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Xiao M, Xue J, Jin E. SPOCK: Master regulator of malignant tumors (Review). Mol Med Rep 2024; 30:231. [PMID: 39392048 PMCID: PMC11487499 DOI: 10.3892/mmr.2024.13355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 08/20/2024] [Indexed: 10/12/2024] Open
Abstract
SPARC/osteonectin, CWCV and Kazal‑like domain proteoglycan (SPOCK) is a family of highly conserved multidomain proteins. In total, three such family members, SPOCK1, SPOCK2 and SPOCK3, constitute the majority of extracellular matrix glycoproteins. The SPOCK gene family has been demonstrated to serve key roles in tumor regulation by affecting MMPs, which accelerates the progression of cancer epithelial‑mesenchymal transition. In addition, they can regulate the cell cycle via overexpression, inhibit tumor cell proliferation by inactivating PI3K/AKT signaling and have been associated with numerous microRNAs that influence the expression of downstream genes. Therefore, the SPOCK gene family are potential cancer‑regulating genes. The present review summarizes the molecular structure, tissue distribution and biological function of the SPOCK family of proteins, in addition to its association with cancer. Furthermore, the present review documents the progress made in investigations into the role of SPOCK, whilst also discussing prospects for the future of SPOCK‑targeted therapy, to provide novel ideas for clinical application and treatment.
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Affiliation(s)
- Mingyuan Xiao
- Department of Rehabilitation, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110134, P.R. China
| | - Jiancheng Xue
- Department of Otolaryngology, Head and Neck Surgery, The Second People's Hospital of Shenzhen, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong 518035, P.R. China
- Shenzhen Clinical Research Center for Otolaryngology Diseases, The Second People's Hospital of Shenzhen, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong 518035, P.R. China
| | - Enli Jin
- Department of Rehabilitation, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110134, P.R. China
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2
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Wei QY, Jin F, Wang ZY, Li BJ, Cao WB, Sun ZY, Mo SJ. MicroRNAs: A novel signature in the metastasis of esophageal squamous cell carcinoma. World J Gastroenterol 2024; 30:1497-1523. [PMID: 38617454 PMCID: PMC11008420 DOI: 10.3748/wjg.v30.i11.1497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 01/12/2024] [Accepted: 03/01/2024] [Indexed: 03/21/2024] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is a malignant epithelial tumor, characterized by squamous cell differentiation, it is the sixth leading cause of cancer-related deaths globally. The increased mortality rate of ESCC patients is predominantly due to the advanced stage of the disease when discovered, coupled with higher risk of metastasis, which is an exceedingly malignant characteristic of cancer, frequently leading to a high mortality rate. Unfortunately, there is currently no specific and effective marker to predict and treat metastasis in ESCC. MicroRNAs (miRNAs) are a class of small non-coding RNA molecules, approximately 22 nucleotides in length. miRNAs are vital in modulating gene expression and serve pivotal regulatory roles in the occurrence, progression, and prognosis of cancer. Here, we have examined the literature to highlight the intimate correlations between miRNAs and ESCC metastasis, and show that ESCC metastasis is predominantly regulated or regulated by genetic and epigenetic factors. This review proposes a potential role for miRNAs as diagnostic and therapeutic biomarkers for metastasis in ESCC metastasis, with the ultimate aim of reducing the mortality rate among patients with ESCC.
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Affiliation(s)
- Qi-Ying Wei
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Feng Jin
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Zhong-Yu Wang
- Department of Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Bing-Jie Li
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Wen-Bo Cao
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Zhi-Yan Sun
- Division of Special Service, Department of Basic Oncology, School of Basic Medicine, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Sai-Jun Mo
- Department of Basic Science of Oncology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China
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3
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Zalaquett Z, Catherine Rita Hachem M, Kassis Y, Hachem S, Eid R, Raphael Kourie H, Planchard D. Acquired resistance mechanisms to osimertinib: The constant battle. Cancer Treat Rev 2023; 116:102557. [PMID: 37060646 DOI: 10.1016/j.ctrv.2023.102557] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 03/26/2023] [Accepted: 04/04/2023] [Indexed: 04/17/2023]
Abstract
Lung cancer is the leading cause of cancer-related mortality worldwide. Detectable driver mutations have now changed the course of lung cancer treatment with the emergence of targeted therapy as a novel strategy that widely improved lung cancer prognosis, especially in metastatic patients. Osimertinib (AZD9291) is an irreversible third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used to treat stage IV EGFR-mutated non-small-cell lung cancer. It was initially designed to target both EGFR-activating mutations and the EGFR T790M mutation as well, which is the most common resistance mechanism to first- and second-generation EGFR-TKIs. Following the FLAURA trial, osimertinib is now widely used in the first-line setting. However, resistance to osimertinib inevitably develops, with numerous mechanisms leading to its resistance, classified into two main categories: EGFR-dependent and EGFR-independent mechanisms. While EGFR-dependent mechanisms consist mainly of the C797S EGFR mutation, EGFR-independent mechanisms include bypass pathways, oncogenic fusions, and phenotypic transformation, among others. This review summarizes the molecular resistance mechanisms to osimertinib, with the aim of identifying novel therapeutic approaches to overcome osimertinib resistance and improve patient outcome.
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Affiliation(s)
- Ziad Zalaquett
- Department of Hematology-Oncology, Hôtel-Dieu de France University Hospital, Saint Joseph University of Beirut, Beirut, Lebanon.
| | - Maria Catherine Rita Hachem
- Department of Hematology-Oncology, Hôtel-Dieu de France University Hospital, Saint Joseph University of Beirut, Beirut, Lebanon
| | - Yara Kassis
- Department of Hematology-Oncology, Hôtel-Dieu de France University Hospital, Saint Joseph University of Beirut, Beirut, Lebanon
| | - Samir Hachem
- Department of Hematology-Oncology, Hôtel-Dieu de France University Hospital, Saint Joseph University of Beirut, Beirut, Lebanon
| | - Roland Eid
- Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France
| | - Hampig Raphael Kourie
- Department of Hematology-Oncology, Hôtel-Dieu de France University Hospital, Saint Joseph University of Beirut, Beirut, Lebanon
| | - David Planchard
- Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France
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Mizuno K, Tanigawa K, Misono S, Suetsugu T, Sanada H, Uchida A, Kawano M, Machida K, Asai S, Moriya S, Inoue H, Seki N. Regulation of Oncogenic Targets by Tumor-Suppressive miR-150-3p in Lung Squamous Cell Carcinoma. Biomedicines 2021; 9:biomedicines9121883. [PMID: 34944699 PMCID: PMC8698895 DOI: 10.3390/biomedicines9121883] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/03/2021] [Accepted: 12/09/2021] [Indexed: 01/02/2023] Open
Abstract
Several recent studies have shown that both strands of certain miRNAs derived from miRNA duplexes are involved in cancer pathogenesis. Our own recent studies revealed that both strands of the miR-150 duplex act as tumor-suppressive miRNAs in lung adenocarcinoma (LUAD) through the targeting of several oncogenes. The aim of the study here was to further investigate the tumor-suppressive roles of miR-150-3p (the passenger strand) in lung squamous cell carcinoma (LUSQ) and its control of cancer-promoting genes in LUSQ cells. The downregulation of miR-150-3p in LUSQ tissues was confirmed by data in The Cancer Genome Atlas (TCGA). The ectopic expression of miR-150-3p attenuated cancer cell aggressive features, e.g., cell cycle arrest, migration and invasive abilities. Our target search strategy successfully identified a total of 49 putative targets that were listed as subjects of miR-150-3p regulation in LUSQ cells. Interestingly, among these targets, 17 genes were categorized as related to the “cell cycle” based on Gene Ontology (GO) classification, namely CENPA, CIT, CCNE1, CCNE2, TIMELESS, BUB1, MCM4, HELLS, SKA3, CDCA2, FANCD2, NUF2, E2F2, SUV39H2, CASC5, ZWILCH and CKAP2). Moreover, we show that the expression of HELLS (helicase, lymphoid specific) is directly controlled by miR-150-3p, and its expression promotes the malignant phenotype of LUSQ cells.
