|
1
|
Lee S, Lee B, Kwon SH, Park J, Kim SH. MCC in the spotlight: Its dual role in signal regulation and oncogenesis. Cell Signal 2025; 131:111756. [PMID: 40118128 DOI: 10.1016/j.cellsig.2025.111756] [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: 01/24/2025] [Revised: 03/13/2025] [Accepted: 03/18/2025] [Indexed: 03/23/2025]
Abstract
The mutated in colorectal cancer (MCC) gene is closely associated with the onset and progression of colorectal cancer. MCC plays a critical role in regulating the cell cycle and various signaling pathways and is recognized to inhibit cancer cell proliferation via the β-catenin signaling pathway. β-catenin is a key component of the WNT signaling pathway that influences cell growth, differentiation, survival, and migration, thereby positioning MCC as an important tumor suppressor. Notably, MCC has also been implicated in other cancer types, including lung, liver, and brain cancers. However, the precise mechanisms by which MCC functions in these malignancies remain inadequately understood. Comprehensive investigations into the interactions among MCC, various signaling pathways, and metabolic processes are essential for uncovering the molecular mechanisms of cancer and the pathological features characteristic of different cancer stages. This review presents the structural characteristics of MCC and its cell growth regulation mechanisms and functional roles within tissues, with the aims of enhancing our understanding of the role of MCC in cancer biology and highlighting potential therapeutic strategies targeting this gene.
Collapse
Affiliation(s)
- Soohyeon Lee
- Department of Pharmacology, College of Medicine, Chungnam National University, Daejeon 35015, South Korea; Department of Medical Science, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon 35015, South Korea
| | - Beomwoo Lee
- Department of Pharmacology, College of Medicine, Chungnam National University, Daejeon 35015, South Korea; Department of Medical Science, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon 35015, South Korea
| | - So Hee Kwon
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 21983, South Korea.
| | - Jongsun Park
- Department of Pharmacology, College of Medicine, Chungnam National University, Daejeon 35015, South Korea; Department of Medical Science, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon 35015, South Korea; Biomedical Research Institute, Chungnam National University Hospital, Daejeon 35015, Republic of Korea.
| | - Seon-Hwan Kim
- Biomedical Research Institute, Chungnam National University Hospital, Daejeon 35015, Republic of Korea; Department of Neurosurgery, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon 35015, South Korea.
| |
Collapse
|
|
2
|
Barjasteh AH, Jaseb Mazhar AleKassar R, Al-Asady AM, Latifi H, Avan A, Khazaei M, Ryzhikov M, Hassanian SM. Therapeutic Potentials of MiRNA for Colorectal Cancer Liver Metastasis Treatment: A Narrative Review. IRANIAN JOURNAL OF MEDICAL SCIENCES 2025; 50:202-219. [PMID: 40255223 PMCID: PMC12008659 DOI: 10.30476/ijms.2024.102910.3622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 11/01/2024] [Accepted: 11/26/2024] [Indexed: 04/22/2025]
Abstract
Colorectal cancer (CRC) ranks among the most prevalent cancers worldwide and is the fourth leading cause of cancer-related deaths. Metastasis poses a significant obstacle in CRC treatment, as distant metastasis, particularly to the liver, remains the primary cause of mortality. Colorectal liver metastasis (CRLM) occurs frequently due to the liver's direct vascular connection to the colorectal region via the portal vein. Standard treatment approaches for CRLM are limited; only a few patients qualify for surgical intervention, resulting in a persistently low survival rate. Additionally, resistance to chemotherapy is common, emphasizing the need for more effective targeted therapies. Emerging evidence highlights the pivotal role of microRNAs (miRNAs) in modulating critical pathways associated with CRLM, including tumor invasion, epithelial-mesenchymal transition, and angiogenesis. MiRNAs exhibit dual functions as tumor suppressors and oncogenes by targeting multiple genes, thus playing a complex role in both the initiation and progression of metastasis. The regulatory mechanisms of miRNAs could help to identify novel biomarkers for early diagnosis and prognosis of CRLM, as well as promising therapeutic targets to overcome chemoresistance. Despite numerous studies on miRNA involvement in CRC metastasis, dedicated reviews focusing on miRNAs and CRLM remain scarce. This review aims to approach targeted therapies by examining the current understanding of miRNA involvement in CRLM and exploring their potential as diagnostic, prognostic, and therapeutic agents. Through an integrative approach, we aim to provide insights that could transform CRLM management and improve patient outcomes.
Collapse
Affiliation(s)
- Amir Hossein Barjasteh
- Metabolic Syndrome Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Rawa Jaseb Mazhar AleKassar
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abdulridha Mohammed Al-Asady
- Department of Medical Sciences, Faculty of Nursing, Warith Al-Anbiyaa University, Iraq
- Department of Medical Sciences, Faculty of Dentistry, University of Kerbala, Iraq
- Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hanieh Latifi
- Metabolic Syndrome Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Faculty of Health, School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, QLD 4059, Australia
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Seyed Mahdi Hassanian
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
|
3
|
Han SH, Mo JS, Yun KJ, Chae SC. MicroRNA 429 regulates MMPs expression by modulating TIMP2 expression in colon cancer cells and inflammatory colitis. Genes Genomics 2024; 46:763-774. [PMID: 38733517 DOI: 10.1007/s13258-024-01520-y] [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: 03/17/2024] [Accepted: 04/24/2024] [Indexed: 05/13/2024]
Abstract
BACKGROUND In a previous study, we found that the expression of microRNA 429 (MIR429) was decreased in dextran sodium sulfate (DSS)-induced mouse colitis tissues. OBJECTIVE In this study, we aimed to investigate the interaction of MIR429 with TIMP metallopeptidase inhibitor 2 (TIMP2), one of its candidate target genes, in human colorectal cancer (CRC) cells and DSS-induced mouse colitis tissues. METHODS A luciferase reporter system was used to confirm the effect of MIR429 on TIMP2 expression. The expression levels of MIR429 and target genes in cells or tissues were evaluated through quantitative RT-PCR, western blotting, or immunohistochemistry. RESULTS We found that the expression level of MIR429 was downregulated in human CRC tissues, and also showed that TIMP2 is a direct target gene of MIR429 in CRC cell lines. Furthermore, MIR429 regulate TIMP2-mediated matrix metallopeptidases (MMPs) expression in CRC cells. We also generated cell lines stably expressing MIR429 in CRC cell lines and showed that MIR429 regulates the expression of MMPs by mediating TIMP2 expression. In addition to human CRC tissues, we found that TIMP2 was highly expressed in mouse colitis tissues and human ulcerative colitis (UC) tissues. CONCLUSIONS Our findings suggest that the expression of endogenous MIR429 was reduced in human CRC tissues and colitis, leading to upregulation of its target gene TIMP2. The upregulation of TIMP2 by decreased MIR429 expression in CRC tissues and inflamed tissues suggests that it may affect extracellular matrix (ECM) remodeling through downregulation of MMPs. Therefore, MIR429 may have therapeutic value for human CRC and colitis.
Collapse
Affiliation(s)
- Seol-Hee Han
- Department of Pathology, School of Medicine, Wonkwang University, Iksan, Chonbuk, 54538, Republic of Korea
| | - Ji-Su Mo
- Digestive Disease Research Institute, Wonkwang University, Iksan, Chonbuk, 54538, Republic of Korea
| | - Ki-Jung Yun
- Department of Pathology, School of Medicine, Wonkwang University, Iksan, Chonbuk, 54538, Republic of Korea
| | - Soo-Cheon Chae
- Department of Pathology, School of Medicine, Wonkwang University, Iksan, Chonbuk, 54538, Republic of Korea.
- Digestive Disease Research Institute, Wonkwang University, Iksan, Chonbuk, 54538, Republic of Korea.
| |
Collapse
|
|
4
|
Zhang F, Li J, Xu J, Jiang X, Chen S, Nasser QA. Circular RNA circLIFR suppresses papillary thyroid cancer progression by modulating the miR-429/TIMP2 axis. J Cancer Res Clin Oncol 2024; 150:323. [PMID: 38914806 PMCID: PMC11196293 DOI: 10.1007/s00432-024-05839-7] [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: 05/02/2024] [Accepted: 06/06/2024] [Indexed: 06/26/2024]
Abstract
PURPOSE Circular RNAs (circRNAs) are increasingly recognized for their important roles in various cancers, including papillary thyroid cancer (PTC). The specific mechanisms by which the circLIF receptor subunit alpha (circLIFR, hsa_circ_0072309) influences PTC progression remain largely unknown. METHODS In our study, CircLIFR, miR-429, and TIMP2 levels were assessed using reverse transcription-quantitative PCR. The roles of circLIFR and miR-429 in PTC cells were determined using Cell Counting Kit-8, colony formation, wound healing, and Transwell assays. Western blotting was utilized to examine the levels of TIMP2. The direct interaction between circLIFR, TIMP2, and miR-429 was confirmed using dual-luciferase reporter, RNA immunoprecipitation, and fluorescence in situ hybridization assays. RESULTS In PTC tissues and cells, a decrease in circLIFR and TIMP2 levels, accompanied by an increase in miR-429 levels, was observed. Overexpression of circLIFR or downregulation of miR-429 effectively suppressed the proliferation and migration of PTC cells. Conversely, the knockdown of circLIFR or overexpression of miR-429 had the opposite effect. Furthermore, circLIFR overexpression suppressed tumor growth in vivo. Mechanistically, circLIFR modulated TIMP2 expression by serving as a sponge for miR-429. Rescue experiments indicated that the antitumor effect of circLIFR could be reversed by miR-429. CONCLUSION This study confirmed circLIFR as a novel tumor suppressor delayed PTC progression through the miR-429/TIMP2 axis. These findings suggested that circLIFR held promise as a potential therapeutic target for PTC.
Collapse
Affiliation(s)
- Fengyuan Zhang
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Jiazheng Li
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Jingjing Xu
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Xugan Jiang
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Shengxia Chen
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, China.
| | - Qais Ahmad Nasser
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, China.
| |
Collapse
|
|
5
|
Zhang W, Huang Z, Xiao Z, Wang H, Liao Q, Deng Z, Wu D, Wang J, Li Y. NF-κB downstream miR-1262 disturbs colon cancer cell malignant behaviors by targeting FGFR1. Acta Biochim Biophys Sin (Shanghai) 2023; 55:1819-1832. [PMID: 37867436 PMCID: PMC10686795 DOI: 10.3724/abbs.2023235] [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: 12/16/2022] [Accepted: 03/23/2023] [Indexed: 10/24/2023] Open
Abstract
Despite substantial advancements in screening, surgery, and chemotherapy, colorectal cancer remains the second most lethal form of the disease. Nuclear factor kappa B (NF-κB) signaling is a critical driver facilitating the malignant transformation of chronic inflammatory bowel diseases. In this study, deregulated miRNAs that could play a role in colon cancer are analyzed and investigated for specific functions in vitro using cancer cells and in vivo using a subcutaneous xenograft model. miRNA downstream targets are analyzed, and predicted binding and regulation are verified. miR-1262, an antitumor miRNA, is downregulated in colon cancer tissue samples and cell lines. miR-1262 overexpression suppresses colon cancer malignant behaviors in vitro and tumor development and metastasis in a subcutaneous xenograft model and a lung metastasis mouse model in vivo. miR-1262 directly targets fibroblast growth factor receptor 1 (FGFR1) and inhibits FGFR1 expression. FGFR1 overexpression shows oncogenic functions through the regulation of cancer cell proliferation, invasion, and migration; when cotransfected, lv-FGFR1 partially attenuates the antitumor effects of agomir-1262. NF-κB binds to the miR-1262 promoter region and inhibits transcription activity. The NF-κB inhibitor CAPE exerts antitumor effects; miR-1262 inhibition partially reverses CAPE effects on colon cancer cells. Conclusively, miR-1262 serves as an antitumor miRNA in colon cancer by targeting FGFR1. The NF-κB/miR-1262/FGFR1 axis modulates colon cancer cell phenotypes, including proliferation, invasion, and migration.
