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Pei S, Zhang D, Li Z, Liu J, Li Z, Chen J, Xie Z. The Role of the Fox Gene in Breast Cancer Progression. Int J Mol Sci 2025; 26:1415. [PMID: 40003882 PMCID: PMC11855465 DOI: 10.3390/ijms26041415] [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: 11/26/2024] [Revised: 01/25/2025] [Accepted: 02/06/2025] [Indexed: 02/27/2025] Open
Abstract
Forkhead box (FOX) genes are a family of transcription factors that participate in many biological activities, from early embryogenesis to the formation of organs, and from regulation of glucose metabolism to regulation of longevity. Given the extensive influence in the multicellular process, FOX family proteins are responsible for the progression of many types of cancers, especially lung cancer, breast cancer, prostate cancer, and other cancers. Breast cancer is the most common cancer among women, and 2.3 million women were diagnosed in 2020. So, various drugs targeting the FOX signaling pathway have been developed to inhibit breast cancer progression. While the role of the FOX family gene in cancer development has not received enough attention, discovering more potential drugs targeting the FOX signaling pathway is urgently demanded. Here, we review the main members in the FOX gene family and summarize their signaling pathway, including the regulation of the FOX genes and their effects on breast cancer progression. We hope this review will emphasize the understanding of the role of the FOX gene in breast cancer and inspire the discovery of effective anti-breast cancer medicines targeting the FOX gene in the future.
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Affiliation(s)
- Shaoxuan Pei
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; (S.P.); (D.Z.); (Z.L.); (J.L.); (Z.L.); (J.C.)
- Medical Department, Queen Mary School, Nanchang University, Nanchang 330031, China
| | - Dechun Zhang
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; (S.P.); (D.Z.); (Z.L.); (J.L.); (Z.L.); (J.C.)
- Medical Department, Queen Mary School, Nanchang University, Nanchang 330031, China
| | - Zhuohan Li
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; (S.P.); (D.Z.); (Z.L.); (J.L.); (Z.L.); (J.C.)
- Medical Department, Queen Mary School, Nanchang University, Nanchang 330031, China
| | - Jinkai Liu
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; (S.P.); (D.Z.); (Z.L.); (J.L.); (Z.L.); (J.C.)
- Medical Department, Queen Mary School, Nanchang University, Nanchang 330031, China
| | - Ziyi Li
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; (S.P.); (D.Z.); (Z.L.); (J.L.); (Z.L.); (J.C.)
- Medical Department, Queen Mary School, Nanchang University, Nanchang 330031, China
| | - Jianrui Chen
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; (S.P.); (D.Z.); (Z.L.); (J.L.); (Z.L.); (J.C.)
- Medical Department, Queen Mary School, Nanchang University, Nanchang 330031, China
| | - Zhenzhen Xie
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; (S.P.); (D.Z.); (Z.L.); (J.L.); (Z.L.); (J.C.)
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Kishta MS, Khamis A, Am H, Elshaar AH, Gül D. Exploring the tumor-suppressive role of miRNA-200c in head and neck squamous cell carcinoma: Potential and mechanisms of exosome-mediated delivery for therapeutic applications. Transl Oncol 2025; 51:102216. [PMID: 39615277 DOI: 10.1016/j.tranon.2024.102216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 11/15/2024] [Accepted: 11/20/2024] [Indexed: 12/11/2024] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) remains a challenging malignancy due to its high rates of recurrence, metastasis, and resistance to conventional therapies. microRNA-200c (miRNA-200c) has emerged as a critical tumor suppressor in HNSCC, with the potential to inhibit epithelial-mesenchymal transition (EMT), which is considered as a key process in cancer metastasis and progression. Interestingly, there are also controversial findings in HNSCC characterizing miRNA-200c as oncogenic factor. This review article provides a comprehensive overview of the current understanding of miRNA-200c's general role in cancer, and particularly in HNSCC, highlighting its mechanisms of action, including the regulation of EMT and other oncogenic pathways. Additionally, the review explores the innovative approach of exosome-mediated delivery of miRNA-200c as a therapeutic strategy. Exosomes, as natural nanocarriers, offer a promising vehicle for the targeted delivery of miRNA-200c to tumor cells, potentially overcoming the limitations of traditional delivery methods and enhancing therapeutic efficacy. The review also discusses the challenges and future directions in the clinical application of miRNA-200c, particularly focusing on its potential to improve outcomes for HNSCC patients. This article seeks to provide valuable insights for researchers and clinicians working towards innovative treatments for this aggressive cancer type.
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Affiliation(s)
- Mohamed S Kishta
- Hormones Department, Medical Research and Clinical Studies Institute, Stem Cell Lab., Center of Excellence for Advanced Sciences, National Research Centre, 33 El Bohouth St., Dokki, 12622 Cairo, Egypt.
| | - Aya Khamis
- Maxillofacial and Oral Surgery, University Medical Center, 55131 Mainz, Germany; Oral Pathology Department, Faculty of Dentistry, Alexandria University, 5372066 Alexandria, Egypt
| | - Hafez Am
- Medical Biochemistry Department Faculty of medicine KafrElSheikh University, Kafr El-Sheikh, Egypt
| | | | - Désirée Gül
- Department of Otorhinolaryngology Head and Neck Surgery, Molecular and Cellular Oncology, University Medical Center, 55131 Mainz, Germany.
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Yadav R, Khatkar R, Yap KCH, Kang CYH, Lyu J, Singh RK, Mandal S, Mohanta A, Lam HY, Okina E, Kumar RR, Uttam V, Sharma U, Jain M, Prakash H, Tuli HS, Kumar AP, Jain A. The miRNA and PD-1/PD-L1 signaling axis: an arsenal of immunotherapeutic targets against lung cancer. Cell Death Discov 2024; 10:414. [PMID: 39343796 PMCID: PMC11439964 DOI: 10.1038/s41420-024-02182-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 08/21/2024] [Accepted: 09/18/2024] [Indexed: 10/01/2024] Open
Abstract
Lung cancer is a severe challenge to the health care system with intrinsic resistance to first and second-line chemo/radiotherapies. In view of the sterile environment of lung cancer, several immunotherapeutic drugs including nivolumab, pembrolizumab, atezolizumab, and durvalumab are currently being used in clinics globally with the intention of releasing exhausted T-cells back against refractory tumor cells. Immunotherapies have a limited response rate and may cause immune-related adverse events (irAEs) in some patients. Hence, a deeper understanding of regulating immune checkpoint interactions could significantly enhance lung cancer treatments. In this review, we explore the role of miRNAs in modulating immunogenic responses against tumors. We discuss various aspects of how manipulating these checkpoints can bias the immune system's response against lung cancer. Specifically, we examine how altering the miRNA profile can impact the activity of various immune checkpoint inhibitors, focusing on the PD-1/PD-L1 pathway within the complex landscape of lung cancer. We believe that a clear understanding of the host's miRNA profile can influence the efficacy of checkpoint inhibitors and significantly contribute to existing immunotherapies for lung cancer patients. Additionally, we discuss ongoing clinical trials involving immunotherapeutic drugs, both as standalone treatments and in combination with other therapies, intending to advance the development of immunotherapy for lung cancer.
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Affiliation(s)
- Ritu Yadav
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Rinku Khatkar
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Kenneth C-H Yap
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Chloe Yun-Hui Kang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Juncheng Lyu
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Rahul Kumar Singh
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Surojit Mandal
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Adrija Mohanta
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Hiu Yan Lam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Elena Okina
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Rajiv Ranjan Kumar
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Vivek Uttam
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Uttam Sharma
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Manju Jain
- Department of Biochemistry, Central University of Punjab, Bathinda, Punjab, India
| | | | | | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| | - Aklank Jain
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India.
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Pathania AS, Chava H, Balusu R, Pasupulati AK, Coulter DW, Challagundla KB. The crosstalk between non-coding RNAs and cell-cycle events: A new frontier in cancer therapy. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200785. [PMID: 38595981 PMCID: PMC10973673 DOI: 10.1016/j.omton.2024.200785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/11/2024]
Abstract
The cell cycle comprises sequential events during which a cell duplicates its genome and divides it into two daughter cells. This process is tightly regulated to ensure that the daughter cell receives identical copied chromosomal DNA and that any errors in the DNA during replication are correctly repaired. Cyclins and their enzyme partners, cyclin-dependent kinases (CDKs), are critical regulators of G- to M-phase transitions during the cell cycle. Mitogenic signals induce the formation of the cyclin/CDK complexes, resulting in phosphorylation and activation of the CDKs. Once activated, cyclin/CDK complexes phosphorylate specific substrates that drive the cell cycle forward. The sequential activation and inactivation of cyclin-CDK complexes are tightly controlled by activating and inactivating phosphorylation events induced by cell-cycle proteins. The non-coding RNAs (ncRNAs), which do not code for proteins, regulate cell-cycle proteins at the transcriptional and translational levels, thereby controlling their expression at different cell-cycle phases. Deregulation of ncRNAs can cause abnormal expression patterns of cell-cycle-regulating proteins, resulting in abnormalities in cell-cycle regulation and cancer development. This review explores how ncRNA dysregulation can disrupt cell division balance and discusses potential therapeutic approaches targeting these ncRNAs to control cell-cycle events in cancer treatment.
