024-05135-5] [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: 07/30/2024] [Accepted: 10/04/2024] [Indexed: 10/19/2024]
Abstract
Osteosarcoma (OSa) is the most prevalent primary malignant bone tumor in children and adolescents, characterized by complex genetic and epigenetic alterations. Traditional treatments face significant challenges due to high rates of drug resistance and lack of targeted therapies. Recent advances in microRNA (miRNA) research have opened new avenues for understanding and treating osteosarcoma. This review explores the many critical functions of miRNAs in osteosarcoma, particularly their potential for clinical use. The review highlights two key areas where miRNAs could be beneficial. Firstly, miRNAs can act as biomarkers for diagnosing osteosarcoma and predicting patient prognosis. Secondly, specific miRNAs can regulate cellular processes like proliferation, cell death, migration, and even resistance to chemotherapy drugs in osteosarcoma. This ability to target multiple pathways within cancer cells makes miRNA-based therapies highly promising. Additionally, though the interaction between miRNAs and circular RNAs (circRNAs) falls outside the scope of the paper, it has also been discussed briefly. While miRNA-based therapies offer exciting possibilities for targeting multiple pathways in osteosarcoma, challenges remain. Efficient delivery, potential off-target effects, tumor complexity, and rigorous testing are hurdles to overcome before these therapies can reach patients. Despite these challenges, continued research and collaboration among scientists, clinicians, and regulatory bodies hold the promise of overcoming them. This collaborative effort can pave the way for the development of safe and effective miRNA-based treatments for osteosarcoma.
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Affiliation(s)
- Mritunjoy Dey
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Cancer Research Institute in Warsaw, 02-781, Warsaw, Poland.
| | - Palina Skipar
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Cancer Research Institute in Warsaw, 02-781, Warsaw, Poland
- Faculty of Medicine, Warsaw Medical University, 02-091, Warsaw, Poland
| | - Ewa Bartnik
- Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, 02-106, Warsaw, Poland
| | - Jakub Piątkowski
- Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, 02-106, Warsaw, Poland
| | - Dorota Sulejczak
- Department of Experimental Pharmacology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
| | - Anna M Czarnecka
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Cancer Research Institute in Warsaw, 02-781, Warsaw, Poland
- Department of Experimental Pharmacology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
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2
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Wang Y, Huang D, Li M, Yang M. MicroRNA-99 family in cancer: molecular mechanisms for clinical applications. PeerJ 2025; 13:e19188. [PMID: 40161350 PMCID: PMC11955196 DOI: 10.7717/peerj.19188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 02/25/2025] [Indexed: 04/02/2025] Open
Abstract
MicroRNAs (miRNAs) are a class of non-coding RNA sequences that regulate gene expression post-transcriptionally. The miR-99 family, which is highly evolutionarily conserved, comprises three homologs: miR-99a, miR-99b, and miR-100. Its members are under-expressed in most cancerous tissues, suggesting their cancer-repressing properties in multiple cancers; however, in some contexts, they also promote malignant lesion progression. MiR-99 family members target numerous genes involved in various tumor-related processes such as tumorigenesis, proliferation, cell-cycle regulation, apoptosis, invasion, and metastasis. We review the recent research on this family, summarize its implications in cancer, and explore its potential as a biomarker and cancer therapeutic target. This review contributes to the clinical translation of the miR-99 family members.
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Affiliation(s)
- Yueyuan Wang
- Department of Breast Surgery, General Surgery Center, The First Hospital of Jilin University, ChangChun, Jilin, China
| | - Dan Huang
- Department of Breast Surgery, General Surgery Center, The First Hospital of Jilin University, ChangChun, Jilin, China
| | - Mingxi Li
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, ChangChun, Jilin, China
| | - Ming Yang
- Department of Breast Surgery, General Surgery Center, The First Hospital of Jilin University, ChangChun, Jilin, China
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3
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Myers BL, Brayer KJ, Paez-Beltran LE, Villicana E, Keith MS, Suzuki H, Newville J, Anderson RH, Lo Y, Mertz CM, Kollipara RK, Borromeo MD, Lu QR, Bachoo RM, Johnson JE, Vue TY. Transcription factors ASCL1 and OLIG2 drive glioblastoma initiation and co-regulate tumor cell types and migration. Nat Commun 2024; 15:10363. [PMID: 39609428 PMCID: PMC11605073 DOI: 10.1038/s41467-024-54750-9] [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: 10/30/2023] [Accepted: 11/20/2024] [Indexed: 11/30/2024] Open
Abstract
Glioblastomas (GBMs) are highly aggressive, infiltrative, and heterogeneous brain tumors driven by complex genetic alterations. The basic-helix-loop-helix (bHLH) transcription factors ASCL1 and OLIG2 are dynamically co-expressed in GBMs; however, their combinatorial roles in regulating the plasticity and heterogeneity of GBM cells are unclear. Here, we show that induction of somatic mutations in subventricular zone (SVZ) progenitor cells leads to the dysregulation of ASCL1 and OLIG2, which then function redundantly and are required for brain tumor formation in a mouse model of GBM. Subsequently, the binding of ASCL1 and OLIG2 to each other's loci and to downstream target genes then determines the cell types and degree of migration of tumor cells. Single-cell RNA sequencing (scRNA-seq) reveals that a high level of ASCL1 is key in specifying highly migratory neural stem cell (NSC)/astrocyte-like tumor cell types, which are marked by upregulation of ribosomal protein, oxidative phosphorylation, cancer metastasis, and therapeutic resistance genes.
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Affiliation(s)
- Bianca L Myers
- Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Kathryn J Brayer
- University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA
| | - Luis E Paez-Beltran
- Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Estrella Villicana
- Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Matthew S Keith
- Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Hideaki Suzuki
- Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Jessie Newville
- Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Rebekka H Anderson
- Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Yunee Lo
- Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Conner M Mertz
- Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Rahul K Kollipara
- McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Mark D Borromeo
- Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Q Richard Lu
- Department of Pediatrics, Brain Tumor Center, EHCB, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Robert M Bachoo
- Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Jane E Johnson
- Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Tou Yia Vue
- Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
- University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA.
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4
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Tang M, Song J, Zhang S, Shu X, Liu S, Ashrafizadeh M, Ertas YN, Zhou Y, Lei M. Innovative theranostic hydrogels for targeted gastrointestinal cancer treatment. J Transl Med 2024; 22:970. [PMID: 39465365 PMCID: PMC11514878 DOI: 10.1186/s12967-024-05749-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Accepted: 10/08/2024] [Indexed: 10/29/2024] Open
Abstract
Gastrointestinal tumors are the main causes of death among the patients. These tumors are mainly diagnosed in the advanced stages and their response to therapy is unfavorable. In spite of the development of conventional therapeutics including surgery, chemotherapy, radiotherapy and immunotherapy, the treatment of these tumors is still challenging. As a result, the new therapeutics based on (nano)biotechnology have been introduced. Hydrogels are polymeric 3D networks capable of absorbing water to swell with favorable biocompatibility. In spite of application of hydrogels in the treatment of different human diseases, their wide application in cancer therapy has been improved because of their potential in drug and gene delivery, boosting chemotherapy and immunotherapy as well as development of vaccines. The current review focuses on the role of hydrogels in the treatment of gastrointestinal tumors. Hydrogels provide delivery of drugs (both natural or synthetic compounds and their co-delivery) along with gene delivery. Along with delivery, hydrogels stimulate phototherapy (photothermal and photodynamic therapy) in the suppression of these tumors. Besides, the ability of hydrogels for the induction of immune-related cells such as dendritic cells can boost cancer immunotherapy. For more specific cancer therapy, the stimuli-responsive types of hydrogels including thermo- and pH-sensitive hydrogels along with their self-healing ability have improved the site specific drug delivery. Moreover, hydrogels are promising for diagnosis, circulating tumor cell isolation and detection of biomarkers in the gastrointestinal tumors, highlighting their importance in clinic. Hence, hydrogels are diagnostic and therapeutic tools for the gastrointestimal tumors.
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Affiliation(s)
- Min Tang
- Department of Oncology, Chongqing General Hospital, Chongqing University, No.104 Pipa Mountain Main Street, Chongqing, 401120, China
| | - Junzhou Song
- Department of Oncology, BoAo Evergrande International Hospital, Qionghai, 571400, Hainan Province, China
| | - Shuyi Zhang
- Department of Health Management Center, Chongqing General Hospital, Chongqing University, Chongqing, 401120, China
| | - Xiaolei Shu
- Radiation Oncology Center, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Shuang Liu
- Department of Ultrasound, Chongqing Health Center for Women and Children, Women and Children's Hospital of Chongqing Medical University, No. 120, Longshan Road, Yubei, Chongqing, 401147, China
| | - Milad Ashrafizadeh
- Department of Radiation Oncology, Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, 250000, Shandong, China.
| | - Yavuz Nuri Ertas
- Department of Biomedical Engineering, Erciyes University, 38039, Kayseri, Türkiye
- Department of Technical Sciences, Western Caspian University, AZ1001, Baku, Azerbaijan
| | - Ya Zhou
- Department of Oncology, Chongqing General Hospital, Chongqing University, No.104 Pipa Mountain Main Street, Chongqing, 401120, China.
| | - Ming Lei
- Department of Nuclear Medicine, Chongqing University FuLing Hospital, Chongqing University, No. 2 Gaosuntang Road, Chongqing, China.
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Yu X, Zhang Y, Luo F, Zhou Q, Zhu L. The role of microRNAs in the gastric cancer tumor microenvironment. Mol Cancer 2024; 23:170. [PMID: 39164671 PMCID: PMC11334576 DOI: 10.1186/s12943-024-02084-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 08/13/2024] [Indexed: 08/22/2024] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the deadliest malignant tumors with unknown pathogenesis. Due to its treatment resistance, high recurrence rate, and lack of reliable early detection techniques, a majority of patients have a poor prognosis. Therefore, identifying new tumor biomarkers and therapeutic targets is essential. This review aims to provide fresh insights into enhancing the prognosis of patients with GC by summarizing the processes through which microRNAs (miRNAs) regulate the tumor microenvironment (TME) and highlighting their critical role in the TME. MAIN TEXT A comprehensive literature review was conducted by focusing on the interactions among tumor cells, extracellular matrix, blood vessels, cancer-associated fibroblasts, and immune cells within the GC TME. The role of noncoding RNAs, known as miRNAs, in modulating the TME through various signaling pathways, cytokines, growth factors, and exosomes was specifically examined. Tumor formation, metastasis, and therapy in GC are significantly influenced by interactions within the TME. miRNAs regulate tumor progression by modulating these interactions through multiple signaling pathways, cytokines, growth factors, and exosomes. Dysregulation of miRNAs affects critical cellular processes such as cell proliferation, differentiation, angiogenesis, metastasis, and treatment resistance, contributing to the pathogenesis of GC. CONCLUSIONS miRNAs play a crucial role in the regulation of the GC TME, influencing tumor progression and patient prognosis. By understanding the mechanisms through which miRNAs control the TME, potential biomarkers and therapeutic targets can be identified to improve the prognosis of patients with GC.
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Affiliation(s)
- Xianzhe Yu
- Department of Medical Oncology, West China Hospital, Sichuan University, Sichuan Province, Cancer Center, Chengdu, 610041, People's Republic of China
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Sichuan Province, Chengdu, 610041, People's Republic of China
- Department of Gastrointestinal Surgery, Chengdu Second People's Hospital, Sichuan Province, No. 10 Qinyun Nan Street, Chengdu, 610041, People's Republic of China
| | - Yin Zhang
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China
- Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
- Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Fengming Luo
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Qinghua Zhou
- Department of Medical Oncology, West China Hospital, Sichuan University, Sichuan Province, Cancer Center, Chengdu, 610041, People's Republic of China.
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Sichuan Province, Chengdu, 610041, People's Republic of China.
| | - Lingling Zhu
- Department of Medical Oncology, West China Hospital, Sichuan University, Sichuan Province, Cancer Center, Chengdu, 610041, People's Republic of China.
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Sichuan Province, Chengdu, 610041, People's Republic of China.
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Licari E, Cricrì G, Mauri M, Raimondo F, Dioni L, Favero C, Giussani A, Starace R, Nucera S, Biondi A, Piazza R, Bollati V, Dander E, D'Amico G. ActivinA modulates B-acute lymphoblastic leukaemia cell communication and survival by inducing extracellular vesicles production. Sci Rep 2024; 14:16083. [PMID: 38992199 PMCID: PMC11239915 DOI: 10.1038/s41598-024-66779-3] [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: 03/13/2024] [Accepted: 07/03/2024] [Indexed: 07/13/2024] Open
Abstract
Extracellular vesicles (EVs) are a new mechanism of cellular communication, by delivering their cargo into target cells to modulate molecular pathways. EV-mediated crosstalk contributes to tumor survival and resistance to cellular stress. However, the role of EVs in B-cell Acute Lymphoblastic Leukaemia (B-ALL) awaits to be thoroughly investigated. We recently published that ActivinA increases intracellular calcium levels and promotes actin polymerization in B-ALL cells. These biological processes guide cytoskeleton reorganization, which is a crucial event for EV secretion and internalization. Hence, we investigated the role of EVs in the context of B-ALL and the impact of ActivinA on this phenomenon. We demonstrated that leukemic cells release a higher number of EVs in response to ActivinA treatment, and they can actively uptake EVs released by other B-ALL cells. Under culture-induced stress conditions, EVs coculture promoted cell survival in B-ALL cells in a dose-dependent manner. Direct stimulation of B-ALL cells with ActivinA or with EVs isolated from ActivinA-stimulated cells was even more effective in preventing cell death. This effect can be possibly ascribed to the increase of vesiculation and modifications of EV-associated microRNAs induced by ActivinA. These data demonstrate that ActivinA boosts EV-mediated B-ALL crosstalk, improving leukemia survival in stress conditions.