Collapse
Affiliation(s)
- Weilin Zhang
- The Second School of Clinical MedicineSouthern Medical UniversityGuangzhou510080China
- Department of Gastrointestinal SurgeryDepartment of General SurgeryGuangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesGuangzhou510080China
- Department of General SurgeryHunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University)Changsha410005China
| | - Zhongcheng Huang
- Department of General SurgeryHunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University)Changsha410005China
| | - Zhigang Xiao
- Department of General SurgeryHunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University)Changsha410005China
| | - Hui Wang
- Department of Cardiovascular MedicineHunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University)Changsha410005China
| | - Qianchao Liao
- Department of Gastrointestinal SurgeryDepartment of General SurgeryGuangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesGuangzhou510080China
| | - Zhengru Deng
- Department of Gastrointestinal SurgeryDepartment of General SurgeryGuangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesGuangzhou510080China
| | - Deqing Wu
- Department of Gastrointestinal SurgeryDepartment of General SurgeryGuangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesGuangzhou510080China
| | - Junjiang Wang
- Department of Gastrointestinal SurgeryDepartment of General SurgeryGuangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesGuangzhou510080China
| | - Yong Li
- The Second School of Clinical MedicineSouthern Medical UniversityGuangzhou510080China
- Department of Gastrointestinal SurgeryDepartment of General SurgeryGuangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesGuangzhou510080China
| |
Collapse
|
|
6
|
Lee KJ, Singh N, Bizuneh M, Kim NH, Kim HS, Kim Y, Lee JJ, Kim JH, Kim J, Jeong SY, Cho HY, Park ST. miR-429 Suppresses Endometrial Cancer Progression and Drug Resistance via DDX53. J Pers Med 2023; 13:1302. [PMID: 37763070 PMCID: PMC10532590 DOI: 10.3390/jpm13091302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 08/22/2023] [Accepted: 08/24/2023] [Indexed: 09/29/2023] Open
Abstract
(1) Background: To examine miR-429-meditated DEAD (Asp-Glu-Ala-Asp) box polypeptide 53 (DDX53) function in endometrial cancer (EC). (2) Methods: DDX53 and miR-429 levels were measured using quantitative real-time polymerase chain reaction and western blotting assays, cell invasion and migration using Transwell invasion and wound healing assays, and cell proliferation using colony-forming/proliferation assays. A murine xenograft model was also generated to examine miR-429 and DDX53 functions in vivo. (3) Results: DDX53 overexpression (OE) promoted key cancer phenotypes (proliferation, migration, and invasion) in EC, while in vivo, DDX53 OE hindered tumor growth in the murine xenograft model. Moreover, miR-429 was identified as a novel miRNA-targeting DDX53, which suppressed EC proliferation and invasion. (4) Conclusions: DDX53 and miR-429 regulatory mechanisms could provide novel molecular therapies for EC.
Collapse
Affiliation(s)
- Kyung-Jun Lee
- Institute of New Frontier Research Team, Hallym University, Chuncheon 24252, Republic of Korea; (K.-J.L.); (N.S.); (N.-H.K.); (H.S.K.); (Y.K.); (J.-J.L.); (S.Y.J.)
| | - Nitya Singh
- Institute of New Frontier Research Team, Hallym University, Chuncheon 24252, Republic of Korea; (K.-J.L.); (N.S.); (N.-H.K.); (H.S.K.); (Y.K.); (J.-J.L.); (S.Y.J.)
| | - Michael Bizuneh
- Institute of New Frontier Research Team, Hallym University, Chuncheon 24252, Republic of Korea; (K.-J.L.); (N.S.); (N.-H.K.); (H.S.K.); (Y.K.); (J.-J.L.); (S.Y.J.)
| | - Nam-Hyeok Kim
- Institute of New Frontier Research Team, Hallym University, Chuncheon 24252, Republic of Korea; (K.-J.L.); (N.S.); (N.-H.K.); (H.S.K.); (Y.K.); (J.-J.L.); (S.Y.J.)
| | - Hyeong Su Kim
- Institute of New Frontier Research Team, Hallym University, Chuncheon 24252, Republic of Korea; (K.-J.L.); (N.S.); (N.-H.K.); (H.S.K.); (Y.K.); (J.-J.L.); (S.Y.J.)
- Division of Hemato-Oncology, Department of Internal Medicine, Kangnam Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Seoul 07441, Republic of Korea;
| | - Youngmi Kim
- Institute of New Frontier Research Team, Hallym University, Chuncheon 24252, Republic of Korea; (K.-J.L.); (N.S.); (N.-H.K.); (H.S.K.); (Y.K.); (J.-J.L.); (S.Y.J.)
| | - Jae-Jun Lee
- Institute of New Frontier Research Team, Hallym University, Chuncheon 24252, Republic of Korea; (K.-J.L.); (N.S.); (N.-H.K.); (H.S.K.); (Y.K.); (J.-J.L.); (S.Y.J.)
- Departments of Anesthesiology and Pain Medicine, Chuncheon Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Chuncheon 24253, Republic of Korea
| | - Jung Han Kim
- Division of Hemato-Oncology, Department of Internal Medicine, Kangnam Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Seoul 07441, Republic of Korea;
| | - Jiye Kim
- Department of Obstetrics and Gynecology, Kangnam Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Seoul 07441, Republic of Korea;
| | - Soo Young Jeong
- Institute of New Frontier Research Team, Hallym University, Chuncheon 24252, Republic of Korea; (K.-J.L.); (N.S.); (N.-H.K.); (H.S.K.); (Y.K.); (J.-J.L.); (S.Y.J.)
- Department of Obstetrics and Gynecology, Kangnam Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Seoul 07441, Republic of Korea;
| | - Hye-Yon Cho
- Institute of New Frontier Research Team, Hallym University, Chuncheon 24252, Republic of Korea; (K.-J.L.); (N.S.); (N.-H.K.); (H.S.K.); (Y.K.); (J.-J.L.); (S.Y.J.)
- Department of Obstetrics and Gynecology, Dongtan Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Kyeonggido 18450, Republic of Korea
| | - Sung Taek Park
- Institute of New Frontier Research Team, Hallym University, Chuncheon 24252, Republic of Korea; (K.-J.L.); (N.S.); (N.-H.K.); (H.S.K.); (Y.K.); (J.-J.L.); (S.Y.J.)
- Department of Obstetrics and Gynecology, Kangnam Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Seoul 07441, Republic of Korea;
| |
Collapse
|
|
7
|
Vishnubalaji R, Shaath H, Al-Alwan M, Abdelalim EM, Alajez NM. Reciprocal interplays between MicroRNAs and pluripotency transcription factors in dictating stemness features in human cancers. Semin Cancer Biol 2022; 87:1-16. [PMID: 36354097 DOI: 10.1016/j.semcancer.2022.10.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 10/26/2022] [Accepted: 10/27/2022] [Indexed: 11/06/2022]
Abstract
The interplay between microRNAs (miRNAs) and pluripotency transcription factors (TFs) orchestrates the acquisition of cancer stem cell (CSC) features during the course of malignant transformation, rendering them essential cancer cell dependencies and therapeutic vulnerabilities. In this review, we discuss emerging themes in tumor heterogeneity, including the clonal evolution and the CSC models and their implications in resistance to cancer therapies, and then provide thorough coverage on the roles played by key TFs in maintaining normal and malignant stem cell pluripotency and plasticity. In addition, we discuss the reciprocal interactions between miRNAs and MYC, OCT4, NANOG, SOX2, and KLF4 pluripotency TFs and their contributions to tumorigenesis. We provide our view on the potential to interfere with key miRNA-TF networks through the use of RNA-based therapeutics as single agents or in combination with other therapeutic strategies, to abrogate the CSC state and render tumor cells more responsive to standard and targeted therapies.
Collapse
Affiliation(s)
- Radhakrishnan Vishnubalaji
- Translational Cancer and Immunity Center (TCIC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Hibah Shaath
- Translational Cancer and Immunity Center (TCIC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Monther Al-Alwan
- Stem Cell and Tissue Re-Engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia; College of Medicine, Al-Faisal University, Riyadh 11533, Saudi Arabia
| | - Essam M Abdelalim
- Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, PO Box 34110, Doha, Qatar; College of Health & Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Nehad M Alajez
- Translational Cancer and Immunity Center (TCIC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar; College of Health & Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar.
| |
Collapse
|
|
8
|
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: 51] [Impact Index Per Article: 17.0] [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.
Collapse
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
| | | |
Collapse
|
|
9
|
Qian S, Lin S, Xu X, Bai H, Yeerken A, Ying X, Li Z, Fei X, Yang J, Tang M, Wang J, Jin M, Chen K. Hypermethylation of tumor suppressor lncRNA MEF2C-AS1 frequently happened in patients at all stages of colorectal carcinogenesis. Clin Epigenetics 2022; 14:111. [PMID: 36064442 PMCID: PMC9446566 DOI: 10.1186/s13148-022-01328-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 08/23/2022] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND The novel long noncoding RNA MEF2C-AS1 has been identified to play suppressor roles during tumorigenesis. DNA methylation has a regulatory effect on gene expression in cancer initiation and progression. However, the methylation status of MEF2C-AS1 and its role in colorectal cancer (CRC) development remain unclear. METHODS The expression and methylation levels of MEF2C-AS1 were systematically analyzed among 31 cancers with available qualified data in GEPIA and UCSC Xena databases. Then, the MEF2C-AS1 methylation status was firstly examined among 12 CRCs by Illumina Infinium MethylationEPIC BeadChip in in-house step 1 and further quantified among 48 CRCs by the MassARRAY method in in-house step 2. Subsequently, its methylation and expression levels were quantified among 81 non-advanced adenomas (NAAs), 81 advanced adenomas (AAs), and 286 CRCs using the MassARRAY method, and among 34 NAAs, 45 AAs, and 75 CRCs by qRT-PCR, in in-house step 3, respectively. The effect of MEF2C-AS1 methylation on CRC survival was analyzed by the Kaplan-Meier method. Additionally, in vitro cell proliferation, migration and invasion assays, and bioinformatics analysis were performed to explore the role of MEF2C-AS1 in colorectal carcinogenesis. RESULTS Lower expression and higher methylation of MEF2C-AS1 were found in CRC by online databases. In the comparisons of lesion tissues with adjacent normal tissues, MEF2C-AS1 hypermethylation of each individual site and mean level was found among CRC patients in in-house step 1 and step 2, more meaningfully, among NAA patients, AA patients, and CRC patients at all stages during colorectal carcinogenesis in in-house step 3 (all p < 0.05). Further comparisons demonstrated significant differences between CRC and NAA (p = 0.025), AA and NAA (p = 0.020). Moreover, MEF2C-AS1 hypermethylation was associated with poorer disease-specific survival of CRC patients (p = 0.044). In addition, hypermethylation and lower expression of MEF2C-AS1 were verified in RKO cells, and the MEF2C-AS1 overexpression significantly suppressed RKO cell proliferation, migration, and invasion. CONCLUSIONS The findings reveal that MEF2C-AS1 hypermethylation might be an early driven event during colorectal carcinogenesis. It might serve as a promising prognostic biomarker for CRC survival. Our study also indicates the potential tumor-suppressing role of MEF2C-AS1 in CRC.
Collapse
Affiliation(s)
- Sangni Qian
- Department of Public Health, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Shujuan Lin
- Department of Public Health, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Xin Xu
- Department of Public Health, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Hao Bai
- Department of Public Health, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Aibuta Yeerken
- Department of Public Health, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Xiaojiang Ying
- Department of Anorectal Surgery, Shaoxing People's Hospital, Shaoxing, 312000, China
| | - Zhenjun Li
- Department of Anorectal Surgery, Shaoxing People's Hospital, Shaoxing, 312000, China
| | - Xinglin Fei
- Jiashan Institute of Cancer Prevention and Treatment, Jiaxing, 314100, China
| | - Jinhua Yang
- Jiashan Institute of Cancer Prevention and Treatment, Jiaxing, 314100, China
| | - Mengling Tang
- Department of Public Health, Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Jianbing Wang
- Department of Public Health, National Clinical Research Center for Child Health of the Children's Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Mingjuan Jin
- Department of Public Health, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
| | - Kun Chen
- Department of Public Health, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
| |
Collapse
|
|
10
|
Zhang CW, Zhou B, Liu YC, Su LW, Meng J, Li SL, Wang XL. LINC00365 inhibited lung adenocarcinoma progression and glycolysis via sponging miR-429/KCTD12 axis. ENVIRONMENTAL TOXICOLOGY 2022; 37:1853-1866. [PMID: 35426242 DOI: 10.1002/tox.23532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 02/15/2022] [Accepted: 03/25/2022] [Indexed: 06/14/2023]
Abstract
This study researched the function of long non-coding RNA LINC00365 in lung adenocarcinoma (LAD) progression. LINC00365, miR-429, and KCTD12 expression in the LAD clinical tissues and cells were detcetd by qRT-PCR and Western blot. LINC00365, miR-429, and KCTD12 effects on H1975 cells malignant phenotype were detected by cell counting kit-8 assay, clone formation experiment, Transwell experiment, and glycolysis. Dual luciferase reporter gene assay and RNA pull-down assay were implemented. LINC00365 effect on H1975 cells in vivo growth was detected. LINC00365 was low expressed in the LAD patients and cells, associating with poor outcome. LINC00365 up-regulation attenuated H1975 cells proliferation, migration, invasion, glycolysis and in vivo growth. LINC00365 inhibited KCTD12 expression by sponging miR-429. miR-429 up-regulation and KCTD12 down-regulation partial reversed LINC00365 inhibition on H1975 cells malignant phenotype. Thus, LINC00365 inhibited LAD progression and glycolysis via targeting miR-429/KCTD12 axis. LINC00365 might be a potential candidate for LAD target treatment clinically.