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Affiliation(s)
- Anup S. Pathania
- Department of Biochemistry and Molecular Biology & The Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Haritha Chava
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Ramesh Balusu
- Department of Hematologic Malignancies and Cellular Therapeutics, Kansas University Medical Center, Kansas City, KS 66160, USA
| | - Anil K. Pasupulati
- Department of Biochemistry, University of Hyderabad, Hyderabad, Telangana 500046, India
| | - Don W. Coulter
- Department of Pediatrics, Division of Hematology/Oncology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Kishore B. Challagundla
- Department of Biochemistry and Molecular Biology & The Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
- The Child Health Research Institute, University of Nebraska Medical Center, Omaha, NE 68198, USA
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Chen Y, Dai X, Chen W, Qiao Y, Bai R, Duan X, Zhang K, Chen X, Li X, Mo S, Cao W, Li X, Liu K, Dong Z, Lu J. Diosmetin suppresses the progression of ESCC by CDK2/Rb/E2F2/RRM2 pathway and synergies with cisplatin. Oncogene 2023:10.1038/s41388-023-02750-2. [PMID: 37349644 DOI: 10.1038/s41388-023-02750-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 05/31/2023] [Accepted: 06/09/2023] [Indexed: 06/24/2023]
Abstract
Cisplatin (CDDP) is the first-line drug in the clinical treatment of esophageal squamous cell carcinoma (ESCC), which has severe nephrotoxicity. Diosmetin (DIOS) can protect kidney from oxidative damage, however, its function in ESCC is unknown. This study aims to explore the effect and mechanism of DIOS on ESCC and its combined effect with CDDP. Herein, we found that DIOS significantly inhibited the progression of ESCC in vitro and in vivo. Furthermore, the anti-tumor effect of DIOS was not statistically different from that of CDDP. Mechanically, transcriptomics revealed that DIOS inhibited the E2F2/RRM2 signaling pathway. The transcriptional regulation of RRM2 by E2F2 was verified by luciferase assay. Moreover, docking model, CETSA, pull-down assay and CDK2 inhibitor assay confirmed that DIOS directly targeted CDK2, leading to significant suppression of ESCC. Additionally, the patient-derived xenografts (PDX) model showed that the combination of DIOS and CDDP significantly inhibited the growth of ESCC. Importantly, the combined treatment with DIOS and CDDP significantly reduced the mRNA expression levels of kidney injury biomarkers KIM-1 and NGAL in renal tissue, as well as the levels of blood urea nitrogen, serum creatinine and blood uric acid compared to the single treatment with CDDP. In conclusion, DIOS could be an effective drug and a potential chemotherapeutic adjuvant for ESCC treatment. Furthermore, DIOS could reduce the nephrotoxicity of CDDP to some extent.
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Affiliation(s)
- Yihuan Chen
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China
| | - Xiaoshuo Dai
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China
| | - Wei Chen
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China
| | - Yan Qiao
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China
- Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province, 450052, PR China
| | - Ruihua Bai
- Department of Pathology, Henan Cancer Hospital, Zhengzhou University, Zhengzhou, Henan Province, 450003, PR China
| | - Xiaoxuan Duan
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China
| | - Kai Zhang
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China
| | - Xinhuan Chen
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China
- Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province, 450052, PR China
| | - Xin Li
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China
- Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province, 450052, PR China
| | - Saijun Mo
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China
- Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province, 450052, PR China
| | - Wenbo Cao
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China
- Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province, 450052, PR China
| | - Xiang Li
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China
- Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province, 450052, PR China
| | - Kangdong Liu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China
- Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province, 450052, PR China
| | - Ziming Dong
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China
- Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province, 450052, PR China
| | - Jing Lu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China.
- Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China.
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province, 450052, PR China.
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Doghish AS, El-Husseiny AA, Abdelmaksoud NM, El-Mahdy HA, Elsakka EGE, Abdel Mageed SS, Mahmoud AMA, Raouf AA, Elballal MS, El-Dakroury WA, AbdelRazek MMM, Noshy M, El-Husseiny HM, Abulsoud AI. The interplay of signaling pathways and miRNAs in the pathogenesis and targeted therapy of esophageal cancer. Pathol Res Pract 2023; 246:154529. [PMID: 37196470 DOI: 10.1016/j.prp.2023.154529] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/06/2023] [Accepted: 05/08/2023] [Indexed: 05/19/2023]
Abstract
Globally, esophageal cancer (EC) is the 6th leading cause of cancer-related deaths and the second deadliest gastrointestinal cancer. Multiple genetic and epigenetic factors, such as microRNAs (miRNAs), influence its onset and progression. miRNAs are short nucleic acid molecules that can regulate multiple cellular processes by regulating gene expression. Therefore, EC initiation, progression, apoptosis evasions, invasion capacity, promotion, angiogenesis, and epithelial-mesenchymal transition (EMT) enhancement are associated with miRNA expression dysregulation. Wnt/-catenin signaling, Mammalian target of rapamycin (mTOR)/P-gp, phosphoinositide-3-kinase (PI3K)/AKT/c-Myc, epidermal growth factor receptor (EGFR), and transforming growth factor (TGF)-β signaling are crucial pathways in EC that are controlled by miRNAs. This review was conducted to provide an up-to-date assessment of the role of microRNAs in EC pathogenesis and their modulatory effects on responses to various EC treatment modalities.
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Affiliation(s)
- Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
| | - Ahmed A El-Husseiny
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt; Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City 11829, Cairo, Egypt
| | - Nourhan M Abdelmaksoud
- Department of Biochemistry and Biotechnology, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Hesham A El-Mahdy
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
| | - Elsayed G E Elsakka
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Abdulla M A Mahmoud
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ahmed Amr Raouf
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Mohammed S Elballal
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Walaa A El-Dakroury
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Mohamed M M AbdelRazek
- Department of Pharmacognosy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Mina Noshy
- Clinical Pharmacy Department, Faculty of Pharmacy, King Salman International University (KSIU), SouthSinai, Ras Sudr 46612, Egypt
| | - Hussein M El-Husseiny
- Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai Cho, Fuchu-shi, Tokyo 183-8509, Japan; Department of Surgery, Anesthesiology, and Radiology, Faculty of Veterinary Medicine, Benha University, Moshtohor, Toukh, Elqaliobiya 13736, Egypt
| | - Ahmed I Abulsoud
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt; Department of Biochemistry and Biotechnology, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
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7
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Song P, Chen X, Zhang P, Zhou Y, Zhou R. miR-200b/MYBL2/CDK1 suppresses proliferation and induces senescence through cell cycle arrest in ovine granulosa cells. Theriogenology 2023; 207:19-30. [PMID: 37257219 DOI: 10.1016/j.theriogenology.2023.05.022] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/21/2023] [Accepted: 05/23/2023] [Indexed: 06/02/2023]
Abstract
Normal growth of granulosa cells (GCs) is essential for follicular development. miR-200b plays a vital role in litter size, estrous cycle, ovulation, and follicular development in sheep. However, it is unclear that the specific effect and regulatory mechanism of miR-200b on ovine GCs. miR-200b mimic inhibited GCs proliferation and induced cellular senescence through downregulating mitochondrial membrane potential (MMP), concentration of ATP and mitochondrial respiratory chain complex Ⅰ, and upregulating SA-β-gal positive rate and ROS production. A total of 597 differentially expressed genes were identified by RNA-Seq in GCs transfected with miR-200b mimic and mimic NC, and they were involved in cell cycle and cellular senescence. miR-200b directly targeted and downregulated MYBL2 and CDK1. Overexpression of MYBL2 promoted GCs proliferation and genes expression (CDK1, CDC20, MAD2L1 and FOXM1), which were suppressed by miR-200b mimic. Furthermore, MYBL2 negatively regulated miR-200b-induced GC senescence. In conclusion, miR-200b/MYBL2/CDK1 regulated proliferation and senescence through cell cycle pathway in ovine granulosa cells. Our study provides a novel insight that miR-200b regulates ovine follicular development.
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Affiliation(s)
- Pengyan Song
- College of Animal Science and Technology, Hebei Agricultural University, Baoding, Hebei Province, 071001, China
| | - Xiaoyong Chen
- College of Animal Science and Technology, Hebei Agricultural University, Baoding, Hebei Province, 071001, China
| | - Peiying Zhang
- College of Animal Science and Technology, Hebei Agricultural University, Baoding, Hebei Province, 071001, China
| | - Ying Zhou
- College of Animal Science and Technology, Hebei Agricultural University, Baoding, Hebei Province, 071001, China
| | - Rongyan Zhou
- College of Animal Science and Technology, Hebei Agricultural University, Baoding, Hebei Province, 071001, China.