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Affiliation(s)
- Eugenia Licari
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Via Pergolesi, 20900, Monza, Italy
| | - Giulia Cricrì
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Via Pergolesi, 20900, Monza, Italy
- Paediatric Nephrology, Dialysis and Transplant Unit, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano, Italy
| | - Mario Mauri
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Francesca Raimondo
- Clinical Proteomics and Metabolomic Unit, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Laura Dioni
- EPIGET Lab, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Chiara Favero
- EPIGET Lab, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Alice Giussani
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Via Pergolesi, 20900, Monza, Italy
| | - Rita Starace
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Via Pergolesi, 20900, Monza, Italy
| | - Silvia Nucera
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Via Pergolesi, 20900, Monza, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Andrea Biondi
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Rocco Piazza
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- Hematology Division and Bone Marrow Unit, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Valentina Bollati
- EPIGET Lab, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
- CRC, Center for Environmental Health, University of Milan, Milan, Italy
- Occupational Health Unit, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy
| | - Erica Dander
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Via Pergolesi, 20900, Monza, Italy
| | - Giovanna D'Amico
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Via Pergolesi, 20900, Monza, Italy.
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7
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Liu C, Li S, Tang Y. Mechanism of cisplatin resistance in gastric cancer and associated microRNAs. Cancer Chemother Pharmacol 2023; 92:329-340. [PMID: 37535106 DOI: 10.1007/s00280-023-04572-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 07/27/2023] [Indexed: 08/04/2023]
Abstract
Gastric cancer (GC) is a common malignant tumor with high morbidity and mortality rates that seriously affects human health worldwide. Although surgery is currently the preferred clinical treatment for GC, chemotherapy remains the first choice for perioperative treatment, adjuvant therapy, and palliative care for patients with advanced GC. Cisplatin (DDP) is an antineoplastic agent that has been used clinically for decades, and it is the first-line chemotherapy for many solid tumors. However, the therapeutic efficacy of DDP is often limited by resistance and the complexity of its resistance mechanisms, which involve multiple proteins and signaling pathways. It is well documented that a variety of microRNAs (miRNAs) differentially expressed in DDP-resistant GC cells play important roles in regulating or reversing DDP resistance via various pathways. In this review, we first provide an introduction to the cytotoxicity and major resistance mechanisms of DDP in GC and then discuss the role and mechanism of miRNAs in regulating the DDP resistance process in GC cells. This work demonstrates the potential of relevant miRNAs to become diagnostic and prognostic biomarkers for gastric cancer and targets of action to enhance chemosensitivity and provides directions for future research.
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Affiliation(s)
- Changqing Liu
- Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Cancer Research Institute of Hengyang Medical School, University of South China, 28 Changsheng Road, Hengyang, 421001, Hunan Province, People's Republic of China
| | - Shan Li
- Department of Pathology, People's Hospital of Shaoyang County, Hengyang, Hunan Province, People's Republic of China
| | - Yunlian Tang
- Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Cancer Research Institute of Hengyang Medical School, University of South China, 28 Changsheng Road, Hengyang, 421001, Hunan Province, People's Republic of China.
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Wu M, Xue L, Guo Y, Dong X, Chen Z, Wei S, Yi X, Li Y, Zhang J, Zhou S, Wu M, Lou X, Dai J, Xia F, Wang S. Microenvironmentally Responsive Chemotherapeutic Prodrugs and CHEK2 Inhibitors Self-Assembled Micelles: Protecting Fertility and Enhancing Chemotherapy. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2023; 35:e2210017. [PMID: 36528787 DOI: 10.1002/adma.202210017] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 11/30/2022] [Indexed: 06/17/2023]
Abstract
Chemotherapy is a widely used and effective adjuvant treatment for cancer, and it has unavoidable damage to female fertility, with statistics showing 38% of women who have received chemotherapy are infertile. How to reduce fertility toxicity while enhancing the oncologic chemotherapy is a clinical challenge. Herein, co-delivery micelles (BML@PMP) are developed, which are composed of a reduction-sensitive paclitaxel prodrug (PMP) for chemotherapy and a CHEK2 inhibitor (BML277) for both fertility protection and chemotherapy enhancement. BML@PMP achieves fertility protection through three actions: (1) Due to the enhanced permeability and retention (EPR) effect, BML@PMP is more enriched in the tumor, while very little in the ovary (about 1/10th of the tumor). (2) Glutathione (GSH) triggers the release of PTX, and with low levels of GSH in the ovary, the amount of PTX released in the ovary is correspondingly reduced. (3) BML277 inhibits oocyte apoptosis by inhibiting the CHEK2-TAp63α pathway. Because of the different downstream targets of CHEK2 in tumor cells and oocytes, BML277 also enhances chemotherapeutic efficacy by reducing DNA damage repair which is activated through the CHEK2 pathway. This bidirectional effect of CHEK2 inhibitor-based co-delivery system represents a promising strategy for improving oncology treatment indices and preventing chemotherapy-associated fertility damage.
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Affiliation(s)
- Meng Wu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, 430030, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, 430030, China
| | - Liru Xue
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, 430030, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, 430030, China
| | - Yican Guo
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, 430030, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, 430030, China
| | - Xiaoqi Dong
- State Key Laboratory of Biogeology and Environmental Geology, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan, 430074, China
| | - Zhaojun Chen
- State Key Laboratory of Biogeology and Environmental Geology, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan, 430074, China
| | - Simin Wei
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, 430030, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, 430030, China
| | - Xiaoqing Yi
- Key Laboratory of Biomaterials and Biofabrication in Tissue Engineering of Jiangxi Province, Gannan Medical University, Ganzhou, 341000, China
| | - Yinuo Li
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, 430030, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, 430030, China
| | - Jinjin Zhang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, 430030, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, 430030, China
| | - Su Zhou
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, 430030, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, 430030, China
| | - Mingfu Wu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, 430030, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, 430030, China
| | - Xiaoding Lou
- State Key Laboratory of Biogeology and Environmental Geology, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan, 430074, China
| | - Jun Dai
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, 430030, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, 430030, China
| | - Fan Xia
- State Key Laboratory of Biogeology and Environmental Geology, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan, 430074, China
| | - Shixuan Wang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, 430030, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, 430030, China
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9
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Alterations in the p53 isoform ratio govern breast cancer cell fate in response to DNA damage. Cell Death Dis 2022; 13:907. [PMID: 36307393 PMCID: PMC9616954 DOI: 10.1038/s41419-022-05349-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 10/13/2022] [Accepted: 10/14/2022] [Indexed: 11/07/2022]
Abstract
Our previous studies have shown that p53 isoform expression is altered in breast cancer and related to prognosis. In particular, a high ∆40p53:p53α ratio is associated with worse disease-free survival. In this manuscript, the influence of altered Δ40p53 and p53α levels on the response to standard of care DNA-damaging agents used in breast cancer treatment was investigated in vitro. Our results revealed that a high Δ40p53:p53α ratio causes cells to respond differently to doxorubicin and cisplatin treatments. Δ40p53 overexpression significantly impairs the cells' sensitivity to doxorubicin through reducing apoptosis and DNA damage, whereas Δ40p53 knockdown has the opposite effect. Further, a high Δ40p53:p53α ratio inhibited the differential expression of several genes following doxorubicin and promoted DNA repair, impairing the cells' canonical response. Overall, our results suggest that the response of breast cancer cells to standard of care DNA-damaging therapies is dependent on the expression of p53 isoforms, which may contribute to outcomes in breast cancer.
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10
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Multi-Omics Analysis Revealed a Significant Alteration of Critical Metabolic Pathways Due to Sorafenib-Resistance in Hep3B Cell Lines. Int J Mol Sci 2022; 23:ijms231911975. [PMID: 36233276 PMCID: PMC9569810 DOI: 10.3390/ijms231911975] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/16/2022] [Accepted: 09/25/2022] [Indexed: 11/09/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the second prominent cause of cancer-associated death worldwide. Usually, HCC is diagnosed in advanced stages, wherein sorafenib, a multiple target tyrosine kinase inhibitor, is used as the first line of treatment. Unfortunately, resistance to sorafenib is usually encountered within six months of treatment. Therefore, there is a critical need to identify the underlying reasons for drug resistance. In the present study, we investigated the proteomic and metabolomics alterations accompanying sorafenib resistance in hepatocellular carcinoma Hep3B cells by employing ultra-high-performance liquid chromatography quadrupole time of flight mass spectrometry (UHPLC-QTOF-MS). The Bruker Human Metabolome Database (HMDB) library was used to identify the differentially abundant metabolites through MetaboScape 4.0 software (Bruker). For protein annotation and identification, the Uniprot proteome for Homo sapiens (Human) database was utilized through MaxQuant. The results revealed that 27 metabolites and 18 proteins were significantly dysregulated due to sorafenib resistance in Hep3B cells compared to the parental phenotype. D-alanine, L-proline, o-tyrosine, succinic acid and phosphatidylcholine (PC, 16:0/16:0) were among the significantly altered metabolites. Ubiquitin carboxyl-terminal hydrolase isozyme L1, mitochondrial superoxide dismutase, UDP-glucose-6-dehydrogenase, sorbitol dehydrogenase and calpain small subunit 1 were among the significantly altered proteins. The findings revealed that resistant Hep3B cells demonstrated significant alterations in amino acid and nucleotide metabolic pathways, energy production pathways and other pathways related to cancer aggressiveness, such as migration, proliferation and drug-resistance. Joint pathway enrichment analysis unveiled unique pathways, including the antifolate resistance pathway and other important pathways that maintain cancer cells' survival, growth, and proliferation. Collectively, the results identified potential biomarkers for sorafenib-resistant HCC and gave insights into their role in chemotherapeutic drug resistance, cancer initiation, progression and aggressiveness, which may contribute to better prognosis and chemotherapeutic outcomes.
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11
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Garrido‐Cano I, Adam‐Artigues A, Lameirinhas A, Blandez JF, Candela‐Noguera V, Rojo F, Zazo S, Madoz‐Gúrpide J, Lluch A, Bermejo B, Sancenón F, Cejalvo JM, Martínez‐Máñez R, Eroles P. miR-99a-5p modulates doxorubicin resistance via the COX-2/ABCG2 axis in triple-negative breast cancer: from the discovery to in vivo studies. CANCER COMMUNICATIONS (LONDON, ENGLAND) 2022; 42:1412-1416. [PMID: 35997029 PMCID: PMC9759767 DOI: 10.1002/cac2.12352] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 06/14/2022] [Accepted: 08/05/2022] [Indexed: 01/25/2023]
Affiliation(s)
- Iris Garrido‐Cano
- Biomedical Research Institute INCLIVAValencia46010Spain,Bioengineering, Biomaterials and Nanomedicine Networking Biomedical Research Centre (CIBER‐BBN)Madrid28029Spain
| | | | | | - Juan F. Blandez
- Bioengineering, Biomaterials and Nanomedicine Networking Biomedical Research Centre (CIBER‐BBN)Madrid28029Spain,Interuniversity Research Institute for Molecular Recognition and Technological Development (IDM)Polytechnic University of ValenciaUniversity of ValenciaValencia46010Spain,Joint Unit CIPF‐UPV of Mechanisms of Diseases and Nanomedicine, ValenciaPolytechnic University of ValenciaPrince Felipe Research CenterValencia46012Spain,Joint Research Unit in Nanomedicine and SensorsPolytechnic University of ValenciaMedical Research Institute Hospital La FeValencia46026Spain
| | - Vicente Candela‐Noguera
- Interuniversity Research Institute for Molecular Recognition and Technological Development (IDM)Polytechnic University of ValenciaUniversity of ValenciaValencia46010Spain
| | - Federico Rojo
- Biomedical Research Networking Center in Oncology (CIBERONC)Madrid28029Spain,Department of PathologyFundación Jiménez Díaz University Hospital Health Research InstituteMadrid28040Spain
| | - Sandra Zazo
- Department of PathologyFundación Jiménez Díaz University Hospital Health Research InstituteMadrid28040Spain
| | - Juan Madoz‐Gúrpide
- Department of PathologyFundación Jiménez Díaz University Hospital Health Research InstituteMadrid28040Spain
| | - Ana Lluch
- Biomedical Research Institute INCLIVAValencia46010Spain,Biomedical Research Networking Center in Oncology (CIBERONC)Madrid28029Spain,Department of Clinical OncologyUniversity Clinical Hospital of ValenciaValencia46010Spain,Department of MedicineUniversity of ValenciaValencia46010Spain
| | - Begoña Bermejo
- Biomedical Research Institute INCLIVAValencia46010Spain,Biomedical Research Networking Center in Oncology (CIBERONC)Madrid28029Spain,Department of Clinical OncologyUniversity Clinical Hospital of ValenciaValencia46010Spain
| | - Felix Sancenón
- Bioengineering, Biomaterials and Nanomedicine Networking Biomedical Research Centre (CIBER‐BBN)Madrid28029Spain,Interuniversity Research Institute for Molecular Recognition and Technological Development (IDM)Polytechnic University of ValenciaUniversity of ValenciaValencia46010Spain,Joint Unit CIPF‐UPV of Mechanisms of Diseases and Nanomedicine, ValenciaPolytechnic University of ValenciaPrince Felipe Research CenterValencia46012Spain,Joint Research Unit in Nanomedicine and SensorsPolytechnic University of ValenciaMedical Research Institute Hospital La FeValencia46026Spain
| | - Juan Miguel Cejalvo
- Biomedical Research Institute INCLIVAValencia46010Spain,Biomedical Research Networking Center in Oncology (CIBERONC)Madrid28029Spain,Department of Clinical OncologyUniversity Clinical Hospital of ValenciaValencia46010Spain
| | - Ramón Martínez‐Máñez
- Bioengineering, Biomaterials and Nanomedicine Networking Biomedical Research Centre (CIBER‐BBN)Madrid28029Spain,Interuniversity Research Institute for Molecular Recognition and Technological Development (IDM)Polytechnic University of ValenciaUniversity of ValenciaValencia46010Spain,Joint Unit CIPF‐UPV of Mechanisms of Diseases and Nanomedicine, ValenciaPolytechnic University of ValenciaPrince Felipe Research CenterValencia46012Spain,Joint Research Unit in Nanomedicine and SensorsPolytechnic University of ValenciaMedical Research Institute Hospital La FeValencia46026Spain
| | - Pilar Eroles
- Biomedical Research Institute INCLIVAValencia46010Spain,Biomedical Research Networking Center in Oncology (CIBERONC)Madrid28029Spain,Department of PhysiologyUniversity of ValenciaValencia46010Spain
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12
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Sadri F, Hosseini SF, Aghayei A, Fereidouni M, Rezaei Z. The Tumor Suppressor Roles and Mechanisms of MiR-491 in Human Cancers. DNA Cell Biol 2022; 41:810-823. [PMID: 35914029 DOI: 10.1089/dna.2022.0274] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
MicroRNAs (miRNAs) are short non-coding RNAs that bind to the 3' untranslated region (3'' UTR) of target mRNAs to control gene expression post-transcriptionally. Recent indications have highlighted their important roles in a variety of pathophysiological conditions as well as human malignancies. Dysregulated miRNAs act as tumor suppressor genes or oncogenes in a variety of cancers. MiR-491 has been shown to have a major effect on tumorigenesis in multiple malignancies through binding to specific genes and signaling cascades, thereby preventing cancer progression. This review provides an overview of miR-491 expression in regulatory mechanisms and biological procedures of tumor cells, as well as the prospective possible treatment effects of various types of human cancers.
