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Putatunda V, Jusakul A, Roberts L, Wang XW. Genetic, Epigenetic, and Microenvironmental Drivers of Cholangiocarcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:362-377. [PMID: 39532242 PMCID: PMC11841490 DOI: 10.1016/j.ajpath.2024.10.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 10/07/2024] [Accepted: 10/10/2024] [Indexed: 11/16/2024]
Abstract
Cholangiocarcinoma (CCA) is an aggressive and heterogeneous malignancy of the biliary tree that carries a poor prognosis. Multiple features at the genetic, epigenetic, and microenvironmental levels have been identified to better characterize CCA carcinogenesis. Genetic alterations, such as mutations in IDH1/2, BAP1, ARID1A, and FGFR2, play significant roles in CCA pathogenesis, with variations across different subtypes, races/ethnicities, and causes. Epigenetic dysregulation, characterized by DNA methylation and histone modifications, further contributes to the complexity of CCA, influencing gene expression and tumor behavior. Furthermore, CCA cells exchange autocrine and paracrine signals with other cancer cells and the infiltrating cell types that populate the microenvironment, including cancer-associated fibroblasts and tumor-associated macrophages, further contributing to an immunosuppressive niche that supports tumorigenesis. This review explores the multifaceted genetic, epigenetic, and microenvironmental drivers of CCA. Understanding these diverse mechanisms is essential for characterizing the complex pathways of CCA carcinogenesis and developing targeted therapies to improve patient outcomes.
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Affiliation(s)
- Vijay Putatunda
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland; Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
| | - Apinya Jusakul
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand; Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | - Lewis Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Xin Wei Wang
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland; Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
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2
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Liu W, Kuai Y, Wang D, Chen J, Xiong F, Wu G, Wang Q, Huang W, Qi Y, Wang B, Chen Y. PPM1G Inhibits Epithelial-Mesenchymal Transition in Cholangiocarcinoma by Catalyzing TET1 Dephosphorylation for Destabilization to Impair Its Targeted Demethylation of the CLDN3 Promoter. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2407323. [PMID: 39477806 DOI: 10.1002/advs.202407323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 10/22/2024] [Indexed: 12/19/2024]
Abstract
Ten-eleven translocation protein 1 (TET1) functions as an epigenetic regulatory molecule, mediating the majority of DNA demethylation, and plays a role in the development of different types of cancers by regulating the expression of proto-oncogenes and oncogenes. Here it is found that TET1 is highly expressed in cholangiocarcinoma (CCA) and is associated with a poor prognosis. In addition, TET1 promotes claudin-3 (CLDN3) transcription by targeting the CLDN3 promoter region between -16 and 512 for demethylation. PPM1G functions as a protein dephosphorylase, catalyzing the dephosphorylation of TET1. This results in the destabilization of the TET1 protein, thereby impairing the targeting of the CLDN3 promoter for demethylation. Two phosphatase inhibitors, staurosporine and AZD0156, inhibit epithelial-to-mesenchymal transition (EMT) in cholangiocarcinoma cells by suppressing TET1 expression. In conclusion, it is also demonstrated that PPM1G can be employed as a therapeutic target to impede the progression of CCA by catalyzing the dephosphorylation of TET1, which diminishes the capacity of TET1 to target the CLDN3 promoter to activate transcription and inhibit EMT in CCA.
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Affiliation(s)
- Wenzheng Liu
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Yiyang Kuai
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Da Wang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Junsheng Chen
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Fei Xiong
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Guanhua Wu
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Qi Wang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Wenhua Huang
- Department of Emergency, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430074, China
| | - Yongqiang Qi
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
| | - Bing Wang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Yongjun Chen
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
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3
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Fagoonee S, Weiskirchen R. MicroRNAs and RNA-Binding Protein-Based Regulation of Bone Metastasis from Hepatobiliary Cancers and Potential Therapeutic Strategies. Cells 2024; 13:1935. [PMID: 39682684 PMCID: PMC11640337 DOI: 10.3390/cells13231935] [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: 10/28/2024] [Revised: 11/15/2024] [Accepted: 11/20/2024] [Indexed: 12/18/2024] Open
Abstract
Hepatobiliary cancers, such as hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are among the deadliest malignancies worldwide, leading to a significant number of cancer-related deaths. While bone metastases from these cancers are rare, they are highly aggressive and linked to poor prognosis. This review focuses on RNA-based molecular mechanisms that contribute to bone metastasis from hepatobiliary cancers. Specifically, the role of two key factors, microRNAs (miRNAs) and RNA-binding proteins (RBPs), which have not been extensively studied in the context of HCC and CCA, is discussed. These molecules often exhibit abnormal expression in hepatobiliary tumors, influencing cancer cell spread and metastasis by disrupting bone homeostasis, thereby aiding tumor cell migration and survival in the bone microenvironment. This review also discusses potential therapeutic strategies targeting these RNA-based pathways to reduce bone metastasis and improve patient outcomes. Further research is crucial for developing effective miRNA- and RBP-based diagnostic and prognostic biomarkers and treatments to prevent bone metastases in hepatobiliary cancers.
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Affiliation(s)
- Sharmila Fagoonee
- Institute of Biostructure and Bioimaging (CNR), Molecular Biotechnology Center “Guido Tarone”, 10126 Turin, Italy
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074 Aachen, Germany
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Chen RX, Liu SC, Kan XC, Wang YR, Wang JF, Wang TL, Li C, Jiang WJ, Chen YAL, Zhou T, Fan SL, Chang J, Xu X, Shi KH, Zhang YD, Wu MY, Yu Y, Li CX, Li XC. CircUGP2 Suppresses Intrahepatic Cholangiocarcinoma Progression via p53 Signaling Through Interacting With PURB to Regulate ADGRB1 Transcription and Sponging miR-3191-5p. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2402329. [PMID: 39120980 PMCID: PMC11481218 DOI: 10.1002/advs.202402329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 07/17/2024] [Indexed: 08/11/2024]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer and its prognosis remains poor. Although growing numbers of studies have verified the involvement of circular RNAs (circRNAs) in various cancer types, their specific functions in ICC remain elusive. Herein, a circRNA, circUGP2 is identified by circRNA sequencing, which is downregulated in ICC tissues and correlated with patients' prognosis. Moreover, circUGP2 overexpression suppresses tumor progression in vitro and in vivo. Mechanistically, circUGP2 functions as a transcriptional co-activator of PURB over the expression of ADGRB1. It can also upregulate ADGRB1 expression by sponging miR-3191-5p. As a result, ADGRB1 prevents MDM2-mediated p53 polyubiquitination and thereby activates p53 signaling to inhibit ICC progression. Based on these findings, circUGP2 plasmid is encapsulated into a lipid nanoparticle (LNP) system, which has successfully targeted tumor site and shows superior anti-tumor effects. In summary, the present study has identified the role of circUGP2 as a tumor suppressor in ICC through regulating ADGRB1/p53 axis, and the application of LNP provides a promising translational strategy for ICC treatment.