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Affiliation(s)
- Keiko Mizuno
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan; (K.M.); (K.T.); (S.M.); (T.S.); (H.S.); (A.U.); (M.K.); (K.M.); (H.I.)
| | - Kengo Tanigawa
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan; (K.M.); (K.T.); (S.M.); (T.S.); (H.S.); (A.U.); (M.K.); (K.M.); (H.I.)
| | - Shunsuke Misono
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan; (K.M.); (K.T.); (S.M.); (T.S.); (H.S.); (A.U.); (M.K.); (K.M.); (H.I.)
| | - Takayuki Suetsugu
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan; (K.M.); (K.T.); (S.M.); (T.S.); (H.S.); (A.U.); (M.K.); (K.M.); (H.I.)
| | - Hiroki Sanada
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan; (K.M.); (K.T.); (S.M.); (T.S.); (H.S.); (A.U.); (M.K.); (K.M.); (H.I.)
| | - Akifumi Uchida
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan; (K.M.); (K.T.); (S.M.); (T.S.); (H.S.); (A.U.); (M.K.); (K.M.); (H.I.)
| | - Minami Kawano
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan; (K.M.); (K.T.); (S.M.); (T.S.); (H.S.); (A.U.); (M.K.); (K.M.); (H.I.)
| | - Kentaro Machida
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan; (K.M.); (K.T.); (S.M.); (T.S.); (H.S.); (A.U.); (M.K.); (K.M.); (H.I.)
| | - Shunichi Asai
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan;
| | - Shogo Moriya
- Department of Biochemistry and Genetics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan;
| | - Hiromasa Inoue
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan; (K.M.); (K.T.); (S.M.); (T.S.); (H.S.); (A.U.); (M.K.); (K.M.); (H.I.)
| | - Naohiko Seki
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan;
- Correspondence: ; Tel.: +81-43-226-2971
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Han J, Rong Y, Gao X. Multiomic analysis of the function of SPOCK1 across cancers: an integrated bioinformatics approach. J Int Med Res 2021; 49:300060520962659. [PMID: 34156309 PMCID: PMC8236807 DOI: 10.1177/0300060520962659] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Objective To investigate SPARC (osteonectin), cwcv and kazal like domains proteoglycan 1 (SPOCK1) gene expression across The Cancer Genome Atlas (TCGA) cancers, both in cancer versus normal tissues and in different stages across the cancer types. Methods This integrated bioinformatics study used data from several bioinformatics databases (Cancer Cell Line Encyclopedia, Genotype-Tissue Expression, TCGA, Tumor Immune Estimation Resource [TIMER]) to define the expression pattern of the SPOCK1 gene. A survival analysis was undertaken across the cancers. The search tool for retrieval of interacting genes (STRING) database was used to identify proteins that interacted with SPOCK1. Gene Set Enrichment Analysis was conducted to determine pathway enrichment. The TIMER database was used to explore the correlation between SPOCK1 and immune cell infiltration. Results This multiomic analysis showed that the SPOCK1 gene was expressed differently between normal tissues and tumours in several cancers and that it was involved in cancer progression. The overexpression of the SPOCK1 gene was associated with poor clinical outcomes. Analysis of gene expression and tumour-infiltrating immune cells showed that SPOCK1 correlated with several immune cells across cancers. Conclusions This research showed that SPOCK1 might serve as a new target for several cancer therapies in the future.
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Affiliation(s)
- Jie Han
- Department of Hepatology, Qilu Hospital, Shandong University, Shandong, China
| | - Yihui Rong
- Infection Disease Center of Peking University International Hospital, Beijing, China
| | - Xudong Gao
- Infection Disease Center of Peking University International Hospital, Beijing, China
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Wang B, Tang D, Liu Z, Wang Q, Xue S, Zhao Z, Feng D, Sheng C, Li J, Zhou Z. LINC00958 promotes proliferation, migration, invasion, and epithelial-mesenchymal transition of oesophageal squamous cell carcinoma cells. PLoS One 2021; 16:e0251797. [PMID: 34003875 PMCID: PMC8130937 DOI: 10.1371/journal.pone.0251797] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 05/03/2021] [Indexed: 02/03/2023] Open
Abstract
Oesophageal cancer is one of the deadliest cancers in the world. Oesophageal squamous cell carcinoma (ESCC) is the most prevalent histological type of oesophageal cancer. Oesophageal cancer has a poor prognosis because of its invasiveness. Thus, it is especially important to seek effective treatment methods. Research indicates that long non-coding RNAs (lncRNAs) play a significant role in the occurrence and development of oesophageal cancer. The aim of this study was to describe the role of LINC00958 in ESCC. Bioinformatics and real-time quantitative polymerase chain reaction (RT-qPCR) methods were utilized to predict and verify the expression of LINC00958 in ESCC. Related functional experiments, including cell proliferation, migration and invasion, were performed. In addition, a western blot and a dual luciferase reporter gene experiment were used to study the detailed carcinogenic mechanism of LINC00958. The results indicated there was a high expression of LINC00958 in ESCC, which promoted proliferation, migration, invasion and Epithelial–Mesenchymal Transition (EMT) of ESCC cells, and this effect may be via regulating miR-510-5p.
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Affiliation(s)
- Biqi Wang
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Faculty of environment and life, Beijing University of Technology, Beijing, China
| | - Duo Tang
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Faculty of environment and life, Beijing University of Technology, Beijing, China
| | - Zijia Liu
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Faculty of environment and life, Beijing University of Technology, Beijing, China
| | - Qian Wang
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Faculty of environment and life, Beijing University of Technology, Beijing, China
| | - Shan Xue
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Faculty of environment and life, Beijing University of Technology, Beijing, China
| | - Zijie Zhao
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Faculty of environment and life, Beijing University of Technology, Beijing, China
| | - Dongdong Feng
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Faculty of environment and life, Beijing University of Technology, Beijing, China
| | - Chao Sheng
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Faculty of environment and life, Beijing University of Technology, Beijing, China
| | - Jintao Li
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Faculty of environment and life, Beijing University of Technology, Beijing, China
| | - Zhixiang Zhou
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Faculty of environment and life, Beijing University of Technology, Beijing, China
- * E-mail:
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7
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Urinary microRNA biomarkers for detecting the presence of esophageal cancer. Sci Rep 2021; 11:8508. [PMID: 33879806 PMCID: PMC8058072 DOI: 10.1038/s41598-021-87925-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 04/05/2021] [Indexed: 12/16/2022] Open
Abstract
Esophageal cancer (EC) including esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) generally exhibits poor prognosis; hence, a noninvasive biomarker enabling early detection is necessary. Age- and sex-matched 150 healthy controls (HCs) and 43 patients with ESCC were randomly divided into two groups: 9 individuals in the discovery cohort for microarray analysis and 184 individuals in the training/test cohort with cross-validation for qRT-PCR analysis. Using 152 urine samples (144 HCs and 8 EACs), we validated the urinary miRNA biomarkers for EAC diagnosis. Among eight miRNAs selected in the discovery cohort, urinary levels of five miRNAs (miR-1273f, miR-619-5p, miR-150-3p, miR-4327, and miR-3135b) were significantly higher in the ESCC group than in the HC group, in the training/test cohort. Consistently, these five urinary miRNAs were significantly different between HC and ESCC in both training and test sets. Especially, urinary miR-1273f and miR-619-5p showed excellent values of area under the curve (AUC) ≥ 0.80 for diagnosing stage I ESCC. Similarly, the EAC group had significantly higher urinary levels of these five miRNAs than the HC group, with AUC values of approximately 0.80. The present study established novel urinary miRNA biomarkers that can early detect ESCC and EAC.