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Affiliation(s)
- Farzad Sadri
- Student Research Committee, Department of Molecular Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Seyede Fatemeh Hosseini
- Department of Nursing, Tabas School of Nursing, Birjand University of Medical Sciences, Birjand, Iran
| | - Atena Aghayei
- Department of Biology, Faculty of Science, Yazd University, Yazd, Iran
| | - Mohammad Fereidouni
- Department of Medical Immunology, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran.,Cellular and Molecular Research Center, Department of Immunology, Birjand University of Medical Sciences, Birjand, Iran
| | - Zohreh Rezaei
- Cellular and Molecular Research Center, Department of Immunology, Birjand University of Medical Sciences, Birjand, Iran.,Department of Biology, University of Sistan and Baluchestan, Zahedan, Iran
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13
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Wang G, Lin X, Han H, Zhang H, Li X, Feng M, Jiang C. lncRNA H19 promotes glioblastoma multiforme development by activating autophagy by sponging miR-491-5p. Bioengineered 2022; 13:11440-11455. [PMID: 35506168 PMCID: PMC9275997 DOI: 10.1080/21655979.2022.2065947] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 04/01/2022] [Accepted: 04/06/2022] [Indexed: 12/20/2022] Open
Abstract
Glioblastoma multiforme (GBM) is a malignant cancer with severely poor survival, and the cells continue to thrive during hypoxia and toxic stress through autophagy. To validate the oncogenic role of long noncoding RNA H19 in GBM progression and examine whether autophagy and/or miR-491-5p participate in the process. The expression of H19 and autophagy-related genes in GBM and healthy control tissues was assessed via quantitative polymerase chain reaction. In addition, cell viability, proliferation, apoptosis and autophagy were respectively determined via cell counting kit-8 assay, clone formation assay, flow cytometry, western blotting and green fluorescent protein-microtubule-associated protein 1 light chain 3 alpha fluorescence analysis in vitro. Furthermore, a rescue assay was performed using rapamycin or miR-491-5p antagomir to examine the role of autophagy or miR-491-5p in H19-mediated regulation of proliferation and apoptosis. RNA pull-down and dual-luciferase reporter assays were employed to analyze the interaction between H19 and miR-491-5p. Additionally, tumor growth in a xenograft-bearing mouse model and autophagy in tumor mass were analyzed in vivo. The expression H19 was increased in GBM and was positively correlated with LC3 or Beclin-1. Silencing H19 inhibited growth and promoted apoptosis in GBM cells both in vitro and in vivo, and miR-491-5p was identified as one of the important mediators. H19 regulated the autophagy signaling pathway at least partly via miR-491-5p. Increased H19 expression in GBM exerts oncogenic effects by sponging miR-491-5p and enhancing autophagy. Therefore, H19 may be explored as a target for GBM therapy.
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Affiliation(s)
- Guo Wang
- Department of Pediatrics, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
- Department of Pediatrics, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou Zhejiang, P.R. China
| | - Xiaoyan Lin
- Department of Pediatrics, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
- Department of Pediatrics, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou Zhejiang, P.R. China
| | - Han Han
- Department of Pediatrics, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
- Department of Pediatrics, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou Zhejiang, P.R. China
| | - Hongxu Zhang
- Department of Ophthalmology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
- Department of Ophthalmology, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou Zhejiang, P.R. China
| | - Xiaoli Li
- Department of Pediatrics, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
- Department of Pediatrics, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou Zhejiang, P.R. China
| | - Mei Feng
- Department of Pediatrics, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
- Department of Pediatrics, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou Zhejiang, P.R. China
| | - Chunming Jiang
- Department of Pediatrics, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
- Department of Pediatrics, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou Zhejiang, P.R. China
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14
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Bazzoni R, Tanasi I, Turazzi N, Krampera M. Update on the role and utility of extracellular vesicles in hematological malignancies. Stem Cells 2022; 40:619-629. [PMID: 35442447 DOI: 10.1093/stmcls/sxac032] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 04/12/2022] [Indexed: 11/12/2022]
Abstract
Extracellular vesicles (EVs) are membrane-surrounded cellular particles released by virtually any cell type, containing numerous bioactive molecules, including lipids, proteins, and nucleic acids. EVs act as a very efficient intercellular communication system by releasing their content into target cells, thus affecting their fate and influencing several biological processes. EVs are released both in physiological and pathological conditions, including several types of cancers. In hematological malignancies (HM), EVs have emerged as new critical players, contributing to tumor-to-stroma, stroma-to-tumor, and tumor-to-tumor cell communication. Therefore, EVs have been shown to play a crucial role in the pathogenesis and clinical course of several HM, contributing to tumor development, progression, and drug resistance. Furthermore, tumor EVs can reprogram the bone marrow (BM) microenvironment and turn it into a sanctuary, in which cancer cells suppress both the normal hematopoiesis and the immunological anti-tumor activity, conferring a therapy-resistant phenotype. Due to their physicochemical characteristics and pro-tumor properties, EVs have been suggested as new diagnostic biomarkers, therapeutic targets, and pharmacological nanocarriers. This review aims to provide an update on the pathogenetic contribution and the putative therapeutic utility of EVs in hematological diseases.
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Affiliation(s)
- Riccardo Bazzoni
- Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, P. le Scuro 10, 37134 Verona, Italy
| | - Ilaria Tanasi
- Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, P. le Scuro 10, 37134 Verona, Italy
| | - Nice Turazzi
- Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, P. le Scuro 10, 37134 Verona, Italy
| | - Mauro Krampera
- Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, P. le Scuro 10, 37134 Verona, Italy
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15
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Wang X, He R, Geng L, Yuan J, Fan H. Ginsenoside Rg3 Alleviates Cisplatin Resistance of Gastric Cancer Cells Through Inhibiting SOX2 and the PI3K/Akt/mTOR Signaling Axis by Up-Regulating miR-429. Front Genet 2022; 13:823182. [PMID: 35309116 PMCID: PMC8927288 DOI: 10.3389/fgene.2022.823182] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 01/26/2022] [Indexed: 12/11/2022] Open
Abstract
Platinum-based cytotoxic chemotherapy is considered the standard treatment for advanced gastric cancer (GC). However, cisplatin chemoresistance often occurs with the mechanisms being not well clarified, which results in the cancer recurrence and poor survival. Ginsenoside Rg3, isolated from the Chinese Herb Panax Ginseng, is recognized as an anti-cancer agent. Herein, we aimed to reveal whether Ginsenoside Rg3 alleviates cisplatin resistance and sensitizes GC cells to cisplatin-induced apoptosis, and draw out the underlying molecular mechanism in cisplatin-resistant GC cells. The lower expression of miR-429 was found in AGSR-CDDP cells; it was also in association with cisplatin-resistance in GC cells and expression of which was restored following Ginsenoside Rg3 treatment. We also demonstrated that miR-429 made a contribution toward chemosensitivity in GC cells partly through SOX2 regulation. SOX2 was found to contribute to developing platinum resistance and was an authentic target for miR-429 in AGSR-CDDP cells. Importantly, enforced expression of SOX2 with a pcDNA3-SOX2 construct lacking the 3′-UTR miRNA binding site diminished the cytotoxic effects of miR-429 in AGSR-CDDP cells. We demonstrated that Ginsenoside Rg3 enhanced chemosensitivity in AGSR-CDDP GC cells, at least in part, through up-regulating miR-429, thereby targeting SOX2 and modulating downstream PI3K/AKT/mTOR signaling. Ginsenoside Rg3 was also found to regulate apoptosis-related genes via miR-429 in cisplatin-resistant GC cells. Ginsenoside Rg3 treatment significantly suppressed the migration rate of AGSR-CDDP GC cells, while following transfection with anti-miR-429, the anti-migratory effects of Ginsenoside Rg3 was partially abolished. This data suggested that Ginsenoside Rg3 may impede the chemoresistance and migration of GC cells mainly mediated through miR-429. We concluded that miR-429-regulated SOX2 expression was one of the main mechanisms by which Ginsenoside Rg3 dramatically promoted its anticancer effects on cisplatin-resistant GC cells. We also underscored a supporting model in which miR-429 adjusted PI3K/AKT/mTOR signaling by regulating SOX2 in cisplatin-resistant GC cells.
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16
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Yue Y, Lin X, Qiu X, Yang L, Wang R. The Molecular Roles and Clinical Implications of Non-Coding RNAs in Gastric Cancer. Front Cell Dev Biol 2021; 9:802745. [PMID: 34966746 PMCID: PMC8711095 DOI: 10.3389/fcell.2021.802745] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 11/29/2021] [Indexed: 01/19/2023] Open
Abstract
Gastric cancer (GC) is one of the most common malignancies in the world. It is also the fifth most common cancer in China. In recent years, a large number of studies have proved that non-coding RNAs (ncRNAs) can regulate cell proliferation, invasion, metastasis, apoptosis, and angiogenesis. NcRNAs also influence the therapeutic resistance of gastric cancer. NcRNAs mainly consist of miRNAs, lncRNAs and circRNAs. In this paper, we summarized ncRNAs as biomarkers and therapeutic targets for gastric cancer, and also reviewed their role in clinical trials and diagnosis. We sum up different ncRNAs and related moleculars and signaling pathway in gastric cancer, like Bcl-2, PTEN, Wnt signaling. In addition, the potential clinical application of ncRNAs in overcoming chemotherapy and radiotherapy resistance in GC in the future were also focused on.
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Affiliation(s)
- Yanping Yue
- Department of Medical Oncology, Affiliated Cancer Hospital, Nantong University, Nantong, China
| | - Xinrong Lin
- Department of Medical Oncology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Xinyue Qiu
- Department of Medical Oncology, Affiliated Cancer Hospital, Nantong University, Nantong, China
| | - Lei Yang
- Department of Medical Oncology, Affiliated Cancer Hospital, Nantong University, Nantong, China
| | - Rui Wang
- Department of Medical Oncology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China
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17
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Liu Y, Ao X, Ji G, Zhang Y, Yu W, Wang J. Mechanisms of Action And Clinical Implications of MicroRNAs in the Drug Resistance of Gastric Cancer. Front Oncol 2021; 11:768918. [PMID: 34912714 PMCID: PMC8667691 DOI: 10.3389/fonc.2021.768918] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/15/2021] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignant tumors of digestive systems worldwide, with high recurrence and mortality. Chemotherapy is still the standard treatment option for GC and can effectively improve the survival and life quality of GC patients. However, with the emergence of drug resistance, the clinical application of chemotherapeutic agents has been seriously restricted in GC patients. Although the mechanisms of drug resistance have been broadly investigated, they are still largely unknown. MicroRNAs (miRNAs) are a large group of small non-coding RNAs (ncRNAs) widely involved in the occurrence and progression of many cancer types, including GC. An increasing amount of evidence suggests that miRNAs may play crucial roles in the development of drug resistance by regulating some drug resistance-related proteins as well as gene expression. Some also exhibit great potential as novel biomarkers for predicting drug response to chemotherapy and therapeutic targets for GC patients. In this review, we systematically summarize recent advances in miRNAs and focus on their molecular mechanisms in the development of drug resistance in GC progression. We also highlight the potential of drug resistance-related miRNAs as biomarkers and therapeutic targets for GC patients.