Collapse
Affiliation(s)
- Cheng-Wei Zhang
- Department of Thoracic Surgery, Capital Medical University Electric Power Teaching Hospital, Beijing, China
| | - Bin Zhou
- Department of Thoracic Surgery, Capital Medical University Electric Power Teaching Hospital, Beijing, China
| | - Yan-Chao Liu
- Department of Thoracic Surgery, Capital Medical University Electric Power Teaching Hospital, Beijing, China
| | - Li-Wei Su
- Department of Thoracic Surgery, Capital Medical University Electric Power Teaching Hospital, Beijing, China
| | - Jie Meng
- Department of Thoracic Surgery, Capital Medical University Electric Power Teaching Hospital, Beijing, China
| | - Shao-Lei Li
- Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Xue-Long Wang
- Department of Thoracic Surgery, Capital Medical University Electric Power Teaching Hospital, Beijing, China
| |
Collapse
|
|
11
|
Piechowska A, Kruszniewska-Rajs C, Kimsa-Dudek M, Kołomańska M, Strzałka-Mrozik B, Gola J, Głuszek S. The role of miR-370 and miR-138 in the regulation of BMP2 suppressor gene expression in colorectal cancer: preliminary studies. J Cancer Res Clin Oncol 2022; 148:1569-1582. [PMID: 35292840 DOI: 10.1007/s00432-022-03977-4] [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: 01/04/2022] [Accepted: 03/06/2022] [Indexed: 12/24/2022]
Abstract
PURPOSE Colorectal cancer (CRC) is the fourth-most common cancer worldwide and the second most common cancer cause of death in the world. The components of the TGFβ-signalling pathway, which are often affected by miRNAs, are involved in the regulation of apoptosis and cell cycle. Therefore, in the current study, the expression of BMP2 gene in CRC tissues at different clinical stages compared to the non-tumour tissues has been assessed. Moreover, the plasma BMP2 protein concentration in the same group of CRC patients has been validated. Due to the constant necessity to conduct further research of the correlation between specific miRNAs and mRNAs in CRC, in silico analysis has been performed to select miRNAs that regulate BMP2 mRNA. METHODS The cDNA samples from tumor and non-tumor tissue were used in a qPCR reaction to determine the mRNA expression of the BMP2 gene and the expression of selected miRNAs. The concentration of BMP2 protein in plasma samples was also measured. RESULTS It was indicated that BMP2 was downregulated in CRC tissue. Moreover, miR-370 and miR-138 expression showed an upward trend. Decreased BMP2 with accompanied increasing miR-370 and miR-138 expression was relevant to the malignant clinicopathological features of CRC and consequently poor patient prognosis. CONCLUSION Our data suggest that miR-370 with its clear expression in plasma samples may be a potential diagnostic marker to determine the severity of the disease in patients at a later stage of colorectal cancer.
Collapse
Affiliation(s)
- Agnieszka Piechowska
- Department of Surgical Medicine With the Laboratory of Medical Genetics, Institute of Medical Sciences, Collegium Medicum, Jan Kochanowski University, Kielce, Poland
| | - Celina Kruszniewska-Rajs
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jednosci 8, 41-200, Sosnowiec, Poland
| | - Magdalena Kimsa-Dudek
- Department of Nutrigenomics and Bromatology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jednosci 8, 41-200, Sosnowiec, Poland
| | - Magdalena Kołomańska
- Department of Anatomy, Institute of Medical Sciences, Collegium Medicum, Jan Kochanowski University, Kielce, Poland
| | - Barbara Strzałka-Mrozik
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jednosci 8, 41-200, Sosnowiec, Poland.
| | - Joanna Gola
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jednosci 8, 41-200, Sosnowiec, Poland
| | - Stanisław Głuszek
- Department of Surgical Medicine With the Laboratory of Medical Genetics, Institute of Medical Sciences, Collegium Medicum, Jan Kochanowski University, Kielce, Poland.,Department of Clinic General Oncological and Endocrinological Surgery, Regional Hospital, Kielce, Poland
| |
Collapse
|
|
12
|
Zhou H, Liu Z, Wang Y, Wen X, Amador EH, Yuan L, Ran X, Xiong L, Ran Y, Chen W, Wen Y. Colorectal liver metastasis: molecular mechanism and interventional therapy. Signal Transduct Target Ther 2022; 7:70. [PMID: 35246503 PMCID: PMC8897452 DOI: 10.1038/s41392-022-00922-2] [Citation(s) in RCA: 151] [Impact Index Per Article: 50.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 01/25/2022] [Accepted: 02/09/2022] [Indexed: 02/08/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most frequently occurring malignancy tumors with a high morbidity additionally, CRC patients may develop liver metastasis, which is the major cause of death. Despite significant advances in diagnostic and therapeutic techniques, the survival rate of colorectal liver metastasis (CRLM) patients remains very low. CRLM, as a complex cascade reaction process involving multiple factors and procedures, has complex and diverse molecular mechanisms. In this review, we summarize the mechanisms/pathophysiology, diagnosis, treatment of CRLM. We also focus on an overview of the recent advances in understanding the molecular basis of CRLM with a special emphasis on tumor microenvironment and promise of newer targeted therapies for CRLM, further improving the prognosis of CRLM patients.
Collapse
Affiliation(s)
- Hui Zhou
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Zhongtao Liu
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Yongxiang Wang
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Xiaoyong Wen
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Eric H Amador
- Department of Physics, The University of Texas, Arlington, TX, 76019, USA
| | - Liqin Yuan
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Xin Ran
- Department of Dermatovenereology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Li Xiong
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China.
| | - Yuping Ran
- Department of Dermatovenereology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Wei Chen
- Department of Physics, The University of Texas, Arlington, TX, 76019, USA.
- Medical Technology Research Centre, Chelmsford Campus, Anglia Ruskin University, Chelmsford, CM1 1SQ, UK.
| | - Yu Wen
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China.
| |
Collapse
|
|
13
|
Zhao Z, Wang Z, Wang P, Liu S, Li Y, Yang X. EPDR1, Which Is Negatively Regulated by miR-429, Suppresses Epithelial Ovarian Cancer Progression via PI3K/AKT Signaling Pathway. Front Oncol 2021; 11:751567. [PMID: 35004274 PMCID: PMC8733570 DOI: 10.3389/fonc.2021.751567] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 11/30/2021] [Indexed: 12/20/2022] Open
Abstract
Epithelial ovarian cancer (EOC) is the main pathological type of ovarian cancer. In this study, we found that ependymin-related 1 (EPDR1) was remarkably downregulated in EOC tissues, and low EPDR1 expression was associated with International Federation of Gynecology and Obstetrics (FIGO) stage, metastasis, and poor prognosis. We confirmed that EPDR1 overexpression dramatically suppressed EOC cell proliferation, migration, and invasion in vitro and in vivo. Mechanistically, EPDR1 inhibited EOC tumorigenesis and progression, at least in part, through the repression of the PI3K (Phosphoinositide 3-kinase)/AKT (AKT Serine/Threonine Kinase 1) signaling pathway. Furthermore, the expression and function of EPDR1 were regulated by miR-429, as demonstrated by luciferase reporter assays and rescue experiments. In conclusion, our study validated that EPDR1, negatively regulated by miR-429, played an important role as a tumor-suppressor gene in EOC development via inhibition of the PI3K/AKT pathway. The miR-429/EPDR1 axis might provide novel therapeutic targets for individualized treatment of EOC patients in the future.
Collapse
Affiliation(s)
- Zhendan Zhao
- Department of Gynecology and Obstetrics, Qilu Hospital of Shandong University, Jinan, China
- Laboratory of Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan, China
| | - Zhiling Wang
- Department of Gynecology and Obstetrics, Qilu Hospital of Shandong University, Jinan, China
- Laboratory of Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan, China
| | - Pengling Wang
- Department of Gynecology and Obstetrics, Qilu Hospital of Shandong University, Jinan, China
- Laboratory of Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan, China
| | - Shujie Liu
- Department of Gynecology and Obstetrics, Qilu Hospital of Shandong University, Jinan, China
- Department of Obstetrics and Gynecology, Zibo Spring Hospital Co., Ltd., Zibo, China
| | - Yingwei Li
- Department of Gynecology and Obstetrics, Qilu Hospital of Shandong University, Jinan, China
| | - Xingsheng Yang
- Department of Gynecology and Obstetrics, Qilu Hospital of Shandong University, Jinan, China
| |
Collapse
|
|
14
|
Quaglio AEV, Santaella FJ, Rodrigues MAM, Sassaki LY, Di Stasi LC. MicroRNAs expression influence in ulcerative colitis and Crohn's disease: A pilot study for the identification of diagnostic biomarkers. World J Gastroenterol 2021; 27:7801-7812. [PMID: 34963743 PMCID: PMC8661377 DOI: 10.3748/wjg.v27.i45.7801] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/14/2021] [Accepted: 11/20/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD) comprises two distinct diseases, Crohn's disease (CD) and ulcerative colitis (UC), both of which are chronic, relapsing inflammatory disorders of the gastrointestinal tract with a mostly unknown etiology. The incidence and prevalence of IBD are continually increasing, indicating the need for further studies to investigate the genetic determinants of these diseases. Since microRNAs (miRNAs) regulate protein translation via complementary binding to mRNA, discovering differentially expressed miRNAs (DE) in UC or CD patients could be important for diagnostic biomarker identification, assisting in the appropriate disease differentiation progressing the understanding of IBD pathogenesis. AIM To determine the miRNA expression profile in UC and CD patients and the potential pathophysiological contributions of differentially expressed miRNA. METHODS A total of 20 formalin-fixed paraffin-embedded colonic samples were collected from the Pathology Department of Botucatu Medical School at São Paulo State University (Unesp). The diagnosis of UC or CD was based on clinical, endoscopic, radiologic, and histological criteria and confirmed by histopathological analysis at the time of selection. The TaqMan™ Array Human MicroRNA A+B Cards Set v3.0 (Applied Biosystems™) platform was used to analyze 754 miRNAs. Targets of DE-miRNAs were predicted using miRNA Data Integration Portal (mirDIP) and the miRNA Target Interaction database (MiRTarBase). All statistical analyses were conducted using GraphPad Prism software. Parametric and nonparametric data were analyzed using t-tests and Mann-Whitney U tests, respectively. RESULTS The results showed that of the 754 miRNAs that were initially evaluated, 643 miRNAs were found to be expressed in at least five of the patients who were diagnosed with either CD or UC; the remaining 111 miRNAs were not considered to be expressed in these patients. The expression levels of 28 miRNAs were significantly different between the CD and UC patients (P ≤ 0.05); 13 miRNAs demonstrated a fold-change in expression level greater than 1. Five miRNAs with a downregulated expression were selected for enrichment analysis. The miRNAs whose expression levels were significantly lower in UC patients than in CD patients were enriched in certain signaling pathways that were mostly correlated with cancer-related processes and respective biomarkers. CONCLUSION MiRNAs could be used to differentiate UC from CD, and differently expressed miRNAs could help explain the distinct pathophysiology of each disease.
Collapse
Affiliation(s)
- Ana Elisa Valencise Quaglio
- Laboratory of Phytomedicines, Pharmacology and Biotechnology (PhytoPharmaTec), Department of Biophysics and Pharmacology, São Paulo State University (Unesp), Institute of Biosciences, Botucatu 18618-689, São Paulo, Brazil
| | - Felipe Jose Santaella
- Department of Pathology, Botucatu Medical School, Sao Paulo State University (Unesp), Botucatu 18618-687, São Paulo, Brazil
| | | | - Ligia Yukie Sassaki
- Department of Internal Medicine, Botucatu Medical School, São Paulo State University (Unesp), Botucatu 18618-687, São Paulo, Brazil
| | - Luiz Claudio Di Stasi
- Laboratory of Phytomedicines, Pharmacology and Biotechnology (PhytoPharmaTec), Department of Biophysics and Pharmacology, São Paulo State University (Unesp), Institute of Biosciences, Botucatu 18618-689, São Paulo, Brazil
| |
Collapse
|
|
15
|
Changes in Exosomal miRNA Composition in Thyroid Cancer Cells after Prolonged Exposure to Real Microgravity in Space. Int J Mol Sci 2021; 22:ijms222312841. [PMID: 34884646 PMCID: PMC8657878 DOI: 10.3390/ijms222312841] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 11/24/2021] [Accepted: 11/25/2021] [Indexed: 12/12/2022] Open
Abstract
As much as space travel and exploration have been a goal since humankind looked up to the stars, the challenges coming with it are manifold and difficult to overcome. Therefore, researching the changes the human organism undergoes following exposure to weightlessness, on a cellular or a physiological level, is imperative to reach the goal of exploring space and new planets. Building on the results of our CellBox-1 experiment, where thyroid cancer cells were flown to the International Space Station, we are now taking advantage of the newest technological opportunities to gain more insight into the changes in cell–cell communication of these cells. Analyzing the exosomal microRNA composition after several days of microgravity might elucidate some of the proteomic changes we have reported earlier. An array scan of a total of 754 miRNA targets revealed more than 100 differentially expressed miRNAs in our samples, many of which have been implicated in thyroid disease in other studies.