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Affiliation(s)
- Rui Xiang Chen
- Hepatobiliary CenterThe First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Liver TransplantationChinese Academy of Medical SciencesNHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)NanjingJiangsu210029China
| | - Shuo Chen Liu
- Hepatobiliary CenterThe First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Liver TransplantationChinese Academy of Medical SciencesNHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)NanjingJiangsu210029China
| | - Xue Chun Kan
- School of MedicineSoutheast UniversityNanjingJiangsu210009China
| | - Yi Rui Wang
- Hepatobiliary CenterThe First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Liver TransplantationChinese Academy of Medical SciencesNHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)NanjingJiangsu210029China
| | - Ji Fei Wang
- Hepatobiliary CenterThe First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Liver TransplantationChinese Academy of Medical SciencesNHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)NanjingJiangsu210029China
| | - Tian Lin Wang
- Hepatobiliary CenterThe First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Liver TransplantationChinese Academy of Medical SciencesNHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)NanjingJiangsu210029China
| | - Chang Li
- Hepatobiliary CenterThe First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Liver TransplantationChinese Academy of Medical SciencesNHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)NanjingJiangsu210029China
| | - Wang Jie Jiang
- Hepatobiliary CenterThe First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Liver TransplantationChinese Academy of Medical SciencesNHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)NanjingJiangsu210029China
| | - Yan An Lan Chen
- Hepatobiliary CenterThe First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Liver TransplantationChinese Academy of Medical SciencesNHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)NanjingJiangsu210029China
| | - Tao Zhou
- Hepatobiliary CenterThe First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Liver TransplantationChinese Academy of Medical SciencesNHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)NanjingJiangsu210029China
| | - Shi Long Fan
- Hepatobiliary CenterThe First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Liver TransplantationChinese Academy of Medical SciencesNHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)NanjingJiangsu210029China
| | - Jiang Chang
- Hepatobiliary CenterThe First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Liver TransplantationChinese Academy of Medical SciencesNHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)NanjingJiangsu210029China
| | - Xiao Xu
- Hepatobiliary CenterThe First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Liver TransplantationChinese Academy of Medical SciencesNHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)NanjingJiangsu210029China
| | - Kuang Heng Shi
- Hepatobiliary CenterThe First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Liver TransplantationChinese Academy of Medical SciencesNHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)NanjingJiangsu210029China
| | - Yao Dong Zhang
- Hepatobiliary CenterThe First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Liver TransplantationChinese Academy of Medical SciencesNHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)NanjingJiangsu210029China
| | - Ming Yu Wu
- The Affiliated Wuxi People's Hospital of Nanjing Medical UniversityWuxi People's HospitalWuxi Medical CenterNanjing Medical UniversityWuxiJiangsu214023China
| | - Yue Yu
- Hepatobiliary CenterThe First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Liver TransplantationChinese Academy of Medical SciencesNHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)NanjingJiangsu210029China
| | - Chang Xian Li
- Hepatobiliary CenterThe First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Liver TransplantationChinese Academy of Medical SciencesNHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)NanjingJiangsu210029China
| | - Xiang Cheng Li
- Hepatobiliary CenterThe First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Liver TransplantationChinese Academy of Medical SciencesNHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)NanjingJiangsu210029China
- The Affiliated Wuxi People's Hospital of Nanjing Medical UniversityWuxi People's HospitalWuxi Medical CenterNanjing Medical UniversityWuxiJiangsu214023China
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Zhang Z, Gu Q, Chen L, Yuan D, Gu X, Qian H, Xie P, Liu Q, Hu Z. Selective microRNA expression of exosomes from retinal pigment epithelial cells by oxidative stress. Vision Res 2024; 220:108388. [PMID: 38593635 DOI: 10.1016/j.visres.2024.108388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 03/15/2024] [Accepted: 03/16/2024] [Indexed: 04/11/2024]
Abstract
The function of exosomal miRNAs (miRs) in retinal degeneration is largely unclear. We were aimed to investigate the functions of exosomes as well as their miRs derived from retinal pigment epithelial (RPE) cells following exposure to oxidative stress (OS). After the OS by lipopolysaccharide and rotenone on RPE cells, interleukin-1 beta (IL-1β), Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-α) were upregulated, along with the decreased mitochondrial membrane potential and upregulated oxidative damage marker 8-OH-dG in RPE cells. RPE-derived exosomes were then isolated, identified, injected into the subretinal space in mice. After subretinal injection, RPE-exosomes after OS not only induced higher ROS level and apoptotic retinal cells, but also elevated IL-1β, IL-6 alongside TNF-α expressions among retina/RPE/choroidal complex. Next, miRs inside the exosomes were sequenced by the next generation sequencing (NGS) technology. NGS revealed that certain miRs were abundant in exosomes, while others were selectively kept by RPE cells. Further, downregulated miRs, like miR-125b-5p, miR-125a-5p, alongside miR-128-3p, and upregulated miR, such as miR-7-5p were validated byRT-qPCR. Finally, Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were used to find the possible target genes of those selective exosomal miRs. Our results proved that the RPE-derived exosomes after OS selectively express certain miRs, providing novel insights into the pathogenesis of age-related macular degeneration (AMD) in future.
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Affiliation(s)
- Zhengyu Zhang
- Department of Ophthalmology, Xuzhou First People's Hospital, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University. Xuzhou, Jiangsu 221116, China
| | - Qinyuan Gu
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University. Nanjing, Jiangsu 210029, China
| | - Lu Chen
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University. Nanjing, Jiangsu 210029, China; Department of Ophthalmology, Xuzhou First People's Hospital, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University. Xuzhou, Jiangsu 221116, China
| | - Dongqing Yuan
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University. Nanjing, Jiangsu 210029, China
| | - Xunyi Gu
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University. Nanjing, Jiangsu 210029, China
| | - Huiming Qian
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University. Nanjing, Jiangsu 210029, China; Department of Ophthalmology, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Ping Xie
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University. Nanjing, Jiangsu 210029, China
| | - Qinghuai Liu
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University. Nanjing, Jiangsu 210029, China.
| | - Zizhong Hu
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University. Nanjing, Jiangsu 210029, China.
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6
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Ni J, Xi X, Xiao S, Xiao X. Tumor Cell-Derived Exosomal miR-191-5p Activates M2-Subtype Macrophages Through SOCS3 to Facilitate Breast Cancer. Mol Biotechnol 2024; 66:1314-1325. [PMID: 38270757 DOI: 10.1007/s12033-023-01034-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 12/12/2023] [Indexed: 01/26/2024]
Abstract
Differential activation of macrophages is associated with poor progression of breast cancer (BC). Many reports have elucidated the important involvement of exosomes produced by cancer cells in remodeling the macrophage activation phenotype to promote tumor expansion and invasion. However, the underlying mechanisms by which exosomes secreted by BC cells facilitate macrophage M2 polarization remain enigmatic and worth exploring. In this study, quantitative real-time PCR (RT-qPCR) was used to investigate miR-191-5p expression in BC tumor tissues and cells. Cell counting kit 8 (CCK-8), transwell, and flow cytometry were applied to assess the functional role of miR-191-5p in BC. Isolated nano-vesicles were identified using transmission electron microscopy and western blotting. We also observed that miR-191-5p was significantly elevated in BC clinical samples and that inhibition of miR-191-5p hindered the growth and metastasis of BC cells. Importantly, BC cells successfully accelerated macrophage M2-like polarization by directly transferring exosomes to macrophages, resulting in increased miR-191-5p levels in macrophages. Mechanistically, exosomal miR-191-5p directly inhibited the suppressors of cytokine signaling 3 (SOCS3) expression in macrophages and aggravated macrophage M2 polarization. Similarly, si-SOCS3 transfected macrophages boosted BC cell migration and invasion in a positive feedback manner. Overall, our results manifested a pro-growth and pro-metastatic role between the two cells by elucidating the crucial role of exosomal miR-191-5p in stimulating M2 macrophage polarization and mediating communication between BC cells and macrophages. These findings opened up new horizons for the development of BC therapeutic strategies.
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Affiliation(s)
- Jun Ni
- Department of Breast Surgery, People's Hospital of Ganzhou City, Ganzhou, 314000, Jiangxi, China
| | - Xun Xi
- Department of Breast Surgery, People's Hospital of Ganzhou City, Ganzhou, 314000, Jiangxi, China
| | - Sujian Xiao
- Department of Breast Surgery, People's Hospital of Ganzhou City, Ganzhou, 314000, Jiangxi, China
| | - Xigang Xiao
- Department of General Surgery, People's Hospital of Ganzhou City, No.16, Meiguan Road, Ganzhou, 314000, Jiangxi, China.
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Mon AM, Intuyod K, Klungsaeng S, Jusakul A, Pongking T, Lert-Itthiporn W, Luvira V, Pairojkul C, Plengsuriyakarn T, Na-Bangchang K, Pinlaor S, Pinlaor P. Overexpression of microRNA-205-5p promotes cholangiocarcinoma growth by reducing expression of homeodomain-interacting protein kinase 3. Sci Rep 2023; 13:22444. [PMID: 38105269 PMCID: PMC10725890 DOI: 10.1038/s41598-023-49694-x] [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: 02/20/2023] [Accepted: 12/11/2023] [Indexed: 12/19/2023] Open
Abstract
The microRNA miR-205-5p has diverse effects in different malignancies, including cholangiocarcinoma (CCA), but its effects on CCA progression is unclear. Here we investigated the role and function of miR-205-5p in CCA. Three CCA cell lines and human serum samples were found to have much higher expression levels of miR-205-5p than seen in typical cholangiocyte cell lines and healthy controls. Inhibition of miR-205-5p suppressed CCA cell motility, invasion and proliferation of KKU-213B whereby overexpression of miR-205-5p promoted cell proliferation and motility of KKU-100 cells. Bioinformatics tools (miRDB, TargetScan, miRWalk, and GEPIA) all predicted various miR-205-5p targets. Experiments using miR-205-5p inhibitor and mimic indicated that homeodomain-interacting protein kinase 3 (HIPK3) was a potential direct target of miR-205-5p. Overexpression of HIPK3 using HIPK3 plasmid cloning DNA suppressed migration and proliferation of KKU-100 cells. Notably, HIPK3 expression was lower in human CCA tissues than in normal adjacent tissues. High HIPK3 expression was significantly associated with longer survival time of CCA patients. Multivariate regression analysis indicated tissue HIPK3 levels as an independent prognostic factor for CCA patients. These findings indicate that overexpression of miR-205-5p promotes CCA cells proliferation and migration partly via HIPK3-dependent way. Therefore, targeting miR-205-5p may be a potential treatment approach for CCA.
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Affiliation(s)
- Aye Myat Mon
- Medical Technology Program, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Kitti Intuyod
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Sirinapha Klungsaeng
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Apinya Jusakul
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Thatsanapong Pongking
- Biomedical Sciences Program, Graduate School, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Worachart Lert-Itthiporn
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Vor Luvira
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Chawalit Pairojkul
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Tullayakorn Plengsuriyakarn
- Graduate Program in Bioclinical Sciences, Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Chulabhorn International College of Medicine, Thammasat University (Rangsit Campus), Pathum Thani, 12120, Thailand
| | - Kesara Na-Bangchang
- Graduate Program in Bioclinical Sciences, Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Chulabhorn International College of Medicine, Thammasat University (Rangsit Campus), Pathum Thani, 12120, Thailand
| | - Somchai Pinlaor
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Porntip Pinlaor
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand.
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.