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Affiliation(s)
- Ying Liu
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China.,School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Xiang Ao
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Guoqiang Ji
- Clinical Laboratory, Linqu People's Hospital, Linqu, China
| | - Yuan Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Wanpeng Yu
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Jianxun Wang
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
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18
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Jin L, Ma X, Zhang N, Zhang Q, Chen X, Zhang Z, Ding G, Yu H. Targeting Oncogenic miR-181a-2-3p Inhibits Growth and Suppresses Cisplatin Resistance of Gastric Cancer. Cancer Manag Res 2021; 13:8599-8609. [PMID: 34815714 PMCID: PMC8605795 DOI: 10.2147/cmar.s332713] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 10/17/2021] [Indexed: 12/12/2022] Open
Abstract
Purpose This study aimed to explore the value of miR-181a-2-3p in cisplatin (DDP) treatment effectiveness prediction, and to reveal the function underlying the reversal of DDP resistance in patients with gastric cancer (GC). Methods miRNA expression dataset of three DDP-resistant GC cell lines and their DDP-sensitive parental cell lines obtained from GEO DataSets and GenBank, and functional miRNAs were annotated by bioinformatics analyses. Serum specimens and tumor samples were collected from 91 GC patients for understanding of the interrelation between chemotherapy response and miRNA expression. RT-qPCR validated these miRNAs at the transcriptional level in both gastric cancer cells and 91 gastric cancer patients. The correlation between the miRNAs expression and clinical parameters of the patients were analyzed. Receiver operating characteristics (ROC) analysis has been utilized to assess the diagnostic performance. The MTT and colony formation assays were performed to assess cell proliferation. Flow cytometry was conducted to detect cell apoptosis. DDP-resistant GC cells and their DDP-sensitive parental cells were transfected with miRNA mimic or inhibitor vector to overexpress or downregulate miRNA expression. Results miR-181a-2-3p as a unique miRNA was found in the common differentially expressed-miRNAs (DE-miRNAs) after miRNA screening and validation from three DDP-resistant and DDP-sensitive gastric cancer cell lines. Clinical data analysis displayed that miR-181a-2-3p expression was apparently increased in larger tumor size (≥5 cm), higher T stage (T4), and chemotherapy resistance. miR-181a-2-3p (AUC=0.926, SE=0.028, 95% CI: 0.872-0.980, p< 0.0001) differentiated chemosensitive GC patients from chemoresistant GC patients. miR-181a-2-3p presented a higher level in gastric cancer, and could serve as a valid biomarker to predict the overall survival of GC patients. Upregulation of miR-181a-2-3p rendered the apoptosis-inducing and anti-proliferative effects of DDP, while downregulating it decreased these effects. Conclusion miR-181a-2-3p can function as a therapeutic target and a tumor biomarker. Targeting oncogenic miR-181a-2-3p inhibits growth and suppresses cisplatin resistance of gastric cancer.
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Affiliation(s)
- Lei Jin
- Department of Vascular Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Xuemei Ma
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Nan Zhang
- Department of Radiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, People's Republic of China
| | - Qian Zhang
- Clinical Epidemiology and EBM Center, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Xueming Chen
- Department of Vascular Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Zhongtao Zhang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Guoqian Ding
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Hongzhi Yu
- Department of Vascular Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China
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Chen D, Ping S, Xu Y, Wang M, Jiang X, Xiong L, Zhang L, Yu H, Xiong Z. Non-Coding RNAs in Gastric Cancer: From Malignant Hallmarks to Clinical Applications. Front Cell Dev Biol 2021; 9:732036. [PMID: 34805143 PMCID: PMC8595133 DOI: 10.3389/fcell.2021.732036] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 10/18/2021] [Indexed: 01/19/2023] Open
Abstract
Gastric cancer (GC) is one of the most lethal malignancies worldwide. However, the molecular mechanisms underlying gastric carcinogenesis remain largely unknown. Over the past decades, advances in RNA-sequencing techniques have greatly facilitated the identification of various non-coding RNAs (ncRNAs) in cancer cells, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Accumulating evidence has revealed that ncRNAs are essential regulators in GC occurrence and development. However, ncRNAs represent an emerging field of cancer research, and their complex functionality remains to be clarified. Considering the lack of viable biomarkers and therapeutic targets in GC, further studies should focus on elucidating the intricate relationships between ncRNAs and GC, which can be translated into clinical practice. In this review, we summarize recent research progress on how ncRNAs modulate the malignant hallmarks of GC, especially in tumor immune escape, drug resistance, and stemness. We also discuss the promising applications of ncRNAs as diagnostic biomarkers and therapeutic targets in GC, aiming to validate their practical value for clinical treatment.
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Affiliation(s)
- Di Chen
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuai Ping
- Department of Orthopaedics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yushuang Xu
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengmeng Wang
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xin Jiang
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lina Xiong
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Li Zhang
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Honglu Yu
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhifan Xiong
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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20
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Mao Q, Zhuang Q, Shen J, Chen Z, Xue D, Ding T, He X. MiRNA-124 regulates the sensitivity of renal cancer cells to cisplatin-induced necroptosis by targeting the CAPN4-CNOT3 axis. Transl Androl Urol 2021; 10:3669-3683. [PMID: 34733662 PMCID: PMC8511534 DOI: 10.21037/tau-21-777] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 09/18/2021] [Indexed: 12/22/2022] Open
Abstract
Background Currently, drug-resistance is a major challenge in the treatment of renal cancer. Although microRNAs (miRNAs) have been reported to contribute to the incidence of drug resistance in renal cancer, the bio-functional roles and underlying regulatory mechanisms of novel miRNAs in cisplatin resistance remain largely unclear. Methods In this study, miRNA microarray analysis was applied to evaluate miRNA changes induced by cisplatin on RCC (renal cell carcinoma) cell lines. Then, Caki-1 and 786-0 cells were transfected with miR (miRNA)-124 mimics to observe cisplatin resistance in RCC cell lines after up-regulation of miR-124. TargetScan was used to identify putative protein-coding gene targets of miR-124. Further, the interaction between calpain small subunit 1 (Capn4) and CCR4-NOT transcription complex subunit 3 (CNOT3) was detected by quantitative real-time PCR (qPCR) and western blotting, and confirmed by co-immunoprecipitation. The effect of Capn4 and/or CNOT3 on cell viability and half maximal inhibitory concentration (IC50) value of miR-124 overexpressed Caki-1 and 786-O cells to cisplatin was evaluated using the Cell Counting Kit-8 (CCK-8) assay. And the effect of Capn4 and/or CNOT3 on the level of necroptosis in miR-124 overexpressed Caki-1 and 786-O cells to cisplatin was evaluated by flow cytometric analysis. Then, four groups of 786-0 cells (miR-124, miR-124+ Capn4, miR-124+ CNOT3, miR-124+ Capn4+ CNOT3) were inoculated into nude mice to observe the effect of cisplatin on tumor formation. Results miR-124 was found to be markedly elevated in renal cancer cells by cisplatin. Functionally, the overexpression of miR-124 reduced the sensitivity of renal cancer cells to cisplatin and CAPN4 was found to be a direct target of miR-124, which can negatively regulated CAPN4 expression. Moreover, ectopic expression of CAPN4 reversed the impairment of miR-124 on cisplatin-sensitivity and cisplatin-induced necroptosis. Mechanically, the present study revealed that CAPN4 could directly interact with CNOT3 and promote its degradation, and that the cisplatin-resistant phenotype was reversed by up-regulation of CNOT3. Conclusions Therefore, miR-124 is an important inhibitor in cisplatin-induced necroptosis, and the miR-124-CAPN4-CNOT3 signaling axis plays a critical role in the emergence of cisplatin-resistance.
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Affiliation(s)
- Qingyan Mao
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Qianfeng Zhuang
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Jie Shen
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Zhen Chen
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Dong Xue
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Tao Ding
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Xiaozhou He
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
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21
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Liu X, Ma R, Yi B, Riker AI, Xi Y. MicroRNAs are involved in the development and progression of gastric cancer. Acta Pharmacol Sin 2021; 42:1018-1026. [PMID: 33037405 PMCID: PMC8208993 DOI: 10.1038/s41401-020-00540-0] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 09/14/2020] [Indexed: 02/08/2023]
Abstract
MicroRNAs (miRNAs) are recognized as an essential component of the RNA family, exerting multiple and intricate biological functions, particularly in the process of tumorigenesis, proliferation, and metastatic progression. MiRNAs are altered in gastric cancer (GC), showing activity as both tumor suppressors and oncogenes, although their true roles have not been fully understood. This review will focus upon the recent advances of miRNA studies related to the regulatory mechanisms of gastric tumor cell proliferation, apoptosis, and cell cycle. We hope to provide an in-depth insight into the mechanistic role of miRNAs in GC development and progression. In particular, we summarize the latest studies relevant to miRNAs' impact upon the epithelial-mesenchymal transition, tumor microenvironment, and chemoresistance in GC cells. We expect to elucidate the molecular mechanisms involving miRNAs for better understanding the etiology of GC, and facilitating the development of new treatment regimens for the treatment of GC.
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Affiliation(s)
- Xiaolin Liu
- Department of Genetics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Department of Oncology, the First Affiliated Hospital of Shandong First Medical University, Jinan, 250014, China
| | - Ruixia Ma
- Department of Genetics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, 221000, China
| | - Bin Yi
- Department of Genetics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Adam I Riker
- Geaton and JoAnn DeCesaris Cancer Institute, Department of Surgery, Anne Arundel Medical Center, Cancer Service Line, Luminis Health, Annapolis, MD, USA.
| | - Yaguang Xi
- Department of Genetics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
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22
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Li H, Xu W, Liu X, Wang T, Wang S, Liu J, Jiang H. JAK2 deficiency improves erectile function in diabetic mice through attenuation of oxidative stress, apoptosis, and fibrosis. Andrology 2021; 9:1662-1671. [PMID: 34085398 PMCID: PMC8672361 DOI: 10.1111/andr.13061] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 05/11/2021] [Accepted: 05/31/2021] [Indexed: 12/13/2022]
Abstract
Background Janus kinase 2 (JAK2) is activated in diabetic mellitus (DM) conditions and may enhance oxidative stress, apoptosis and fibrosis in many tissues. Whether JAK2 activation is involved in the occurrence of diabetic erectile dysfunction (ED) is unknown. Objectives We performed this study to investigate the effect of JAK2 deficiency on diabetic ED. Materials and methods Conditional JAK2 gene knockout mice (Cre+/+‐JAK2fl/fl) were used, in which JAK2 gene knockout could be induced by tamoxifen. Mice fell into four groups: control, JAK2 knockout (JAK2−/−), DM, and DM with JAK2−/−. DM was induced by intraperitoneal injection of streptozotocin. Two months later, JAK2 gene knockout was induced with tamoxifen in Cre+/+‐JAK2fl/fl mice. After another 2 months, erectile function was measured by electrical stimulation of the cavernous nerve, and penile tissues were harvested. Ratio of maximal intracavernosal pressure (MIP) to mean arterial blood pressure (MAP), expression and phosphorylation of JAK2, oxidative stress level, NO/Cyclic Guanosine Monophosphate (cGMP) pathway, apoptosis, fibrosis, and transforming growth factor beta 1 (TGF‐β1)/Smad/Collagen IV pathway in corpus cavernosum, were measured. Results JAK2 expression was remarkably decreased after induction with tamoxifen. JAK2 was activated in penile tissues of diabetic mice, and JAK2 deficiency could improve the impaired erectile function caused by DM. However, in mice without DM, JAK2 deficiency had no apparent influence on erectile function. Levels of oxidative stress, apoptosis, fibrosis, and TGF‐β1/Smad/Collagen IV pathway were all elevated by DM, whereas JAK2 deficiency lessened these alterations in diabetic mice. Moreover, JAK2 deficiency improved the expression of the down‐regulated NO/cGMP pathway in diabetic mice. In non‐diabetic mice, no apparent changes were found in aforementioned parameters after JAK2 gene knockout. Discussion and conclusion Our study showed that JAK2 deficiency could improve erectile function in diabetic mice, which might be mediated by reduction in oxidative stress, apoptosis, and fibrosis in corpus cavernosum.