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Guo T, Wang Y, Jia J, Mao X, Stankiewicz E, Scandura G, Burke E, Xu L, Marzec J, Davies CR, Lu JJ, Rajan P, Grey A, Tipples K, Hines J, Kudahetti S, Oliver T, Powles T, Alifrangis C, Kohli M, Shaw G, Wang W, Feng N, Shamash J, Berney D, Wang L, Lu YJ. The Identification of Plasma Exosomal miR-423-3p as a Potential Predictive Biomarker for Prostate Cancer Castration-Resistance Development by Plasma Exosomal miRNA Sequencing. Front Cell Dev Biol 2021; 8:602493. [PMID: 33490068 PMCID: PMC7817948 DOI: 10.3389/fcell.2020.602493] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 11/30/2020] [Indexed: 12/18/2022] Open
Abstract
Castration-resistant prostate cancer (CRPC) is the major cause of death from prostate cancer. Biomarkers to improve early detection and prediction of CRPC especially using non-invasive liquid biopsies could improve outcomes. Therefore, we investigated the plasma exosomal miRNAs associated with CRPC and their potential for development into non-invasive early detection biomarkers for resistance to treatment. RNA-sequencing, which generated approximately five million reads per patient, was performed to identify differentially expressed plasma exosomal miRNAs in 24 treatment-naive prostate cancer and 24 CRPC patients. RT-qPCR was used to confirm the differential expressions of six exosomal miRNAs, miR-423-3p, miR-320a, miR-99a-5p, miR-320d, miR-320b, and miR-150-5p (p = 7.3 × 10-8, 0.0020, 0.018, 0.0028, 0.0013, and 0.0058, respectively) firstly in a validation cohort of 108 treatment-naive prostate cancer and 42 CRPC patients. The most significant differentially expressed miRNA, miR-423-3p, was shown to be associated with CRPC with area under the ROC curve (AUC) = 0.784. Combining miR-423-3p with prostate-specific antigen (PSA) enhanced the prediction of CRPC (AUC = 0.908). A separate research center validation with 30 treatment-naive and 30 CRPC patients also confirmed the differential expression of miR-423-3p (p = 0.016). Finally, plasma exosomal miR-423-3p expression in CRPC patients was compared to 36 non-CRPC patients under androgen depletion therapy, which showed significantly higher expression in CRPC than treated non-CRPC patients (p < 0.0001) with AUC = 0.879 to predict CRPC with no difference between treatment-naive and treated non-CRPC patients. Therefore, our findings demonstrate that a number of plasma exosomal miRNAs are associated with CRPC and miR-423-3p may serve as a biomarker for early detection/prediction of castration-resistance.
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Affiliation(s)
- Tianyu Guo
- Centre for Cancer Biomarker and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.,Department of Cell Biology, Zhejiang University School of Medicine, The Second Affiliated Hospital, Hangzhou, China
| | - Yang Wang
- Centre for Cancer Biomarker and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.,Department of Urology, Affiliated Wuxi No. 2 Hospital of Nanjing Medical University, Wuxi, China
| | - Jing Jia
- Department of Tumor Biology, H. Lee Moffitt Cancer Center, Tampa, FL, United States
| | - Xueying Mao
- Centre for Cancer Biomarker and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Elzbieta Stankiewicz
- Centre for Cancer Biomarker and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Glenda Scandura
- Centre for Cancer Biomarker and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Edwina Burke
- Centre for Cancer Biomarker and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Lei Xu
- Centre for Cancer Biomarker and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.,Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jacek Marzec
- Centre for Cancer Biomarker and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.,Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia
| | - Caitlin R Davies
- Centre for Cancer Biomarker and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Jiaying Jasmin Lu
- Centre for Cancer Biomarker and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Prabhakar Rajan
- Centre for Cancer Biomarker and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.,Department of Urology, Barts Health NHS, London, United Kingdom.,Division of Surgery and Interventional Sciences, University College London, London, United Kingdom.,Department of Uro-oncology, University College London NHS Foundation Trust, London, United Kingdom
| | - Alistair Grey
- Department of Urology, Barts Health NHS, London, United Kingdom.,Division of Surgery and Interventional Sciences, University College London, London, United Kingdom
| | - Karen Tipples
- Department of Urology, Barts Health NHS, London, United Kingdom
| | - John Hines
- Department of Urology, Barts Health NHS, London, United Kingdom.,Department of Uro-oncology, University College London NHS Foundation Trust, London, United Kingdom
| | - Sakunthala Kudahetti
- Centre for Cancer Biomarker and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Tim Oliver
- Centre for Cancer Biomarker and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Thomas Powles
- Centre for Cancer Biomarker and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Constantine Alifrangis
- Department of Urology, Barts Health NHS, London, United Kingdom.,Department of Uro-oncology, University College London NHS Foundation Trust, London, United Kingdom
| | - Manish Kohli
- Department of Medicine, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, United States.,Department of Oncology, Mayo Clinic, Rochester, MN, United States
| | - Greg Shaw
- Department of Urology, Barts Health NHS, London, United Kingdom.,Division of Surgery and Interventional Sciences, University College London, London, United Kingdom.,Department of Uro-oncology, University College London NHS Foundation Trust, London, United Kingdom
| | - Wen Wang
- Division of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London, United Kingdom
| | - Ninghan Feng
- Department of Urology, Affiliated Wuxi No. 2 Hospital of Nanjing Medical University, Wuxi, China
| | - Jonathan Shamash
- Department of Medical Oncology, Barts Health NHS, London, United Kingdom
| | - Daniel Berney
- Centre for Cancer Biomarker and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Liang Wang
- Department of Tumor Biology, H. Lee Moffitt Cancer Center, Tampa, FL, United States
| | - Yong-Jie Lu
- Centre for Cancer Biomarker and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.,Department of Urology, Affiliated Wuxi No. 2 Hospital of Nanjing Medical University, Wuxi, China
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Shinden Y, Hirashima T, Nohata N, Toda H, Okada R, Asai S, Tanaka T, Hozaka Y, Ohtsuka T, Kijima Y, Seki N. Molecular pathogenesis of breast cancer: impact of miR-99a-5p and miR-99a-3p regulation on oncogenic genes. J Hum Genet 2020; 66:519-534. [PMID: 33177704 DOI: 10.1038/s10038-020-00865-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 10/08/2020] [Accepted: 10/09/2020] [Indexed: 12/23/2022]
Abstract
Our recent research has revealed that passenger strands of certain microRNAs (miRNAs) function as tumor-suppressive miRNAs in cancer cells, e.g., miR-101-5p, miR-143-5p, miR-144-5p, miR-145-3p, and miR-150-3p. Thus, they are important in cancer pathogenesis. Analysis of the miRNA expression signature of breast cancer (BrCa) showed that the expression levels of two miRNAs derived from pre-miR-99a (miR-99a-5p and miR-99a-3p) were suppressed in cancerous tissues. The aim of this study was to identify oncogenic genes controlled by pre-miR-99a that are closely involved in the molecular pathogenesis of BrCa. A total of 113 genes were identified as targets of pre-miR-99a regulation (19 genes modulated by miR-99a-5p, and 95 genes regulated by miR-99a-3p) in BrCa cells. Notably, FAM64A was targeted by both of the miRNAs. Among these targets, high expression of 16 genes (C5orf22, YOD1, SLBP, F11R, C12orf49, SRPK1, ZNF250, ZNF695, CDK1, DNMT3B, TRIM25, MCM4, CDKN3, PRPS, FAM64A, and DESI2) significantly predicted reduced survival of BrCa patients based upon The Cancer Genome Atlas (TCGA) database. In this study, we focused on FAM64A and investigated the relationship between FAM64A expression and molecular pathogenesis of BrCa subtypes. The upregulation of FAM64A was confirmed in BrCa clinical specimens. Importantly, the expression of FAM64A significantly differed between patients with Luminal-A and Luminal-B subtypes. Our data strongly suggest that the aberrant expression of FAM64A is involved in the malignant transformation of BrCa. Our miRNA-based approaches (identification of tumor-suppressive miRNAs and their controlled targets) will provide novel information regarding the molecular pathogenesis of BrCa.