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8
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Wu D, Li Y, Li C, Zhong S, Liu B, Hang H, Wang H. MDM2 Antagonist Nutlin-3 Stimulates Global DNA Hydroxymethylation by Enhancing p53-TET1 Signaling Axis. ACS Chem Biol 2023; 18:2240-2248. [PMID: 37463352 DOI: 10.1021/acschembio.3c00247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/20/2023]
Abstract
DNA hydroxymethylation is involved in many biological processes, including nuclear reprogramming, embryonic development, and tumor suppression. In this study, we report that an anticancer agent, nutlin-3, selectively stimulates global DNA hydroxymethylation in TP53 wild-type cancer cells as manifested by the elevation of 5-hydroxymethylcytosine (5hmC) in genomic DNA. In contrast, nutlin 3 fails to enhance DNA hydroxymethylation in TP53-mutated cancer cells. Consistently, nutlin-3 as a MDM2 antagonist only activates wild-type but not mutated TP53. Furthermore, nutlin-3 does not alter the expression of TET1 but slightly reduces the expression of TET2 and TET3 proteins. These TET family proteins are responsible for converting 5-methylcytosine (5mC) to 5hmC. Interestingly, TET1 knockdown could significantly block the nutlin-3-induced DNA hydroxymethylation as well as TP53 and P21 activation. Immunoprecipitation analysis supports that p53 strongly interacts with TET1 proteins. These results suggest that nutlin-3 activates TP53 and promotes p53-TET1 interaction. As positive feedback, the p53-TET1 interaction further enhances p53 activation and promotes apoptosis. Collectively, we demonstrate that nutlin-3 stimulates DNA hydroxymethylation and apoptosis via a positive feedback mechanism.
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Affiliation(s)
- Danni Wu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- China General Microbiological Culture Collection Center, State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yao Li
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Cuiping Li
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Shangwei Zhong
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Baodong Liu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Haiying Hang
- Key Laboratory for Protein and Peptide Pharmaceuticals, National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Hailin Wang
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- China General Microbiological Culture Collection Center, State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- School of Environment, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310000, P. R. China
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9
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Ma S, Ma Y, Qi F, Lei J, Chen F, Sun W, Wang D, Zhou S, Liu Z, Lu Z, Zhang D. HSDL2 knockdown promotes the progression of cholangiocarcinoma by inhibiting ferroptosis through the P53/SLC7A11 axis. World J Surg Oncol 2023; 21:293. [PMID: 37718459 PMCID: PMC10506268 DOI: 10.1186/s12957-023-03176-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 09/09/2023] [Indexed: 09/19/2023] Open
Abstract
BACKGROUND Human hydroxysteroid dehydrogenase-like 2 (HSDL2), which regulates cancer progression, is involved in lipid metabolism. However, the role of HSDL2 in cholangiocarcinoma (CCA) and the mechanism by which it regulates CCA progression by modulating ferroptosis are unclear. METHODS HSDL2 expression levels in CCA cells and tissues were determined by quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry. The overall survival and disease-free survival of patients with high vs. low HSDL2 expression were evaluated using Kaplan-Meier curves. The proliferation, migration, and invasion of CCA cells were assessed using Cell Counting Kit-8, colony formation, 5-ethynyl-2'-deoxyuridine DNA synthesis, and transwell assays. The effect of p53 on tumor growth was explored using a xenograft mouse model. The expression of SLC7A11 in patients with CCA was analyzed using immunofluorescence. Ferroptosis levels were measured by flow cytometry, malondialdehyde assay, and glutathione assay. HSDL2-regulated signaling pathways were analyzed by transcriptome sequencing. The correlation between p53 and SLC7A11 was assessed using bioinformatics and luciferase reporter assays. RESULTS HSDL2 expression was lower in primary human CCA tissues than in matched adjacent non-tumorous bile duct tissues. HSDL2 downregulation was a significant risk factor for shorter overall survival and disease-free survival in patients with CCA. In addition, HSDL2 knockdown enhanced the proliferation, migration, and invasion of CCA cells. The transcriptome analysis of HSDL2 knockdown cells showed that differentially expressed genes were significantly enriched in the p53 signaling pathway, and HSDL2 downregulation increased SLC7A11 levels. These findings were consistent with the qRT-PCR and western blotting results. Other experiments showed that p53 expression modulated the effect of HSDL2 on CCA proliferation in vivo and in vitro and that p53 bound to the SLC7A11 promoter to inhibit ferroptosis. CONCLUSIONS HSDL2 knockdown promotes CCA progression by inhibiting ferroptosis through the p53/SLC7A11 axis. Thus, HSDL2 is a potential prognostic marker and therapeutic target for CCA.
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Affiliation(s)
- Shuoshuo Ma
- Department of General Surgery, The First Affiliated Hospital of Bengbu Medical College, NO. 287, Changhuai Road, Longzihu district, Bengbu, 233000, Anhui, China
- Liver Transplantation Center and Hepatobiliary and Pancreatic Surgery, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yang Ma
- Department of General Surgery, The First Affiliated Hospital of Bengbu Medical College, NO. 287, Changhuai Road, Longzihu district, Bengbu, 233000, Anhui, China
| | - Feiyu Qi
- Department of General Surgery, The First Affiliated Hospital of Bengbu Medical College, NO. 287, Changhuai Road, Longzihu district, Bengbu, 233000, Anhui, China
| | - Jiasheng Lei
- Department of General Surgery, The First Affiliated Hospital of Bengbu Medical College, NO. 287, Changhuai Road, Longzihu district, Bengbu, 233000, Anhui, China
| | - Fangfang Chen
- Department of General Surgery, The First Affiliated Hospital of Bengbu Medical College, NO. 287, Changhuai Road, Longzihu district, Bengbu, 233000, Anhui, China
| | - Wanliang Sun
- Department of General Surgery, The First Affiliated Hospital of Bengbu Medical College, NO. 287, Changhuai Road, Longzihu district, Bengbu, 233000, Anhui, China
| | - Dongdong Wang
- Department of General Surgery, The First Affiliated Hospital of Bengbu Medical College, NO. 287, Changhuai Road, Longzihu district, Bengbu, 233000, Anhui, China
| | - Shuo Zhou
- Department of General Surgery, The First Affiliated Hospital of Bengbu Medical College, NO. 287, Changhuai Road, Longzihu district, Bengbu, 233000, Anhui, China
| | - Zhong Liu
- Department of General Surgery, The First Affiliated Hospital of Bengbu Medical College, NO. 287, Changhuai Road, Longzihu district, Bengbu, 233000, Anhui, China
| | - Zheng Lu
- Department of General Surgery, The First Affiliated Hospital of Bengbu Medical College, NO. 287, Changhuai Road, Longzihu district, Bengbu, 233000, Anhui, China.
| | - Dengyong Zhang
- Department of General Surgery, The First Affiliated Hospital of Bengbu Medical College, NO. 287, Changhuai Road, Longzihu district, Bengbu, 233000, Anhui, China.
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, 77030, USA.
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10
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Zhang X, Zhang Y, Wang C, Wang X. TET (Ten-eleven translocation) family proteins: structure, biological functions and applications. Signal Transduct Target Ther 2023; 8:297. [PMID: 37563110 PMCID: PMC10415333 DOI: 10.1038/s41392-023-01537-x] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 05/24/2023] [Accepted: 06/05/2023] [Indexed: 08/12/2023] Open
Abstract
Ten-eleven translocation (TET) family proteins (TETs), specifically, TET1, TET2 and TET3, can modify DNA by oxidizing 5-methylcytosine (5mC) iteratively to yield 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxycytosine (5caC), and then two of these intermediates (5fC and 5caC) can be excised and return to unmethylated cytosines by thymine-DNA glycosylase (TDG)-mediated base excision repair. Because DNA methylation and demethylation play an important role in numerous biological processes, including zygote formation, embryogenesis, spatial learning and immune homeostasis, the regulation of TETs functions is complicated, and dysregulation of their functions is implicated in many diseases such as myeloid malignancies. In addition, recent studies have demonstrated that TET2 is able to catalyze the hydroxymethylation of RNA to perform post-transcriptional regulation. Notably, catalytic-independent functions of TETs in certain biological contexts have been identified, further highlighting their multifunctional roles. Interestingly, by reactivating the expression of selected target genes, accumulated evidences support the potential therapeutic use of TETs-based DNA methylation editing tools in disorders associated with epigenetic silencing. In this review, we summarize recent key findings in TETs functions, activity regulators at various levels, technological advances in the detection of 5hmC, the main TETs oxidative product, and TETs emerging applications in epigenetic editing. Furthermore, we discuss existing challenges and future directions in this field.
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Affiliation(s)
- Xinchao Zhang
- Department of Pathology, Ruijin Hospital and College of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yue Zhang
- Department of Pathology, Ruijin Hospital and College of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Chaofu Wang
- Department of Pathology, Ruijin Hospital and College of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Xu Wang
- Department of Pathology, Ruijin Hospital and College of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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11
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Jalil AT, Abdulhadi MA, Al-Ameer LR, Khaleel LA, Abdulameer SJ, Hadi AM, Merza MS, Zabibah RS, Ali A. Small but mighty: How microRNAs drive the deadly progression of cholangiocarcinoma. Pathol Res Pract 2023; 247:154565. [PMID: 37267725 DOI: 10.1016/j.prp.2023.154565] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 05/17/2023] [Accepted: 05/20/2023] [Indexed: 06/04/2023]
Abstract
Cholangiocarcinoma, also referred to as CCA, is a highly complex epithelial malignancy that can impact various organs and regions of the body, including the perihilar, intrahepatic, and distal organs. This cancer is characterized by the malignant growth of the epithelial lining in the bile ducts, which spans the entire biliary tree and is accountable for disease progression. The current state of affairs concerning CCA is concerning, with poor prognoses, high recurrence rates, and dismal long-term survival rates significantly burden healthcare facilities worldwide. Studies have identified numerous signaling pathways and molecules involved in the development and progression of CCA, including microRNAs, an important class of non-coding RNAs that have the ability to modulate these cellular signaling pathways significantly. In addition, microRNAs may serve as an innovative target for developing novel therapeutic approaches for CCA. In this review, we explore the underlying mechanisms and signaling pathways implicated in the initiation and progression of CCA, focusing on the future direction of utilizing microRNAs as a promising treatment option for this challenging malignancy.