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Affiliation(s)
- Hao Li
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenchao Xu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaming Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shaogang Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jihong Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongyang Jiang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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23
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Gallardo Martin E, Cousillas Castiñeiras A. Vitamin D modulation and microRNAs in gastric cancer: prognostic and therapeutic role. Transl Cancer Res 2021; 10:3111-3127. [PMID: 35116620 PMCID: PMC8797897 DOI: 10.21037/tcr-20-2813] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 10/10/2020] [Indexed: 12/11/2022]
Abstract
Gastric adenocarcinoma arises after a complex interaction between the host and environmental factors. Tumor location and TNM are the tools that currently guide treatment decisions. Surgery is the only curative treatment, but relapse is common. After relapse or advanced staged disease survival is poor and systemic treatment has modestly improved survival. An association between sun exposure, vitamin D status and gastric cancer (GC) incidence and mortality has been reported. The molecular differences of the histological subtypes and the new molecular classifications account for the great heterogeneity of this disease and are the basis for the discovery of new therapeutic targets. New prognostic and predictive factors are essential and microRNAs (miRNAs) are endogenous small non-coding RNA molecules with a great potential for diagnosis, prognosis and treatment of cancer. There are hundreds of miRNAs with altered expression in tumor gastric tissue when compared to normal gastric tissue. Many of these miRNAs are associated with clinicopathological variables and survival in patients with GC. Furthermore, the expression of some of these miRNAs with prognostic importance in CG is influenced by vitamin D and others are mediators of some of the actions of this vitamin. This review aims to update the evidence on several miRNAs with prognostic value and therapeutic potential in GC, whose expression may be influenced by vitamin D or may regulate vitamin D signaling.
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Affiliation(s)
- Elena Gallardo Martin
- Medical Oncology Department in Complejo Hospitalario Universitario de Pontevedra, University Hospital of Pontevedra, CP 36001 Pontevedra, Spain
| | - Antia Cousillas Castiñeiras
- Medical Oncology Department in Complejo Hospitalario Universitario de Pontevedra, University Hospital of Pontevedra, CP 36001 Pontevedra, Spain
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24
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Zhou E, Li Y, Wu F, Guo M, Xu J, Wang S, Tan Q, Ma P, Song S, Jin Y. Circulating extracellular vesicles are effective biomarkers for predicting response to cancer therapy. EBioMedicine 2021; 67:103365. [PMID: 33971402 PMCID: PMC8121992 DOI: 10.1016/j.ebiom.2021.103365] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 03/28/2021] [Accepted: 04/14/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer remains one of the most challenging diseases, as many patients show limited therapeutic response to treatment. Liquid biopsy is a minimally invasive method that has the advantage of providing real-time disease information with the least damage to cancer patients. Extracellular vesicles (EVs) released by the parental cells and protected by lipid bilayer membrane structure represent an emerging liquid biopsy modality. Apart from promoting cell growth, proliferation, and migration, EVs and their cargos (mainly miRNAs and proteins) are also biomarkers for cancer diagnosis and prognosis. Furthermore, their alterations pre- and post-therapy can guide therapeutic strategy determinations for better-stratified therapy. In this review, we summarize the potential clinical significance of EVs and their cargos in therapeutic response monitoring and prediction in several cancers (mainly lung cancer, prostate cancer, breast cancer, melanoma, lymphoma, glioblastoma, and head and neck squamous cell carcinoma) and discuss the questions that require future investigation.
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Affiliation(s)
- E Zhou
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei 430022, P.R. China
| | - Yumei Li
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei 430022, P.R. China
| | - Feng Wu
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei 430022, P.R. China
| | - Mengfei Guo
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei 430022, P.R. China
| | - Juanjuan Xu
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei 430022, P.R. China
| | - Sufei Wang
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei 430022, P.R. China
| | - Qi Tan
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei 430022, P.R. China
| | - Pei Ma
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei 430022, P.R. China
| | - Siwei Song
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei 430022, P.R. China
| | - Yang Jin
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei 430022, P.R. China.
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25
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Taheri M, Shoorei H, Tondro Anamag F, Ghafouri-Fard S, Dinger ME. LncRNAs and miRNAs participate in determination of sensitivity of cancer cells to cisplatin. Exp Mol Pathol 2021; 123:104602. [PMID: 33422487 DOI: 10.1016/j.yexmp.2021.104602] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 12/27/2020] [Accepted: 12/31/2020] [Indexed: 02/08/2023]
Abstract
Cisplatin is an extensively used chemotherapeutic substance for various types of human malignancies including sarcomas, carcinomas and lymphomas. Yet, the vast application of this drug is hampered by the emergence of chemoresistance in some treated patients. Several mechanisms such as degradation of the membrane transporters by cisplatin have been implicated in the pathogenesis of this event. Recent researches have also indicated the role of long non-coding RNAs (lncRNAs) as well as micoRNAs (miRNAs) in the emergence of resistance to cisplatin in several cancer types. For instance, up-regulation of miR-21 has been associated with resistance to this agent in ovarian cancer, oral squamous cell cancer, gastric malignancy and non-small cell lung cancer (NSCLC). On the other hand, down-regulation of miR-218 has been implicated in emergence of chemoresistance in breast cancer and esophageal squamous cell carcinoma. MALAT1 is implicated in the chemoresistance of bladder cancer cells, NSCLC, gastric cancer and cervical cancer. Most notably, the expression profile of resistance-associated miRNAs and lncRNAs can predict overall survival of cancer patients. Mechanistic assays have revealed that interference with expression of some miRNAs and lncRNAs can reverse the resistance phenotype in cancer cells. In this paper, we review the scientific writings on the role of lncRNAs and miRNAs in the evolution of chemoresistance to cisplatin in cancer cells.
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Affiliation(s)
- Mohammad Taheri
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Shoorei
- Department of Anatomical Sciences, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | | | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Marcel E Dinger
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
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Non-coding RNAs underlying chemoresistance in gastric cancer. Cell Oncol (Dordr) 2020; 43:961-988. [PMID: 32495294 DOI: 10.1007/s13402-020-00528-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 04/17/2020] [Accepted: 04/24/2020] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Gastric cancer (GC) is a major health issue in the Western world. Current clinical imperatives for this disease include the identification of more effective biomarkers to detect GC at early stages and enhance the prevention and treatment of metastatic and chemoresistant GC. The advent of non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs) and long-non coding RNAs (lncRNAs), has led to a better understanding of the mechanisms by which GC cells acquire features of therapy resistance. ncRNAs play critical roles in normal physiology, but their dysregulation has been detected in a variety of cancers, including GC. A subset of ncRNAs is GC-specific, implying their potential application as biomarkers and/or therapeutic targets. Hence, evaluating the specific functions of ncRNAs will help to expand novel treatment options for GC. CONCLUSIONS In this review, we summarize some of the well-known ncRNAs that play a role in the development and progression of GC. We also review the application of such ncRNAs in clinical diagnostics and trials as potential biomarkers. Obviously, a deeper understanding of the biology and function of ncRNAs underlying chemoresistance can broaden horizons toward the development of personalized therapy against GC.
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27
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Eniafe J, Jiang S. MicroRNA-99 family in cancer and immunity. WILEY INTERDISCIPLINARY REVIEWS-RNA 2020; 12:e1635. [PMID: 33230974 DOI: 10.1002/wrna.1635] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 11/02/2020] [Accepted: 11/04/2020] [Indexed: 12/19/2022]
Abstract
The microRNA (miR)-99 family comprising miR-99a, miR-99b, and miR-100 is an evolutionarily conserved family with existence dating prior to the bilaterians. Members are typically oncogenic in leukemia while their functional roles in other cancers alternate between that of a tumor suppressor and a tumor promoter. Targets of the miR-99 family rank in the lists of oncogenes and tumor suppressors, thereby illustrating the dual role of this miR family as oncogenic miRs (oncomiRs) and tumor suppressing miRs (TSmiRs) in different cellular contexts. In addition to their functional roles in cancers, miR-99 family is implicated in the modulation of macrophage inflammatory responses and T-cell subsets biology, thereby exerting critical roles in the maintenance of tissue homeostasis, establishment of peripheral tolerance as well as resolution of an inflammatory reaction. Here, we review emerging knowledge of this miR family and discuss remaining concerns linked to their activities. A better dissection of the functional roles of miR-99 family members in cancer and immunity will help in the development of novel miR-99-based therapeutics for the treatment of human cancer and immune-related diseases. This article is categorized under: RNA in Disease and Development > RNA in Disease.
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Affiliation(s)
- Joseph Eniafe
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA
| | - Shuai Jiang
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA
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28
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Sun G, Li Z, He Z, Wang W, Wang S, Zhang X, Cao J, Xu P, Wang H, Huang X, Xia Y, Lv J, Xuan Z, Jiang T, Fang L, Yang J, Zhang D, Xu H, Xu Z. Circular RNA MCTP2 inhibits cisplatin resistance in gastric cancer by miR-99a-5p-mediated induction of MTMR3 expression. J Exp Clin Cancer Res 2020; 39:246. [PMID: 33198772 PMCID: PMC7670601 DOI: 10.1186/s13046-020-01758-w] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 11/01/2020] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Cisplatin (CDDP) is the first-line chemotherapy for gastric cancer (GC). The poor prognosis of GC patients is partially due to the development of CDDP resistance. Circular RNAs (circRNAs) are a subclass of noncoding RNAs that function as microRNA (miRNA) sponges. The role of circRNAs in CDDP resistance in GC has not been evaluated. METHODS RNA sequencing was used to identify the differentially expressed circRNAs between CDDP-resistant and CDDP-sensitive GC cells. qRT-PCR was used to detect the expression of circMCTP2 in GC tissues. The effects of circMCTP2 on CDDP resistance were investigated in vitro and in vivo. Pull-down assays and luciferase reporter assays were performed to confirm the interactions among circMCTP2, miR-99a-5p, and myotubularin-related protein 3 (MTMR3). The protein expression levels of MTMR3 were detected by western blotting. Autophagy was evaluated by confocal microscopy and transmission electron microscopy (TEM). RESULTS CircMCTP2 was downregulated in CDDP-resistant GC cells and tissues compared to CDDP-sensitive GC cells and tissues. A high level of circMCTP2 was found to be a favorable factor for the prognosis of patients with GC. CircMCTP2 inhibited proliferation while promoting apoptosis of CDDP-resistant GC cells in response to CDDP treatment. CircMCTP2 was also found to reduce autophagy in CDDP-resistant GC cells. MiR-99a-5p was verified to be sponged by circMCTP2. Inhibition of miR-99a-5p could sensitize GC cells to CDDP. MTMR3 was confirmed to be a direct target of miR-99a-5p. Knockdown of MTMR3 reversed the effects of circMCTP2 on the proliferation, apoptosis and autophagy of CDDP-resistant GC cells. CircMCTP2 was also confirmed to inhibit CDDP resistance in vivo in a nude mouse xenograft model. CONCLUSIONS CircMCTP2 sensitizes GC to CDDP through the upregulation of MTMR3 by sponging miR-99a-5p. Overexpression of CircMCTP2 could be a new therapeutic strategy for counteracting CDDP resistance in GC.
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Affiliation(s)
- Guangli Sun
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, China
| | - Zheng Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, China
| | - Zhongyuan He
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, China
| | - Weizhi Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, China
| | - Sen Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, China
| | - Xing Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, China
| | - Jiacheng Cao
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, China
| | - Penghui Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, China
| | - Haixiao Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, China
| | - Xiaoxu Huang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, China
| | - Yiwen Xia
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, China
| | - Jialun Lv
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, China
| | - Zhe Xuan
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, China
| | - Tianlu Jiang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, China
| | - Lang Fang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, China
| | - Jing Yang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, China
| | - Diancai Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, China
| | - Hao Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, China
| | - Zekuan Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, China.
- Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu province, China.
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Wang R, Lu X, Yu R. lncRNA MALAT1 Promotes EMT Process and Cisplatin Resistance of Oral Squamous Cell Carcinoma via PI3K/AKT/m-TOR Signal Pathway. Onco Targets Ther 2020; 13:4049-4061. [PMID: 32494159 PMCID: PMC7231756 DOI: 10.2147/ott.s251518] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 04/22/2020] [Indexed: 11/29/2022] Open
Abstract
Background Cisplatin (DDP) is the first-line chemotherapy agent for the treatment of oral squamous cell carcinoma (OSCC). The emergence of DDP resistance leads to diminished drug efficacy and survival benefit. lncRNA MALAT1 has been considered as one of the most important factors in OSCC. It has also been reported to enhance chemo-resistance in other kinds of carcinomas. However, little is known about the role of lncRNA MALAT1 in DDP resistance of OSCC. Materials and Methods Two kinds of human DDP-resistant cell lines (CAL-27R and SCC-9R) were developed from cisplatin-naïve cell lines (CAL-27 and SCC-9, respectively) as in vitro cell models. Cell transfection was performed to overexpress or knockdown MALAT1 in these cells. Mouse xenograft models were also established. The following measurements were performed: cell proliferation, colony formation, wound healing, transwell, and TUNEL assays, as well as Western blot and immunofluorescence staining. Results DDP-resistant cells showed higher expression level of MALAT1 compared to cisplatin-naïve cells. The overexpression of MALAT1 in cisplatin-naïve cells enhanced DDP resistance and suppressed apoptosis in OSCC cells. However, the knockdown of MALAT1 in DDP-resistance cells induced apoptotic cell death and restored the sensitivity to DDP. Further analyses suggested that MALAT1 might promote DDP resistance via regulating P-glycoprotein expression, epithelial–mesenchymal transition process, and the activation of PI3K/AKT/m-TOR signaling pathway. Conclusion MALAT1 might be a potential therapeutic target for the treatment of DDP-resistant OSCC.