Collapse
|
|
16
|
Mao L, Chen J, Lu X, Yang C, Ding Y, Wang M, Zhang Y, Tian Y, Li X, Fu Y, Yang Y, Gu Y, Gao F, Huang J, Liao L. Proteomic analysis of lung cancer cells reveals a critical role of BCAT1 in cancer cell metastasis. Theranostics 2021; 11:9705-9720. [PMID: 34646394 PMCID: PMC8490523 DOI: 10.7150/thno.61731] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Accepted: 09/03/2021] [Indexed: 12/14/2022] Open
Abstract
Metastasis is the major cause of high mortality in lung cancer. Exploring the underlying mechanisms of metastasis thus holds promise for identifying new therapeutic strategies that may enhance survival. Methods: We applied quantitative mass spectrometry to compare protein expression profiles between primary and metastatic lung cancer cells whilst investigating metastasis-related molecular features. Results: We discovered that BCAT1, the key enzyme in branched-chain amino acid metabolism, is overexpressed at the protein level in metastatic lung cancer cells, as well as in metastatic tissues from lung cancer patients. Analysis of transcriptomic data available in the TCGA database revealed that increased BCAT1 transcription is associated with poor overall survival of lung cancer patients. In accord with a critical role in metastasis, shRNA-mediated knockdown of BCAT1 expression reduced migration of metastatic cells in vitro and the metastasis of these cells to distal organs in nude mice. Mechanistically, high levels of BCAT1 depleted α-ketoglutarate (α-KG) and promoted expression of SOX2, a transcription factor regulating cancer cell stemness and metastasis. Conclusion: Our findings suggest that BCAT1 plays an important role in promoting lung cancer cell metastasis, and may define a novel pathway to target as an anti-metastatic therapy.
Collapse
|
|
17
|
Abstract
The proliferation, metastasis and therapy response of tumour cells are tightly regulated by interaction among various signalling networks. The microRNAs (miRNAs) can bind to 3'-UTR of mRNA and down-regulate expression of target gene. The miRNAs target various molecular pathways in regulating biological events such as apoptosis, differentiation, angiogenesis and migration. The aberrant expression of miRNAs occurs in cancers and they have both tumour-suppressor and tumour-promoting functions. On the contrary, SOX proteins are capable of binding to DNA and regulating gene expression. SOX2 is a well-known member of SOX family that its overexpression in different cancers to ensure progression and stemness. The present review focuses on modulatory impact of miRNAs on SOX2 in affecting growth, migration and therapy response of cancers. The lncRNAs and circRNAs can function as upstream mediators of miRNA/SOX2 axis in cancers. In addition, NF-κB, TNF-α and SOX17 are among other molecular pathways regulating miRNA/SOX2 axis in cancer. Noteworthy, anti-cancer compounds including bufalin and ovatodiolide are suggested to regulate miRNA/SOX2 axis in cancers. The translation of current findings to clinical course can pave the way to effective treatment of cancer patients and improve their prognosis.
Collapse
|
|
18
|
Beklen H, Yildirim E, Kori M, Turanli B, Arga KY. Systems-level biomarkers identification and drug repositioning in colorectal cancer. World J Gastrointest Oncol 2021. [DOI: 10.4251/wjgo.v13.i7.463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
|
|
19
|
Beklen H, Yildirim E, Kori M, Turanli B, Arga KY. Systems-level biomarkers identification and drug repositioning in colorectal cancer. World J Gastrointest Oncol 2021; 13:638-661. [PMID: 34322194 PMCID: PMC8299930 DOI: 10.4251/wjgo.v13.i7.638] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 04/20/2021] [Accepted: 05/25/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the most commonly diagnosed fatal cancer in both women and men worldwide. CRC ranked second in mortality and third in incidence in 2020. It is difficult to diagnose CRC at an early stage as there are no clinical symptoms. Despite advances in molecular biology, only a limited number of biomarkers have been translated into routine clinical practice to predict risk, prognosis and response to treatment. In the last decades, systems biology approaches at the omics level have gained importance. Over the years, several biomarkers for CRC have been discovered in terms of disease diagnosis and prognosis. On the other hand, a few drugs are being developed and used in clinics for the treatment of CRC. However, the development of new drugs is very costly and time-consuming as the research and development takes about 10 years and more than $1 billion. Therefore, drug repositioning (DR) could save time and money by establishing new indications for existing drugs. In this review, we aim to provide an overview of biomarkers for the diagnosis and prognosis of CRC from the systems biology perspective and insights into DR approaches for the prevention or treatment of CRC.
Collapse
Affiliation(s)
- Hande Beklen
- Department of Bioengineering, Marmara University, Istanbul 34722, Turkey
| | - Esra Yildirim
- Department of Bioengineering, Marmara University, Istanbul 34722, Turkey
| | - Medi Kori
- Department of Bioengineering, Marmara University, Istanbul 34722, Turkey
| | - Beste Turanli
- Department of Bioengineering, Marmara University, Istanbul 34722, Turkey
| | - Kazim Yalcin Arga
- Department of Bioengineering, Marmara University, Istanbul 34722, Turkey
| |
Collapse
|
|
20
|
Pavlič A, Urh K, Štajer K, Boštjančič E, Zidar N. Epithelial-Mesenchymal Transition in Colorectal Carcinoma: Comparison Between Primary Tumor, Lymph Node and Liver Metastases. Front Oncol 2021; 11:662806. [PMID: 34046357 PMCID: PMC8144630 DOI: 10.3389/fonc.2021.662806] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 04/12/2021] [Indexed: 01/06/2023] Open
Abstract
There is emerging evidence suggesting that epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) play an important role in colorectal carcinoma (CRC), but their exact role remains controversial. Our aim was to analyze the miR-200 family as EMT markers and their target genes expression at invasive tumor front and in nodal and liver metastases. Sixty-three formalin-fixed paraffin-embedded tissue samples from 19 patients with CRC were included. Using a micropuncture technique, tissue was obtained from central part and invasive front of the primary tumor, and nodal and liver metastases. Expression of the miR-200 family and their target genes CDKN1B, ONECUT2, PTPN13, RND3, SOX2, TGFB2 and ZEB2 was analyzed using real-time PCR. We found miR-200 family down-regulation at invasive front compared to central part, and up-regulation of miRNA-200a/b/c and miR-429 in metastases compared to invasive front. At invasive front, TGFB2 was the only gene with inverse expression to the miR-200 family, whereas in metastases inverse expression was found for ONECUT2 and SOX2. CDKN1B, PTPN13 and ZEB2 were down-regulated at invasive front and up-regulated in metastases. Our results suggest the involvement of partial EMT at invasive tumor front, and partial MET in metastases in CRC, based on miR-200 family and its target genes expression.
Collapse
Affiliation(s)
- Ana Pavlič
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Kristian Urh
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Katarina Štajer
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Emanuela Boštjančič
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Nina Zidar
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| |
Collapse
|
|
21
|
Wen B, Zhu R, Jin H, Zhao K. Differential expression and role of miR-200 family in multiple tumors. Anal Biochem 2021; 626:114243. [PMID: 33964251 DOI: 10.1016/j.ab.2021.114243] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 04/23/2021] [Accepted: 05/01/2021] [Indexed: 01/02/2023]
Abstract
microRNA (miRNA) can maintain the homeostasis of the human by participating in the regulation of cell proliferation, apoptosis, differentiation, and metabolism. During the entire stage of tumorigenesis, miRNA can maintain the heterogeneity of cancer stem cells by regulating the formation and metastasis of the tumor, which leads to chemotherapy resistance. miR-200 family consists of five members, which can regulate the proliferation, invasion, and migration of cancer cells by inhibiting the transcription of downstream genes (including zinc finger E-box binding homeobox 1 and 2, E-cadherin, N-cadherin, transforming growth factor-β, and cancer stem cell related-proteins). Meanwhile, Long non-coding RNA can bind to miR-200s to regulate the proliferation and apoptosis of cancer cells. Besides, the expression of the miR-200 family can affect the mechanism of chemotherapy resistance.
Collapse
Affiliation(s)
- Bin Wen
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, PR China
| | - Rong Zhu
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, PR China
| | - Hai Jin
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, PR China
| | - Kui Zhao
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, PR China.
| |
Collapse
|
|
22
|
Dos Santos IL, Penna KGBD, Dos Santos Carneiro MA, Libera LSD, Ramos JEP, Saddi VA. Tissue micro-RNAs associated with colorectal cancer prognosis: a systematic review. Mol Biol Rep 2021; 48:1853-1867. [PMID: 33598796 DOI: 10.1007/s11033-020-06075-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 12/10/2020] [Indexed: 01/05/2023]
Abstract
Colorectal cancer (CRC) is a multifactorial disease commonly diagnosed worldwide, with high mortality rates. Several studies demonstrate important associations between differential expression of micro-RNAs (miRs) and the prognosis of CRC. The present study aimed to identify differentially expressed tissue miRs associated with prognostic factors in CRC patients, through a systematic review of the Literature. Using the PubMed database, Cochrane Library and Web of Science, studies published in English evaluating miRs differentially expressed in tumor tissue and significantly associated with the prognostic aspects of CRC were selected. All the included studies used RT-PCR (Taqman or SYBR Green) for miR expression analysis and the period of publication was from 2009 to 2018. A total of 115 articles accomplished the inclusion criteria and were included in the review. The studies investigated the expression of 100 different miRs associated with prognostic aspects in colorectal cancer patients. The most frequent oncogenic miRs investigated were miR-21, miR-181a, miR-182, miR-183, miR-210 and miR-224 and the hyperexpression of these miRs was associated with distant metastasis, lymph node metastasis and worse survival in patients with CRC. The most frequent tumor suppressor miRs were miR-126, miR-199b and miR-22 and the hypoexpression of these miRs was associated with distant metastasis, worse prognosis and a higher risk of disease relapse (worse disease-free survival). Specific tissue miRs are shown to be promising prognostic biomarkers in patients with CRC, given their strong association with the prognostic aspects of these tumors, however, new studies are necessary to establish the sensibility and specificity of the individual miRs in order to use them in clinical practice.
Collapse
Affiliation(s)
- Igor Lopes Dos Santos
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil.
| | - Karlla Greick Batista Dias Penna
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil
| | | | | | - Jéssica Enocencio Porto Ramos
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil
| | - Vera Aparecida Saddi
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil
| |
Collapse
|
|
23
|
MiR-429 Involves in the Pathogenesis of Colorectal Cancer via Directly Targeting LATS2. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:5316276. [PMID: 33414893 PMCID: PMC7769676 DOI: 10.1155/2020/5316276] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 09/18/2020] [Accepted: 12/10/2020] [Indexed: 11/17/2022]
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related death around the world whose recurrence and metastasis rate is high. Due to the underlying unclear pathogenesis, it is hard so far to predict the tumorigenesis and prevent its recurrence. YAP/TAZ has been reported to be activated and functioned as a potential oncogene in multiple cancer types and proved to be essential for the carcinogenesis of most solid tumors. In the present study, we found that YAP/TAZ was markedly upregulated in CRC tissues comparing with the adjacent noncancerous tissues due to the downregulation of LATS2, the main upstream regulator. We further identified miR-429 as a direct regulator of LATS2-YAP/TAZ activation, suggesting that the miR-429-LATS2-YAP/TAZ might be novel effective diagnostic axis and therapeutic targets for CRC.
Collapse
|
|
24
|
Functional characterization of SOX2 as an anticancer target. Signal Transduct Target Ther 2020; 5:135. [PMID: 32728033 PMCID: PMC7391717 DOI: 10.1038/s41392-020-00242-3] [Citation(s) in RCA: 125] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/01/2020] [Accepted: 06/22/2020] [Indexed: 02/07/2023] Open
Abstract
SOX2 is a well-characterized pluripotent factor that is essential for stem cell self-renewal, reprogramming, and homeostasis. The cellular levels of SOX2 are precisely regulated by a complicated network at the levels of transcription, post-transcription, and post-translation. In many types of human cancer, SOX2 is dysregulated due to gene amplification and protein overexpression. SOX2 overexpression is associated with poor survival of cancer patients. Mechanistically, SOX2 promotes proliferation, survival, invasion/metastasis, cancer stemness, and drug resistance. SOX2 is, therefore, an attractive anticancer target. However, little progress has been made in the efforts to discover SOX2 inhibitors, largely due to undruggable nature of SOX2 as a transcription factor. In this review, we first briefly introduced SOX2 as a transcription factor, its domain structure, normal physiological functions, and its involvement in human cancers. We next discussed its role in embryonic development and stem cell-renewal. We then mainly focused on three aspects of SOX2: (a) the regulatory mechanisms of SOX2, including how SOX2 level is regulated, and how SOX2 cross-talks with multiple signaling pathways to control growth and survival; (b) the role of SOX2 in tumorigenesis and drug resistance; and (c) current drug discovery efforts on targeting SOX2, and the future perspectives to discover specific SOX2 inhibitors for effective cancer therapy.