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8
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Darvish L, Bahreyni Toossi MT, Azimian H, Shakeri M, Dolat E, Ahmadizad Firouzjaei A, Rezaie S, Amraee A, Aghaee-Bakhtiari SH. The role of microRNA-induced apoptosis in diverse radioresistant cancers. Cell Signal 2023; 104:110580. [PMID: 36581218 DOI: 10.1016/j.cellsig.2022.110580] [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: 09/18/2022] [Revised: 12/07/2022] [Accepted: 12/21/2022] [Indexed: 12/27/2022]
Abstract
Resistance to cancer radiotherapy is one of the biggest concerns for success in treating and preventing recurrent disease. Malignant tumors may develop when they block genetic mutations associated with apoptosis or abnormal expression of apoptosis; Tumor treatment may induce the expression of apoptosis-related genes to promote tumor cell apoptosis. MicroRNAs have been shown to contribute to forecasting prognosis, distinguishing between cancer subtypes, and affecting treatment outcomes in cancer. Constraining these miRNAs may be an attractive treatment strategy to help overcome radiation resistance. The delivery of these future treatments is still challenging due to the excess downstream targets that each miRNA can control. Understanding the role of miRNAs brings us one step closer to attaining patient treatment and improving patient outcomes. This review summarized the current information on the role of microRNA-induced apoptosis in determining the radiosensitivity of various cancers.
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Affiliation(s)
- Leili Darvish
- Department of Medical Physics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Hosein Azimian
- Department of Medical Physics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Physics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahsa Shakeri
- Department of Medical Physics and Biomedical Engineering, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Research Center for Molecular and Cellular Imaging, Tehran University of Medical Sciences, Tehran, Iran
| | - Elham Dolat
- Department of Medical Physics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Ahmadizad Firouzjaei
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Samaneh Rezaie
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Azadeh Amraee
- Department of Medical Physics, Faculty of Medicine, School of Medicine, Lorestan University of Medical Sciences, khorramabad, Iran
| | - Seyed Hamid Aghaee-Bakhtiari
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Bioinformatics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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9
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Klicka K, Grzywa TM, Mielniczuk A, Klinke A, Włodarski PK. The role of miR-200 family in the regulation of hallmarks of cancer. Front Oncol 2022; 12:965231. [PMID: 36158660 PMCID: PMC9492973 DOI: 10.3389/fonc.2022.965231] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 08/04/2022] [Indexed: 11/16/2022] Open
Abstract
MiRNAs are short non-coding RNAs that regulate gene expression post-transcriptionally contributing to the development of different diseases including cancer. The miR-200 family consists of five members, miR-200a, miR-200b, miR-200c, miR-141, and miR-429. Their expression is dysregulated in cancer tissue and their level is altered in the body fluids of cancer patients. Moreover, the levels of miR-200 family members correlate with clinical parameters such as cancer patients' survival which makes them potentially useful as diagnostic and prognostic biomarkers. MiRNAs can act as either oncomiRs or tumor suppressor miRNAs depending on the target genes and their role in the regulation of key oncogenic signaling pathways. In most types of cancer, the miR-200 family acts as tumor suppressor miRNA and regulates all features of cancer. In this review, we summarized the expression pattern of the miR-200 family in different types of cancer and their potential utility as biomarkers. Moreover, we comprehensively described the role of miR-200 family members in the regulation of all hallmarks of cancer proposed by Hanahan and Weinberg with the focus on the epithelial-mesenchymal transition, invasiveness, and metastasis of tumor cells.
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Affiliation(s)
- Klaudia Klicka
- Department of Methodology, Medical University of Warsaw, Warsaw, Poland
- Doctoral School, Medical University of Warsaw, Warsaw, Poland
| | - Tomasz M. Grzywa
- Department of Methodology, Medical University of Warsaw, Warsaw, Poland
- Department of Immunology, Medical University of Warsaw, Warsaw, Poland
- Laboratory of Experimental Medicine, Medical University of Warsaw, Warsaw, Poland
| | | | - Alicja Klinke
- Department of Methodology, Medical University of Warsaw, Warsaw, Poland
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10
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Chu CY, Wang R, Liu XL. Roles of Wnt/β-catenin signaling pathway related microRNAs in esophageal cancer. World J Clin Cases 2022; 10:2678-2686. [PMID: 35434118 PMCID: PMC8968815 DOI: 10.12998/wjcc.v10.i9.2678] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 10/25/2021] [Accepted: 02/16/2022] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are endogenous, noncoding, single-stranded small RNAs that regulate expression of tumor suppressor genes and oncogenes and are involved in almost all tumor-related processes. MiRNA dysregulation plays an important role in the occurrence and development of esophageal cancer through specific signal pathways, including the Wnt/β-catenin signaling pathway, and is closely related to the malignant characteristics of esophageal cancer. The interaction between miRNAs and the Wnt/β-catenin signaling pathway, which is specifically expressed in esophageal cancer tissues, shows potential as a new biomarker and therapeutic target. This article reviews the role of miRNAs related to the Wnt pathway in the carcinogenesis of esophageal carcinoma and its role in Wnt signal transduction. The content of this review can be used as the basis for formulating or improving the treatment strategy of esophageal cancer.
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Affiliation(s)
- Chao-Yang Chu
- Gastrointestinal Surgery, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, Henan Province, China
| | - Rui Wang
- Oncology, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, Henan Province, China
| | - Xian-Li Liu
- Gastrointestinal Surgery, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, Henan Province, China
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11
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Yu L, Zheng Y, Gao L. MiRNA-disease association prediction based on meta-paths. Brief Bioinform 2022; 23:6501422. [PMID: 35018405 DOI: 10.1093/bib/bbab571] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 12/02/2021] [Accepted: 12/11/2021] [Indexed: 01/09/2023] Open
Abstract
Since miRNAs can participate in the posttranscriptional regulation of gene expression, they may provide ideas for the development of new drugs or become new biomarkers for drug targets or disease diagnosis. In this work, we propose an miRNA-disease association prediction method based on meta-paths (MDPBMP). First, an miRNA-disease-gene heterogeneous information network was constructed, and seven symmetrical meta-paths were defined according to different semantics. After constructing the initial feature vector for the node, the vector information carried by all nodes on the meta-path instance is extracted and aggregated to update the feature vector of the starting node. Then, the vector information obtained by the nodes on different meta-paths is aggregated. Finally, miRNA and disease embedding feature vectors are used to calculate their associated scores. Compared with the other methods, MDPBMP obtained the highest AUC value of 0.9214. Among the top 50 predicted miRNAs for lung neoplasms, esophageal neoplasms, colon neoplasms and breast neoplasms, 49, 48, 49 and 50 have been verified. Furthermore, for breast neoplasms, we deleted all the known associations between breast neoplasms and miRNAs from the training set. These results also show that for new diseases without known related miRNA information, our model can predict their potential miRNAs. Code and data are available at https://github.com/LiangYu-Xidian/MDPBMP.
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Affiliation(s)
- Liang Yu
- School of Computer Science and Technology, Xidian University, Xi'an 710071, P.R. China
| | - Yujia Zheng
- School of Computer Science and Technology, Xidian University, Xi'an 710071, P.R. China
| | - Lin Gao
- School of Computer Science and Technology, Xidian University, Xi'an 710071, P.R. China
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12
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The Roles of the Colon Cancer Associated Transcript 2 (CCAT2) Long Non-Coding RNA in Cancer: A Comprehensive Characterization of the Tumorigenic and Molecular Functions. Int J Mol Sci 2021; 22:ijms222212491. [PMID: 34830370 PMCID: PMC8620102 DOI: 10.3390/ijms222212491] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/17/2021] [Accepted: 11/17/2021] [Indexed: 12/12/2022] Open
Abstract
Colon cancer-associated transcript 2 (CCAT2) is an intensively studied lncRNA with important regulatory roles in cancer. As such, cumulative studies indicate that CCAT2 displays a high functional versatility due to its direct interaction with multiple RNA binding proteins, transcription factors, and other species of non-coding RNA, especially microRNA. The definitory mechanisms of CCAT2 are its role as a regulator of the TCF7L2 transcription factor, enhancer of MYC expression, and activator of the WNT/β-catenin pathway, as well as a role in promoting and maintaining chromosome instability through the BOP1–AURKB pathway. Additionally, we highlight how the encompassing rs6983267 SNP has been shown to confer CCAT2 with allele-specific functional and structural particularities, such as the allelic-specific reprogramming of glutamine metabolism. Additionally, we emphasize CCAT2’s role as a competitive endogenous RNA (ceRNA) for multiple tumor suppressor miRNAs, such as miR-4496, miR-493, miR-424, miR-216b, miR-23b, miR-34a, miR-145, miR-200b, and miR-143 and the pro-tumorigenic role of the altered regulatory axis. Additionally, due to its upregulation in tumor tissues, wide distribution across cancer types, and presence in serum samples, we outline CCAT2’s potential as a biomarker and disease indicator and its implications for the development of resistance against current cancer therapy regiments and metastasis.