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Affiliation(s)
- Yoshiaki Shinden
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Tadahiro Hirashima
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | | | - Hiroko Toda
- Department of Breast Surgery, School of Medicine, Fujita Health University, Toyoake, Aichi, Japan
| | - Reona Okada
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba, 260-8670, Japan
| | - Shunichi Asai
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba, 260-8670, Japan
| | - Takako Tanaka
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Yuto Hozaka
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Takao Ohtsuka
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Yuko Kijima
- Department of Breast Surgery, School of Medicine, Fujita Health University, Toyoake, Aichi, Japan
| | - Naohiko Seki
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba, 260-8670, Japan.
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10
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Abstract
Glycosylation is a sophisticated informational system that controls specific biological functions at the cellular and organismal level. Dysregulation of glycosylation may underlie some of the most complex and common diseases of the modern era. In the past 5 years, microRNAs have come to the forefront as a critical regulator of the glycome. Herein, we review the current literature on miRNA regulation of glycosylation and how this work may point to a new way to identify the biological importance of glycosylation enzymes.
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Affiliation(s)
- Chu T Thu
- Biomedical Chemistry Institute, Department of Chemistry, New York University, New York, New York 10003, United States
| | - Lara K Mahal
- Biomedical Chemistry Institute, Department of Chemistry, New York University, New York, New York 10003, United States
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11
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Kawagoe K, Wada M, Idichi T, Okada R, Yamada Y, Moriya S, Okubo K, Matsushita D, Arigami T, Kurahara H, Maemura K, Natsugoe S, Seki N. Regulation of aberrantly expressed SERPINH1 by antitumor miR-148a-5p inhibits cancer cell aggressiveness in gastric cancer. J Hum Genet 2020; 65:647-656. [PMID: 32235846 DOI: 10.1038/s10038-020-0746-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 03/12/2020] [Accepted: 03/12/2020] [Indexed: 12/21/2022]
Abstract
RNA-sequencing-based microRNA (miRNA) expression signatures have revealed that miR-148a-5p (the passenger strand of the miR-148a-duplex) is downregulated in various kinds of cancer tissues. Analysis of The Cancer Genome Atlas (TCGA) database showed that low expression of miR-148a-5p was predictive of a lower survival rate (p = 0.041) in patients with gastric cancer (GC). Downregulation of miR-148a-5p was confirmed in GC clinical specimens, and its ectopic expression attenuated GC cell proliferation. Our search for miRNA target genes identified a total of 18 oncogenic targets of miR-148a-5p in GC cells. Among these targets, high expression levels of six genes (THBS2, P4HA3, SERPINH1, CDH11, BCAT1, and KCNG3) were closely associated with a poor prognosis (10-year survival rates) in GC patients (p < 0.05) according to TCGA database analyses. Furthermore, we focused on SERPINH1 as a chaperone protein involved in collagen folding in humans. Aberrant expression of SERPINH1 (mRNA and protein levels) was confirmed in GC clinical specimens. Knockdown assays of SERPINH1 using siRNAs resulted in inhibition of the aggressive phenotype of GC cells. Exploring the molecular networks controlled by miRNAs (including miRNA passenger strands) will broaden our understanding of the molecular pathogenesis of GC.
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Affiliation(s)
- Kosuke Kawagoe
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Masumi Wada
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Tetsuya Idichi
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Reona Okada
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yasutaka Yamada
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Shogo Moriya
- Department of Biochemistry and Genetics, Graduate School of Medicine, Chiba, Japan
| | - Keishi Okubo
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Daisuke Matsushita
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Takaaki Arigami
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Hiroshi Kurahara
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Kosei Maemura
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Shoji Natsugoe
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Naohiko Seki
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba, Japan.
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12
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Long noncoding RNA ZFAS1 promotes tumorigenesis through regulation of miR-150-5p/RAB9A in melanoma. Melanoma Res 2020; 29:569-581. [PMID: 30889053 DOI: 10.1097/cmr.0000000000000595] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Melanoma is the deadliest form of skin cancer and one of the most aggressive cancers. ZFAS1 is a newly identified lncRNA, playing an oncogenic role in several types of cancer. The present study aimed to investigate the function and mechanism of ZFAS1-induced regulation of melanoma. ZFAS1 expression was increased in melanoma tissues and cells compared with normal controls. ZFAS1 expression in metastatic tissues was higher than that in nonmetastatic subjects. Higher expression of ZFAS1 predicted lower survival rates. Knockdown of ZFAS1 decreased proliferation, increased apoptosis, decreased migration and invasion, and reduced epithelial-mesenchymal transition potential in melanoma cells. Moreover, ZFAS1 knockdown inhibited tumor growth in nude mice. There was a direct binding between ZFAS1 and miR-150-5p. ZFAS1 negatively regulated miR-150-5p expression and upregulation of miR-150-5p was involved in ZFAS1 knockdown-induced effect on proliferation, apoptosis, migration, and invasion. Using bioinformatics, we predicted the binding between RAB9A and miR-150-5p, and the direct interaction between RAB9A and miR-150-5p was confirmed by luciferase reporter and RNA immunoprecipitation assays. We also showed that RAB9A expression was regulated negatively by miR-150-5p, but was regulated positively by ZFAS1. Downregulation of RAB9A significantly inhibited the increase in proliferation, decrease in apoptosis, and increase in migration and invasion induced by miR-150-5p inhibitors. Moreover, RAB9A knockdown decreased proliferation, increased apoptosis, and decreased migration and invasion in melanoma cells. In summary, we confirmed the tumor-promoting role of ZFAS1 in melanoma and provide evidence for the role and mechanism of the ZFAS1/miR-150-5p/RAB9A axis. These findings may lead to novel therapeutic strategies for melanoma.