Collapse
|
|
25
|
Sartorius K, Swadling L, An P, Makarova J, Winkler C, Chuturgoon A, Kramvis A. The Multiple Roles of Hepatitis B Virus X Protein (HBx) Dysregulated MicroRNA in Hepatitis B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) and Immune Pathways. Viruses 2020; 12:v12070746. [PMID: 32664401 PMCID: PMC7412373 DOI: 10.3390/v12070746] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/08/2020] [Accepted: 07/09/2020] [Indexed: 12/11/2022] Open
Abstract
Currently, the treatment of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) [HBV-HCC] relies on blunt tools that are unable to offer effective therapy for later stage pathogenesis. The potential of miRNA to treat HBV-HCC offer a more targeted approach to managing this lethal carcinoma; however, the complexity of miRNA as an ancillary regulator of the immune system remains poorly understood. This review examines the overlapping roles of HBx-dysregulated miRNA in HBV-HCC and immune pathways and seeks to demonstrate that specific miRNA response in immune cells is not independent of their expression in hepatocytes. This interplay between the two pathways may provide us with the possibility of using candidate miRNA to manipulate this interaction as a potential therapeutic option.
Collapse
Affiliation(s)
- Kurt Sartorius
- Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg 2050, South Africa
- Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4041, South Africa;
- UKZN Gastrointestinal Cancer Research Centre, Durban 4041, South Africa
- Correspondence:
| | - Leo Swadling
- Division of Infection and Immunity, University College London, London WC1E6BT, UK;
| | - Ping An
- Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc. Frederick Nat. Lab. for Cancer Research, Frederick, MD 20878, USA; (P.A.); (C.W.)
| | - Julia Makarova
- National Research University Higher School of Economics, Faculty of Biology and Biotechnology, 10100 Moscow, Russia;
| | - Cheryl Winkler
- Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc. Frederick Nat. Lab. for Cancer Research, Frederick, MD 20878, USA; (P.A.); (C.W.)
| | - Anil Chuturgoon
- Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4041, South Africa;
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2050, South Africa;
| |
Collapse
|
|
26
|
Wang J, Wang C, Li Q, Guo C, Sun W, Zhao D, Jiang S, Hao L, Tian Y, Liu S, Sun MZ. miR-429-CRKL axis regulates clear cell renal cell carcinoma malignant progression through SOS1/MEK/ERK/MMP2/MMP9 pathway. Biomed Pharmacother 2020; 127:110215. [PMID: 32413671 DOI: 10.1016/j.biopha.2020.110215] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 04/24/2020] [Accepted: 04/28/2020] [Indexed: 02/07/2023] Open
Abstract
The pathogenesis and tumorigenesis of clear cell renal cell carcinoma (ccRCC) remain unclear. The deregulations of miR-429, a member of miR-200 family, and v-crk sarcoma virus CT10 oncogene homologue (avian)-like (CRKL), an adaptor protein of CRK family, are involved in the development, metastasis and prognosis of various cancers. Current study aimed to demonstrate the differential expressions of miR-429 and CRKL with their correlationship and molecular regulation mechanism in ccRCC malignancy. miR-429 and CRKL separately showed suppressing and promoting effects in ccRCC. Lower miR-429 expression and higher CRKL expression were negatively correlated in surgical cancerous tissues by promoting the advance of ccRCC. By binding to the 3'-UTR of CRKL, miR-429 reversely regulated CRKL for its functionalities in ccRCC cells. CRKL knockdown and overexpression separately decreased and increased the in vitro migration and invasion of 786-O cells, which were consistent with the influences of miR-429 overexpression and knockdown on 786-O through respectively downregulating and upregulating CRKL via SOS1/MEK/ERK/MMP2/MMP9 pathway. The enhancements of CRKL expression, migration and invasion abilities and SOS1/MEK/ ERK/MMP2/MMP9 activation induced by TGF-β stimulation in 786-O cells could be antagonized by miR-429 overexpression. Exogenous re-expression of CRKL abrogated miR-429 suppression on the migration and invasion of 786-O cells. Collectively, miR-429 deficiency negatively correlated with CRKL overexpression promoted the aggressiveness of cancer cells and advanced the clinical progression of ccRCC patients. miR-429-CRKL axial regulation provides new clues to the fundamental research, diagnosis and treatment of ccRCC.
Collapse
Affiliation(s)
- Jinxia Wang
- Department of Biotechnology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China; Department of Biochemistry, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Chengyi Wang
- Department of Biotechnology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Qian Li
- Department of Biochemistry, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Chunmei Guo
- Department of Biotechnology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Weibin Sun
- Department of Urology, The Second Affiliated Hospital, Dalian Medical University, Dalian 116027, China
| | - Dongting Zhao
- Department of Biotechnology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Sixiong Jiang
- Department of Urology, The Second Affiliated Hospital, Dalian Medical University, Dalian 116027, China
| | - Lihong Hao
- Department of Anatomy, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Yuxiang Tian
- Department of Biochemistry, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Shuqing Liu
- Department of Biochemistry, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China.
| | - Ming-Zhong Sun
- Department of Biotechnology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China.
| |
Collapse
|
|
27
|
Pan HW, Du LT, Li W, Yang YM, Zhang Y, Wang CX. Biodiversity and richness shifts of mucosa-associated gut microbiota with progression of colorectal cancer. Res Microbiol 2020; 171:107-114. [PMID: 31982498 DOI: 10.1016/j.resmic.2020.01.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 01/14/2020] [Accepted: 01/14/2020] [Indexed: 12/19/2022]
Abstract
The host-associated gut microbiota is considered critical for the occurrence and progression of colorectal cancer (CRC); however, systematic evaluations of the changes in the biodiversity and richness of mucosa-associated gut microbiota with the development of CRC have been limited. Twenty-three paired samples from colorectal tumor sites and the surrounding non-tumor tissues were collected from stage I to IV CRC patients. The microbial compositions of the samples were analyzed by Illumina MiSeq sequencing of the V4 region of the 16S rRNA gene. Gut bacterial alterations at the tumor sites and surrounding healthy tissue sites collected from the different stages of CRC patients were analyzed. No significant differences were observed in the overall microbial richness and biodiversity between the CRC tissue and surrounding non-CRC tissue samples, however, composition and community segregation of the gut microbiota with the progression of CRC were observed. A general increasing trend of Bacteroidetes, Firmicutes, and Fusobacteria and decreasing trend of Proteobacteria were observed at the phylum level with the development of CRC. Further analysis revealed that thirty-four taxa differed significantly with the progression of CRC. Conclusively, our findings provide a comprehensive view of the human mucosa-associated gut microbiota, in association with the different stages of CRC.
Collapse
Affiliation(s)
- Hong-Wei Pan
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, 250012, Shandong Province, China
| | - Lu-Tao Du
- Department of Clinical Laboratory, Second Hospital of Shandong University, Jinan, 250033, Shandong Province, China
| | - Wei Li
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, 250012, Shandong Province, China
| | - Yong-Mei Yang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, 250012, Shandong Province, China
| | - Yi Zhang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, 250012, Shandong Province, China
| | - Chuan-Xin Wang
- Department of Clinical Laboratory, Second Hospital of Shandong University, Jinan, 250033, Shandong Province, China.
| |
Collapse
|
|
28
|
Preventive and Therapeutic Roles of Berberine in Gastrointestinal Cancers. BIOMED RESEARCH INTERNATIONAL 2019; 2019:6831520. [PMID: 31950049 PMCID: PMC6949668 DOI: 10.1155/2019/6831520] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Revised: 10/20/2019] [Accepted: 11/01/2019] [Indexed: 12/20/2022]
Abstract
Berberine (BBR) is an isoquinoline alkaloid isolated from various types of plants, including those from the Berberidaceae, Ranunculaceae, and Papaveraceae families. It has long been used in traditional Chinese medicine for treating diarrhea and gastrointestinal disorders. The medicinal properties of BBR include antimicrobial, anti-inflammatory, antioxidative, lipid-regulatory, and antidiabetic actions. Importantly, the efficacy of BBR against cancers has been assessed in several experimental studies and clinical trials. Gastrointestinal (GI) cancers are a group of the most prevalent cancers worldwide that are associated with high morbidity and mortality, and their associated mortality has been increasing over the years. Thus, GI cancers have become a burden to the patients and health care systems. This review summarizes the cellular and molecular mechanisms underlying the therapeutic effects of BBR and explores its potential preventive and therapeutic applications against GI cancers.
Collapse
|
|
29
|
Jevšinek Skok D, Hauptman N, Boštjančič E, Zidar N. The integrative knowledge base for miRNA-mRNA expression in colorectal cancer. Sci Rep 2019; 9:18065. [PMID: 31792281 PMCID: PMC6889159 DOI: 10.1038/s41598-019-54358-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 11/13/2019] [Indexed: 12/12/2022] Open
Abstract
"miRNA colorectal cancer" (https://mirna-coadread.omics.si/) is a freely available web application for studying microRNA and mRNA expression and their correlation in colorectal cancer. To the best of our knowledge, "miRNA colorectal cancer" has the largest knowledge base of miRNA-target gene expressions and correlations in colorectal cancer, based on the largest available sample size from the same source of data. Data from high-throughput molecular profiling of 295 colon and rectum adenocarcinoma samples from The Cancer Genome Atlas was analyzed and integrated into our knowledge base. The objective of developing this web application was to help researchers to discover the behavior and role of miRNA-target gene interactions in colorectal cancer. For this purpose, results of differential expression and correlation analyses of miRNA and mRNA data collected in our knowledge base are available through web forms. To validate our knowledge base experimentally, we selected genes FN1, TGFB2, RND3, ZEB1 and ZEB2 and miRNAs hsa-miR-200a/b/c-3p, hsa-miR-141-3p and hsa-miR-429. Both approaches revealed a negative correlation between miRNA hsa-miR-200b/c-3p and its target gene FN1 and between hsa-miR-200a-3p and its target TGFB2, thus supporting the usefulness of the developed knowledge base.
Collapse
Affiliation(s)
- Daša Jevšinek Skok
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia. .,Agricultural Institute of Slovenia, Ljubljana, Slovenia.
| | - Nina Hauptman
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Emanuela Boštjančič
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Nina Zidar
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| |
Collapse
|
|
30
|
MiR-200 family and cancer: From a meta-analysis view. Mol Aspects Med 2019; 70:57-71. [DOI: 10.1016/j.mam.2019.09.005] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 09/12/2019] [Accepted: 09/17/2019] [Indexed: 12/20/2022]
|
|
31
|
Lan C, Long L, Xie K, Liu J, Zhou L, Pan S, Liang J, Tu Z, Gao Z, Tang Y. miRNA-429 suppresses osteogenic differentiation of human adipose-derived mesenchymal stem cells under oxidative stress via targeting SCD-1. Exp Ther Med 2019; 19:696-702. [PMID: 31885708 PMCID: PMC6913378 DOI: 10.3892/etm.2019.8246] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 11/08/2019] [Indexed: 12/15/2022] Open
Abstract
Role of microRNA-429 (miRNA-429) in osteogenic differentiation of hADMSCs was elucidated to explore the potential mechanism. Serum level of miRNA-429 in osteoporosis patients and controls was determined by quantitative real-time polymerase chain reaction (qRT-PCR). After H2O2 induction in hADMSCs, cell viability and reactive oxygen species (ROS) level were determined by cell-counting kit (CCK-8) assay and flow cytometry, respectively. Alkaline phosphatase (ALP) activity in H2O2-induced hADMSCs was also detected. The binding condition between miRNA-429 and SCD-1 was verified by dual-luciferase reporter gene assay. Relative levels of osteogenesis-related genes influenced by SCD-1 and miRNA-429 were detected by qRT-PCR. Furthermore, regulatory effects of SCD-1 and miRNA-429 on ALP activity and calcification ability of hADMSCs were evaluated. miRNA-429 was significantly upregulated in serum of osteoporosis patients. During the process of osteogenesis differentiation, H2O2 induction gradually upregulated miRNA-429 in hADMSCs. Overexpression of miRNA-429 markedly reduced ALP activity. Subsequent dual-luciferase reporter gene assay verified that miRNA-429 could bind to SCD-1 and negatively regulated its protein level in hADMSCs. SCD-1 was obviously downregulated in the osteogenesis differentiation of hADMSCs under oxidative stress. Moreover, silencing of SCD-1 suppressed expression of osteogenesis-related gene, ALP activity and calcification ability. Notably, SCD-1 knockdown partially reversed the regulatory effect of miRNA-429 on the osteogenic differentiation of hADMSCs. miRNA-429 suppresses the osteogenic differentiation of hADMSCs under oxidative stress via downregulating SCD-1.