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Affiliation(s)
| | - Mohanad Ali Abdulhadi
- Department of Medical Laboratory Techniques, Al-maarif University College, Al-Anbar, Iraq
| | | | - Luay Ali Khaleel
- College of Dentistry, National University of Science and Technology, Dhi Qar, Iraq
| | - Sada Jasim Abdulameer
- Biology Department, College of Education for Pure Science, Wasit University, Kut, Wasit, Iraq
| | | | - Muna S Merza
- Prosthetic dental Techniques Department, Al-Mustaqbal university College, Babylon, 51001, Iraq
| | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Ahmed Ali
- Medical technical college, Al-Farahidi University, Baghdad, Iraq
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12
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Papadimitriou MA, Panoutsopoulou K, Pilala KM, Scorilas A, Avgeris M. Epi-miRNAs: Modern mediators of methylation status in human cancers. WILEY INTERDISCIPLINARY REVIEWS. RNA 2023; 14:e1735. [PMID: 35580998 DOI: 10.1002/wrna.1735] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 04/07/2022] [Accepted: 04/11/2022] [Indexed: 02/01/2023]
Abstract
Methylation of the fundamental macromolecules, DNA/RNA, and proteins, is remarkably abundant, evolutionarily conserved, and functionally significant in cellular homeostasis and normal tissue/organism development. Disrupted methylation imprinting is strongly linked to loss of the physiological equilibrium and numerous human pathologies, and most importantly to carcinogenesis, tumor heterogeneity, and cancer progression. Mounting recent evidence has documented the active implication of miRNAs in the orchestration of the multicomponent cellular methylation machineries and the deregulation of methylation profile in the epigenetic, epitranscriptomic, and epiproteomic levels during cancer onset and progression. The elucidation of such regulatory networks between the miRNome and the cellular methylation machineries has led to the emergence of a novel subclass of miRNAs, namely "epi-miRNAs" or "epi-miRs." Herein, we have summarized the existing knowledge on the functional role of epi-miRs in the methylation dynamic landscape of human cancers and their clinical utility in modern cancer diagnostics and tailored therapeutics. This article is categorized under: RNA in Disease and Development > RNA in Disease.
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Affiliation(s)
- Maria-Alexandra Papadimitriou
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Konstantina Panoutsopoulou
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Katerina-Marina Pilala
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Andreas Scorilas
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Margaritis Avgeris
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece.,Laboratory of Clinical Biochemistry - Molecular Diagnostics, Second Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, "P. & A. Kyriakou" Children's Hospital, Athens, Greece
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13
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Kim M, Delgado E, Ko S. DNA methylation in cell plasticity and malignant transformation in liver diseases. Pharmacol Ther 2023; 241:108334. [PMID: 36535346 PMCID: PMC9841769 DOI: 10.1016/j.pharmthera.2022.108334] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/09/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022]
Abstract
The liver possesses extraordinary regenerative capacity mainly attributable to the ability of hepatocytes (HCs) and biliary epithelial cells (BECs) to self-replicate. This ability is left over from their bipotent parent cell, the hepatoblast, during development. When this innate regeneration is compromised due to the absence of proliferative parenchymal cells, such as during cirrhosis, HCs and BEC can transdifferentiate; thus, adding another layer of complexity to the process of liver repair. In addition, dysregulated lineage maintenance in these two cell populations has been shown to promote malignant growth in experimental conditions. Here, malignant transformation, driven in part by insufficient maintenance of lineage reprogramming, contributes to end-stage liver disease. Epigenetic changes are key drivers for cell fate decisions as well as transformation by finetuning overall transcription and gene expression. In this review, we address how altered DNA methylation contributes to the initiation and progression of hepatic cell fate conversion and cancer formation. We also discussed the diagnostic and therapeutic potential of targeting DNA methylation in liver cancer, its current limitations, and what future research is necessary to facilitate its contribution to clinical translation.
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Affiliation(s)
- Minwook Kim
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America
| | - Evan Delgado
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America; Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America
| | - Sungjin Ko
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America; Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America.
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14
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Brown ZJ, Patwardhan S, Bean J, Pawlik TM. Molecular diagnostics and biomarkers in cholangiocarcinoma. Surg Oncol 2022; 44:101851. [PMID: 36126350 DOI: 10.1016/j.suronc.2022.101851] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 08/26/2022] [Accepted: 09/09/2022] [Indexed: 10/14/2022]
Abstract
Regardless of anatomic origin, cholangiocarcinoma is generally an aggressive malignancy with a relatively high case fatality. Surgical resection with curative intent remains the best opportunity to achieve meaningful long-term survival. Most patients present, however, with advanced disease and less than 20% of patients are candidates for surgical resection. Unfortunately, even patients who undergo resection have a 5-year survival that ranges from 20 to 40%. Biomarkers are indicators of normal, pathologic, or biologic responses to an intervention and can range from a characteristic (i.e., blood pressure reading which can detect hypertension) to specific genetic mutations or proteins (i.e., carcinoembryonic antigen level). Novel biomarkers and improved molecular diagnostics represent an attractive opportunity to improve detection as well as to identify novel therapeutic targets for patients with cholangiocarcinoma. We herein review the latest advances in molecular diagnostics and biomarkers related to the early detection and treatment of patients with cholangiocarcinoma.
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Affiliation(s)
- Zachary J Brown
- Department of Surgery, The State Wexner Medical Center, Columbus, OH, USA.
| | - Satyajit Patwardhan
- Dept of HPB Surgery and Liver Transplantation, Global Hospital, Mumbai, India
| | - Joal Bean
- Department of Surgery, The State Wexner Medical Center, Columbus, OH, USA
| | - Timothy M Pawlik
- Department of Surgery, The State Wexner Medical Center, Columbus, OH, USA.
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15
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Calycosin Inhibits the Malignant Behaviors of Lung Adenocarcinoma Cells by Regulating the circ_0001946/miR-21/GPD1L/HIF-1α Signaling Axis. DISEASE MARKERS 2022; 2022:3969389. [PMID: 35996717 PMCID: PMC9392641 DOI: 10.1155/2022/3969389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 07/25/2022] [Accepted: 07/27/2022] [Indexed: 11/18/2022]
Abstract
Objective To clarify the potential function and molecular mechanism of calycosin in lung adenocarcinoma (LUAD) cells. Methods LUAD cells (A549 and H1299) were treated with calycosin at different concentrations (25 nM, 50 nM, and 100 nM) for 24 h. The colony formation, invasion, and migration of the cells were assessed by colony formation, transwell, and scratch assays, respectively. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed to determine the mRNA expression level of circ_0001946, miR-21, glycerol-3-phosphate dehydrogenase 1 like (GPD1L), and hypoxia-inducible factor-1α (HIF-1α) in clinical tissue samples and LUAD cells. RNA pull-down assay and dual-luciferase reporter assay were performed to verify the relationship among circ_0001946, miR-21, GPD1L, and HIF-1α. Western blot was performed to detect the protein expression of epithelial-mesenchymal transition (EMT) process-related genes (E-cadherin, N-cadherin, and snail) and GPD1L as well as HIF-1α. Results Calycosin inhibited colony formation, invasion, migration, and EMT progression in A549 and H1299 cells. Besides, calycosin was able to regulate the expression of circ_0001946, miR-21, GPD1L, and HIF-1α in LUAD cells. According to the findings of QRT-PCR, the expression level of circ_0001946 and GPD1L in LUAD tissues was significantly lower than that in adjacent noncancerous normal tissues, and the expression of miR-21 and HIF-1α was also significantly increased in clinical tissue samples. In addition, there was a targeted regulatory relationship among the above four expressions. Knockdown of circ_0001946 expression in A549 cells treated with calycosin enhanced the malignant behavior of A549 cells and inhibited the anticancer effect of calycosin. However, the knockdown of miR-21 promoted the anticancer effect of calycosin and inhibited the malignant behavior of A549. Conclusion Calycosin can inhibit colony formation, invasion, migration, and EMT process of LUAD cells via regulating the circ_0001946/miR-21/GPD1L/HIF-1α signaling axis and could be a promising therapeutic drug for LUAD.