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13
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Wang J, Yao R, Luo Q, Tan L, Jia B, Ouyang N, Li Y, Tong J, Li J. miR‑200b upregulation promotes migration of BEAS‑2B cells following long‑term exposure to cigarette smoke by targeting ETS1. Mol Med Rep 2021; 24:562. [PMID: 34109431 PMCID: PMC8201442 DOI: 10.3892/mmr.2021.12201] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 05/18/2021] [Indexed: 12/24/2022] Open
Abstract
Cigarette smoking is the leading cause of all histological types of lung cancer, and the role that microRNAs (miRNAs) serve in its pathogenesis is being increasingly recognized. The aim of the present study was to investigate the role of miR‑200b on migration in cigarette smoke‑induced malignant transformed cells. In the present study, miR‑200b expression was found to be increased in cigarette smoke (CS)‑exposed BEAS‑2B cells, lung cancer cell lines and tumor tissue samples. Using wound healing and Transwell migration assays, the migratory ability was shown to be increased in miR‑200b‑overexpressing cells, whereas miR‑200b knockdown resulted in reduced migration. Additionally, the expression of E‑Cadherin was downregulated, whereas that of N‑Cadherin was upregulated in miR‑200b mimic‑transfected cells, suggesting an increase in epithelial‑mesenchymal transition. Downstream, using four target gene prediction tools, six target genes of miR‑200b were predicted, amongst which, ETS proto‑oncogene 1 transcription factor (ETS1) was shown to be significantly associated with tumor invasion depth and negatively associated with miR‑200b expression. The interaction between miR‑200b and ETS1 was confirmed using a dual‑luciferase reporter assay. Using rescue experiments, the increased migratory ability of the miR‑200b‑overexpressing cells was reversed by ETS1 overexpression. In summary, this study showed that miR‑200b overexpression serves a carcinogenic role and promotes the migration of BEAS‑2B cells following long‑term exposure to CS by targeting ETS1.
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Affiliation(s)
- Jin Wang
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Ruixin Yao
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Qiulin Luo
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Lirong Tan
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Beibei Jia
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Nan Ouyang
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Yezhou Li
- School of Medicine, University of Manchester, M13 9PL Manchester, UK
| | - Jian Tong
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Jianxiang Li
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
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14
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Wu X, Fan Y, Liu Y, Shen B, Lu H, Ma H. Long Non-Coding RNA CCAT2 Promotes the Development of Esophageal Squamous Cell Carcinoma by Inhibiting miR-200b to Upregulate the IGF2BP2/TK1 Axis. Front Oncol 2021; 11:680642. [PMID: 34386421 PMCID: PMC8353391 DOI: 10.3389/fonc.2021.680642] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 05/21/2021] [Indexed: 01/14/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) have been shown to play important roles in human cancers, including esophageal squamous cell carcinoma (ESCC). In the current study, we identified CCAT2 as a relevant lncRNA and investigated its role in the progression of ESCC. RT-qPCR was adopted to detect CCAT2 expression in collected clinical samples, ESCC cell lines, and a normal cell line. We tested the correlation between CCAT2 expression and the prognosis of ESCC. RT-qPCR or immunoblotting was adopted to detect the expression of relevant factors in ESCC tissues or cells. Cell proliferation, apoptosis, migration, and invasion were examined by colony formation assay, flow cytometry, scratch assay, and Transwell assay, respectively, while subcutaneous tumorigenesis in nude mice was adopted to examine the role of CCAT2 in tumorigenesis of ESCC cells in vivo. Bioinformatics analysis, dual luciferase reporter assay, and RIP were conducted for the target relationship profiling. Me-RIP was adopted to detect m6A modification level of TK1 in ESCC tissues or cells. Upregulated CCAT2, IGF2BP2, and TK1 expression and inhibited miR-200b expression were observed in ESCC cells and tissues. CCAT2 bound to miR-200b and reduced its expression, leading to upregulated IGF2BP2 expression. IGF2BP2 improved TK1 mRNA stability to enhance its expression by recognizing its m6A modification. CCAT2 promoted the migration and invasion of ESCC cells in vitro, and tumorigenesis in vivo by upregulating TK1 expression, while overexpression of miR-200b reversed these effects of CCAT2. Overall, this study suggests that CCAT2 competitively binds to miR-200b to alleviate its inhibitory effects on IGF2BP2 expression, resulting in elevated TK1 expression, and an ensuing promotion of the development of ESCC.
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Affiliation(s)
- Xiaodan Wu
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.,Department of Thoracic Surgery, Nantong Tumor Hospital, Nantong, China
| | - Yihui Fan
- Department of Thoracic Surgery, Nantong Tumor Hospital, Nantong, China
| | - Yupeng Liu
- Department of Thoracic Surgery, Nantong Tumor Hospital, Nantong, China
| | - Biao Shen
- Department of Thoracic Surgery, Nantong Tumor Hospital, Nantong, China
| | - Haimin Lu
- Department of Thoracic Surgery, Nantong Tumor Hospital, Nantong, China
| | - Haitao Ma
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
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15
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miRNAs Involved in Esophageal Carcinogenesis and miRNA-Related Therapeutic Perspectives in Esophageal Carcinoma. Int J Mol Sci 2021; 22:ijms22073640. [PMID: 33807389 PMCID: PMC8037581 DOI: 10.3390/ijms22073640] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/26/2021] [Accepted: 03/29/2021] [Indexed: 12/24/2022] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that play a pivotal role in many aspects of cell biology, including cancer development. Within esophageal cancer, miRNAs have been proved to be involved in all phases of carcinogenesis, from initiation to metastatic spread. Several miRNAs have been found to be dysregulated in esophageal premalignant lesions, namely Barrett’s esophagus, Barrett’s dysplasia, and squamous dysplasia. Furthermore, numerous studies have investigated the alteration in the expression levels of many oncomiRNAs and tumor suppressor miRNAs in esophageal squamous cell carcinoma and esophageal adenocarcinoma, thus proving how miRNAs are able modulate crucial regulatory pathways of cancer development. Considering these findings, miRNAs may have a role not only as a diagnostic and prognostic tool, but also as predictive biomarker of response to anti-cancer therapies and as potential therapeutic targets. This review aims to summarize several studies on the matter, focusing on the possible diagnostic–therapeutic implications.
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16
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MicroRNA profiling identifies Forkhead box transcription factor M1 (FOXM1) regulated miR-186 and miR-200b alterations in triple negative breast cancer. Cell Signal 2021; 83:109979. [PMID: 33744419 DOI: 10.1016/j.cellsig.2021.109979] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 03/09/2021] [Accepted: 03/10/2021] [Indexed: 02/07/2023]
Abstract
Breast cancer (BC) is the most commonly diagnosed malignancy. MicroRNAs (miRNAs) play important roles in the tumorigenesis, metastasis and progression of BC. Forkhead Box M1 (FOXM1) oncogenic transcription factor is involved in events considered as hallmarks of cancer. However, the specific mechanism by which FOXM1 exerts its oncogenic effects remains unclear and little is known about its effects on the regulation of miRNA expression. We have found that FOXM1 is upregulated in breast cancer cells and that its expression is associated with shortened overall survival and poor prognosis in patients with BC. Using microarray technology, we assessed the expression profiles of 752 miRNAs in highly aggressive and metastatic triple negative breast cancer (TNBC) cells in response to FOXM1 knockdown and identified 13 differentialy expressed miRNAs (3 miRNAs upregulated and 10 miRNAs down-regulated). We validated the results of the miRNA expression profile in two different TNBC cells by performing qRT-PCR and identified that miR-186-5p and miR-200b-5p were consistently down- or up-regulated, respectively, after knockdown of FOXM1. We further performed KEGG pathway analysis and GO enrichment analysis for miR-186-5p and miR-200b-5p, and identified that these miRNAs are associated with cancer development and progression involving toll-like receptor signaling, cell cycle, AMPK, p53 and NF-kappa B signaling pathways. Taken together, our results suggest that increased FOXM1 expression is associated with poor patient survival and leads to induction of oncomiR miR-186-5p expression and tumor-suppressor inhibition miR-200b-5p, suggesting that the FOXM1/miRNA signaling pathway may contribute to poor patient prognosis and may be a potential therapeutic target in TNBC.
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17
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Jin HF, Wang JF, Song TT, Zhang J, Wang L. MiR-200b Inhibits Tumor Growth and Chemoresistance via Targeting p70S6K1 in Lung Cancer. Front Oncol 2020; 10:643. [PMID: 32435616 PMCID: PMC7218114 DOI: 10.3389/fonc.2020.00643] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 04/07/2020] [Indexed: 01/17/2023] Open
Abstract
Downregulation of microRNA-200b (miR-200b) has been identified in a range of cancers, yet the specific mechanisms whereby it influences lung cancer growth require further exploration. We determined that lung cancer patient tumor samples exhibit decreased miR-200b expression, and we further found this miRNA to inhibit tumor growth via interfering with ERK1/2 and AKT signaling, targeting p70S6K1 to suppress HIF-1α expression. This miRNA further rendered H1299 cells more sensitive to cisplatin while impairing their proliferative and invasive potential through its ability to target and inhibit the activity of p70S6K1. These results were further confirmed in a murine xenograft model in which miR-200b also inhibited the growth of tumor and suppressed p70S6K1, p-AKT, p-ERK1/2, and HIF-1α expression. These findings clearly demonstrate a role for miR-200b in suppressing lung cancer development, making it a potentially relevant target for future diagnostic and therapeutic interventions.