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Wada M, Goto Y, Tanaka T, Okada R, Moriya S, Idichi T, Noda M, Sasaki K, Kita Y, Kurahara H, Maemura K, Natsugoe S, Seki N. RNA sequencing-based microRNA expression signature in esophageal squamous cell carcinoma: oncogenic targets by antitumor miR-143-5p and miR-143-3p regulation. J Hum Genet 2020; 65:1019-1034. [PMID: 32623445 DOI: 10.1038/s10038-020-0795-x] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 06/16/2020] [Accepted: 06/22/2020] [Indexed: 12/16/2022]
Abstract
Aberrantly expressed microRNAs (miRNAs) disrupt intracellular RNA networks and contribute to malignant transformation of cancer cells. Utilizing the latest RNA sequencing technology, we newly created the miRNA expression signature of esophageal squamous cell carcinoma (ESCC). A total of 47 miRNAs were downregulated in ESCC tissues, and these miRNAs were candidates for antitumor miRNAs in ESCC cells. Analysis of the signature revealed that several passenger strands of miRNAs were significantly downregulated in ESCC, e.g., miR-28-3p, miR-30a-3p, miR-30c-3p, miR-133a-3p, miR-139-3p, miR-143-5p, and miR-145-3p. Recent studies indicate that some passenger strands of miRNAs closely involved in cancer pathogenesis. In this study, we focused on both strands of pre-miR-143, and investigated their antitumor roles and target oncogenes in ESCC. Ectopic expression of miR-143-5p and miR-143-3p significantly attenuated malignant phenotypes (e.g., proliferation, migration, and invasive abilities) in ESCC cell lines. We revealed that six genes (HN1, HMGA2, NETO2, STMN1, TCF3, and MET) were putative targets of miR-143-5p regulation, and one gene (KRT80) was a putative target of miR-143-3p regulation in ESCC cells. Our ESCC miRNA signature and analysis strategy provided important insights into the molecular pathogenesis of ESCC.
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Affiliation(s)
- Masumi Wada
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Yusuke Goto
- Department of Functional Genomics, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Takako Tanaka
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Reona Okada
- Department of Functional Genomics, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Shogo Moriya
- Department of Biochemistry and Genetics, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tetsuya Idichi
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Masahiro Noda
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Ken Sasaki
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Yoshiaki Kita
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Hiroshi Kurahara
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Kosei Maemura
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Shoji Natsugoe
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Naohiko Seki
- Department of Functional Genomics, Graduate School of Medicine, Chiba University, Chiba, Japan.
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14
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Sun LR, Li SY, Guo QS, Zhou W, Zhang HM. SPOCK1 Involvement in Epithelial-to-Mesenchymal Transition: A New Target in Cancer Therapy? Cancer Manag Res 2020; 12:3561-3569. [PMID: 32547193 PMCID: PMC7244346 DOI: 10.2147/cmar.s249754] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 04/22/2020] [Indexed: 12/24/2022] Open
Abstract
Background Cancer metastasis is the main obstacle to increasing the lifespan of cancer patients. Epithelial-to-mesenchymal transition (EMT) plays a significant role in oncogenic processes, including tumor invasion, intravasation, and micrometastasis formation, and is especially critical for cancer invasion and metastasis. The extracellular matrix (ECM) plays a crucial role in the occurrence of EMT corresponding to the change in adhesion between cells and matrices. Conclusion SPOCK1 is a critical regulator of the ECM and mediates EMT in cancer cells. This suggests an important role for SPOCK1 in tumorigenesis, migration and invasion. SPOCK1 is a critical regulator of some processes involved in cancer progression, including cancer cell proliferation, apoptosis and migration. Herein, the functions of SPOCK1 in cancer progression are expounded, revealing the association between SPOCK1 and EMT in cancer metastasis. SPOCK1 is a positive downstream regulator of transforming growth factor-β, and SPOCK1-mediated EMT regulates invasion and metastasis through the Wnt/β-catenin pathway and PI3K/Akt signaling pathway. It is of significance that SPOCK1 may be an attractive prognostic biomarker and therapeutic target in cancer treatment.
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Affiliation(s)
- Li-Rui Sun
- Department of Pharmacy, The First Hospital of Jilin University, Changchun, Jilin, People's Republic of China
| | - Si-Yu Li
- Department of Pathology, Hangzhou Third Hospital, Hangzhou, Zhejiang, People's Republic of China
| | - Qiu-Shi Guo
- Department of Pharmacy, The First Hospital of Jilin University, Changchun, Jilin, People's Republic of China
| | - Wei Zhou
- Department of Pharmacy, The First Hospital of Jilin University, Changchun, Jilin, People's Republic of China
| | - Hong-Mei Zhang
- Department of Pharmacy, The First Hospital of Jilin University, Changchun, Jilin, People's Republic of China
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15
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Zou SL, Chen YL, Ge ZZ, Qu YY, Cao Y, Kang ZX. Downregulation of serum exosomal miR-150-5p is associated with poor prognosis in patients with colorectal cancer. Cancer Biomark 2020; 26:69-77. [PMID: 31306108 DOI: 10.3233/cbm-190156] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Growing evidence have revealed the serum exosomal miRNAs emerged as biomarkers for various cancer types, including colorectal cancer (CRC). Here, we sought to explore the potential clinical significance of serum exosomal miR-150-5p in CRC. A total of 133 CRC patients and 60 healthy volunteers as control group were recruited in this study. Exosomes were isolated from the serum of all the participants. The total RNA was isolated from the exosomes and the serum exosomal miR-150-5p levels were measured by quantitative reverse transcription-polymerase chain reaction. The findings showed that the serum exosomal miR-150-5p levels were significantly reduced in CRC cases compared with those in the control group. Serum exosomal miR-150-5p levels in post-operative blood samples were greatly upregulated one month after surgical treatment. In addition, decreased serum exosomal miR-150-5p expression was closely correlated with poorly differentiation, positive lymph node metastasis and advanced TNM stage. Moreover, receiver operating characteristic (ROC) curve analysis showed serum exosomal miR-150-5p level had good performance to identify CRC cases from healthy volunteers, and a combination of serum exosomal miR-150-5p and carcinoembryonic antigen (CEA) could improve the diagnostic accuracy with an increased the area under the ROC curve (AUC) value. Furthermore, the survival time of patients with higher serum exosomal miR-150-5p expression was significantly longer than those with lower expression. Serum exosomal miR-150-5p was confirmed as an independent prognostic indicator in CRC. Mechanistically, ZEB1 was identified as a direct downstream target of miR-150-5p. Collectively, serum exosomal miR-150-5p might be a novel noninvasive biomarker for CRC diagnosis and prognosis.