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16
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Gao H, He Z, Gao C, Liu N, Zhang Z, Niu W, Niu J, Peng C. Exosome-transmitted miR-3124-5p promotes cholangiocarcinoma development via targeting GDF11. Front Oncol 2022; 12:936507. [PMID: 35978818 PMCID: PMC9376483 DOI: 10.3389/fonc.2022.936507] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 07/08/2022] [Indexed: 11/30/2022] Open
Abstract
Objective Cholangiocarcinoma (CHOL) is a deadly cancer worldwide with limited available therapies. The aim of this study was to investigate key exosomal miRNAs and their functions in CHOL development. Methods Serum exosomes were isolated from patients with CHOL and healthy controls, followed by miRNA sequencing for identifying differentially expressed miRNAs (DEMs) and their functions. Then, the expression of key DEMs was experimentally validated in exosomes from clinical CHOL patients and CHOL cells. The effects of overexpression of key DEMs on CHOL cell migration and proliferation were investigated. A key exosomal DEM miR-3124-5p was identified. The effects of overexpression or knockdown of exosomal miR-3124-5p on the proliferation, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs) were investigated. Moreover, the function of exosomal miR-3124-5p on tumor growth in vivo was explored. Results A total of 632 exosomal DEMs were identified between CHOL and control samples. Target genes of DEMs were significantly enriched in pathways, such as the p53 signaling pathway. miR-3124-5p was upregulated in serum exosomes from CHOL patients and exosomes from CHOL cells, and overexpression of miR-3124-5p promoted RBE cell migration and viability. Moreover, overexpression of exosomal miR-3124-5p promoted the proliferation, migration, and angiogenesis of HUVECs, while knockdown of miR-3124-5p had the opposite effect. miR-3124-5p could target growth differentiation factor 11 (GDF11) and downregulate GDF11 expression. Furthermore, exosomal miR-3124-5p promoted tumor growth in vivo. Conclusions Our findings revealed that exosome-encapsulated miR-3124-5p promoted the malignant progression of CHOL by targeting GDF11. Exosomal miR-3124-5p and GDF11 could be promising biomarkers or therapeutic targets for CHOL.
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Affiliation(s)
- Huijie Gao
- Department of Hepatobiliary Surgery, General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Institute of Laparoscopic Minimally Invasive Surgery of Shandong University, Jinan, China
| | - Zhaobin He
- Department of Hepatobiliary Surgery, General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Institute of Laparoscopic Minimally Invasive Surgery of Shandong University, Jinan, China
| | - Chao Gao
- Department of Hepatobiliary Surgery, General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Institute of Laparoscopic Minimally Invasive Surgery of Shandong University, Jinan, China
| | - Naiqing Liu
- Department of General Surgery, Linyi Central Hospital, Linyi, China
| | - Zhaoyang Zhang
- The Institute of Laparoscopic Minimally Invasive Surgery of Shandong University, Jinan, China
- Department of Emergency Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Weibo Niu
- Department of Hepatobiliary Surgery, General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Institute of Laparoscopic Minimally Invasive Surgery of Shandong University, Jinan, China
| | - Jun Niu
- Department of Hepatobiliary Surgery, General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Institute of Laparoscopic Minimally Invasive Surgery of Shandong University, Jinan, China
| | - Cheng Peng
- Department of Hepatobiliary Surgery, General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Institute of Laparoscopic Minimally Invasive Surgery of Shandong University, Jinan, China
- *Correspondence: Cheng Peng,
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Micro-RNA in Cholangiocarcinoma: Implications for Diagnosis, Prognosis, and Therapy. JOURNAL OF MOLECULAR PATHOLOGY 2022. [DOI: 10.3390/jmp3020009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Bile-duct cancers (BDC) are a group of solid tumors arising from the biliary tree. Despite their classification as rare cancers, the incidence of BDC is increasing worldwide. Poor prognosis is a common feature of this type of cancer and is mainly determined by the following factors: late diagnosis, lack of effective therapeutic approaches, and resistance to conventional treatments. In the past few years, next-generation sequencing technologies has allowed us to study the genome, exome, and transcriptome of BDC deeper, revealing a previously underestimated class of RNA: the noncoding RNA (ncRNA). MicroRNAs (miRNAs) are small ncRNAs that play an important regulatory role in gene expression. The aberrant expression of miRNAs and their pivotal role as oncogenes or tumor suppressors in biliary carcinogenesis has been widely described in BDC. Due to their ability to regulate multiple gene networks, miRNAs are involved in all cancer hallmarks, including sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing/accessing vasculature, activating invasion and metastasis, reprogramming cellular metabolism, and avoiding immune destruction. Their use as diagnostic, prognostic, and predictive biomarkers has been widely explored in several human cancers, including BDC. Furthermore, miRNA-based therapeutic strategies are currently the subject of numerous clinical trials that are providing evidence of their efficacy as potent anticancer agents. In this review, we will provide a detailed update of miRNAs affecting BDC, discussing their regulatory function in processes underlying the molecular pathology of BDC. Finally, an overview of their potential use as biomarkers or therapeutic tools in BDC will be further addressed.
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Czaja AJ. Examining micro-ribonucleic acids as diagnostic and therapeutic prospects in autoimmune hepatitis. Expert Rev Clin Immunol 2022; 18:591-607. [PMID: 35510750 DOI: 10.1080/1744666x.2022.2074839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Micro-ribonucleic acids modulate the immune response by affecting the post-transcriptional expression of genes that influence the proliferation and function of activated immune cells, including regulatory T cells. Individual expressions or patterns in peripheral blood and liver tissue may have diagnostic value, reflect treatment response, or become therapeutic targets. The goals of this review are to present the properties and actions of micro-ribonucleic acids, indicate the key individual expressions in autoimmune hepatitis, and describe prospective clinical applications in diagnosis and management. AREAS COVERED Abstracts were identified in PubMed using the search words "microRNAs", "microRNAs in liver disease", and "microRNAs in autoimmune hepatitis". The number of abstracts reviewed exceeded 2000, and the number of full-length articles reviewed was 108. EXPERT OPINION Individual micro-ribonucleic acids, miR-21, miR-122, and miR-155, have been associated with biochemical severity, histological grade of inflammation, and pivotal pathogenic mechanisms in autoimmune hepatitis. Antisense oligonucleotides that down-regulate deleterious individual gene expressions, engineered molecules that impair targeting of gene products, and drugs that non-selectively up-regulate the biogenesis of potentially deficient gene regulators are feasible treatment options. Micro-ribonucleic acids constitute an under-evaluated area in autoimmune hepatitis that promises to improve diagnosis, pathogenic concepts, and therapy.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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19
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Włodarczyk M, Nowicka G, Ciebiera M, Ali M, Yang Q, Al-Hendy A. Epigenetic Regulation in Uterine Fibroids-The Role of Ten-Eleven Translocation Enzymes and Their Potential Therapeutic Application. Int J Mol Sci 2022; 23:2720. [PMID: 35269864 PMCID: PMC8910916 DOI: 10.3390/ijms23052720] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 02/23/2022] [Accepted: 02/25/2022] [Indexed: 02/01/2023] Open
Abstract
Uterine fibroids (UFs) are monoclonal, benign tumors that contain abnormal smooth muscle cells and the accumulation of extracellular matrix (ECM). Although benign, UFs are a major source of gynecologic and reproductive dysfunction, ranging from menorrhagia and pelvic pain to infertility, recurrent miscarriage, and preterm labor. Many risk factors are involved in the pathogenesis of UFs via genetic and epigenetic mechanisms. The latter involving DNA methylation and demethylation reactions provide specific DNA methylation patterns that regulate gene expression. Active DNA demethylation reactions mediated by ten-eleven translocation proteins (TETs) and elevated levels of 5-hydroxymethylcytosine have been suggested to be involved in UF formation. This review paper summarizes the main findings regarding the function of TET enzymes and their activity dysregulation that may trigger the development of UFs. Understanding the role that epigenetics plays in the pathogenesis of UFs may possibly lead to a new type of pharmacological fertility-sparing treatment method.
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Affiliation(s)
- Marta Włodarczyk
- Department of Biochemistry and Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland;
- Centre for Preclinical Research, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland
| | - Grażyna Nowicka
- Department of Biochemistry and Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland;
- Centre for Preclinical Research, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland
| | - Michał Ciebiera
- The Center of Postgraduate Medical Education, Second Department of Obstetrics and Gynecology, 01-809 Warsaw, Poland;
| | - Mohamed Ali
- Clinical Pharmacy Department, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt;
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA; (Q.Y.); (A.A.-H.)
| | - Qiwei Yang
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA; (Q.Y.); (A.A.-H.)
| | - Ayman Al-Hendy
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA; (Q.Y.); (A.A.-H.)
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20
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Pavicevic S, Reichelt S, Uluk D, Lurje I, Engelmann C, Modest DP, Pelzer U, Krenzien F, Raschzok N, Benzing C, Sauer IM, Stintzing S, Tacke F, Schöning W, Schmelzle M, Pratschke J, Lurje G. Prognostic and Predictive Molecular Markers in Cholangiocarcinoma. Cancers (Basel) 2022; 14:1026. [PMID: 35205774 PMCID: PMC8870611 DOI: 10.3390/cancers14041026] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/09/2022] [Accepted: 02/09/2022] [Indexed: 02/05/2023] Open
Abstract
Cholangiocarcinoma (CCA) is the second most common primary liver cancer and subsumes a heterogeneous group of malignant tumors arising from the intra- or extrahepatic biliary tract epithelium. A rising mortality from CCA has been reported worldwide during the last decade, despite significant improvement of surgical and palliative treatment. Over 50% of CCAs originate from proximal extrahepatic bile ducts and constitute the most common CCA entity in the Western world. Clinicopathological characteristics such as lymph node status and poor differentiation remain the best-studied, but imperfect prognostic factors. The identification of prognostic molecular markers as an adjunct to traditional staging systems may not only facilitate the selection of patients who would benefit the most from surgical, adjuvant or palliative treatment strategies, but may also be helpful in defining the aggressiveness of the disease and identifying patients at high-risk for tumor recurrence. The purpose of this review is to provide an overview of currently known molecular prognostic and predictive markers and their role in CCA.