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Affiliation(s)
- Hui-Fang Jin
- Department of Blood Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ju-Feng Wang
- Department of Oncology, Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Ting-Ting Song
- Department of Obstetrics and Gynecology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Jun Zhang
- Department of Thoracic Surgery, Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Lin Wang
- Department of Blood Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
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18
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Dysregulated NF-κB signal promotes the hub gene PCLAF expression to facilitate nasopharyngeal carcinoma proliferation and metastasis. Biomed Pharmacother 2020; 125:109905. [PMID: 32070873 DOI: 10.1016/j.biopha.2020.109905] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Revised: 12/22/2019] [Accepted: 12/30/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Nasopharyngeal carcinoma (NPC) is common in Southern China. The molecular mechanism underlying NPC genesis and progression has been comprehensively investigated, but the key gene (s) or pathway (s) pertaining to NPC are unidentified. METHODS We explored some key genes and pathways involved in NPC through using meta-analysis of deposited expression of microarray data of NPC. The expression of proliferating cell nuclear antigen clamp associated factor (PCLAF) was determined by real-time PCR and western blots. CCK-8 assay, colony formation assay, transwell migration assay, cell wound healing assay, cell cycle analysis and cell apoptosis were carried out to assess biological behaviors caused by downregulation and overexpression of PCLAF in vitro. CHIP was utilized to determine the direct upstream regulatory transcription factors of PCLAF. RESULTS PCLAF was the key gene of NPC, which was significantly up-regulated in NPC cell line compared to the normal nasopharyngeal cell line. Additionally, in vitro assay has demonstrated the down-regulation and overexpression of PCLAF, resulted in significantly suppressed and enhanced NPC proliferation, metastasis and invasion respectively. Furthermore, the up-regulation of PCLAF in NPC is induced by direct binding of dysregulated NF-κB p50/RelB complex to the promoter of PCLAF. CONCLUSION Our results offer a strategy for re-using the deposited data to find the key genes and pathways involved in pathogenesis of cancer. Our study has provided evidence of supporting the role of PCLAF in NPC genesis and progression.
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Yang F, Fu Z, Yang M, Sun C, Li Y, Chu J, Zhang Y, Li W, Huang X, Li J, Wu H, Ding X, Yin Y. Expression pattern of microRNAs related with response to trastuzumab in breast cancer. J Cell Physiol 2019; 234:16102-16113. [PMID: 30770556 DOI: 10.1002/jcp.28268] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2018] [Revised: 01/08/2019] [Accepted: 01/10/2019] [Indexed: 01/24/2023]
Abstract
BACKGROUND Although an immense effort has been made to develop a novel biomarker for response to trastuzumab, no reliable biomarkers are available to guide management, expect for HER2. The aim of this study was to examine the relationship between microRNA (miRNA) expression and resistance to trastuzumab. METHODS Differentially expressed miRNAs between trastuzumab-resistant and trastuzumab-sensitive cell lines were analyzed using microarrays. We performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to determine the functions of differentially expressed miRNA and their targeted genes. Furthermore, the protein-protein interactions (PPI) network was analyzed. Serum samples were collected from patients with HER2-positive breast cancer who were treated with trastuzumab. We validated the miRNAs expression levels by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) in these serums. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive performance of the miRNA. RESULTS Using miRNA microarrays, 151 miRNAs that significant differentially expressed between the trastuzumab-resistant and sensitive cells were identified, including 46 upregulated and 105 downregulated miRNAs. Results of real-time PCR confirmed seven miRNAs in cell lines. PI3K-Akt signaling pathway was involved in regulating biological function according to KEGG analysis. Compared with the serums of trastuzumab-sensitive patients, three miRNAs, namely miR-200b, miR-135b, and miR-29a, were identified to be upregulated, and miR-224 was downregulated in the trastuzumab-resistant serums. ROC analysis showed that four miRNAs were correlated with trastuzumab resistance. Furthermore, three subnetwork modules of PPI network were obtained. CONCLUSION The results indicated that miRNAs were reliable predictive biomarkers for response to trastuzumab.
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Affiliation(s)
- Fan Yang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,The First Clinical College of Nanjing Medical University, Nanjing, China
| | - Ziyi Fu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Nanjing Maternal and Child Health Institute, The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Mengzhu Yang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,The First Clinical College of Nanjing Medical University, Nanjing, China
| | - Chunxiao Sun
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,The First Clinical College of Nanjing Medical University, Nanjing, China
| | - Yongfei Li
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,The First Clinical College of Nanjing Medical University, Nanjing, China
| | - Jiahui Chu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,The First Clinical College of Nanjing Medical University, Nanjing, China
| | - Yanhong Zhang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,The First Clinical College of Nanjing Medical University, Nanjing, China
| | - Wei Li
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiang Huang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jun Li
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hao Wu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaorong Ding
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,The First Clinical College of Nanjing Medical University, Nanjing, China
| | - Yongmei Yin
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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20
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Li Y, Guan B, Liu J, Zhang Z, He S, Zhan Y, Su B, Han H, Zhang X, Wang B, Li X, Zhou L, Zhao W. MicroRNA-200b is downregulated and suppresses metastasis by targeting LAMA4 in renal cell carcinoma. EBioMedicine 2019; 44:439-451. [PMID: 31130475 PMCID: PMC6604878 DOI: 10.1016/j.ebiom.2019.05.041] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 05/15/2019] [Accepted: 05/15/2019] [Indexed: 01/14/2023] Open
Abstract
Background Metastasis is the primary cause of tumor death in renal cell carcinoma (RCC). Improved diagnostic markers of metastasis are critically needed for RCC. MicoRNAs are demonstrated to be stable and significant biomarkers for several malignancies. In this study, we aimed to explore the metastasis related microRNAs and its mechanism in RCC. Methods The relationship between microRNAs expression and prognosis and metastasis of RCC patients were explored by data mining through expression profiles from The Cancer Genome Atlas (TCGA). A total of 80 RCC tissues and adjacent normal kidney tissues were obtained from Department of Urology, Peking University First Hospital. Expression of microRNA-200b (miR-200b) in RCC tissues and cell lines were determined by bioinformatic data mining and quantitative real-time PCR (qRT-PCR). The effects of miR-200b on cell proliferation, migration and invasion were determined by cell counting kit-8 and colony formation assay, wound healing assay and Boyden chamber assay. Mouse cell-derived xenograft and patient-derived xenograft model were also performed to evaluate the effects of miR-200b on tumor growth and metastasis in vivo. The molecular mechanism of miR-200b function was investigated using bioinformatic target predication and high-throughput cDNA sequencing (RNA-seq) and validated by luciferase reporter assay, qRT-PCR, Western blot and immunostaining in vitro and in vivo. Findings Our findings indicates that miR-200b is frequently downregulated and have potential utility as a biomarker of metastasis and prognosis in RCC. Interestingly, ectopic expression of miR-200b in the Caki-1 and OSRC-2 cell lines suppresses cell migration and invasion in vitro as well as tumor metastases in vivo. However, miR-200b has no effect on cell proliferation in vitro and tumor growth in vivo. In addition, bioinformatics target predication and RNA-seq results reveals that Laminin subunit alpha 4 (LAMA4) is one target of miR-200b and significantly inhibited by miR-200b in vitro and in vivo. Interpretation These results demonstrate a previously undescribed role of miR-200b as a suppressor of tumor metastasis in RCC by directly destabilizing LAMA4 mRNA.
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Affiliation(s)
- Yifan Li
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, China
| | - Bao Guan
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, China
| | - Jingtao Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Pharmacy Department, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Zhongyuan Zhang
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, China
| | - Shiming He
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, China
| | - Yonghao Zhan
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, China
| | - Boxing Su
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, China
| | - Haibo Han
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Xiaochun Zhang
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, China
| | - Boqing Wang
- Department of Hepatopancreatobiliary Surgery, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830011, China
| | - Xuesong Li
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, China.
| | - Liqun Zhou
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, China.
| | - Wei Zhao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital & Institute, Beijing 100142, China.
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21
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Li W, Jia MX, Deng J, Wang JH, Lin QL, Tang JX, Zeng XX, Cai F, Ma L, Su W, Liu XY, Liu C, Wang SS, Zhou LY. Down-regulation of microRNA-200b is a potential prognostic marker of lung cancer in southern-central Chinese population. Saudi J Biol Sci 2019; 26:173-177. [PMID: 30622423 PMCID: PMC6319082 DOI: 10.1016/j.sjbs.2018.08.023] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 08/17/2018] [Accepted: 08/22/2018] [Indexed: 12/30/2022] Open
Abstract
MicroRNAs (miRNAs) may regulate diverse biological processes and play an important role in cancer. And MiRNAs have been proposed as a useful tool for lung cancer diagnosis and therapeutics in cancer. The purpose of the present study was to investigate the association among the expression level of mature miR-200b-5p in peripheral blood and the risk of lung cancer and clinic pathological characteristics. This case-control study included 24 patients with lung cancer and 12 healthy controls. MiR-200b expression was deleted using real-time PCR. and the miR-200b expression of normal controls was significantly higher than that in lung cancer patients (1732.13 pg/mL vs 881.67 pg/mL, P < 0.05), no difference with age, sex, tissue type and clinical stage of lung cancer patients (P > 0.05). Furthermore, miR-200b expression level fluctuated with tumor progression in lung cancer, and there was highly significant for clinical stage II compared with the clinical stage III (P < 0.05). In addition, the down-regulation of miR-200b showed a highly discriminative receiver operating characteristic (ROC) curve profile, clearly distinguishing cancer patients from cancer-free subjects with an area under the ROC curve (AUROC) of 0.87. The detection of miR-200b expression yielded 83.30% sensitivity and 100.00% specificity in the diagnosis of lung cancer. Therefore, these findings suggested that miR-200b may be used as a marker for the detection and diagnosis of lung cancer in peripheral blood.