Collapse
Affiliation(s)
- Changgong Lan
- The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China.,Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, Guangxi 533000, P.R. China
| | - Lizhen Long
- Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, Guangxi 533000, P.R. China
| | - Kegong Xie
- Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, Guangxi 533000, P.R. China
| | - Jia Liu
- Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, Guangxi 533000, P.R. China
| | - Landao Zhou
- Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, Guangxi 533000, P.R. China
| | - Shengcai Pan
- Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, Guangxi 533000, P.R. China
| | - Junqing Liang
- Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, Guangxi 533000, P.R. China
| | - Zhenyang Tu
- Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, Guangxi 533000, P.R. China
| | - Ziran Gao
- Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, Guangxi 533000, P.R. China
| | - Yujin Tang
- The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China.,Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, Guangxi 533000, P.R. China
| |
Collapse
|
|
32
|
Epithelial-Mesenchymal Transition-Related MicroRNAs and Their Target Genes in Colorectal Cancerogenesis. J Clin Med 2019; 8:jcm8101603. [PMID: 31623346 PMCID: PMC6832722 DOI: 10.3390/jcm8101603] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 09/26/2019] [Accepted: 09/27/2019] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs of the miR-200 family have been shown experimentally to regulate epithelial-mesenchymal transition (EMT). Although EMT is the postulated mechanism of development and progression of colorectal cancer (CRC), there are still limited and controversial data on expression of miR-200 family and their target genes during CRC cancerogenesis. Our study included formalin-fixed paraffin-embedded biopsy samples of 40 patients (10 adenomas and 30 cases of CRC with corresponding normal mucosa). Expression of miR-141, miR-200a/b/c and miR-429 and their target genes (CDKN1B, ONECUT2, PTPN13, RND3, SOX2, TGFB2 and ZEB2) was analysed using quantitative real-time PCR. Expression of E-cadherin was analysed using immunohistochemistry. All miRNAs were down-regulated and their target genes showed the opposite expression in CRC compared to adenoma. Down-regulation of the miR-200 family at the invasive front in comparison to the central part of tumour was observed as well as a correlation of expression of miR-200b, CDKN1B, ONECUT2 and ZEB2 expression to nodal metastases. Expression of the miR-200 family and SOX2 also correlated with E-cadherin staining. These results suggest that the miR-200 family and their target genes contribute to progression of adenoma to CRC, invasive properties and development of metastases. Our results strongly support the postulated hypotheses of partial EMT and intra-tumour heterogeneity during CRC cancerogenesis.
Collapse
|
|
33
|
Yuan L, Bing Z, Yan P, Li R, Wang C, Sun X, Yang J, Shi X, Zhang Y, Yang K. Integrative data mining and meta-analysis to investigate the prognostic role of microRNA-200 family in various human malignant neoplasms: A consideration on heterogeneity. Gene 2019; 716:144025. [DOI: 10.1016/j.gene.2019.144025] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 07/26/2019] [Accepted: 07/29/2019] [Indexed: 12/15/2022]
|
|
34
|
Dimitrakopoulos C, Hindupur SK, Häfliger L, Behr J, Montazeri H, Hall MN, Beerenwinkel N. Network-based integration of multi-omics data for prioritizing cancer genes. Bioinformatics 2019; 34:2441-2448. [PMID: 29547932 PMCID: PMC6041755 DOI: 10.1093/bioinformatics/bty148] [Citation(s) in RCA: 105] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 03/13/2018] [Indexed: 12/21/2022] Open
Abstract
Motivation Several molecular events are known to be cancer-related, including genomic aberrations, hypermethylation of gene promoter regions and differential expression of microRNAs. These aberration events are very heterogeneous across tumors and it is poorly understood how they affect the molecular makeup of the cell, including the transcriptome and proteome. Protein interaction networks can help decode the functional relationship between aberration events and changes in gene and protein expression. Results We developed NetICS (Network-based Integration of Multi-omics Data), a new graph diffusion-based method for prioritizing cancer genes by integrating diverse molecular data types on a directed functional interaction network. NetICS prioritizes genes by their mediator effect, defined as the proximity of the gene to upstream aberration events and to downstream differentially expressed genes and proteins in an interaction network. Genes are prioritized for individual samples separately and integrated using a robust rank aggregation technique. NetICS provides a comprehensive computational framework that can aid in explaining the heterogeneity of aberration events by their functional convergence to common differentially expressed genes and proteins. We demonstrate NetICS’ competitive performance in predicting known cancer genes and in generating robust gene lists using TCGA data from five cancer types. Availability and implementation NetICS is available at https://github.com/cbg-ethz/netics. Supplementary information Supplementary data are available at Bioinformatics online.
Collapse
Affiliation(s)
- Christos Dimitrakopoulos
- Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland.,SIB Swiss Institute of Bioinformatics, Basel, Switzerland
| | | | - Luca Häfliger
- Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland
| | - Jonas Behr
- Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland.,SIB Swiss Institute of Bioinformatics, Basel, Switzerland
| | - Hesam Montazeri
- Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland.,SIB Swiss Institute of Bioinformatics, Basel, Switzerland
| | | | - Niko Beerenwinkel
- Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland.,SIB Swiss Institute of Bioinformatics, Basel, Switzerland
| |
Collapse
|
|
35
|
Ding Q, Li X, Sun Y, Zhang X. Schizandrin A inhibits proliferation, migration and invasion of thyroid cancer cell line TPC-1 by down regulation of microRNA-429. Cancer Biomark 2019; 24:497-508. [PMID: 30909188 DOI: 10.3233/cbm-182222] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Schizandrin A (SchA) exerts anticancer potential. However, the effects of SchA on thyroid cancer (TC) have not been clear illuminated. Therefore, we investigated the effects of SchA on TC cell line TPC-1 and the underlying mechanisms. METHODS TPC-1 cells were treated with SchA and/or transfected with miR-429 mimic, anti-miR-429 and their corresponding negative controls (NC). Cell viability, proliferation, migration, invasion and cell apoptosis were examined by CCK-8 assay, bromodeoxyuridine, modified two-chamber migration assay, Millicell Hanging Cell Culture and flow cytometry analysis, respectively. The expression of miR-429, p16, Cyclin D1, cyclin-dependent kinases 4 (CDK4), matrix metalloprotein (MMP)-2, MMP-9 and Vimentin was detected by qRT-PCR. All protein expression was examined by western blot. RESULTS SchA inhibited cell proliferation, metastasis and induced cell apoptosis. Moreover, SchA negatively regulated miR-429 expression. Treatment with miR-429 mimic and SchA reversed the results led by SchA and NC. Furthermore, the phosphorylation β-catenin, mitogen-activated protein kinase (MEK) and extracellular signal-regulated kinase (ERK) were statistically down-regulated by SchA while co-treatment with miR-429 mimic and SchA led to the opposite trend. Moreover, miR-429 knockdown showed contrary results. CONCLUSION SchA inhibits cell proliferation, migration, invasion and inactivates Wnt/β-catenin and MEK/ERK signaling pathways by down regulating miR-429.
Collapse
|
|
36
|
Yu C, Wan H, Shan R, Wen W, Li J, Luo D, Wan R. The Prognostic Value of the MiR-200 Family in Colorectal Cancer: A Meta-analysis with 1882 Patients. J Cancer 2019; 10:4009-4016. [PMID: 31417645 PMCID: PMC6692621 DOI: 10.7150/jca.27529] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Accepted: 05/13/2019] [Indexed: 12/27/2022] Open
Abstract
Background: MicroRNAs are small non-coding RNAs containing 18-22 nucleotides which play a role in RNA silencing and post-transcriptional regulation of their target genes. The MiR-200 family comprises miR-141, miR-200a, miR-200b, miR-200c and miR-429. Increasing evidence indicates that miR-200 microRNAs play a role in cancer metastasis. For example, miR-200 microRNAs were reported to influence the prognosis in colorectal cancer patients by regulating the expression of genes related to the epithelial-mesenchymal transition6. Previous studies have shown that the high expression of miR-200 microRNAs has an impact on the overall survival and Relapse-free Survival of CRC patients. However, the study results were inconsistent. Results: Data from a total of 1882 patients from 9 studies was included in the meta-analysis. Poorer Relapse-free Survival (RFS) was observed in patients with high expression levels of miR-200 microRNAs (HR=1.13, 95% CI 1.04-1.23). Additionally, subgroup analysis of sample types revealed a significant association between higher expression of the miR-200 family in the plasma and poorer OS (HR=1.23, 95% CI 1.08-1.41) and RFS (HR=2.39, 95% CI 1.20-4.77), which indicates that the miR-200 family can be used as an easily detectable biomarker for evaluation of the prognosis of patients with colorectal cancer. Conclusions: High expression levels of miR-200 microRNAs were associated with poor clinical outcomes in colorectal cancer patients. The miR-200 family can therefore potentially serve as a prognostic biomarker. Further studies should be performed to verify the clinical utility of the miR-200 family in colorectal cancer.
Collapse
Affiliation(s)
- Chengpeng Yu
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Haiting Wan
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Renfeng Shan
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Wu Wen
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jianfeng Li
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Daya Luo
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University, Nanchang, China
| | - Renhua Wan
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| |
Collapse
|
|
37
|
The role of SOX family members in solid tumours and metastasis. Semin Cancer Biol 2019; 67:122-153. [PMID: 30914279 DOI: 10.1016/j.semcancer.2019.03.004] [Citation(s) in RCA: 265] [Impact Index Per Article: 44.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 03/07/2019] [Accepted: 03/21/2019] [Indexed: 02/07/2023]
Abstract
Cancer is a heavy burden for humans across the world with high morbidity and mortality. Transcription factors including sex determining region Y (SRY)-related high-mobility group (HMG) box (SOX) proteins are thought to be involved in the regulation of specific biological processes. The deregulation of gene expression programs can lead to cancer development. Here, we review the role of the SOX family in breast cancer, prostate cancer, renal cell carcinoma, thyroid cancer, brain tumours, gastrointestinal and lung tumours as well as the entailing therapeutic implications. The SOX family consists of more than 20 members that mediate DNA binding by the HMG domain and have regulatory functions in development, cell-fate decision, and differentiation. SOX2, SOX4, SOX5, SOX8, SOX9, and SOX18 are up-regulated in different cancer types and have been found to be associated with poor prognosis, while the up-regulation of SOX11 and SOX30 appears to be favourable for the outcome in other cancer types. SOX2, SOX4, SOX5 and other SOX members are involved in tumorigenesis, e.g. SOX2 is markedly up-regulated in chemotherapy resistant cells. The SoxF family (SOX7, SOX17, SOX18) plays an important role in angio- and lymphangiogenesis, with SOX18 seemingly being an attractive target for anti-angiogenic therapy and the treatment of metastatic disease in cancer. In summary, SOX transcription factors play an important role in cancer progression, including tumorigenesis, changes in the tumour microenvironment, and metastasis. Certain SOX proteins are potential molecular markers for cancer prognosis and putative potential therapeutic targets, but further investigations are required to understand their physiological functions.
Collapse
|
|
38
|
Paul S, Brahma D. An Integrated Approach for Identification of Functionally Similar MicroRNAs in Colorectal Cancer. IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2019; 16:183-192. [PMID: 29990005 DOI: 10.1109/tcbb.2017.2765332] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Colorectal cancer (CRC) is one of the most prevalent cancers around the globe. However, the molecular reasons for pathogenesis of CRC are still poorly understood. Recently, the role of microRNAs or miRNAs in the initiation and progression of CRC has been studied. MicroRNAs are small, endogenous noncoding RNAs found in plants, animals, and some viruses, which function in RNA silencing and posttranscriptional regulation of gene expression. Their role in CRC development is studied and they are found to be potential biomarkers in diagnosis and treatment of CRC. Therefore, identification of functionally similar CRC related miRNAs may help in the development of a prognostic tool. In this regard, this paper presents a new algorithm, called μSim. It is an integrative approach for identification of functionally similar miRNAs associated with CRC. It integrates judiciously the information of miRNA expression data and miRNA-miRNA functionally synergistic network data. The functional similarity is calculated based on both miRNA expression data and miRNA-miRNA functionally synergistic network data. The effectiveness of the proposed method in comparison to other related methods is shown on four CRC miRNA data sets. The proposed method selected more significant miRNAs related to CRC as compared to other related methods.
Collapse
|
|
39
|
Mo JS, Han SH, Yun KJ, Chae SC. MicroRNA 429 regulates the expression of CHMP5 in the inflammatory colitis and colorectal cancer cells. Inflamm Res 2018; 67:985-996. [PMID: 30334065 DOI: 10.1007/s00011-018-1194-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Revised: 09/06/2018] [Accepted: 10/10/2018] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVE AND DESIGN MicroRNAs (miRNAs) play an important role in the pathogenesis of human diseases by regulating the expression of target genes in specific cells or tissues. In this study, we analyzed the association between the MIR429 and its target gene, charged multivesicular body protein 5 (CHMP5), in human colon cancer cells and in a DSS-induced colitis mouse model. MATERIALS AND METHODS A luciferase reporter system was used to confirm the effect of MIR429 on CHMP5 expression. Protein or mRNA expression of the target gene and associated molecules were measured by Western blot or quantitative RT-PCR (qRT-PCR), respectively. Flow cytometry was used to compare cell viability or cell cycle progression. RESULTS CHMP5 mRNA and protein expression was directly down-regulated by MIR429. We found that MIR429 inhibited colon cancer cell growth and cell cycle progression, and CHMP5 was overexpressed in the DSS-induced colitis mouse model and human ulcerative colitis (UC) tissues. CONCLUSIONS Our findings show that CHMP5 is a direct target of MIR429 in human colon cancer cell lines and suggest that CHMP5 up-regulation as a result of reduced MIR429 expression in DSS-induced mice colitis tissues and human UC tissues may restrict apoptosis and promote cell proliferation.