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Affiliation(s)
- Sandra Pavicevic
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Sophie Reichelt
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Deniz Uluk
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Isabella Lurje
- Department of Gastroenterology and Hepatology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (C.E.); (F.T.)
| | - Cornelius Engelmann
- Department of Gastroenterology and Hepatology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (C.E.); (F.T.)
| | - Dominik P. Modest
- Department of Hematology, Oncology and Cancer Immunology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (D.P.M.); (U.P.); (S.S.)
| | - Uwe Pelzer
- Department of Hematology, Oncology and Cancer Immunology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (D.P.M.); (U.P.); (S.S.)
| | - Felix Krenzien
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Nathanael Raschzok
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Christian Benzing
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Igor M. Sauer
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Sebastian Stintzing
- Department of Hematology, Oncology and Cancer Immunology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (D.P.M.); (U.P.); (S.S.)
| | - Frank Tacke
- Department of Gastroenterology and Hepatology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (C.E.); (F.T.)
| | - Wenzel Schöning
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Moritz Schmelzle
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Johann Pratschke
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Georg Lurje
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
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21
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Tang J, Wang R, Tang R, Gu P, Han J, Huang W. CircRTN4IP1 regulates the malignant progression of intrahepatic cholangiocarcinoma by sponging miR-541-5p to induce HIF1A production. Pathol Res Pract 2022; 230:153732. [PMID: 34974242 DOI: 10.1016/j.prp.2021.153732] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 12/01/2021] [Accepted: 12/03/2021] [Indexed: 01/15/2023]
Abstract
BACKGROUND Recent studies indicate that circular RNA (circRNA) serves important roles in the development of intrahepatic cholangiocarcinoma (ICC). However, the role of circRNA reticulon 4 interacting protein 1 (circRTN4IP1) in ICC progression remains unknown. METHODS Expression of circRTN4IP1, microRNA-541-5p (miR-541-5p), hypoxia inducible factor 1 subunit alpha (HIF1A) and other indicated protein markers was detected by quantitative real-time polymerase chain reaction or Western blot. The functional effects of circRTN4IP1 knockdown in ICC cells were analyzed by cell counting kit-8, cell colony formation, flow cytometry analysis, Western blot, glucose and lactate kit assays. The positive expression rate of HIF1A was detected by immunohistochemistry assay. The interaction between miR-541-5p and circRTN4IP1 or HIF1A was identified by dual-luciferase reporter, RNA immunoprecipitation or RNA pull-down assays. Xenograft mouse model assay was performed to determine the effect of circRTN4IP1 depletion on tumor formation. RESULTS In contrast, ICC tissues and cells showed high expression of circRTN4IP1 and HIF1A, but low expression of miR-541-5p. Knockdown of circRTN4IP1 led to repression of cell proliferation and glucose metabolism, but promotion of cell apoptosis; however, circRTN4IP1 overexpression had opposite effects. In mechanism, circRTN4IP1 acted as a sponge for miR-541-5p, which was found to target HIF1A. MiR-541-5p inhibitors could remit circRTN4IP1 knockdown-mediated action. Also, HIF1A participated in the regulation of miR-541-5p in ICC progression. In support, circRTN4IP1 depletion impeded tumor formation in vivo. CONCLUSION CircRTN4IP1 knockdown inhibited ICC cell malignancy by miR-541-5p/HIF1A axis, providing us with a reliable target for the therapy of ICC.
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Affiliation(s)
- Jintian Tang
- Department of Hepatopancreatobiliary, Cancer Hospital Affiliated to Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Ruibin Wang
- Department of Hepatopancreatobiliary, The Third Clinical Medical College of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Runjuan Tang
- Department of Rehabilitation, the Second Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Peng Gu
- Department of Interventional, Cancer Hospital Affiliated to Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Jing Han
- Office of drug clinical trial institutions, Cancer Hospital Affiliated to Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Wukui Huang
- Department of Interventional, Cancer Hospital Affiliated to Xinjiang Medical University, Urumqi, Xinjiang, China.
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22
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Liu W, Wu G, Xiong F, Chen Y. Advances in the DNA methylation hydroxylase TET1. Biomark Res 2021; 9:76. [PMID: 34656178 PMCID: PMC8520278 DOI: 10.1186/s40364-021-00331-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 10/03/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The ten-eleven translocation 1 (TET1) protein is a 5-methylcytosine hydroxylase that belongs to the TET protein family of human α-ketoglutarate oxygenases. TET1 recognizes and binds to regions of high genomic 5'-CpG-3' dinucleotide density, such as CpG islands, initiates the DNA demethylation program, and maintains DNA methylation and demethylation balance to maintain genomic methylation homeostasis and achieve epigenetic regulation. This article reviews the recent research progress of TET1 in the mechanism of demethylation, stem cells and immunity, various malignant tumours and other clinical diseases. CONCLUSION TET1 acts as a key factor mediating demethylation, the mechanism of which still remains to be investigated in detail. TET1 is also critical in maintaining the differentiation pluripotency of embryonic stem cells and plays anti- or oncogenic roles in combination with different signalling pathways in different tumours. In certain tumours, its role is still controversial. In addition, the noncatalytic activity of TET1 has gradually attracted attention and has become a new direction of research in recent years.
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Affiliation(s)
- Wenzheng Liu
- Department of Biliary and Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China
| | - Guanhua Wu
- Department of Biliary and Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China
| | - Fei Xiong
- Department of Biliary and Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China
| | - Yongjun Chen
- Department of Biliary and Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China.
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23
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Characterization of microRNA expression in B cells derived from Japanese black cattle naturally infected with bovine leukemia virus by deep sequencing. PLoS One 2021; 16:e0256588. [PMID: 34506539 PMCID: PMC8432782 DOI: 10.1371/journal.pone.0256588] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 08/10/2021] [Indexed: 12/21/2022] Open
Abstract
Bovine leukemia virus (BLV) is the causative agent of enzootic bovine leukosis (EBL), a malignant B cell lymphoma. However, the mechanisms of BLV-associated lymphomagenesis remain poorly understood. Here, after deep sequencing, we performed comparative analyses of B cell microRNAs (miRNAs) in cattle infected with BLV and those without BLV. In BLV-infected cattle, BLV-derived miRNAs (blv-miRNAs) accounted for 38% of all miRNAs in B cells. Four of these blv-miRNAs (blv-miR-B1-5p, blv-miR-B2-5p, blv-miR-B4-3p, and blv-miR-B5-5p) had highly significant positive correlations with BLV proviral load (PVL). The read counts of 90 host-derived miRNAs (bta-miRNAs) were significantly down-regulated in BLV-infected cattle compared to those in uninfected cattle. Only bta-miR-375 had a positive correlation with PVL in BLV-infected cattle and was highly expressed in the B cell lymphoma tissue of EBL cattle. There were a few bta-miRNAs that correlated with BLV tax/rex gene expression; however, BLV AS1 expression had a significant negative correlation with many of the down-regulated bta-miRNAs that are important for tumor development and/or tumor suppression. These results suggest that BLV promotes lymphomagenesis via AS1 and blv-miRNAs, rather than tax/rex, by down-regulating the expression of bta-miRNAs that have a tumor-suppressing function, and this downregulation is linked to increased PVL.
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24
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Qin W, Scicluna BP, van der Poll T. The Role of Host Cell DNA Methylation in the Immune Response to Bacterial Infection. Front Immunol 2021; 12:696280. [PMID: 34394088 PMCID: PMC8358789 DOI: 10.3389/fimmu.2021.696280] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 07/15/2021] [Indexed: 12/12/2022] Open
Abstract
Host cells undergo complex transcriptional reprogramming upon infection. Epigenetic changes play a key role in the immune response to bacteria, among which DNA modifications that include methylation have received much attention in recent years. The extent of DNA methylation is well known to regulate gene expression. Whilst historically DNA methylation was considered to be a stable epigenetic modification, accumulating evidence indicates that DNA methylation patterns can be altered rapidly upon exposure of cells to changing environments and pathogens. Furthermore, the action of proteins regulating DNA methylation, particularly DNA methyltransferases and ten-eleven translocation methylcytosine dioxygenases, may be modulated, at least in part, by bacteria. This review discusses the principles of DNA methylation, and recent insights about the regulation of host DNA methylation during bacterial infection.
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Affiliation(s)
- Wanhai Qin
- Center of Experimental & Molecular Medicine, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Brendon P Scicluna
- Center of Experimental & Molecular Medicine, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.,Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Tom van der Poll
- Center of Experimental & Molecular Medicine, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.,Division of Infectious Diseases, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
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25
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The Role of microRNAs in Cholangiocarcinoma. Int J Mol Sci 2021; 22:ijms22147627. [PMID: 34299246 PMCID: PMC8306241 DOI: 10.3390/ijms22147627] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/10/2021] [Accepted: 07/15/2021] [Indexed: 02/07/2023] Open
Abstract
Cholangiocarcinoma (CCA), an aggressive malignancy, is typically diagnosed at an advanced stage. It is associated with dismal 5-year postoperative survival rates, generating an urgent need for prognostic and diagnostic biomarkers. MicroRNAs (miRNAs) are a class of non-coding RNAs that are associated with cancer regulation, including modulation of cell cycle progression, apoptosis, metastasis, angiogenesis, autophagy, therapy resistance, and epithelial–mesenchymal transition. Several miRNAs have been found to be dysregulated in CCA and are associated with CCA-related risk factors. Accumulating studies have indicated that the expression of altered miRNAs could act as oncogenic or suppressor miRNAs in the development and progression of CCA and contribute to clinical diagnosis and prognosis prediction as potential biomarkers. Furthermore, miRNAs and their target genes also contribute to targeted therapy development and aid in the determination of drug resistance mechanisms. This review aims to summarize the roles of miRNAs in the pathogenesis of CCA, their potential use as biomarkers of diagnosis and prognosis, and their utilization as novel therapeutic targets in CCA.