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Affiliation(s)
- Wen Li
- Key Laboratory of Biological Nanomaterials and Devices, College of Life Sciences and Chemistry, Hunan University of Technology, Zhuzhou, Hunan 412007, China.,National Engineering Laboratory for Rice and Byproduct s Deep Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
| | - Ming Xi Jia
- Key Laboratory of Biological Nanomaterials and Devices, College of Life Sciences and Chemistry, Hunan University of Technology, Zhuzhou, Hunan 412007, China
| | - Jing Deng
- Key Laboratory of Biological Nanomaterials and Devices, College of Life Sciences and Chemistry, Hunan University of Technology, Zhuzhou, Hunan 412007, China.,National Engineering Laboratory for Rice and Byproduct s Deep Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China.,Key Laboratory of Advanced Packaging Materials and Technology, College of Packaging and Material Engineering, Hunan University of Technology, Zhuzhou, Hunan 412007, China
| | - Jian Hui Wang
- School of Chemistry and Bioengineering, Changsha University of Science and Technology, Changsha 410114, China
| | - Qin Lu Lin
- National Engineering Laboratory for Rice and Byproduct s Deep Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
| | - Jian Xin Tang
- Key Laboratory of Biological Nanomaterials and Devices, College of Life Sciences and Chemistry, Hunan University of Technology, Zhuzhou, Hunan 412007, China
| | - Xiao Xi Zeng
- Key Laboratory of Biological Nanomaterials and Devices, College of Life Sciences and Chemistry, Hunan University of Technology, Zhuzhou, Hunan 412007, China
| | - Fang Cai
- School of Foreign Language, Hunan University of Technology, Zhuzhou, Hunan 412007, China
| | - Liang Ma
- Key Laboratory of Biological Nanomaterials and Devices, College of Life Sciences and Chemistry, Hunan University of Technology, Zhuzhou, Hunan 412007, China
| | - Wei Su
- Key Laboratory of Biological Nanomaterials and Devices, College of Life Sciences and Chemistry, Hunan University of Technology, Zhuzhou, Hunan 412007, China
| | - Xue Ying Liu
- Key Laboratory of Biological Nanomaterials and Devices, College of Life Sciences and Chemistry, Hunan University of Technology, Zhuzhou, Hunan 412007, China
| | - Cun Liu
- Key Laboratory of Biological Nanomaterials and Devices, College of Life Sciences and Chemistry, Hunan University of Technology, Zhuzhou, Hunan 412007, China
| | - Sha Sha Wang
- Key Laboratory of Biological Nanomaterials and Devices, College of Life Sciences and Chemistry, Hunan University of Technology, Zhuzhou, Hunan 412007, China
| | - Li Yi Zhou
- Key Laboratory of Biological Nanomaterials and Devices, College of Life Sciences and Chemistry, Hunan University of Technology, Zhuzhou, Hunan 412007, China.,National Engineering Laboratory for Rice and Byproduct s Deep Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
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22
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Shimonosono M, Idichi T, Seki N, Yamada Y, Arai T, Arigami T, Sasaki K, Omoto I, Uchikado Y, Kita Y, Kurahara H, Maemura K, Natsugoe S. Molecular pathogenesis of esophageal squamous cell carcinoma: Identification of the antitumor effects of miR‑145‑3p on gene regulation. Int J Oncol 2018; 54:673-688. [PMID: 30535463 DOI: 10.3892/ijo.2018.4657] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 10/19/2018] [Indexed: 11/06/2022] Open
Abstract
Although miR‑145‑5p (the guide strand of the miR‑145 duplex) is established as a tumor suppressive microRNA (miRNA or miR), the functional significance of miR‑145‑3p (the passenger strand of the miR‑145 duplex) in cancer cells and its targets remains obscure. In our continuing analysis of esophageal squamous cell carcinoma (ESCC) pathogenesis, the aim of the present study was to identify important oncogenes and proteins that are controlled by miR‑145‑3p. Overexpression of miR‑145‑3p significantly reduced cancer cell proliferation, migration and invasive abilities, and further increased apoptotic abilities. In ESCC cells, 30 possible oncogenic targets were identified that might be regulated by miR‑145‑3p. Among these targets, dehydrogenase/reductase member 2 (DHRS2) and myosin IB (MYO1B) were focused on to investigate their functional roles in ESCC cells. DHRS2 and MYO1B were directly regulated by miR‑145‑3p in ESCC cells by dual luciferase reporter assays. Aberrantly expressed DHRS2 and MYOIB were detected in ESCC clinical specimens, and their overexpression enhanced cancer cell aggressiveness. Genes regulated by antitumor miR‑145‑3p were closely associated with the molecular pathogenesis of ESCC. The approach based on antitumor miRNAs may contribute to the understanding of ESCC molecular pathogenesis.
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Affiliation(s)
- Masataka Shimonosono
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima 890‑8520, Japan
| | - Tetsuya Idichi
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima 890‑8520, Japan
| | - Naohiko Seki
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba 260‑8670, Japan
| | - Yasutaka Yamada
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba 260‑8670, Japan
| | - Takayuki Arai
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba 260‑8670, Japan
| | - Takaaki Arigami
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima 890‑8520, Japan
| | - Ken Sasaki
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima 890‑8520, Japan
| | - Itaru Omoto
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima 890‑8520, Japan
| | - Yasuto Uchikado
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima 890‑8520, Japan
| | - Yoshiaki Kita
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima 890‑8520, Japan
| | - Hiroshi Kurahara
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima 890‑8520, Japan
| | - Kosei Maemura
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima 890‑8520, Japan
| | - Shoji Natsugoe
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima 890‑8520, Japan
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23
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Talukdar FR, di Pietro M, Secrier M, Moehler M, Goepfert K, Lima SSC, Pinto LFR, Hendricks D, Parker MI, Herceg Z. Molecular landscape of esophageal cancer: implications for early detection and personalized therapy. Ann N Y Acad Sci 2018; 1434:342-359. [PMID: 29917250 DOI: 10.1111/nyas.13876] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 05/08/2018] [Accepted: 05/14/2018] [Indexed: 12/12/2022]
Abstract
Esophageal cancer (EC) is one of the most lethal cancers and a public health concern worldwide, owing to late diagnosis and lack of efficient treatment. Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are main histopathological subtypes of EC that show striking differences in geographical distribution, possibly due to differences in exposure to risk factors and lifestyles. ESCC and EAC are distinct diseases in terms of cell of origin, epidemiology, and molecular architecture of tumor cells. Past efforts aimed at translating potential molecular candidates into clinical practice proved to be challenging, underscoring the need for identifying novel candidates for early diagnosis and therapy of EC. Several major international efforts have brought about important advances in identifying molecular landscapes of ESCC and EAC toward understanding molecular mechanisms and critical molecular events driving the progression and pathological features of the disease. In our review, we summarize recent advances in the areas of genomics and epigenomics of ESCC and EAC, their mutational signatures and immunotherapy. We also discuss implications of recent advances in characterizing the genome and epigenome of EC for the discovery of diagnostic/prognostic biomarkers and development of new targets for personalized treatment and prevention.
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Affiliation(s)
- Fazlur Rahman Talukdar
- Section of Mechanisms of Carcinogenesis, International Agency for Research on Cancer (WHO), Lyon, France
| | | | - Maria Secrier
- Department of Genetics, Evolution and Environment, University College London, London, UK
| | - Markus Moehler
- First Department of Internal Medicine, Johannes Gutenberg-University of Mainz, Mainz, Germany
| | - Katrin Goepfert
- First Department of Internal Medicine, Johannes Gutenberg-University of Mainz, Mainz, Germany
| | | | | | - Denver Hendricks
- Division of Medical Biochemistry & Structural Biology, University of Cape Town, Cape Town, South Africa
| | - Mohamed Iqbal Parker
- Division of Medical Biochemistry & Structural Biology, University of Cape Town, Cape Town, South Africa
| | - Zdenko Herceg
- Section of Mechanisms of Carcinogenesis, International Agency for Research on Cancer (WHO), Lyon, France
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24
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Chen X, Cai S, Li B, Zhang X, Li W, Linag H, Cao X. Identification of key genes and pathways for esophageal squamous cell carcinoma by bioinformatics analysis. Exp Ther Med 2018; 16:1121-1130. [PMID: 30112053 PMCID: PMC6090437 DOI: 10.3892/etm.2018.6316] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 04/06/2018] [Indexed: 12/17/2022] Open
Abstract
The aim of the present study was to identify the differentially expressed genes (DEGs) in esophageal squamous-cellcarcinoma (ESCC) and provide potential therapeutic targets. The microarray dataset GSE20347 was downloaded from the Gene Expression Omnibus (GEO) database, and included 17 tissue samples and 13 normal adjacent tissue samples from patients with ESCC. A total of 22,277 DEGs were identified. A heat map for the DEGs was constructed with the Morpheus online tool and the top 200 genes (100 upregulated and 100 downregulated) were selected for further bioinformatics analysis, including analysis of gene ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, protein-protein interaction networks and Spearman's correlation tests. The results of the GO analysis indicated that the upregulated DEGs were most significantly enriched in membrane-bounded vesicles in the cellular component (CC) category, but were not significantly enriched in any GO terms of the categories biological process (BP) or molecular function (MF); furthermore, the downregulated DEGs were most significantly enriched in regulation of DNA metabolic processes, nucleotide binding and chromosomes in the categories BP, MF and CC, respectively. The KEGG analysis indicated that the downregulated DEGs were enriched in the regulation of cell cycle pathways. The top 10 hub proteins in the protein-protein interaction network were cyclin-dependent kinase 4, budding uninhibited by benzimidazoles 1, cyclin B2, heat shock protein 90AA1, aurora kinase A, H2A histone family member Z, replication factor C subunit 4, and minichromosome maintenance complex component 2, −4 and −7. These proteins are mainly involved in regulating tumor progression. The genes in the four top modules were mainly implicated in regulating cell cycle pathways. Secreted Ly-6/uPAR-related protein (SLURP) was the hub gene, and SLURP and its interacting genes were most enriched in the chromosomal part in the CC category, organelle organization in the BP category and protein binding in the MF category, and were involved in pathways including DNA replication, cell cycle and P53 signaling. The expression of SLURP-1 in fifteen patients with esophageal carcinoma was detected using quantitative polymerase chain reaction analysis, and the results indicated that SLURP-1 expression was significantly decreased in the tumor samples relative to that in normal adjacent tissues. These results suggest that several hub proteins and the hub gene SLURP-1 may serve as potential therapeutic targets, and that gene dysfunction may be involved in the tumorigenesis of ESCC.