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16
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Zhong X, Huang G, Ma Q, Liao H, Liu C, Pu W, Xu L, Cai Y, Guo X. Identification of crucial miRNAs and genes in esophageal squamous cell carcinoma by miRNA-mRNA integrated analysis. Medicine (Baltimore) 2019; 98:e16269. [PMID: 31277149 PMCID: PMC6635243 DOI: 10.1097/md.0000000000016269] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is a malignancy that severely threatens human health and carries a high incidence rate and a low 5-year survival rate. MicroRNAs (miRNAs) are commonly accepted as a key regulatory function in human cancer, but the potential regulatory mechanisms of miRNA-mRNA related to ESCC remain poorly understood.The GSE55857, GSE43732, and GSE6188 miRNA microarray datasets and the gene expression microarray datasets GSE70409, GSE29001, and GSE20347 were downloaded from Gene Expression Omnibus databases. The differentially expressed miRNAs (DEMs) and differentially expressed genes (DEGs) were obtained using GEO2R. Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for DEGs were performed by Database for Annotation, Visualization and Integrated Discovery (DAVID). A protein-protein interaction (PPI) network and functional modules were established using the STRING database and were visualized by Cytoscape. Kaplan-Meier analysis was constructed based on The Cancer Genome Atlas (TCGA) database.In total, 26 DEMs and 280 DEGs that consisted of 96 upregulated and 184 downregulated genes were screened out. A functional enrichment analysis showed that the DEGs were mainly enriched in the ECM-receptor interaction and cytochrome P450 metabolic pathways. In addition, MMP9, PCNA, TOP2A, MMP1, AURKA, MCM2, IVL, CYP2E1, SPRR3, FOS, FLG, TGM1, and CYP2C9 were considered to be hub genes owing to high degrees in the PPI network. MiR-183-5p was with the highest connectivity target genes in hub genes. FOS was predicted to be a common target gene of the significant DEMs. Hsa-miR-9-3p, hsa-miR-34c-3p and FOS were related to patient prognosis and higher expression of the transcripts were associated with a poor OS in patients with ESCC.Our study revealed the miRNA-mediated hub genes regulatory network as a model for predicting the molecular mechanism of ESCC. This may provide novel insights for unraveling the pathogenesis of ESCC.
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Affiliation(s)
- Xiaowu Zhong
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College
- Translational Medicine Research Center
- Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, Sichuan, China
| | - Guangcheng Huang
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College
| | - Qiang Ma
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College
| | | | - Chang Liu
- Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, Sichuan, China
| | - Wenjie Pu
- Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, Sichuan, China
| | - Lei Xu
- Translational Medicine Research Center
| | - Yan Cai
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College
| | - Xiaolan Guo
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College
- Translational Medicine Research Center
- Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, Sichuan, China
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Molecular Pathogenesis of Gene Regulation by the miR-150 Duplex: miR-150-3p Regulates TNS4 in Lung Adenocarcinoma. Cancers (Basel) 2019; 11:cancers11050601. [PMID: 31052206 PMCID: PMC6562801 DOI: 10.3390/cancers11050601] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 04/23/2019] [Accepted: 04/28/2019] [Indexed: 12/17/2022] Open
Abstract
Based on our miRNA expression signatures, we focused on miR-150-5p (the guide strand) and miR-150-3p (the passenger strand) to investigate their functional significance in lung adenocarcinoma (LUAD). Downregulation of miR-150 duplex was confirmed in LUAD clinical specimens. In vitro assays revealed that ectopic expression of miR-150-5p and miR-150-3p inhibited cancer cell malignancy. We performed genome-wide gene expression analyses and in silico database searches to identify their oncogenic targets in LUAD cells. A total of 41 and 26 genes were identified as miR-150-5p and miR-150-3p targets, respectively, and they were closely involved in LUAD pathogenesis. Among the targets, we investigated the oncogenic roles of tensin 4 (TNS4) because high expression of TNS4 was strongly related to poorer prognosis of LUAD patients (disease-free survival: p = 0.0213 and overall survival: p = 0.0003). Expression of TNS4 was directly regulated by miR-150-3p in LUAD cells. Aberrant expression of TNS4 was detected in LUAD clinical specimens and its aberrant expression increased the aggressiveness of LUAD cells. Furthermore, we identified genes downstream from TNS4 that were associated with critical regulators of genomic stability. Our approach (discovery of anti-tumor miRNAs and their target RNAs for LUAD) will contribute to the elucidation of molecular networks involved in the malignant transformation of LUAD.
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Fukuhisa H, Seki N, Idichi T, Kurahara H, Yamada Y, Toda H, Kita Y, Kawasaki Y, Tanoue K, Mataki Y, Maemura K, Natsugoe S. Gene regulation by antitumor miR-130b-5p in pancreatic ductal adenocarcinoma: the clinical significance of oncogenic EPS8. J Hum Genet 2019; 64:521-534. [DOI: 10.1038/s10038-019-0584-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 02/07/2019] [Accepted: 02/07/2019] [Indexed: 12/15/2022]
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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 2019; 54:673-688. [PMID: 30535463 DOI: 10.3892/ijo.2018.4657] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [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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Misono S, Seki N, Mizuno K, Yamada Y, Uchida A, Arai T, Kumamoto T, Sanada H, Suetsugu T, Inoue H. Dual strands of the miR-145 duplex (miR-145-5p and miR-145-3p) regulate oncogenes in lung adenocarcinoma pathogenesis. J Hum Genet 2018; 63:1015-1028. [PMID: 30082847 DOI: 10.1038/s10038-018-0497-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 07/18/2018] [Accepted: 07/21/2018] [Indexed: 12/15/2022]
Abstract
Our original microRNA (miRNA) expression signatures (based on RNA sequencing) revealed that both strands of the miR-145 duplex (miR-145-5p, the guide strand, and miR-145-3p, the passenger strand) were downregulated in several types of cancer tissues. Involvement of passenger strands of miRNAs in cancer pathogenesis is a new concept in miRNA biogenesis. In our continuing analysis of lung adenocarcinoma (LUAD) pathogenesis, we aimed here to identify important oncogenes that were controlled by miR-145-5p and miR-145-3p. Downregulation of miR-145-5p and miR-145-3p was confirmed in LUAD clinical specimens. Functional assays showed that miR-145-3p significantly blocked the malignant abilities in LUAD cells, e.g., cancer cell proliferation, migration and invasion. Thus, the data showed that expression of the passenger strand of the miR-145-duplex acted as an anti-tumor miRNA. In LUAD cells, we identified four possible target genes (LMNB2, NLN, SIX4, and DDC) that might be regulated by both strands of miR-145. Among the possible targets, high expression of LMNB2 predicted a significantly poorer prognosis of LUAD patients (disease-free survival, p = 0.0353 and overall survival, p = 0.0017). Overexpression of LMNB2 was detected in LUAD clinical specimens and its aberrant expression promoted malignant transformation of LUAD cells. Genes regulated by anti-tumor miR-145-5p and miR-145-3p are closely involved in the molecular pathogenesis of LUAD. We suggest that they are promising prognostic markers for this disease. Our approach, based on the roles of anti-tumor miRNAs, will contribute to improved understanding of the molecular pathogenesis of LUAD.