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26
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Cao B, Guo X, Huang L, Wang B, Wang W, Han D, Zhang W, Zhong K. Methylation silencing CDH23 is a poor prognostic marker in diffuse large B-cell lymphoma. Aging (Albany NY) 2021; 13:17768-17788. [PMID: 34252883 PMCID: PMC8312441 DOI: 10.18632/aging.203268] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 05/17/2021] [Indexed: 12/20/2022]
Abstract
Cadherin-23(CDH23) mediates homotypic and heterotypic cell-cell adhesions in cancer cells. However, the epigenetic regulation, the biological functions, the mechanisms and the prognostic value of CDH23 in diffuse large B-cell lymphoma (DLBCL) are still unclear. The Gene Expression Profiling Interactive Analysis (GEPIA) and the Gene Expression Omnibus (GEO) database were employed to analyze the CDH23 expression level in DLBCL. The correlation of CDH23 expression and methylation was analyzed by LinkedOmics database. The prognostic value was analyzed via GEPIA. Correlated genes, target kinase, target miRNA, target transcription factor and biological functions were identified by LinkedOmics and GeneMANIA database. The relationship between CDH23 and the immune cell infiltration was explored by the Tumor Immune Estimation Resource (TIMER). The expression of CDH23 was reduced by DNA methylation significantly in DLBCL tissue. Reduction of CDH23 represented poor outcome of DLBCL patients. Functional enrichment analysis showed that CDH23 mainly enriched in cancer cell growth, cell metastasis, cell adhesion, cell cycle, drug catabolic process, leukocyte mediated immunity and DNA repair by some cancer related kinases, miRNAs and transcription factors. These results indicated that methylated reduction of CDH23 represented poor outcome of DLBCL. CDH23 is associated with essential biological functions and key molecules in DLBCL. CDH23 may play crucial roles in DLBCL tumorigenesis. Our results lay a foundation for further investigation of the role of CDH23 in DLBCL tumorigenesis.
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Affiliation(s)
- Baoping Cao
- Department of Lymphoma, Beijing Shijitan Hospital, Capital Medical University, Haidian 100038, Beijing, China
| | - Xiaochuan Guo
- Department of Lymphoma, Beijing Shijitan Hospital, Capital Medical University, Haidian 100038, Beijing, China
| | - Lefu Huang
- Department of Lymphoma, Beijing Shijitan Hospital, Capital Medical University, Haidian 100038, Beijing, China
| | - Bin Wang
- Department of Lymphoma, Beijing Shijitan Hospital, Capital Medical University, Haidian 100038, Beijing, China
| | - Weixia Wang
- Department of Lymphoma, Beijing Shijitan Hospital, Capital Medical University, Haidian 100038, Beijing, China
| | - Dong Han
- Department of Lymphoma, Beijing Shijitan Hospital, Capital Medical University, Haidian 100038, Beijing, China
| | - Weijing Zhang
- Department of Lymphoma, Beijing Shijitan Hospital, Capital Medical University, Haidian 100038, Beijing, China
| | - Kaili Zhong
- Department of Lymphoma, Beijing Shijitan Hospital, Capital Medical University, Haidian 100038, Beijing, China
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Yang H, Shi G, Ge C, Huang J, Wan L, Wang Z, Liu Y, Jia R, Wang M, Zhang L, Zhang Z, Yan X. Functionalized graphene oxide as a nanocarrier for multiple suppressive miRNAs to inhibit human intrahepatic cholangiocarcinoma. NANO SELECT 2021. [DOI: 10.1002/nano.202000130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Affiliation(s)
- Hui Yang
- College of Life Science and Bioengineering Faculty of Environmental and Life Sciences Beijing University of Technology Beijing 100124 China
- Institute of Health Service and Transfusion Medicine Stem Cell and Regenerative Medicine Lab AMMS Beijing 100850 China
| | - Gaona Shi
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia Medica Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100050 China
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Hainan Provincial Key Laboratory of Tropical Medicine Hainan Medical University Haikou 571101 China
| | - Chen Ge
- College of Life Science and Bioengineering Faculty of Environmental and Life Sciences Beijing University of Technology Beijing 100124 China
| | - Jie Huang
- CAS Key Laboratory of Nano‐Bio Interface Division of Nanobiomedicine Suzhou Institute of Nano‐Tech & Nano‐bionics Chinese Academy of Sciences Suzhou 215123 China
| | - Lingfei Wan
- College of Life Science and Bioengineering Faculty of Environmental and Life Sciences Beijing University of Technology Beijing 100124 China
| | - Zhaohai Wang
- Department of Hepatobiliary surgery Fifth Medical Center of Chinese PLA General Hospital Beijing 100039 China
| | - Yunhui Liu
- College of Life Science and Bioengineering Faculty of Environmental and Life Sciences Beijing University of Technology Beijing 100124 China
| | - Runqing Jia
- College of Life Science and Bioengineering Faculty of Environmental and Life Sciences Beijing University of Technology Beijing 100124 China
| | - Minglian Wang
- College of Life Science and Bioengineering Faculty of Environmental and Life Sciences Beijing University of Technology Beijing 100124 China
| | - Liming Zhang
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Hainan Provincial Key Laboratory of Tropical Medicine Hainan Medical University Haikou 571101 China
| | - Zhijun Zhang
- CAS Key Laboratory of Nano‐Bio Interface Division of Nanobiomedicine Suzhou Institute of Nano‐Tech & Nano‐bionics Chinese Academy of Sciences Suzhou 215123 China
| | - Xinlong Yan
- College of Life Science and Bioengineering Faculty of Environmental and Life Sciences Beijing University of Technology Beijing 100124 China
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The ATO/miRNA-885-5p/MTPN axis induces reversal of drug-resistance in cholangiocarcinoma. Cell Oncol (Dordr) 2021; 44:907-916. [PMID: 34170484 DOI: 10.1007/s13402-021-00610-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/13/2021] [Indexed: 10/21/2022] Open
Abstract
PURPOSE Cholangiocarcinoma (CCA) is the second most malignant tumor of the hepatobiliary system. Due to its cumbersome early diagnosis and rapid progression, chemotherapy has become the main treatment option. Primary drug resistance is a major cause of the poor efficacy of chemotherapeutic drugs. Therefore, it is considered urgent to explore new drugs to overcome primary drug resistance of CCA. METHODS Western blot and qRT-PCR assays were used to assess the expression of myotrophin (MTPN) and microRNA-885-5p (miR-885-5p) in CCA tissues and cells. The viability of CCA cells treated with arsenic trioxide (ATO), 5-fluorouracil (5-Fu) and cisplatin (CDDP) was analyzed using a CCK-8 assay. A luciferase reporter assay was used to assess the interaction between miR-885-5p and MTPN. Kaplan-Meier analyses were used for survival assessments. RESULT We found that ATO can reduce the resistance of CCA cells to 5-Fu and CDDP and promote the killing effect of 5-Fu and CDDP. Low-dose ATO showed an anti-drug-resistance effect through up-regulation of the expression of miR-885-5p. Combined with sequencing results and database predictions, we found that MTPN may serve as a direct target of miR-885-5p. After MTPN knockdown, the sensitivity of CCA cells to 5-FU and CDDP was increased. Finally, we found that ATO can reverse chemotherapy resistance induced by overexpression of MTPN. CONCLUSION Our data indicate that the ATO/miR-885-5p/MTPN axis may serve as a target for improving the sensitivity of CCA cells to chemotherapy.
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Molecular Pathogenesis and Regulation of the miR-29-3p-Family: Involvement of ITGA6 and ITGB1 in Intra-Hepatic Cholangiocarcinoma. Cancers (Basel) 2021; 13:cancers13112804. [PMID: 34199886 PMCID: PMC8200054 DOI: 10.3390/cancers13112804] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/27/2021] [Accepted: 05/31/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Even today, there are no effective targeted therapies for intrahepatic cholangiocarcinoma (ICC) patients. Clarifying the molecular pathogenesis of ICC will contribute to the development of treatment strategies for this disease. In this study, we searched for the role of the miR-29-3p-family and its association with oncogenic pathway. Interestingly, aberrant expression of ITGA6 and ITGB1 was directly regulated by the miR-29-3p-family which are involved in multiple oncogenic pathways in ICC, and enhanced malignant transformation of ICC cells. Furthermore, SP1 which is a transcriptional activator of ITGA6/ITGB1, is regulated by the miR-29-3p-family. These molecules may be novel therapeutic targets for ICC. Abstract The aggressive nature of intrahepatic cholangiocarcinoma (ICC) renders it a particularly lethal solid tumor. Searching for therapeutic targets for ICC is an essential challenge in the development of an effective treatment strategy. Our previous studies showed that the miR-29-3p-family members (miR-29a-3p, miR-29b-3p and miR-29c-3p) are key tumor-suppressive microRNAs that control many oncogenic genes/pathways in several cancers. In this study, we searched for therapeutic targets for ICC using the miR-29-3p-family as a starting point. Our functional studies of cell proliferation, migration and invasion confirmed that the miR-29-3p-family act as tumor-suppressors in ICC cells. Moreover, in silico analysis revealed that “focal adhesion”, “ECM-receptor”, “endocytosis”, “PI3K-Akt signaling” and “Hippo signaling” were involved in oncogenic pathways in ICC cells. Our analysis focused on the genes for integrin-α6 (ITGA6) and integrin-β1 (ITGB1), which are involved in multiple pathways. Overexpression of ITGA6 and ITGB1 enhanced malignant transformation of ICC cells. Both ITGA6 and ITGB1 were directly regulated by the miR-29-3p-family in ICC cells. Interestingly, expression of ITGA6/ITGB1 was positively controlled by the transcription factor SP1, and SP1 was negatively controlled by the miR-29-3p-family. Downregulation of the miR-29-3p-family enhanced SP1-mediated ITGA6/ITGB1 expression in ICC cells. MicroRNA-based exploration is an attractive strategy for identifying therapeutic targets for ICC.