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Affiliation(s)
- Xiaohua Chen
- Department of Oncology, Panyu Central Hospital, Cancer Institute of Panyu, Guangzhou, Guangdong 511400, P.R. China
| | - Sina Cai
- Department of Oncology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong 510630, P.R. China
| | - Baoxia Li
- State Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Xiaona Zhang
- Graceland Medical Center, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Wenhui Li
- Department of Oncology, Panyu Central Hospital, Cancer Institute of Panyu, Guangzhou, Guangdong 511400, P.R. China
| | - Henglun Linag
- Department of Oncology, Panyu Central Hospital, Cancer Institute of Panyu, Guangzhou, Guangdong 511400, P.R. China
| | - Xiaolong Cao
- Department of Oncology, Panyu Central Hospital, Cancer Institute of Panyu, Guangzhou, Guangdong 511400, P.R. China
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25
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The role of microRNAs in the occurrence and development of esophageal squamous cell carcinoma. ACTA ACUST UNITED AC 2017. [DOI: 10.31491/csrc.2017.12.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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26
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Gao X, Xie Z, Wang Z, Cheng K, Liang K, Song Z. Overexpression of miR-191 Predicts Poor Prognosis and Promotes Proliferation and Invasion in Esophageal Squamous Cell Carcinoma. Yonsei Med J 2017; 58:1101-1110. [PMID: 29047233 PMCID: PMC5653474 DOI: 10.3349/ymj.2017.58.6.1101] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Revised: 07/25/2017] [Accepted: 07/27/2017] [Indexed: 12/19/2022] Open
Abstract
PURPOSE Accumulating evidence has shown that dysregulation of microRNA-191 (miR-191) is closely associated with tumorigenesis and progression in a wide range of cancers. This study aimed to explore the potential role of miR-191 in esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS miR-191 expression was assessed in 93 ESCC tissue specimens by real-time polymerase chain reaction, and survival analysis was performed via Kaplan-Meier and Cox regression analyses. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, plate colony-forming, BrdU, and Transwell assays were conducted to observe the effect of miR-191 on ESCC proliferation and invasion. Luciferase reporter and western blot assays were taken to identify target genes of miR-191. RESULTS miR-191 was overexpressed in 93 cases of ESCC, compared with adjacent normal tissues, and miR-191 expression was significantly related to differentiation, depth of invasion, TNM stage, lymph node metastasis, and distant metastasis of tumor. Kaplan-Meier and Cox regression analyses demonstrated that overexpression of miR-191 was an independent and significant predictor of ESCC prognosis. Both gain-of-function and loss-of-function experiments showed that miR-191 promoted ESCC cell proliferation and invasion activities in vitro. Early growth response 1 (EGR1), a tumor suppressor, was predicted as a direct target of miR-191. Luciferase reporter and western blot assays proved that miR-191 reduced EGR1 expression by directly binding its 3' untranslated region. Moreover, EGR1 knockdown by siRNA enhanced ESCC cell growth and invasion. CONCLUSION Our findings provide specific biological roles of miR-191 in ESCC survival and progression. Targeting the novel miR-191/EGR1 axis represents a potential new therapeutic way to block ESCC development.
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Affiliation(s)
- Xiaotian Gao
- Department of Cardiac Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhanqiang Xie
- Department of Cardiothoracic Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Zhigang Wang
- Department of Cardiothoracic Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Keluo Cheng
- Department of Cardiothoracic Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Ke Liang
- Department of Cardiothoracic Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Zeqing Song
- Department of Internal Medicine, Guangdong Medical University Affiliated Longhua Central Hospital, Shenzhen, China.
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27
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Liu Z, Zhang H. LncRNA plasmacytoma variant translocation 1 is an oncogene in bladder urothelial carcinoma. Oncotarget 2017; 8:64273-64282. [PMID: 28969069 PMCID: PMC5610001 DOI: 10.18632/oncotarget.19604] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 06/12/2017] [Indexed: 12/14/2022] Open
Abstract
Bladder cancer (BC) is the most lethal malignant cancer of the genitourinary system, and bladder urothelial carcinoma (BUC) is the most common type of BC. The long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) is overexpressed in several malignant tumors, including BC. Using a lncRNA array and quantitative real-time PCR, we detected greater expression of PVT1 in BUC tissues and cell lines resistant to doxorubicin (DOX) and cisplatin (DDP) than in DOX- and DDP-sensitive cells. PVT1 knockdown reduced proliferation and invasion by a DOX- and DDP-resistant T24/DR BUC cells, arrested cells in G1 phase, and increased apoptosis. PVT1 knockdown also sensitized T24/DR cells to DOX and DDP, and suppressed expression of multidrug resistance 1 (MDR1) and multidrug resistance associated protein 1 (MRP1). Wnt/β-catenin pathway activation in T24/DR cells reversed the effects of PVT1 knockdown on metastasis-associated behavior and chemoresistance. In sum, lncRNA PVT1 is overexpressed in multidrug resistant BUC tissues and cell lines, and PVT1 knockdown reduces BUC cell proliferation, invasiveness, and chemoresistance by modulating Wnt/β-catenin signaling. These results provide new insight into BUC chemoresistance mechanisms and suggest potential therapeutic targets for anti-BUC therapeutics.
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Affiliation(s)
- Zhongyuan Liu
- Department of Urinary Surgery, Shengjing Hospital, China Medical University, Shenyang 110004, China
| | - Hui Zhang
- Department of Urinary Surgery, Shengjing Hospital, China Medical University, Shenyang 110004, China
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28
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Li D, Wang H, Song H, Xu H, Zhao B, Wu C, Hu J, Wu T, Xie D, Zhao J, Shen Q, Fang L. The microRNAs miR-200b-3p and miR-429-5p target the LIMK1/CFL1 pathway to inhibit growth and motility of breast cancer cells. Oncotarget 2017; 8:85276-85289. [PMID: 29156719 PMCID: PMC5689609 DOI: 10.18632/oncotarget.19205] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Accepted: 06/28/2017] [Indexed: 12/18/2022] Open
Abstract
Triple-negative breast cancer (TNBC) has the worst prognosis of all subtypes of breast cancer (BC), with limited options for conventional therapy and no targeted therapies. MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate gene expression. In this study, we aimed to determine whether two members of the miR-200 family, miR-200b-3p and miR-429-5p, are involved in BC cell proliferation and motility and to elucidate their target genes and pathways. We performed a meta-analysis that reveals down-regulated expression of miR-200b-3p and miR-429-5p in BC tissues and cell lines, consistent with a lower expression of miR-200b-3p and miR-429-5p in MDA-MB-231 and HCC1937 cells than in MCF-7 and MCF-10 cells. Overexpression of miR-200b-3p and miR-429-5p significantly inhibited the proliferation, migration, and invasion of TNBC cells; suppressed the expression of markers for proliferation and metastasis in TNBC cells. We next demonstrated that LIM domain kinase 1 (LIMK1) is a direct target gene of miR-200b-3p and miR-429-5p. Inhibition of LIMK1 reduced the expression and phosphorylation of cofilin 1 (CFL1), which polymerizes and depolymerizes F-actin and G-actin to reorganize cellular actin cytoskeleton. In addition, transfection with mimics for miR-200b-3p and miR-429-5p arrested G2/M and G0/G1 cell cycles respectively, suppressed the expression of the cell cycle–related complexes, cyclin D1/CDK4/CDK6 and cyclin E1/CDK2, in TNBC cells. In conclusion, miR-200b-3p and miR-429-5p suppress proliferation, migration, and invasion in TNBC cells, via the LIMK1/CFL1 pathway. These results provide insight into how specific miRNAs regulate TNBC progression and suggest that the LIMK1/CFL1 pathway is a therapeutic target for treating TNBC.