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Affiliation(s)
- Ran Wang
- Department of Stomatology, Beijing Shijitan Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Xinxing Lu
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Riyue Yu
- Department of Stomatology, Beijing Shijitan Hospital, Capital Medical University, Beijing, People's Republic of China
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30
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Ahadi A. Dysregulation of miRNAs as a signature for diagnosis and prognosis of gastric cancer and their involvement in the mechanism underlying gastric carcinogenesis and progression. IUBMB Life 2020; 72:884-898. [DOI: 10.1002/iub.2259] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Accepted: 02/08/2020] [Indexed: 02/06/2023]
Affiliation(s)
- Alireza Ahadi
- Department of Medical Genetics, School of MedicineShahid Beheshti University of Medical Sciences Tehran Iran
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Kazmierczak D, Jopek K, Sterzynska K, Ginter-Matuszewska B, Nowicki M, Rucinski M, Januchowski R. The Significance of MicroRNAs Expression in Regulation of Extracellular Matrix and Other Drug Resistant Genes in Drug Resistant Ovarian Cancer Cell Lines. Int J Mol Sci 2020; 21:ijms21072619. [PMID: 32283808 PMCID: PMC7177408 DOI: 10.3390/ijms21072619] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 04/02/2020] [Accepted: 04/07/2020] [Indexed: 12/11/2022] Open
Abstract
Ovarian cancer rates the highest mortality among all gynecological malignancies. The main reason for high mortality is the development of drug resistance. It can be related to increased expression of drug transporters and increased expression of extracellular matrix (ECM) proteins. Our foremost aim was to exhibit alterations in the miRNA expression levels in cisplatin (CIS), paclitaxel (PAC), doxorubicin (DOX), and topotecan (TOP)-resistant variants of the W1 sensitive ovarian cancer cell line-using miRNA microarray. The second goal was to identify miRNAs responsible for the regulation of drug-resistant genes. According to our observation, alterations in the expression of 40 miRNAs were present. We could observe that, in at least one drug-resistant cell line, the expression of 21 miRNAs was upregulated and that of 19 miRNAs was downregulated. We identified target genes for 22 miRNAs. Target analysis showed that miRNA regulates key genes responsible for drug resistance. Among others, we observed regulation of the ATP-binding cassette subfamily B member 1 gene (ABCB1) in the paclitaxel-resistant cell line by miR-363 and regulation of the collagen type III alpha 1 chain gene (COL3A1) in the topotekan-resistant cell line by miR-29a.
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Zhou J, Kang Y, Chen L, Wang H, Liu J, Zeng S, Yu L. The Drug-Resistance Mechanisms of Five Platinum-Based Antitumor Agents. Front Pharmacol 2020; 11:343. [PMID: 32265714 PMCID: PMC7100275 DOI: 10.3389/fphar.2020.00343] [Citation(s) in RCA: 273] [Impact Index Per Article: 54.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 03/09/2020] [Indexed: 01/17/2023] Open
Abstract
Platinum-based anticancer drugs, including cisplatin, carboplatin, oxaliplatin, nedaplatin, and lobaplatin, are heavily applied in chemotherapy regimens. However, the intrinsic or acquired resistance severely limit the clinical application of platinum-based treatment. The underlying mechanisms are incredibly complicated. Multiple transporters participate in the active transport of platinum-based antitumor agents, and the altered expression level, localization, or activity may severely decrease the cellular platinum accumulation. Detoxification components, which are commonly increasing in resistant tumor cells, can efficiently bind to platinum agents and prevent the formation of platinum–DNA adducts, but the adducts production is the determinant step for the cytotoxicity of platinum-based antitumor agents. Even if adequate adducts have formed, tumor cells still manage to survive through increased DNA repair processes or elevated apoptosis threshold. In addition, autophagy has a profound influence on platinum resistance. This review summarizes the critical participators of platinum resistance mechanisms mentioned above and highlights the most potential therapeutic targets or predicted markers. With a deeper understanding of the underlying resistance mechanisms, new solutions would be produced to extend the clinical application of platinum-based antitumor agents largely.
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Affiliation(s)
- Jiabei Zhou
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yu Kang
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Lu Chen
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Hua Wang
- Department of Urology, Cancer Hospital of Zhejiang Province, Hangzhou, China
| | - Junqing Liu
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Su Zeng
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Lushan Yu
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
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33
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Wei L, Sun J, Zhang N, Zheng Y, Wang X, Lv L, Liu J, Xu Y, Shen Y, Yang M. Noncoding RNAs in gastric cancer: implications for drug resistance. Mol Cancer 2020; 19:62. [PMID: 32192494 PMCID: PMC7081551 DOI: 10.1186/s12943-020-01185-7] [Citation(s) in RCA: 324] [Impact Index Per Article: 64.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Accepted: 03/12/2020] [Indexed: 12/18/2022] Open
Abstract
Gastric cancer is the fourth most common malignancy and the third leading cause of cancer-related deaths worldwide. Advanced gastric cancer patients can notably benefit from chemotherapy including adriamycin, platinum drugs, 5-fluorouracil, vincristine, and paclitaxel as well as targeted therapy drugs. Nevertheless, primary drug resistance or acquisition drug resistance eventually lead to treatment failure and poor outcomes of the gastric cancer patients. The detailed mechanisms involved in gastric cancer drug resistance have been revealed. Interestingly, different noncoding RNAs (ncRNAs), such as microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), are critically involved in gastric cancer development. Multiple lines of evidences demonstrated that ncRNAs play a vital role in gastric cancer resistance to chemotherapy reagents and targeted therapy drugs. In this review, we systematically summarized the emerging role and detailed molecular mechanisms of ncRNAs impact drug resistance of gastric cancer. Additionally, we propose the potential clinical implications of ncRNAs as novel therapeutic targets and prognostic biomarkers for gastric cancer.
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Affiliation(s)
- Ling Wei
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Jujie Sun
- Department of Pathology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Nasha Zhang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Yan Zheng
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Xingwu Wang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Liyan Lv
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Jiandong Liu
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Yeyang Xu
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Yue Shen
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Ming Yang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China.
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Dong C, Yin F, Zhu D, Cai X, Chen C, Liu X. NCALD affects drug resistance and prognosis by acting as a ceRNA of CX3CL1 in ovarian cancer. J Cell Biochem 2020; 121:4470-4483. [PMID: 32030795 DOI: 10.1002/jcb.29670] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 01/10/2020] [Indexed: 01/01/2023]
Abstract
Drug resistance, an impenetrable barrier in the treatment of ovarian cancer (OC), is often associated with poor outcomes. Hence, it is urgent to discover new factors controlling drug resistance and survival. The association between neurocalcin delta (NCALD) and cancer drug resistance is poorly understood. Here, we reveal that NCALD messenger RNA expression, probably regulated by DNA methylation and microRNAs, was significantly downregulated in at least three independent microarrays covering 633 ovarian carcinomas and 16 normal controls, which includes the Cancer Genome Atlas (TCGA) ovarian cohort. In the sub-groups of the TCGA cohort, NCALD was suppressed in 90 platinum-resistant tissues vs in 197 sensitive tissues. It is consistent with the quantitative reverse transcription polymerase chain reaction results revealing gene downregulation in carboplatin-resistant SKOV3 and HeyA8 OC cells as compared with that in controls. Low expression of NCALD predicted poor overall survival (OS) in sub-groups of 1656 patients, progression-free survival (PFS) in 1435 patients, and post-progression survival (PPS) in 782 patients according to Kaplan-Meier plotter covering 1815 OC patients. Comprehensive bioinformatic analyses strongly implicated NCALD in the regulation of drug resistance, probably via competing for endogenous RNA (ceRNA) interactions with CX3CL1 and tumor immune-microenvironment. NCALD acted as a ceRNA for CX3CL1 in 21 different cancers includes OC according to Starbase. These two genes negatively correlated with tumor purity and positively correlated with infiltration levels of neutrophils and dendritic cells in OC. The combined low expression of NCALD and CX3CL1 showed better prognosis potential for OS, PFS, and PPS in the 1815 OC patients than any of the individually tested genes. In summary, NCALD acts as a ceRNA for CX3CL1, and its downregulation may affect drug resistance and prognosis in OC. Thus, NCALD could be a new therapeutic target for anticancer therapy and a new biomarker for survival prediction in OC.
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Affiliation(s)
- Caihua Dong
- Key Laboratory of Longevity and Ageing-Related Disease of Chinese Ministry of Education, Centre for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi, China
| | - Fuqiang Yin
- Life Sciences Institute, Guangxi Medical University, Nanning, Guangxi, China.,Key Laboratory of High-Incidence-Tumor Prevention and Treatment (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China
| | - Dan Zhu
- Pharmaceutical College, Guangxi Medical University, Nanning, Guangxi, China
| | - Xiangxue Cai
- Life Sciences Institute, Guangxi Medical University, Nanning, Guangxi, China
| | - Cuilan Chen
- Life Sciences Institute, Guangxi Medical University, Nanning, Guangxi, China
| | - Xia Liu
- Key Laboratory of Longevity and Ageing-Related Disease of Chinese Ministry of Education, Centre for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi, China
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35
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Zhao X, Hu GF, Shi YF, Xu W. Research Progress in microRNA-Based Therapy for Gastric Cancer. Onco Targets Ther 2019; 12:11393-11411. [PMID: 31920330 PMCID: PMC6935305 DOI: 10.2147/ott.s221354] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Accepted: 12/10/2019] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer (GC) is one of the leading causes of tumor-related mortality. In addition to surgery and endoscopic resection, systemic therapy remains the main treatment option for GC, especially for advanced-stage disease and for cases not suitable for surgical therapy. Hence, improving the efficacy of systemic therapy is still an urgent problem to overcome. In the past decade, the essential roles of microRNAs (miRNAs) in tumor treatment have been increasingly recognized. In particular, miRNAs were recently shown to reverse the resistance to chemotherapy drugs such as 5-fluorouracil, cisplatin, and doxorubicin. Synthesized nanoparticles loaded with mimics or inhibitors of miRNAs can directly target tumor cells to suppress their growth. Moreover, exosomes may serve as promising safe carriers for mimics or inhibitors of miRNAs to treat GC. Some miRNAs have also been shown to play roles in the mechanism of action of other anti-tumor drugs. Therefore, in this review, we highlight the research progress on microRNA-based therapy in GC and discuss the challenges and prospects associated with this strategy. We believe that microRNA-based therapy has the potential to offer a clinical benefit to GC patients, and this review would contribute to and motivate further research to promote this field toward this ultimate goal.
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Affiliation(s)
- Xu Zhao
- Department of Hepatology, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
| | - Gao-Feng Hu
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China.,Department of Clinical Laboratory, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
| | - Yan-Fen Shi
- Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, People's Republic of China
| | - Wei Xu
- Department of Clinical Laboratory, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
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36
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Yang L, Yu Y, Zhang Q, Li X, Zhang C, Mao T, Liu S, Tian Z. Anti-gastric cancer effect of Salidroside through elevating miR-99a expression. ARTIFICIAL CELLS, NANOMEDICINE, AND BIOTECHNOLOGY 2019; 47:3500-3510. [PMID: 31432697 DOI: 10.1080/21691401.2019.1652626] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 07/22/2019] [Accepted: 08/01/2019] [Indexed: 12/14/2022]
Abstract
Salidroside is an active ingredient extracted from Rhodiola rosea that has anti-tumor activities. The current paper attempted to assess the impact of Salidroside on gastric cancer (GC) and explore the potential mechanism. GC cell lines (SNU-216 and MGC803) and gastric epithelial cell line GES-1 were treated with Salidroside. CCK-8 assay, colony formation assay, flow cytometry and Transwell assay were respectively performed to evaluate GC cells phenotype. qRT-PCR and western blot were conducted to reveal the downstream genes and signaling of Salidroside. We found that 800 μM Salidroside was capable of reducing GC cells viability, while has no such impacts on GES-1 cells. Salidroside inhibited GC cells proliferation, migration, invasion and promoted apoptosis, which coupled with the down-regulation of p21, Bcl-2, MMP2, RhoA, p-ROCK1, Vimentin and the up-regulations of CyclinD1, Bax, cleaved caspases. miR-99a was found to be highly expressed in response to Salidroside treatment. Besides, the inhibition of MAPK/ERK and PI3K/AKT signaling induced by Salidroside was attenuated by miR-99a silence and in this process, IGF1R worked as a target of miR-99a. The anti-GC effect of Salidroside was also confirmed in a mouse model of GC. The promoting effect of Salidroside on miR-99a expression was also verified in vivo. Furthermore, Salidroside promoted the cisplatin-sensitivity of SGC7901/DDP cells. In conclusion, this study demonstrated that Salidroside possessed anti-GC effects through regulating miR-99a/IGF1R axis and inhibiting MAPK/ERK and PI3K/AKT pathways.