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Affiliation(s)
- Shunsuke Misono
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, 890-8520, Japan
| | - Naohiko Seki
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba, 260-8670, Japan.
| | - Keiko Mizuno
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, 890-8520, Japan
| | - Yasutaka Yamada
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba, 260-8670, Japan
| | - Akifumi Uchida
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, 890-8520, Japan
| | - Takayuki Arai
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba, 260-8670, Japan
| | - Tomohiro Kumamoto
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, 890-8520, Japan
| | - Hiroki Sanada
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, 890-8520, Japan
| | - Takayuki Suetsugu
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, 890-8520, Japan
| | - Hiromasa Inoue
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, 890-8520, Japan
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Involvement of anti-tumor miR-124-3p and its targets in the pathogenesis of pancreatic ductal adenocarcinoma: direct regulation of ITGA3 and ITGB1 by miR-124-3p. Oncotarget 2018; 9:28849-28865. [PMID: 29988949 PMCID: PMC6034741 DOI: 10.18632/oncotarget.25599] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2018] [Accepted: 05/24/2018] [Indexed: 01/02/2023] Open
Abstract
MicroRNAs (miRNAs) are unique in that a single miRNA molecule regulates a vast number of RNA transcripts. Thus, aberrantly expressed miRNAs disrupt tightly controlled RNA networks in cancer cells. Our functional screening showed that expression of miR-124-3p was downregulated in pancreatic ductal adenocarcinoma (PDAC) tissues. Here, we aimed to investigate the anti-tumor roles of miR-124-3p in PDAC cells and to identify miR-124-3p-mediated oncogenic signaling in this disease. Ectopic expression of miR-124-3p inhibited cancer cell migration and invasion in PDAC cells. Moreover, restoration of miR-124-3p suppressed oncogenic signaling, as demonstrated by reduced phosphorylation of focal adhesion kinase, AKT, and extracellular signal-regulated kinase, in PDAC cells. Our in silico database analyses and luciferase reporter assays showed that two cell-surface matrix receptors, integrin α3 (ITGA3) and integrin β1 (ITGB1), were directly regulated by miR-124-3p in PDAC cells. Overexpression of ITGA3 and ITGB1 was confirmed in PDAC clinical specimens. Interestingly, a large number of cohort analyses from TCGA database showed that high expressions of ITGA3 and ITGB1 were significantly associated with poor prognosis of patients with PDAC. Knockdown of ITGA3 and ITGB1 by siRNAs markedly suppressed the migration and invasion abilities of PDAC cells. Moreover, downstream oncogenic signaling was inhibited by ectopic expression of miR-124-3p or knockdown of the two integrins. The discovery of anti-tumor miRNAs and miRNA-mediated oncogenic signaling may provide novel therapeutic targets for the treatment of PDAC.
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Idichi T, Seki N, Kurahara H, Fukuhisa H, Toda H, Shimonosono M, Okato A, Arai T, Kita Y, Mataki Y, Kijima Y, Maemura K, Natsugoe S. Molecular pathogenesis of pancreatic ductal adenocarcinoma: Impact of passenger strand of pre-miR-148a on gene regulation. Cancer Sci 2018; 109:2013-2026. [PMID: 29660218 PMCID: PMC5989856 DOI: 10.1111/cas.13610] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 04/05/2018] [Accepted: 04/06/2018] [Indexed: 01/05/2023] Open
Abstract
We previously used RNA sequencing to establish the microRNA (miRNA) expression signature of pancreatic ductal adenocarcinoma (PDAC). We found that both strands of pre-miR-148a (miR-148a-5p: the passenger strand and miR-148a-3p: the guide strand) were downregulated in cancer tissues. Ectopic expression of miR-148a-5p and miR-148a-3p significantly inhibited cancer cell migration and invasion, indicating that both strands of pre-miR-148a had tumor-suppressive roles in PDAC cells. In silico database and genome-wide gene expression analyses identified a total of 15 genes that were putative targets regulated by these miRNAs. High expression of miR-148a-5p targets (PHLDA2, LPCAT2 and AP1S3) and miR-148a-3p targets (SMA, ENDOD1 and UHMK1) was associated with poor prognosis of patients with PDAC. Moreover, knockdown of PHLDA2 expression inhibited cancer cell aggressiveness, suggesting PHLDA2 acted as an oncogene in PDAC cells. Involvement of the passenger strand of pre-miR-148a (miR-148-5p) is a new concept in cancer research. Novel approaches that identify tumor-suppressive miRNA regulatory networks in lethal PDAC might provide new prognostic markers and therapeutic targets for this disease.
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Affiliation(s)
- Tetsuya Idichi
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Naohiko Seki
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Hiroshi Kurahara
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Haruhi Fukuhisa
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Hiroko Toda
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Masataka Shimonosono
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Atsushi Okato
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Takayuki Arai
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yoshiaki Kita
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Yuko Mataki
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Yuko Kijima
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Kosei Maemura
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Shoji Natsugoe
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
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Suetsugu T, Koshizuka K, Seki N, Mizuno K, Okato A, Arai T, Misono S, Uchida A, Kumamoto T, Inoue H. Downregulation of matrix metalloproteinase 14 by the antitumor miRNA, miR-150-5p, inhibits the aggressiveness of lung squamous cell carcinoma cells. Int J Oncol 2017; 52:913-924. [PMID: 29286099 DOI: 10.3892/ijo.2017.4232] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Accepted: 11/24/2017] [Indexed: 11/06/2022] Open
Abstract
In the present study, in order to elucidate the aggressive nature of lung squamous cell carcinoma (LUSQ), we investigated the oncogenic RNA networks regulated by antitumor microRNAs (miRNAs or miRs) in LUSQ cells. The analysis of our original miRNA expression signatures of human cancers revealed that microRNA‑150‑5p (miR‑150‑5p) was downregulated in various types of cancer, indicating that miR‑150‑5p acts as an antitumor miRNA by targeting several oncogenic genes. Thus, the aims of this study were to investigate the antitumor roles of miR‑150‑5p in LUSQ cells and to identify oncogenes regulated by miR‑150‑5p that are involved in the aggressive behavior of LUSQ. The downregulation of miR‑150‑5p was validated in clinical samples of LUSQ and cell lines (SK-MES‑1 and EBC‑1). The ectopic overexpression of miR‑150‑5p significantly suppressed cancer cell aggressiveness. Comprehensive gene expression analyses revealed that miR‑150‑5p regulated 9 genes in the LUSQ cells. Among these, matrix metalloproteinase 14 (MMP14) was found to be a direct target of miR‑150‑5p, as shown by luciferase reporter assay. The knockdown of MMP14 using siRNA against MMP14 (si-MMP14) significantly inhibited cancer cell migration and invasion. The overexpression of MMP14 was detected in clinical specimens of LUSQ by immunohistochemistry. On the whole, these findings suggest that the downregulation of miR‑150‑5p and the overexpression of MMP14 may be deeply involved in the pathogenesis of LUSQ.