Collapse
Affiliation(s)
- Ji-Su Mo
- Department of Pathology, School of Medicine, Wonkwang University, Iksan, Chonbuk, 54538, Republic of Korea
- Digestive Disease Research Institute, Wonkwang University, Iksan, Chonbuk, 54538, Republic of Korea
| | - Seol-Hee Han
- Department of Pathology, School of Medicine, Wonkwang University, Iksan, Chonbuk, 54538, Republic of Korea
| | - Ki-Jung Yun
- Department of Pathology, School of Medicine, Wonkwang University, Iksan, Chonbuk, 54538, Republic of Korea
| | - Soo-Cheon Chae
- Department of Pathology, School of Medicine, Wonkwang University, Iksan, Chonbuk, 54538, Republic of Korea.
- Digestive Disease Research Institute, Wonkwang University, Iksan, Chonbuk, 54538, Republic of Korea.
| |
Collapse
|
|
40
|
Huang S, Tan X, Huang Z, Chen Z, Lin P, Fu SW. microRNA biomarkers in colorectal cancer liver metastasis. J Cancer 2018; 9:3867-3873. [PMID: 30410589 PMCID: PMC6218777 DOI: 10.7150/jca.28588] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 08/20/2018] [Indexed: 12/26/2022] Open
Abstract
Liver metastasis is a primary factor of prognosis and long-term survival for patients diagnosed with colorectal cancer (CRC). Colorectal cancer liver metastasis (CRCLM), is a complex biological process involving multiple factors and steps, and its mechanisms are yet to be discovered. In recent years, small noncoding RNAs, especially microRNAs (miRNAs) have been proven to play an important role in tumorigenesis, progression and metastasis in a variety of cancers, including CRC. Increasing evidence suggests that miRNAs, including those from exosomes secreted by tumor cells in circulation, could be used as promising biomarkers in early cancer detection, treatment, and prognosis. In this review, we focus on the functional roles and clinical applications of miRNAs, especially those from circulating exosomes secreted by tumor cells related to CRCLM.
Collapse
Affiliation(s)
- Shulin Huang
- Department of Medicine (Division of Genomic Medicine), The George Washington University School of Medicine and Health Sciences, Washington, DC.,Department of Breast and Thyroid Surgery, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan, China
| | - Xiaohui Tan
- Department of Medicine (Division of Genomic Medicine), The George Washington University School of Medicine and Health Sciences, Washington, DC
| | - Zhongcheng Huang
- Department of Colorectal and Anal Surgery, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan, China
| | - Zihua Chen
- Hepatobiliary and enteric Surgery Research Center/Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Paul Lin
- Department of Surgery, The George Washington University School of Medicine and Health Sciences, Washington, DC
| | - Sidney W Fu
- Department of Medicine (Division of Genomic Medicine), The George Washington University School of Medicine and Health Sciences, Washington, DC
| |
Collapse
|
|
41
|
Fu S, Zhang J, Zhang S. Knockdown of miR-429 Attenuates Aβ-Induced Neuronal Damage by Targeting SOX2 and BCL2 in Mouse Cortical Neurons. Neurochem Res 2018; 43:2240-2251. [DOI: 10.1007/s11064-018-2643-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Revised: 08/23/2018] [Accepted: 09/19/2018] [Indexed: 12/26/2022]
|
|
42
|
De Robertis M, Poeta ML, Signori E, Fazio VM. Current understanding and clinical utility of miRNAs regulation of colon cancer stem cells. Semin Cancer Biol 2018; 53:232-247. [PMID: 30130662 DOI: 10.1016/j.semcancer.2018.08.008] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 08/10/2018] [Accepted: 08/17/2018] [Indexed: 02/07/2023]
Abstract
Cancer stem cells (CSCs) in colorectal tumorigenesis are suggested to be responsible for initiation, development and propagation of colorectal cancer (CRC) and have been extensively characterized by the expression of phenotypic determinants, such as surface or intracellular proteins. The generation of CSCs is likely due to a dysregulation of the signaling pathways that principally control self-renewal and pluripotency in normal intestinal stem cells (ISCs) through different (epi)genetic changes that define cell fate, identity, and phenotype of CSCs. These aspects are currently under intense investigation. In the framework of the oncogenic signaling pathways controlled by microRNAs (miRNAs) during CRC development, a plethora of data suggests that miRNAs can play a key role in several regulatory pathways involving CSCs biology, epithelial-mesenchymal transition (EMT), angiogenesis, metastatization, and pharmacoresistance. This review examines the most relevant evidences about the role of miRNAs in the etiology of CRC, through the regulation of colon CSCs and the principal differences between colorectal CSCs and benign stem cells. In this perspective, the utility of the principal CSCs-related miRNAs changes is explored, emphasizing their use as potential biomarkers to aid in diagnosis, prognosis and predicting response to therapy in CRC patients, but also as promising targets for more effective and personalized anti-CRC treatments.
Collapse
Affiliation(s)
- Mariangela De Robertis
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari "A. Moro", Via Orabona 4, 70126 Bari, Italy; Laboratory of Molecular Medicine and Biotechnology, University Campus Bio-Medico of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy; Laboratory of Molecular Pathology and Experimental Oncology, Institute of Translational Pharmacology, Consiglio Nazionale delle Ricerche (CNR), Via Fosso del Cavaliere 100, 00133 Rome, Italy.
| | - Maria Luana Poeta
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari "A. Moro", Via Orabona 4, 70126 Bari, Italy
| | - Emanuela Signori
- Laboratory of Molecular Medicine and Biotechnology, University Campus Bio-Medico of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy; Laboratory of Molecular Pathology and Experimental Oncology, Institute of Translational Pharmacology, Consiglio Nazionale delle Ricerche (CNR), Via Fosso del Cavaliere 100, 00133 Rome, Italy.
| | - Vito Michele Fazio
- Laboratory of Molecular Medicine and Biotechnology, University Campus Bio-Medico of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy; IRCCS "Casa Sollievo della Sofferenza", viale dei Cappuccini, 71013 San Giovanni Rotondo (FG), Italy
| |
Collapse
|
|
43
|
Yin Y, Song WW, Wang Y, Zhao W, Wu J, Xu W. MicroRNA-200 families and prognostic value in various carcinomas: A systematic review and meta-analysis. Aging Med (Milton) 2018; 1:39-45. [PMID: 31942478 PMCID: PMC6880694 DOI: 10.1002/agm2.12005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 12/14/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Recently, some studies have showed that miR-200 families act as novel biomarkers for the prediction of cancer outcomes. AIMS This meta-analysis was designed to investigate the associations between miR-200 families and the prognosis of patients with various cancers. MATERIALS & METHODS Eligible published databases including PubMed, Embase and Chinese National Knowledge Infrastructure (CNKI) databases were searched for articles until October 18, 2016. We performed a meta-analysis by calculating pooled hazard ratios (HR) and 95% confidence intervals (CI). Data were extracted from studies comparing overall survival (OS), progression-free survival (PFS) or recurrence-free survival (RFS). RESULTS For OS, the pooled HR was 1.54 (95% CI: 1.01-2.33), showing that high miR-200 family was clearly related to poor survival in various carcinomas, but no significantly association was found in PFS or RFS. Subgroup analysis indicated that upregulated miR-200 family was linked to poor OS in Asians (HR = 2.19, 95% CI: 1.27-3.78) but not in Caucasians (HR = 0.94, 95% CI: 0.46-1.91). Similarly, high miR-200 expression could not clearly predict the relationship with PFS and RFS. For cancer type, high miR-200 also predicted poor OS among lung cancer patients (HR = 3.09, 95% CI: 1.75-5.46). Besides, only elevated miR-200c of the miR-200 family indicated a significantly poor OS (HR = 2.25, 95% CI: 1.39-3.64). DISCUSSION Aberrant expression of miRNAs played a crucial role in the area of human carcinomas. Many studies have indicated that miRNAs are considered promising tumor biomarkers for prognosis and potential targets for clinical treatment. We have testified that high levels of miR-200 family expression (predominantly miR-200c) are significantly associated with poor survival and prognostic outcomes of patients with cancers, especially in lung cancer. However, no statistically significant results were calculated for miR-200a/b and miR-429, and this might result from a relatively small number of articles about them. In other tumor models except lung cancer, our results indicated that high miR-200 family was not obviously associated with OS (Gastric or Colorectal cancer; Ovarian cancer; Others). In addition, some other records showed the opposite results, for they exhibited that upregulated miR-200 family level was linked to longer survival. For ethnic group, our stratified analyses showed that the Asian population predicted poor OS. While the Caucasian population did not exhibit an significant association with OS. This discrepancy might result from different hereditary backgrounds and environment exposure. Although these results have indicated that miR-200 families were promising biomarkers to predict prognosis for patients with cancers, there were several limitations in this analysis that would impact its quality. Generally, further studies should be warranted to clarify this question and to provide a new novel idea for routine clinical application. CONCLUSION Our findings suggest that miR-200 family might be a potentially useful biomarker for predicting cancer prognosis, especially for lung cancer in Asians.
Collapse
Affiliation(s)
- Yuan Yin
- Nanjing Medical UniversityJiangning District, NanjingChina
| | - Wei Wei Song
- Department of GeriatricsThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Yu Wang
- Department of GeriatricsThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Weihong Zhao
- Department of GeriatricsThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Jianqing Wu
- Department of GeriatricsThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Wei Xu
- Department of GeriatricsThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| |
Collapse
|
|
44
|
Kim CG, Lee H, Gupta N, Ramachandran S, Kaushik I, Srivastava S, Kim SH, Srivastava SK. Role of Forkhead Box Class O proteins in cancer progression and metastasis. Semin Cancer Biol 2018; 50:142-151. [PMID: 28774834 PMCID: PMC5794649 DOI: 10.1016/j.semcancer.2017.07.007] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Revised: 07/24/2017] [Accepted: 07/30/2017] [Indexed: 01/10/2023]
Abstract
It is now widely accepted that several gene alterations including transcription factors are critically involved in cancer progression and metastasis. Forkhead Box Class O proteins (FoxOs) including FoxO1/FKHR, FoxO3/FKHRL1, FoxO4/AFX and FoxO6 transcription factors are known to play key roles in proliferation, apoptosis, metastasis, cell metabolism, aging and cancer biology through their phosphorylation, ubiquitination, acetylation and methylation. Though FoxOs are proved to be mainly regulated by upstream phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3 K)/Akt signaling pathway, the role of FoxOs in cancer progression and metastasis still remains unclear so far. Thus, with previous experimental evidences, the present review discussed the role of FoxOs in association with metastasis related molecules including cannabinoid receptor 1 (CNR1), Cdc25A/Cdk2, Src, serum and glucocorticoid inducible kinases (SGKs), CXCR4, E-cadherin, annexin A8 (ANXA8), Zinc finger E-box-binding homeobox 2 (ZEB2), human epidermal growth factor receptor 2 (HER2) and mRNAs such as miR-182, miR-135b, miR-499-5p, miR-1274a, miR-150, miR-34b/c and miR-622, subsequently analyzed the molecular mechanism of some natural compounds targeting FoxOs and finally suggested future research directions in cancer progression and metastasis.