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Affiliation(s)
- Lin Yang
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University , Qingdao , China
| | - Yanan Yu
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University , Qingdao , China
| | - Qi Zhang
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University , Qingdao , China
| | - Xiaoyu Li
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University , Qingdao , China
| | - Cuiping Zhang
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University , Qingdao , China
| | - Tao Mao
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University , Qingdao , China
| | - Siliang Liu
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University , Qingdao , China
| | - Zibin Tian
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University , Qingdao , China
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Luo YJ, Huang QM, Ren Y, Liu ZL, Xu CF, Wang H, Xiao JW. Non-coding RNA in drug resistance of gastric cancer. World J Gastrointest Oncol 2019; 11:957-970. [PMID: 31798777 PMCID: PMC6883183 DOI: 10.4251/wjgo.v11.i11.957] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 09/21/2019] [Accepted: 10/03/2019] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer (GC) is the third leading cause of cancer-related mortality worldwide. The poorly prognosis and survival of GC are due to diagnose in an advanced, non-curable stage and with a limited response to chemotherapy. The acquisition of drug resistance accounts for the majority of therapy failure of chemotherapy in GC patients. Although the mechanisms of anticancer drug resistance have been broadly studied, the regulation of these mechanisms has not been completely understood. Accumulating evidence has recently highlighted the role of non-coding RNAs (ncRNAs), including long non-coding RNAs and microRNAs, in the development and maintenance of drug resistance due to their regulatory features in specific genes involved in the chemoresistant phenotype of GC. We review the literature on ncRNAs in drug resistance of GC. This review summarizes the current knowledge about the ncRNAs’ characteristics, their regulation of the genes involved in chemoresistance and their potential as targeted therapies for personalized treatment in resistant GC.
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Affiliation(s)
- Ya-Jun Luo
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China
| | - Qing-Mei Huang
- Department of Oncology, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Yan Ren
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Zi-Lin Liu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Cheng-Fei Xu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Hao Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Jiang-Wei Xiao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
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Chen T, Yu Q, Shao S, Guo L. Circular RNA circFNDC3B protects renal carcinoma by miR-99a downregulation. J Cell Physiol 2019; 235:4399-4406. [PMID: 31637704 DOI: 10.1002/jcp.29316] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 09/30/2019] [Indexed: 12/15/2022]
Abstract
Various circular RNAs (circRNAs) have been reported to involve in carcinoma. This study explored the role and mechanism of circRNA circFNDC3B (circFNDC3B) in renal carcinoma (RC). The detection indicators in this paper were viability, colony, and migration, which respectively investigated by Cell Counting Kit-8, colony formation, and migration assay. Reverse transcriptase quantitative polymerase chain reaction tested and cell transfection changed circFNDC3B and miR-99a expression. Moreover, western blot tested relate-proteins of proliferation, migration, and cell pathways were examined by western blot. circFNDC3B was upregulated at RC tissues. circFNDC3B enhanced cell viability, colony and migration, and miR-99a mimic played reverse impacts. Furthermore, circFNDC3B negatively regulated miR-99aand circFNDC3B restrained the janus kinase 1/signal transducer and activator of transcription 3 (JAK1/STAT3) and extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathways by miR-99a downregulation. Overexpression of circFNDC3B enhanced cell viability, colony formation and migration by miR-99a downregulation via JAK1/STAT3 and MEK/ERK pathways.
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Affiliation(s)
- Tao Chen
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qinchao Yu
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Shixiu Shao
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lei Guo
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, China
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Lu L, Wu M, Lu Y, Zhao Z, Liu T, Fu W, Li W. MicroRNA-424 regulates cisplatin resistance of gastric cancer by targeting SMURF1 based on GEO database and primary validation in human gastric cancer tissues. Onco Targets Ther 2019; 12:7623-7636. [PMID: 31571913 PMCID: PMC6756437 DOI: 10.2147/ott.s208275] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 08/29/2019] [Indexed: 12/24/2022] Open
Abstract
PURPOSE Cisplatin (DDP) based chemotherapy regimens are widely used in advanced gastric cancer (GC). Drug resistance often limited the clinical benefits of cisplatin regimen. The mechanisms of cisplatin resistance have not been fully revealed. Therefore, further exploration of the relevant molecular mechanisms is urgently needed. PATIENTS AND METHODS DDP resistance associated miRNA of GC microarray dataset GSE86195 was obtained from the National Center for Biotechnology Information (NCBI) GEO database, GEO2R was applied to compare the samples in two different groups under the same experimental conditions. |log2(Fold Change) | (log2(FC)) was selected as the criteria to screen the statistically significant DE-miRNAs. StarBaseV3.0 was used to predict the target genes of the DE-miRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of target genes of DE-miRNAs were carried out using DAVID. The STRING database was applied to estimate the correlations between target genes. Analysis of hubgenes by coremine and The Human Protein Atlas (THPA). Initial expression validations of miR-424 and miR-491-5p, SMURF1 and BCL2L1 were carried out using clinical pathological specimens by RT-PCR. RESULTS A total of 13 Differential expression-miRNAs (DE-miRNAs) were identified in DDP chemoresistant cells, including 9 upregulated miRNAs and 4 downregulated miRNAs. SMURF1 and BCL2L1 were screened as the critical genes in DDP-resistant GC, which were regulated by miR-424 and miR-491-5p respectively. The results of validation of hub genes expression in GC tissues indicated that in DFS<1-year group, the expression of miR-424 decreased significantly, notably upregulated expression of SMURF1 was also detected. CONCLUSION Our results implied that miR-424, as a tumor suppressor, could deregulate SMURF1 in DDP-resistant GC cells.
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Affiliation(s)
- Li Lu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China
| | - Menglin Wu
- Radiology Department, Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China
| | - Yaoheng Lu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China
| | - Zhicheng Zhao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China
| | - Tong Liu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China
| | - Weihua Fu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China
| | - Weidong Li
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China
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40
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Li H, Chen LP, Wang T, Wang SG, Liu JH. Calpain inhibition improves erectile function in diabetic mice via upregulating endothelial nitric oxide synthase expression and reducing apoptosis. Asian J Androl 2019; 20:342-348. [PMID: 29319007 PMCID: PMC6038160 DOI: 10.4103/aja.aja_63_17] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Calpain activation contributes to hyperglycemia-induced endothelial dysfunction and apoptosis. This study was designed to investigate the role of calpain inhibition in improving diabetic erectile dysfunction (ED) in mice. Thirty-eight-week-old male C57BL/6J mice were divided into three groups: (1) nondiabetic control group, (2) diabetic mice + vehicle group, and (3) diabetic mice + MDL28170 (an inhibitor of calpain) group. Type 1 diabetes was induced by intraperitoneal injection of streptozotocin at 60 mg kg−1 body weight for 5 consecutive days. Thirteen weeks later, diabetic mice were treated with MDL28170 or vehicle for 4 weeks. The erectile function was assessed by electrical stimulation of the cavernous nerve. Penile tissues were collected for measurement of calpain activity and the endothelial nitric oxide synthase (eNOS)-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway. Terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick end labeling (TUNEL) staining was used to evaluate apoptosis. Caspase-3 expression and activity were also measured to determine apoptosis. Our results showed that erectile function was enhanced by MDL28170 treatment in diabetic mice compared with the vehicle diabetic group. No differences in calpain-1 and calpain-2 expressions were observed among the three groups. However, calpain activity was increased in the diabetic group and reduced by MDL28170. The eNOS-NO-cGMP pathway was upregulated by MDL28170 treatment in diabetic mice. Additionally, MDL28170 could attenuate apoptosis and increase the endothelium and smooth muscle levels in corpus cavernosum. Inhibition of calpain could improve erectile function, probably by upregulating the eNOS-NO-cGMP pathway and reducing apoptosis.
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Affiliation(s)
- Hao Li
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Li-Ping Chen
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Tao Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Shao-Gang Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ji-Hong Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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41
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Zhao X, Tang DY, Zuo X, Zhang TD, Wang C. Identification of lncRNA-miRNA-mRNA regulatory network associated with epithelial ovarian cancer cisplatin-resistant. J Cell Physiol 2019; 234:19886-19894. [PMID: 30950060 DOI: 10.1002/jcp.28587] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 03/10/2019] [Accepted: 03/19/2019] [Indexed: 12/12/2022]
Abstract
To construct a long noncoding RNA (lncRNA)-microRNA (miRNA)-messenger RNA (mRNA) regulatory network related to epithelial ovarian cancer (EOC) cisplatin-resistant, differentially expressed genes (DEGs), differentially expressed lncRNAs (DELs), and differentially expressed miRNAs (DEMs) between MDAH and TOV-112D cells lines were identified. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted to analyze the biological functions of DEGs. Downstream mRNAs or upstream lncRNAs for miRNAs were analyzed at miRTarBase 7.0 or DIANA-LncBase V2, respectively. A total of 485 significant DEGs, 85 DELs, and 5 DEMs were identified. Protein-protein interaction (PPI) network of DEGs contrains 81 nodes and 141 edges was constructed, and 25 hub genes related to EOC cisplatin-resistant were identified. Subsequently, a lncRNA-miRNA-mRNA regulatory network contains 4 lncRNAs, 4 miRNAs, and 35 mRNAs was established. Taken together, our study provided evidence concerning the alteration genes involved in EOC cisplatin-resistant, which will help to unravel the mechanisms underlying drug resistant.
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Affiliation(s)
- Xin Zhao
- Department of Pharmacy, Xinxiang Central Hospital, Xinxiang, Henan, P. R. China
| | - Dong-Yang Tang
- Department of Experimental Management Center, Henan Institute of Science and Technology, Xinxiang, Henan, P. R. China
| | - Xu Zuo
- Department of Pharmacy, Xinxiang Central Hospital, Xinxiang, Henan, P. R. China
| | - Tian-Dong Zhang
- Department of Pharmacy, Xinxiang Central Hospital, Xinxiang, Henan, P. R. China
| | - Cheng Wang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, P. R. China
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42
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Feng W, Su Z, Yin Q, Zong W, Shen X, Ju S. ncRNAs associated with drug resistance and the therapy of digestive system neoplasms. J Cell Physiol 2019; 234:19143-19157. [PMID: 30941775 DOI: 10.1002/jcp.28551] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 02/25/2019] [Accepted: 03/05/2019] [Indexed: 12/19/2022]
Abstract
Digestive system cancer remains a common cancer and the main cause of cancer-related death worldwide. Drug resistance is a major challenge in the therapy of digestive system cancer, and represents a primary obstacle in the treatment of cancer by restricting the efficiency of both traditional chemotherapy and biological therapies. Existing studies indicate that noncoding RNAs play an important role in the evolution and progression of drug resistance in digestive system cancer, mainly by modulating drug transporter-related proteins, DNA damage repair, cell-cycle-related proteins, cell apoptosis-related proteins, drug target-related proteins, and the tumor microenvironment. In this review, we address the potential mechanisms of ncRNAs underlying drug resistance in digestive system tumors and discuss the possible application of ncRNAs against drug resistance in digestive system tumors.
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Affiliation(s)
- Wei Feng
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Zhangyao Su
- School of Medicine, Nantong University, Nantong, China
| | - Qingqing Yin
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Wei Zong
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Xianjuan Shen
- Clinical Medical Research Center, Affiliated Hospital of Nantong University, Nantong, China
| | - Shaoqing Ju
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
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43
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Chen L, Hu J, Pan L, Yin X, Wang Q, Chen H. Diagnostic and prognostic value of serum miR-99a expression in oral squamous cell carcinoma. Cancer Biomark 2019; 23:333-339. [PMID: 30223386 DOI: 10.3233/cbm-181265] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Despite progress in the treatment of oral squamous cell carcinoma (OSCC) over past years, the prognosis for OSCC patients remains dismal. MicroRNA-99a (miR-99a) has been found to involve in the development of many cancer types, but its clinical role in OSCC is unclear. OBJECTIVE The aim of this study was to explore the clinical implications of serum miR-99a in OSCC. METHODS This study detected serum miR-99a levels in 121 OSCC cases and 55 healthy controls by using quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis. RESULTS The data showed that serum miR-99a expression was significantly decreased in OSCC patients compared with normal controls. OSCC patients with low miR-99a expression experienced more frequent poor differentiation and advanced clinical stage. Furthermore, in screening OSCC cases from normal controls, miR-99a could yield a receiver-operating characteristic (ROC) area under the curve (AUC) of 0.911 with 83.6% specificity and 80.2% sensitivity. Notably, patients with high miR-99a expression had longer overall survival and recurrence free survival. Finally, serum miR-99a was identified to be an independent prognostic indicator for OSCC. CONCLUSIONS These results suggested that miR-99a might be a valuable marker for the prediction of early detection and prognosis in OSCC.