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Affiliation(s)
- Takayuki Suetsugu
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890‑8520, Japan
| | - Keiichi Koshizuka
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba 260‑8670, Japan
| | - Naohiko Seki
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba 260‑8670, Japan
| | - Keiko Mizuno
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890‑8520, Japan
| | - Atsushi Okato
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba 260‑8670, Japan
| | - Takayuki Arai
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba 260‑8670, Japan
| | - Shunsuke Misono
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890‑8520, Japan
| | - Akifumi Uchida
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890‑8520, Japan
| | - Tomohiro Kumamoto
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890‑8520, Japan
| | - Hiromasa Inoue
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890‑8520, Japan
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Koshizuka K, Hanazawa T, Kikkawa N, Katada K, Okato A, Arai T, Idichi T, Osako Y, Okamoto Y, Seki N. Antitumor miR-150-5p and miR-150-3p inhibit cancer cell aggressiveness by targeting SPOCK1 in head and neck squamous cell carcinoma. Auris Nasus Larynx 2017; 45:854-865. [PMID: 29233721 DOI: 10.1016/j.anl.2017.11.019] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Revised: 11/04/2017] [Accepted: 11/29/2017] [Indexed: 01/06/2023]
Abstract
OBJECTIVE Our recent studies have revealed that both strands of pre-miRNAs, the guide strand and the passenger strand, are involved in cancer pathogenesis. Analyses of miRNA expression signatures by RNA sequencing in head and neck squamous cell carcinoma (HNSCC) showed that both of the strands of pre-miR-150 (miR-150-5p and miR-150-3p) were significantly downregulated, and that these miRNAs acted as antitumor miRNAs in HNSCC cells. The aim of this study was to identify oncogenic genes in HNSCC cells that were regulated by miR-150-5p and miR-150-3p. METHODS Genome-wide gene expression studies, in silico analyses and dual-luciferase reporter assays were carried out to predict miR-150-5p and miR-150-3p regulation in HNSCC cells. Knockdown assay was applied to investigate the functional significance of the target gene. Overall patient survival as a function of target gene expression was estimated by The Cancer Genome Atlas (TCGA) database. RESULTS A total of 19 genes were putative targets of both miR-150-5p and miR-150-3p regulation. Among them, SPOCK1 (SPARC/osteonectin, cwcv and kazal-like domains proteoglycan 1) was directly regulated by both miRNAs in HNSCC cells. Knockdown studies using si-SPOCK1 showed that expression of SPOCK1 enhanced HNSCC cell aggressiveness. Overexpression of SPOCK1/SPOCK1 was confirmed in HNSCC clinical specimens. Interestingly, analysis of a large number of patients in the TCGA database (n=248) demonstrated that patients with high SPOCK1 expression had significantly shorter survival than did those with low SPOCK1 expression (P=0.0003). Moreover, 15 pathways were identified as SPOCK1-mediated downstream pathways. CONCLUSION Downregulation of both strands of pre-miR-150 (miR-150-5p and miR-150-3p) and overexpression of SPOCK1 contribute to the aggressive nature of HNSCC. The involvement of passenger strand miRNA in the regulation of HNSCC pathogenesis is a novel concept in RNA research.
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Affiliation(s)
- Keiichi Koshizuka
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba, Japan; Department of Otorhinolaryngology/Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Toyoyuki Hanazawa
- Department of Otorhinolaryngology/Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Naoko Kikkawa
- Department of Otorhinolaryngology/Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Koji Katada
- Department of Otorhinolaryngology/Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Atsushi Okato
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Takayuki Arai
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Tetsuya Idichi
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Yusaku Osako
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Yoshitaka Okamoto
- Department of Otorhinolaryngology/Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Naohiko Seki
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba, Japan.
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Sun H, He L, Ma L, Lu T, Wei J, Xie K, Wang X. LncRNA CRNDE promotes cell proliferation, invasion and migration by competitively binding miR-384 in papillary thyroid cancer. Oncotarget 2017; 8:110552-110565. [PMID: 29299168 PMCID: PMC5746403 DOI: 10.18632/oncotarget.22819] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 11/13/2017] [Indexed: 12/15/2022] Open
Abstract
Thyroid cancer is one of the most prevalent endocrine neoplasm. The present study examined the effects of Colorectal Neoplasia Differentially Expressed (CRNDE) on the progression of papillary thyroid cancer (PTC), and explored the underlying molecular mechanisms. Quantitative real-time PCR was used to detect CRNDE, miR-384 and pleiotrophin (PTN) mRNA expression. Western blot was used to measure PTN protein levels. Cell proliferation, cell growth, cell invasion and migration of PTC cells were determined by CCK-8, colony formation, transwell invasion and migration assays, respectively. CRNDE was up-regulated in PTC tissues and cell lines. Overexpression of CRNDE promoted BCPAP cell proliferation, invasion and migration, while knock-down of CRNDE suppressed K1 cell proliferation, invasion and migration. CRNDE negatively regulated the expression of miR-384 in PTC cells, which was further confirmed by luciferase reporter assay. MiR-384 was down-regulated and inversely correlated with CRNDE expression in PTC tissues. MiR-384 suppressed cell proliferation, invasion and migration in PTC cells, and enforced expression of miR-384 attenuated the oncogenic effects of CRNDE in PTC cells. PTN was predicted as a downstream target of miR-384, which was confirmed by luciferase reporter assay, and PTN was up-regulated in PTC tissues, and was negatively correlated with miR-384 expression and positively correlated with CRNDE expression in PTC tissues. In summary, our results suggested that the CRNDE/miR-384/PTN axis may play an important role in the regulation of PTC progression, which provides us with new insights into understanding the PTC.
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Affiliation(s)
- Honggang Sun
- Clinical Laboratory Center, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, Zhejiang Province, China
| | - Liqin He
- Department of Rehabilitation, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, Zhejiang Province, China
| | - Lan Ma
- Department of Rehabilitation, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, Zhejiang Province, China
| | - Tao Lu
- Clinical Laboratory Center, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, Zhejiang Province, China
| | - Jianguo Wei
- Department of Pathology, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, Zhejiang Province, China
| | - Kejie Xie
- Clinical Laboratory Center, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, Zhejiang Province, China
| | - Xingmu Wang
- Clinical Laboratory Center, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, Zhejiang Province, China
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Yamada Y, Koshizuka K, Hanazawa T, Kikkawa N, Okato A, Idichi T, Arai T, Sugawara S, Katada K, Okamoto Y, Seki N. Passenger strand of miR-145-3p acts as a tumor-suppressor by targeting MYO1B in head and neck squamous cell carcinoma. Int J Oncol 2017; 52:166-178. [PMID: 29115582 PMCID: PMC5743364 DOI: 10.3892/ijo.2017.4190] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 10/23/2017] [Indexed: 12/18/2022] Open
Abstract
Analysis of the microRNA (miRNA) expression signature of head and neck squamous cell carcinoma (HNSCC) based on RNA sequencing showed that dual strands of pre-miR-145 (miR-145-5p, guide strand; and miR-145-3p, passenger strand) were significantly reduced in cancer tissues. In miRNA biogenesis, passenger strands of miRNAs are degraded and have no biological activities in cells. The aims of this study were to investigate the functional significance of the passenger strand of miR-145 and to identify miR-145-3p-regulated oncogenic genes in HNSCC cells. Expression levels of miR-145-5p and miR-145-3p were significantly downregulated in HNSCC tissues and cell lines (SAS and HSC3 cells). Ectopic expression of miR-145-3p inhibited cancer cell proliferation, migration and invasion, similar to miR-145-5p, in HNSCC cells. Myosin 1B (MYO1B) was directly regulated by miR-145-3p, and knockdown of MYO1B by siRNA inhibited cancer cell aggressiveness. Overexpression of MYO1B was confirmed in HNSCC clinical specimens by analysis of protein and mRNA levels. Interestingly, high expression of MYO1B was associated with poor prognosis in patients with HNSCC by analysis of The Cancer Genome Atlas database (p=0.00452). Our data demonstrated that the passenger strand of miR-145 acted as an antitumor miRNA through targeting MYO1B in HNSCC cells. The involvement of dual strands of pre-miR-145 (miR-145-5p and miR-145-3p) in the regulation of HNSCC pathogenesis is a novel concept in present RNA research.
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Affiliation(s)
- Yasutaka Yamada
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Keiichi Koshizuka
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Toyoyuki Hanazawa
- Department of Otorhinolaryngology/Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Naoko Kikkawa
- Department of Otorhinolaryngology/Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Atsushi Okato
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Tetsuya Idichi
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8580, Japan
| | - Takayuki Arai
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Sho Sugawara
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Koji Katada
- Department of Otorhinolaryngology/Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Yoshitaka Okamoto
- Department of Otorhinolaryngology/Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Naohiko Seki
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
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