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Affiliation(s)
- Dengfeng Li
- Department of Thyroid and Breast, Division of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China.,Department of Clinical Cancer Prevention, Division of Cancer Prevention and Population Science, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, United States
| | - Hong Wang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, People's Republic of China.,Department of Clinical Cancer Prevention, Division of Cancer Prevention and Population Science, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, United States
| | - Hongming Song
- Department of Thyroid and Breast, Division of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China
| | - Hui Xu
- Department of Thyroid and Breast, Division of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China
| | - Bingkun Zhao
- Department of Thyroid and Breast, Division of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China
| | - Chenyang Wu
- Department of Thyroid and Breast, Division of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China
| | - Jiashu Hu
- Department of Thyroid and Breast, Division of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China
| | - Tianqi Wu
- Department of Thyroid and Breast, Division of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China
| | - Dan Xie
- Department of Thyroid and Breast, Division of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China
| | - Junyong Zhao
- Department of Thyroid and Breast, Division of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China
| | - Qiang Shen
- Department of Clinical Cancer Prevention, Division of Cancer Prevention and Population Science, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, United States
| | - Lin Fang
- Department of Thyroid and Breast, Division of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China
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29
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Li Z, Wu X, Gu L, Shen Q, Luo W, Deng C, Zhou Q, Chen X, Li Y, Lim Z, Wang X, Wang J, Yang X. Long non-coding RNA ATB promotes malignancy of esophageal squamous cell carcinoma by regulating miR-200b/Kindlin-2 axis. Cell Death Dis 2017. [PMID: 28640252 PMCID: PMC5520904 DOI: 10.1038/cddis.2017.245] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the leading causes of cancer-related death, especially in China. In addition, the prognosis of late stage patients is extremely poor. However, the biological significance of the long non-coding RNA lnc-ATB and its potential role in ESCC remain to be documented. In this study, we investigated the role of lnc-ATB and the underlying mechanism promoting its oncogenic activity in ESCC. Expression of lnc-ATB was higher in ESCC tissues and cell lines than that in normal counterparts. Upregulated lnc-ATB served as an independent prognosis predictor of ESCC patients. Moreover, loss-of-function assays in ESCC cells showed that knockdown of lnc-ATB inhibited cell proliferation and migration both in vitro and in vivo. Mechanistic investigation indicated that lnc-ATB exerted oncogenic activities via regulating Kindlin-2, as the anti-migration role of lnc-ATB silence was attenuated by ectopic expression of Kindlin-2. Further analysis showed that lnc-ATB functions as a molecular sponge for miR-200b and Kindlin-2. Dysregulated miR-200b/Kindlin-2 signaling mediated the oncogenic activity of lnc-ATB in ESCC. Our results suggest that lnc-ATB predicts poor prognosis and may serve as a potential therapeutic target for ESCC patients.
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Affiliation(s)
- Zhongwen Li
- Department of Oncology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Xiaoliang Wu
- Department of Oncology, Guizhou Provincial People's Hospital, Guiyang, China.,State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ling Gu
- State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Puer University, Puer, China
| | - Qi Shen
- Department of Oncology, Guizhou Provincial People's Hospital, Guiyang, China
| | - Wen Luo
- Department of Oncology, Guizhou Provincial People's Hospital, Guiyang, China
| | - Chuangzhong Deng
- State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Qianghua Zhou
- State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xinru Chen
- State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yanjie Li
- The 3rd Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - ZuanFu Lim
- WVU Cancer Institute, Mary Babb Randolph Cancer Institute, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV, USA
| | - Xing Wang
- State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jiahong Wang
- State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Xianzi Yang
- State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
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Zhou S, Cui Y, Yu D, Liang J, Zhang M, Ye W. MicroRNA-381 enhances radiosensitivity in esophageal squamous cell carcinoma by targeting X-linked inhibitor of apoptosis protein. Onco Targets Ther 2017; 10:2527-2538. [PMID: 28546757 PMCID: PMC5436762 DOI: 10.2147/ott.s134551] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Background Increasing evidence indicates that radioresistance remains a major problem in the treatment of patients with esophageal squamous cell carcinoma (ESCC). This study was designed to investigate the expression of microRNA-381 (miR-381) and its function in the radioresistance of ESCC. Methods In this study, miR-381 expression was first detected in ESCC cell lines and tissue samples by quantitative real-time polymerase chain reaction (qRT-PCR). Then, the effects of miR-381 expression on growth, apoptosis, and radiosensitivity of ESCC cells were analyzed by MTT, colony formation, and flow cytometry, respectively. Dual-luciferase reporter assays were performed to validate the regulation of a putative target of miR-381, in corroboration with qRT-PCR and Western blotting assays. Results ESCC cell lines or tissues were found to express significantly lower miR-381 than normal esophageal epithelial cells or adjacent normal tissues, respectively. Ectopic expression of miR-381 in ESCC cell lines blocked proliferation, reduced colony formation, enhanced apoptosis, and increased radiosensitivity by enhancing irradiation-induced apoptosis. In addition, dual-luciferase reporter assays showed that miR-381 binds to the 3′-untranslated region of X-linked inhibitor of apoptosis protein (XIAP), suggesting that XIAP should be a direct target of miR-381. Re-expression of miR-381 suppressed XIAP protein expression in ESCC cells, and the effects of miR-381 upregulation on ESCC cells were found to be similar with silencing of XIAP. In addition, XIAP mRNA expression significantly increased in ESCC tissues and was inversely correlated with miR-381 expression. Conclusion The results of this study suggest that miR-381/XIAP pathway contributed to the growth inhibition, increase in apoptosis, and enhancement of radiosensitivity in ESCC cells Therefore, miR-381 may be a potential therapeutic target in human ESCC.
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Affiliation(s)
| | | | | | | | - Mingxin Zhang
- Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Wenguang Ye
- Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
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Qin Y, Zhang Y, Tang Q, Jin L, Chen Y. SQLE induces epithelial-to-mesenchymal transition by regulating of miR-133b in esophageal squamous cell carcinoma. Acta Biochim Biophys Sin (Shanghai) 2017; 49:138-148. [PMID: 28069586 DOI: 10.1093/abbs/gmw127] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Indexed: 12/30/2022] Open
Abstract
Increasing evidence suggests that microRNAs, which control gene expression at the post-transcriptional level, are aberrantly expressed in cancers and play significant roles in carcinogenesis and cancer progression. In this study, we show differential miR-133b down-expression in human esophageal squamous cell carcinoma (ESCC) cells and tissues. In addition, squalene epoxidase (SQLE), a key enzyme of cholesterol synthesis, is identified as the direct downstream target gene of miR-133b by luciferase gene reporter assay. Furthermore, ectogenic miR-133b expression and SQLE knockdown can inhibit proliferation, invasion, and metastasis, and diminish epithelial-to-mesenchymal transition (EMT) traits of ESCC in vitro, implying that miR-133b-dependent SQLE can induce tumorigenicity and that SQLE is an EMT inducer. Xenograft experiment results also proved the biological function of SQLE in vivo. Therefore, we conclude that miR-133b-dependent SQLE plays a critical role in the potential metastasis mechanisms in ESCC.
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Affiliation(s)
- Yi Qin
- Department of Gastroenterology, First People's Hospital of Yancheng City, Yancheng 224001, China
| | - Yi Zhang
- Department of Oncology, Jimin Hospital, Shanghai 200052, China
| | - Qinting Tang
- College of Nursing, Yancheng Vocational Institute of Health Sciences, Yancheng 224006, China
| | - Li Jin
- Sichuan Cancer Hospital, Chengdu 610041, China
| | - Yong'an Chen
- Department of Oncology, Jimin Hospital, Shanghai 200052, China
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C-Terminal Binding Protein is Involved in Promoting to the Carcinogenesis of Human Glioma. Mol Neurobiol 2016; 54:6121-6132. [PMID: 27699603 DOI: 10.1007/s12035-016-0159-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Accepted: 09/22/2016] [Indexed: 12/13/2022]
Abstract
C-terminal binding protein (CtBP) is responsible for regulating the pathogenesis of a lot of cancer types. However, whether CtBP1/2 is involved in regulating the growth and development of human glioma is still obscure. In the present study presented here, our results firstly reveal that CtBP1/2 deficiency, induced by siRNA interference, disrupts the functional integrity of the MRN complex that is responsible for DNA repair in human glioma cells. The dysfunction of the MRN complex further contributes to the up-regulation of ATM and Rad3-related kinase (ATR) and Chk1 signaling pathway, which inhibits cell cycle progression mediated by CDK2, preparing for the initiation of DNA repair. Under the condition of hypoxia, hypoxia-inducible factor-1α (HIF-1α) can be directly regulated by CDK2 on protein level, playing coordinately regulatory role in the carcinogenesis of human glioma cells. Overall, our findings reveal that CtBP1/2 is essential to promote to human glioma cell growth through maintaining the DNA stability regulated by the MRN/ATR/Chk1/CDK2/HIF-1α signaling pathway.
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