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Affiliation(s)
- Liang Chen
- Department of Endodontics, Jinan Stomatological Hospital, Jinan, Shandong, China.,Department of Endodontics, Jinan Stomatological Hospital, Jinan, Shandong, China
| | - Jing Hu
- Department of Stomatology, PLA Army General Hospital, Beijing, China.,Department of Endodontics, Jinan Stomatological Hospital, Jinan, Shandong, China
| | - Lina Pan
- Department of Endodontics, Jinan Stomatological Hospital, Jinan, Shandong, China
| | - Xiaochun Yin
- Department of Endodontics, Jinan Stomatological Hospital, Jinan, Shandong, China
| | - Qibao Wang
- Department of Endodontics, Jinan Stomatological Hospital, Jinan, Shandong, China
| | - Hui Chen
- Department of Endodontics, Jinan Stomatological Hospital, Jinan, Shandong, China
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Chen C, Tang X, Liu Y, Zhu J, Liu J. Induction/reversal of drug resistance in gastric cancer by non-coding RNAs (Review). Int J Oncol 2019; 54:1511-1524. [PMID: 30896792 PMCID: PMC6438417 DOI: 10.3892/ijo.2019.4751] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 02/21/2019] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer (GC) is one of the most prevalent and malignant types of cancer worldwide. In China, it is the second most common type of cancer and the malignancy with the highest incidence and mortality rate. Chemotherapy for GC is not always effective due to the development of drug resistance. Drug resistance, which is frequently observed in GC, undermines the success rate of chemotherapy and the survival of patients with GC. The dysregulation of non‑coding RNAs (ncRNAs), primarily microRNAs (miRNAs or miRs) and long non‑coding RNAs (lncRNAs), is involved in the development of GC drug resistance via numerous mechanisms. These mechanisms contribute to the involvement of a large and complex network of ncRNAs in drug resistance. In this review, we focus on and summarize the latest research on the specific mechanisms of action of miRNAs and lncRNAs that modulate drug resistance in GC. In addition, we discuss future prospects and clinical applications of ncRNAs as potential targeted therapies against the chemoresistance of GC.
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Affiliation(s)
- Chao Chen
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Xiaohuan Tang
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Yuanda Liu
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Jiaming Zhu
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Jingjing Liu
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
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Qian K, Qian H, Cai J, Yue W, Yu X, Liu B. Evaluation of cisplatin-hydrogel for improving localized antitumor efficacy in gastric cancer. Pathol Res Pract 2019; 215:755-760. [PMID: 30718098 DOI: 10.1016/j.prp.2019.01.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 12/14/2018] [Accepted: 01/05/2019] [Indexed: 10/27/2022]
Abstract
Gastric cancer, one of the most common disease, has become a major public health problem worldwide. Cisplatin (DDP) has been a widely used drug for the treatment of cancer, also usually applied in gastric cancer in clinic. However, the side effects including toxicity and drug-resistance restricted the usage of DDP in clinic, so we prepared a DDP-complexed hydrogel (DDP-Gel) and investigated its efficacy in gastric cancer. For in vivo studies, MKN45-Luc cells were injected into BLAB/C node mice subcutaneously to establish gastric cancer with orthotopically grown tumors. Mice bearing tumors were treated with normal saline, DDP and DDP-Gel. Body weight and survival condition were observed and recorded. The treatment efficacy in vivo was detected by luciferase imaging and histological evaluation was performed by H&E staining of different organs. Additionally, normal ICR mice were treated with different doses of DDP/DDP-Gel to calculate their LD50 in vivo. The results showed that DDP-Gel prolonged survival time and ameliorated body weight changes of mice bearing tumors. DDP-Gel exhibited higher efficacy to inhibit tumor growth and metastasis, compared to DDP. Besides, LD50 of DDP-Gel was 166.0 mg/kg, 13.2 folds higher than DDP. As a conclusion, DDP-Gel showed a more effective and safer function than DDP in gastric cancer, which indicating that DDP-Gel might be a novel strategy for gastric cancer therapy.
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Affiliation(s)
- Keyang Qian
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, 210008, China
| | - Hanqing Qian
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, 210008, China
| | - Juan Cai
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, 210008, China
| | - Wuheng Yue
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210008, China
| | - Xiaoxiao Yu
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210000, China
| | - Baorui Liu
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, 210008, China.
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Zhai J, Yao GD, Wang JY, Yang QL, Wu L, Chang ZY, Sun YP. Metformin Regulates Key MicroRNAs to Improve Endometrial Receptivity Through Increasing Implantation Marker Gene Expression in Patients with PCOS Undergoing IVF/ICSI. Reprod Sci 2019; 26:1439-1448. [PMID: 30599813 DOI: 10.1177/1933719118820466] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
To some extent, the use of metformin may improve endometrial receptivity and pregnancy outcomes of women with polycystic ovarian syndrome (PCOS) undergoing in vitro fertilization/intracytoplasmic sperm injection. However, the mechanism is not well-known. The endometrium of metformin-treated group (metformin-treated patients with PCOS) and the control group (non-metformin-treated patients with PCOS) were analyzed for the expression of homeobox A10 (HOXA10) and integrin beta-3 (ITGB3) and differential micro RNA (miRNA) expression profiles. On this basis, miRDB and Target Scan databases were used to predict and screen out that miR-491-3p and miR-1910-3p may target HOXA10 and ITGB3. Furthermore, we verified the effects of metformin on the expression of HOXA10 and ITGB3, and regulatory effects of miR-1910-3p and miR-491-3p on HOXA10 and ITGB3 using Ishikawa cell line. Metformin induced a significant dose-dependent upregulation of HOXA10 and ITGB3. The results from the microarray analyses showed there were 40 differentially expressed miRNAs between the 2 groups. Among them, miR-1910-3p and miR-491-3p were the 2 significantly downregulated miRNAs. Bioinformatics prediction indicated that HOXA10 and ITGB3 are potential target genes for miR-1910-3p and miR-491-3p. In Ishikawa cells transfected with miR-491-3p mimics, the expression of HOXA10 and ITGB3 on both messenger RNA (mRNA) and protein level were lower than those in control group (P < .001). Also, the expression of HOXA10 mRNA and protein was lower in Ishikawa cells transfected with miR-1910-3p mimics (P < .001). However, no significant changes in ITGB3 levels were observed in cells transfected with miR-1910-3p mimics (P > .05). Metformin likely improves endometrial receptivity through downregulating the expression of miR-491-3p and miR-1910-3p, thereby increasing the expression of HOXA10 and ITGB3 in the endometrium of PCOS women.
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Affiliation(s)
- Jun Zhai
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Gui-Dong Yao
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Jing-Yuan Wang
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Qing-Ling Yang
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Liang Wu
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Zi-Yin Chang
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Ying-Pu Sun
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
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Capn4 expression is modulated by microRNA-520b and exerts an oncogenic role in prostate cancer cells by promoting Wnt/β-catenin signaling. Biomed Pharmacother 2018; 108:467-475. [DOI: 10.1016/j.biopha.2018.09.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 08/28/2018] [Accepted: 09/04/2018] [Indexed: 12/20/2022] Open
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Calpain system protein expression and activity in ovarian cancer. J Cancer Res Clin Oncol 2018; 145:345-361. [PMID: 30448882 PMCID: PMC6373250 DOI: 10.1007/s00432-018-2794-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 11/12/2018] [Indexed: 01/06/2023]
Abstract
Purpose Expression of members of the calpain system are associated with clinical outcome of patients with, amongst others, breast and ovarian cancers, with calpain-2 expression in ovarian cancer being implicated in chemo-resistance and survival. This study aimed, using a large patient cohort and in vitro models, to verify its importance and further investigate the role in ovarian cancer chemoresponse. Methods Calpain-1, calpain-2, calpain-4 and calpastatin expression were evaluated in primary ovarian carcinomas (n = 575) by immunohistochemistry. Protein expression was assessed, via western blotting, in five ovarian cancer cell lines with various sensitivities towards cisplatin/carboplatin. In vitro calpain activity was inhibited by calpeptin treatment to assess changes in platinum sensitivity by proliferation assay, with expression of genes associated with epithelial–mesenchymal transition being examined by RT2 Profiler™ PCR Array. Results The current study confirmed previous data that high calpain-2 expression is associated with poor overall survival (P = 0.026) and that calpain-1 was not associated with overall survival or progression-free survival. Low expression of calpastatin (P = 0.010) and calpain-4 (P = 0.003) were also associated with adverse survival. Such prognostic associations do not seem to be linked with altered tumour sensitivity towards platinum-based chemotherapy. Interestingly, low calpain-1 expression was more frequent in patients with confined tumours (stage 1) (χ2 = 11.310, df = 1, P = 0.001). Calpain and calpastatin expression varied among ovarian cancer cell lines yet their expression levels were similar between chemo-sensitive cells and resistant counterparts. Moreover, calpeptin treatment did not alter cellular response to platinum-based chemotherapy or epithelial–mesenchymal transition-related gene expression. Conclusions The conventional calpains and calpastatin have been confirmed to play an important role in ovarian cancer; however, the precise mechanisms whereby they exert effects remain to be elucidated. Electronic supplementary material The online version of this article (10.1007/s00432-018-2794-2) contains supplementary material, which is available to authorized users.
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Kashyap D, Tuli HS, Garg VK, Goel N, Bishayee A. Oncogenic and Tumor-Suppressive Roles of MicroRNAs with Special Reference to Apoptosis: Molecular Mechanisms and Therapeutic Potential. Mol Diagn Ther 2018; 22:179-201. [PMID: 29388067 DOI: 10.1007/s40291-018-0316-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
MicroRNAs (miRNAs) are the non-coding class of minute RNA molecules that negatively control post-transcriptional regulation of various functional genes. These miRNAs are transcribed from the loci present in the introns of functional or protein-coding genes, exons of non-coding genes, or even in the 3'-untranslated region (3'-UTR). They have potential to modulate the stability or translational efficiency of a variety of target RNA [messenger RNA (mRNA)]. The regulatory function of miRNAs has been elucidated in several pathological conditions, including neurological (Alzheimer's disease and Parkinson's disease) and cardiovascular conditions, along with cancer. Importantly, miRNA identification in cancer progression and invasion has evolved as an incipient era in cancer treatment. Several studies have shown the influence of miRNAs on various cancer processes, including apoptosis, invasion, metastasis and angiogenesis. In particular, apoptosis induction in tumor cells through miRNA has been extensively studied. The biphasic mode (up- and down-regulation) of miRNA expression in apoptosis and other cancer processes has already been determined. The findings of these studies could be utilized to develop potential therapeutic strategies for the management of various cancers. The present review critically describes the oncogenic and tumor suppressor role of miRNAs in apoptosis and other cancer processes, therapy resistance, and use of their presence in the body fluids as biomarkers.
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Affiliation(s)
- Dharambir Kashyap
- Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, Punjab, India
| | - Hardeep Singh Tuli
- Department of Biotechnology, Maharishi Markandeshwar University, Mullana-Ambala, 133207, Haryana, India.
| | - Vivek Kumar Garg
- Department of Biochemistry, Government Medical College and Hospital, Chandigarh, 160030, Punjab, India
| | - Neelam Goel
- Department of Information Technology, University Institute of Engineering and Technology, Panjab University, Chandigarh, 160014, Punjab, India
| | - Anupam Bishayee
- Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, Miami, FL, 33169, USA.
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Lu Y, Han D, Liu W, Huang R, Ou J, Chen X, Zhang X, Wang X, Li S, Wang L, Liu C, Miao S, Wang L, Ma C, Song W. RNF138 confers cisplatin resistance in gastric cancer cells via activating Chk1 signaling pathway. Cancer Biol Ther 2018; 19:1128-1138. [PMID: 30260263 PMCID: PMC6301830 DOI: 10.1080/15384047.2018.1480293] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 05/17/2018] [Accepted: 05/20/2018] [Indexed: 12/14/2022] Open
Abstract
Chemotherapy resistance represents a major issue associated with gastric cancer (GC) treatment, and arises through multiple mechanisms, including modulation of the cell-cycle check point. Several ubiquitin kinases, including RING finger protein 138 (RNF138), have been reported to mediate the G2/M phase arrest. In this study, we investigated the role of RNF138 in the development of cisplatin resistance of two GC cell lines. We show that RNF138 levels are higher in cisplatin-resistant cell lines, compared with cisplatin-sensitive cells, and RNF138 expression was elevated during drug withdrawal following the cisplatin treatment. Using gene overexpression and silencing, we analyzed the impact of altering RNF138 level on GC cell viability, apoptosis, and cell cycle phenotypes in two isogenic cisplatin-sensitive and resistant cell lines. We show that RNF138 overexpression increased GC cell viability, decreased apoptosis and delayed cell cycle progression in the cisplatin-sensitive GC cells. Conversely, RNF138 silencing produced opposite phenotypes in the cisplatin-resistant cells. Moreover, RNF138-dependent phosphorylation of Chk1 was seen in GC cells, indicating a novel connection between cisplatin-induced DNA damage and apoptosis. Collectively, these data suggest that RNF138 modulates the cisplatin resistance in the GC cells, thus serving as a potential drug target to challenge chemotherapy failure. In addition, RNF138 can also be used as a marker to monitor the development of cisplatin resistance in GC treatment.
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Affiliation(s)
- Yalan Lu
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing China
| | - Deqiang Han
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing China
| | - Wenjie Liu
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing China
| | - Rong Huang
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing China
| | - Jinhuan Ou
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing China
| | - Xiaoqiao Chen
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing China
| | - Xizhe Zhang
- Department of Medical Oncology, Chifeng Municipal Hospital, Chifeng China
| | - Xuezhi Wang
- Department of Medical Oncology, Chifeng Municipal Hospital, Chifeng China
| | - Shijun Li
- Department of Medical Oncology, Chifeng Municipal Hospital, Chifeng China
| | - Lin Wang
- Department of Physiology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing China
| | - Changzheng Liu
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing China
| | - Shiying Miao
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing China
| | - Linfang Wang
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing China
| | - Changwu Ma
- Department of Medical Oncology, Chifeng Municipal Hospital, Chifeng China
| | - Wei Song
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing China
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