Collapse
Affiliation(s)
- Chang Geun Kim
- Cancer Molecular Target Herbal Research Center, College of Korean Medicine, Kyunghee University, Seoul, Republic of Korea
| | - Hyemin Lee
- Cancer Molecular Target Herbal Research Center, College of Korean Medicine, Kyunghee University, Seoul, Republic of Korea
| | - Nehal Gupta
- Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
| | - Sharavan Ramachandran
- Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
| | - Itishree Kaushik
- Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
| | | | - Sung-Hoon Kim
- Cancer Molecular Target Herbal Research Center, College of Korean Medicine, Kyunghee University, Seoul, Republic of Korea.
| | - Sanjay K Srivastava
- Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA; Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA.
| |
Collapse
|
|
45
|
Gao S, Zhao ZY, Wu R, Zhang Y, Zhang ZY. Prognostic value of microRNAs in colorectal cancer: a meta-analysis. Cancer Manag Res 2018; 10:907-929. [PMID: 29750053 PMCID: PMC5935085 DOI: 10.2147/cmar.s157493] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background Numerous studies have shown that miRNA levels are closely related to the survival time of patients with colon, rectal, or colorectal cancer (CRC). However, the outcomes of different investigations have been inconsistent. Accordingly, a meta-analysis was conducted to study associations among the three types of cancers. Materials and methods Studies published in English that estimated the expression levels of miRNAs with survival curves in CRC were identified until May 20, 2017 by online searches in PubMed, Embase, Web of Science, and the Cochrane Library by two independent authors. Pooled HRs with 95% CIs were used to estimate the correlation between miRNA expression and overall survival. Results A total of 63 relevant articles regarding 13 different miRNAs, with 10,254 patients were ultimately included. CRC patients with high expression of blood miR141 (HR 2.52, 95% CI 1.68-3.77), tissue miR21 (HR 1.31, 95% CI 1.12-1.53), miR181a (HR 1.52, 95% CI 1.26-1.83), or miR224 (HR 2.12, 95% CI 1.04-4.34), or low expression of tissue miR126 (HR 1.55, 95% CI 1.24-1.93) had significantly poor overall survival (P<0.05). Conclusion In general, blood miR141 and tissue miR21, miR181a, miR224, and miR126 had significant prognostic value. Among these, blood miR141 and tissue miR224 were strong biomarkers of prognosis for CRC.
Collapse
Affiliation(s)
- Song Gao
- Second Department of Clinical Oncology, Shengjing Hospital of China Medical University
| | - Zhi-Ying Zhao
- School of Computer Science and Engineering, Northeastern University, Shenyang
| | - Rong Wu
- Second Department of Clinical Oncology, Shengjing Hospital of China Medical University
| | - Yue Zhang
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Zhen-Yong Zhang
- Second Department of Clinical Oncology, Shengjing Hospital of China Medical University
| |
Collapse
|
|
46
|
Wuebben EL, Rizzino A. The dark side of SOX2: cancer - a comprehensive overview. Oncotarget 2018; 8:44917-44943. [PMID: 28388544 PMCID: PMC5546531 DOI: 10.18632/oncotarget.16570] [Citation(s) in RCA: 169] [Impact Index Per Article: 24.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 03/16/2017] [Indexed: 12/14/2022] Open
Abstract
The pluripotency-associated transcription factor SOX2 is essential during mammalian embryogenesis and later in life, but SOX2 expression can also be highly detrimental. Over the past 10 years, SOX2 has been shown to be expressed in at least 25 different cancers. This review provides a comprehensive overview of the roles of SOX2 in cancer and focuses on two broad topics. The first delves into the expression and function of SOX2 in cancer focusing on the connection between SOX2 levels and tumor grade as well as patient survival. As part of this discussion, we address the developing connection between SOX2 expression and tumor drug resistance. We also call attention to an under-appreciated property of SOX2, its levels in actively proliferating tumor cells appear to be optimized to maximize tumor growth - too little or too much SOX2 dramatically alters tumor growth. The second topic of this review focuses on the exquisite array of molecular mechanisms that control the expression and transcriptional activity of SOX2. In addition to its complex regulation at the transcriptional level, SOX2 expression and activity are controlled carefully by microRNAs, long non-coding RNAs, and post-translational modifications. In the Conclusion and Future Perspectives section, we point out that there are still important unanswered questions. Addressing these questions is expected to lead to new insights into the functions of SOX2 in cancer, which will help design novels strategies for more effectively treating some of the most deadly cancers.
Collapse
Affiliation(s)
- Erin L Wuebben
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Angie Rizzino
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.,Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| |
Collapse
|
|
47
|
Kim ES, Choi YE, Hwang SJ, Han YH, Park MJ, Bae IH. IL-4, a direct target of miR-340/429, is involved in radiation-induced aggressive tumor behavior in human carcinoma cells. Oncotarget 2018; 7:86836-86856. [PMID: 27895317 PMCID: PMC5349958 DOI: 10.18632/oncotarget.13561] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Accepted: 11/07/2016] [Indexed: 12/12/2022] Open
Abstract
Radiotherapy induces the production of cytokines, thereby increasing aggressive tumor behavior. This radiation effect results in the failure of radiotherapy and increases the mortality rate in patients. We found that interleukin-4 (IL-4) and IL-4Rα (IL-4 receptor) are highly expressed in various human cancer cells subsequent to radiation treatment. In addition, IL-4 is highly overexpressed in metastatic carcinoma tissues compared with infiltrating carcinoma tissues. High expression of IL-4 in patients with cancer is strongly correlated with poor survival. The results of this study suggest that radiation-induced IL-4 contributes to tumor progression and metastasis. Radiation-induced IL-4 was associated with tumorigenicity and metastasis. IL-4 expression was downregulated by miR-340 and miR-429, which were decreased by ionizing radiation (IR). Radiation-regulated miR-340/429-IL4 signaling increased tumorigenesis and metastasis by inducing the production of Sox2, Vimentin, VEGF, Ang2, and MMP-2/9 via activating JAK, JNK, β-catenin, and Stat6 in vitro and in vivo. Our study presents a conceptual advance in our understanding of the modification of tumor microenvironment by radiation and suggests that combining radiotherapy with genetic therapy to inhibit IL-4 may be a promising strategy for preventing post-radiation recurrence and metastasis in patients.
Collapse
Affiliation(s)
- Eun Sook Kim
- Division of Basic Radiation Bioscience, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea
| | - Young Eun Choi
- Division of Basic Radiation Bioscience, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea
| | - Su Jin Hwang
- Division of Basic Radiation Bioscience, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea
| | - Young-Hoon Han
- Division of Basic Radiation Bioscience, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea
| | - Myung-Jin Park
- Division of Basic Radiation Bioscience, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea
| | - In Hwa Bae
- Division of Basic Radiation Bioscience, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea
| |
Collapse
|
|
48
|
Ye W, Li J, Fang G, Cai X, Zhang Y, Zhou C, Chen L, Yang W. Expression of microRNA 638 and sex-determining region Y-box 2 in hepatocellular carcinoma: Association between clinicopathological features and prognosis. Oncol Lett 2018; 15:7255-7264. [PMID: 29731884 DOI: 10.3892/ol.2018.8208] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Accepted: 01/19/2018] [Indexed: 12/12/2022] Open
Abstract
The aim of the present study was to determine the expression profile of microRNA 638 (miR-638) and sex-determining region Y-box 2 (SOX2) in hepatocellular carcinoma (HCC), and to investigate their association with clinicopathological features and survival. Reverse transcription-quantitative polymerase chain reaction analysis was used to investigate miR-638 and SOX2 expression in 78 patients with HCC. Western blot and immunohistochemical analyses were performed in order to determine SOX2 protein expression in HCC samples. Combined with the clinical postoperative follow-up data, the expression of miR-638 and SOX2 and the association between this and the prognostic values of patients with HCC were statistically analyzed. The results of the present study confirmed that miR-638 expression in tumor tissues was significantly downregulated (P<0.001), while SOX2 expression was significantly increased, compared with healthy control tissues (P<0.05). In addition, a significant inverse correlation between miR-638 and SOX2 expression was also observed in the HCC tissues (r=-0.675; P<0.05). Clinicopathological correlation analysis demonstrated that reduced miR-638 and elevated SOX2 expression was significantly associated with the Tumor-Node-Metastasis stage and portal vascular invasion (P<0.05). However, no significant differences were observed in other clinicopathological features, including age, sex, tumor size, tumor differentiation and hepatitis status (P>0.05). Notably, follow-up analysis revealed that patients with HCC with low miR-638 expression and high SOX2 expression tended to have a significantly shorter postoperative survival time (P<0.001). It was concluded that miR-638 may serve a vital role in the occurrence and progression of HCC by regulating SOX2 expression and thus, that miR-638 and SOX2 may be critical as novel diagnostic and prognostic biomarkers for HCC.
Collapse
Affiliation(s)
- Weikang Ye
- Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Jieke Li
- Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Guan Fang
- Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Xiupeng Cai
- Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Yan Zhang
- Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Chaojun Zhou
- Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Lei Chen
- Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Wenjun Yang
- Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| |
Collapse
|
|
49
|
Wu CL, Ho JY, Hung SH, Yu DS. miR-429 expression in bladder cancer and its correlation with tumor behavior and clinical outcome. Kaohsiung J Med Sci 2018; 34:335-340. [PMID: 29747777 DOI: 10.1016/j.kjms.2018.01.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Revised: 12/26/2017] [Accepted: 01/03/2018] [Indexed: 01/18/2023] Open
Abstract
We previously showed that microRNA-429 (miR-429) played an important role in epithelial-mesenchymal transition (EMT) of urothelial cell carcinoma of the bladder. We herein evaluated the expression of miR-429 in bladder cancer and its potential relevance to clinicopathological characteristics and patient survival. Relative expression levels of miR-429 in surgical bladder cancer tissue specimens obtained from 76 patients with bladder cancer were measured by chromogenic in situ hybridization. miR-429 expression was significantly higher in specimens from alive patients than expired patients in both of 5-year overall survival (OS) (0.59 ± 0.09 vs. 0.27 ± 0.12; p < 0.05) and 5-year recurrence-free survival (RFS) (0.63 ± 0.10 vs. 0.33 ± 0.10; p < 0.05). The univariate Cox proportional hazards analysis revealed that tumor grade, stage, and miR-429 expression were significantly associated with patient survival. In multivariate analysis, tumor stage and miR-429 expression were significantly associated with 5-year OS (hazard ratio [HR] 4.70, p < 0.001) and 5-year-RFS (HR 2.20, p < 0.05). The Kaplan-Meier analysis showed that patients with miR-429 expression had significantly better 5-year OS and 5-year RFS rates than those without miR-429 expression (84.4% vs. 61.4%, p < 0.05 and 71.9% vs. 45.5%, p < 0.05, respectively). miR-429 may be considered as an adjunctive prognostic marker in addition to tumor grade and stage in bladder cancer.
Collapse
Affiliation(s)
- Chia-Lun Wu
- Division of Urology, Department of Surgery, Tri-Service General Hospital, Taipei, Taiwan; Graduate Institute of Life Science, National Defense Medical Center, Taipei, Taiwan
| | - Jar-Yi Ho
- Graduate Institute of Life Science, National Defense Medical Center, Taipei, Taiwan; Graduate Institute of Pathology and Parasitology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Shun-Hsing Hung
- Division of Urology, Department of Surgery, Chi-Mei Medical Center, Tainan, Taiwan
| | - Dah-Shyong Yu
- Division of Urology, Department of Surgery, Tri-Service General Hospital, Taipei, Taiwan; Department of Surgery, National Defense Medical Center, Taipei, Taiwan.
| |
Collapse
|
|
50
|
Yang L, Luo P, Song Q, Fei X. DNMT1/miR-200a/GOLM1 signaling pathway regulates lung adenocarcinoma cells proliferation. Biomed Pharmacother 2018; 99:839-847. [PMID: 29710483 DOI: 10.1016/j.biopha.2018.01.161] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Revised: 01/22/2018] [Accepted: 01/29/2018] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES Lung adenocarcinoma (LAD) comprises about 80% of all diagnosed lung cancers. However, the underlying regulatory mechanism of LAD cell proliferation is largely unclear. The emergence of microRNAs and molecular-targeted therapies adds a new dimension in our efforts to combat this deadly disease. METHOD In this work, the A549 and H1650 human lung cancer cell lines were used in this study. The proliferation was evaluated by the MTT and BrdU assay. The expression level of related proteins was detected by western blot. RESULT We reported GOLM1 was highly expressed in LAD cells and associated with low survival ratio and higher grade malignancy. Knockdown of GOLM1 repressed the LAD cell proliferation. Overexpression of GOLM1 promoted the cell proliferation. Further we found that the level of microRNA-200a (miR-200a) expression was low in LAD cells. miR-200a repress GOLM1 expression by directly targeting its 3? UTR. Overexpression of miR-200a repressed the cell proliferation and blocked the increase of LAD cell proliferation caused by GOLM1 overexpression. Further, we found that miR-200 was downregulated by DNMT1.Overexpression of DNMT1 blocked the function of miR-200a on repressing proliferation. We then found that knockdown of DNMT1 repressed LAD cell proliferation, which could be rescued by GOLM1 overexpression. CONCLUSION This work revealed the critical function of GOLM1/miR-200a/DNMT1 signaling pathway on regulating LAD cell proliferation, and might lay the foundation for further clinical treatment of LAD.
Collapse
Affiliation(s)
- Longqiu Yang
- Department of Anesthesiology, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi, 435000, China
| | - Pengcheng Luo
- Department of Urology Surgery, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi, 435000, China
| | - Qiong Song
- Department of Anesthesiology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, 195 Tongbai Road, Zhengzhou, Henan, 450007, China.
| | - Xuejie Fei
- Department of Intensive Care Unit, Shuguang Hospital Affiliated With Shanghai University of Traditional Chinese Medicine, Shanghai, 200021, China.
| |
Collapse
|