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Lang SA, Bednarsch J, Joechle K, Amygdalos I, Czigany Z, Heij L, Ulmer TF, Neumann UP. Prognostic biomarkers for cholangiocarcinoma (CCA): state of the art. Expert Rev Gastroenterol Hepatol 2021; 15:497-510. [PMID: 33970740 DOI: 10.1080/17474124.2021.1912591] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Introduction:Although advances in understanding the molecular basis of cholangiocarcinoma (CCA) have been made, surgery is the only curative therapy option and the overall prognosis of patients suffering from the disease remains poor. Therefore, estimation of prognosis based on known and novel biomarkers is essential for therapy guidance of CCA in both, curative and palliative settings.Areas covered:An extensive literature search on biomarkers for CCA with special emphasis on prognosis was performed. Based on this, prognostic biomarkers from serum, tumor tissue and other compartments that are currently in use or under evaluation for CCA were summarized in this review. Furthermore, an overview of new biomarkers was provided including those determined from extracellular vesicles (EVs), metabolites and nucleic acids. Finally, prognostic markers associated with potential new therapy options for the treatment of CCA were summed up.Expert opinion:So far, an optimal prognostic biomarker for CCA has not been described. However, based on the increasing knowledge about the molecular basis of CCA but also due to novel, innovative technologies, a plethora of novel prognostic biomarkers is currently under evaluation and will be available for CCA in future.
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Affiliation(s)
- Sven A Lang
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Jan Bednarsch
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Katharina Joechle
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Iakovos Amygdalos
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Zoltan Czigany
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Lara Heij
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Tom F Ulmer
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Ulf P Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
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Huang Z, Xu Y, Wan M, Zeng X, Wu J. miR-340: A multifunctional role in human malignant diseases. Int J Biol Sci 2021; 17:236-246. [PMID: 33390846 PMCID: PMC7757049 DOI: 10.7150/ijbs.51123] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 11/09/2020] [Indexed: 12/24/2022] Open
Abstract
MicroRNAs (miRNAs) are a class of short non-coding RNAs of approximately 22 nucleotides in length, which function by binding to the 3' UTR sequences of their target mRNAs. It has been reported that dysregulated miRNAs play pivotal roles in numerous diseases, including cancers, such as gastric, breast, colorectal, ovarian, and other cancers. Recent research efforts have been devoted to translating these basic discoveries into clinical applications that could improve the therapeutic outcome in patients with cancer. Early studies have shown that miR-340 may act either as an oncogene or a tumor suppressor by targeting genes related to proliferation, apoptosis, and metastasis, as well as those associated with diagnosis, treatment, chemoresistance, and prognosis. miR-340 has been shown to have a role in other diseases, such as autoimmune diseases, acute stroke, and alcoholic steatohepatitis. Nevertheless, the roles of miR-340 in human malignancies are still unclear, and the associated mechanisms are complex, involving a variety of signaling pathways, such as Wnt/β-catenin and the JAK-STAT pathways. Herein, we review the crucial roles of miR-340 in human cancers through the analysis of the latest research studies, with the aim of clarifying miR-340 function in malignant disease diagnosis, treatment, and prognosis, and to propose further investigations.
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Affiliation(s)
- Zheng Huang
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325035, Zhejiang, P.R. China
- Department of Anesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, P.R. China
| | - Yesha Xu
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325035, Zhejiang, P.R. China
| | - Maoping Wan
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325035, Zhejiang, P.R. China
| | - Xixi Zeng
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325035, Zhejiang, P.R. China
| | - Jianmin Wu
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325035, Zhejiang, P.R. China
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Shi T, Gong J, Fujita K, Nishiyama N, Iwama H, Liu S, Nakahara M, Yoneyama H, Morishita A, Nonura T, Kobara H, Okano K, Suzuki Y, Masaki T. Aspirin inhibits cholangiocarcinoma cell proliferation via cell cycle arrest in vitro and in vivo. Int J Oncol 2020; 58:199-210. [PMID: 33491760 PMCID: PMC7864011 DOI: 10.3892/ijo.2020.5165] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 10/23/2020] [Indexed: 12/21/2022] Open
Abstract
Cholangiocarcinoma is the most common biliary duct malignancy and the second most common primary liver cancer, accounting for 10-20% of hepatic malignancies. With high mortality and poor prognosis, the 5-year survival rate of cholangiocarcinoma is only 10%. A previous study demonstrated a significant association between aspirin use and a decreased risk of cholangiocarcinoma. However, the effect of aspirin on cholangiocarcinoma remains unknown. Therefore, the aim of the present study was to investigate the effects of aspirin on cholangiocarcinoma in vitro and in vivo. Three cholangiocarcinoma cell lines were used to analyze the effect of aspirin on cell proliferation, cell cycle progression, apoptosis, and the regulation of microRNAs. MicroRNAs are known to regulate the development and progression of various types of cancer. An HuCCT-1 xenograft model was used for the in vivo study. It was determined that aspirin inhibited the proliferation of human cholangiocarcinoma cells (except TKKK cells). Aspirin induced cell cycle arrest in the G0/G1 phase and regulated cell-cycle related proteins in cholangiocarcinoma cells (HuCCT-1 cells) but did not induce apoptosis. The expression of miR-340-5p was significantly upregulated after treatment, and overexpression of miR-340-5p inhibited the proliferation of HuCCT-1 cells and decreased the levels of cyclin D1. TKKK cells had low miR-340-5p expression, which may explain why aspirin had no effect on their proliferation. In vivo, aspirin reduced the growth of xenografted tumors. In conclusion, the present study indicated that aspirin partially inhibited cholangiocarcinoma cell proliferation and tumor growth by inducing G0/G1 phase cell cycle arrest, potentially through the miR-340-5p/cyclin D1 axis.
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Affiliation(s)
- Tingting Shi
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Jian Gong
- Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Noriko Nishiyama
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Hisakazu Iwama
- Life Science Research Center, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Shi Liu
- Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Takako Nonura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Keiichi Okano
- Department of Digestive Surgery, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Yasuyuki Suzuki
- Department of Digestive Surgery, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
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Li H, Jiang W, Liu XN, Yuan LY, Li TJ, Li S, Xu SS, Zhang WH, Gao HL, Han X, Wang WQ, Wu CT, Yu XJ, Xu HX, Liu L. TET1 downregulates epithelial-mesenchymal transition and chemoresistance in PDAC by demethylating CHL1 to inhibit the Hedgehog signaling pathway. Oncogene 2020; 39:5825-5838. [PMID: 32753651 DOI: 10.1038/s41388-020-01407-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 07/05/2020] [Accepted: 07/23/2020] [Indexed: 12/14/2022]
Abstract
Chemoresistance is a major obstacle to prolonging pancreatic ductal adenocarcinoma (PDAC) patient survival. TET1 is identified as the most important epigenetic modification enzyme that facilitates chemoresistance in cancers. However, the chemoresistance mechanism of TET1 in PDAC is unknown. This study aimed to determine the role of TET1 in the chemoresistance of PDAC. TET1-associated chemoresistance in PDAC was investigated in vitro and in vivo. The clinical significance of TET1 was analyzed in 228 PDAC patients by tissue microarray profiling. We identified that TET1 downregulation is caused by its promoter hypermethylation and correlates with poor survival in PDAC patients. In vitro and in vivo functional studies performed by silencing or overexpressing TET1 suggested that TET1 is able to suppress epithelial-mesenchymal transition (EMT) and sensitize PDAC cells to 5FU and gemcitabine. Then RNA-seq, whole genome bisulfite sequencing (WGBS) and ChIP-seq were used to explore the TET1-associated pathway, and showed that TET1 promotes the transcription of CHL1 by binding and demethylating the CHL1 promoter, which consequently inhibits the Hedgehog pathway. Additionally, inhibiting Hedgehog signaling by CHL1 overexpression or the Hedgehog pathway inhibitor, GDC-0449, reversed the chemoresistance induced by TET1 silencing. Regarding clinical significance, we found that high TET1 and high CHL1 expression predicted a better prognosis in resectable PDAC patients. In summary, we demonstrated that TET1 reverses chemoresistance in PDAC by downregulating the CHL1-associated Hedgehog signaling pathway. PDAC patients with a high expression levels of TET1 and CHL1 have a better prognosis.
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MESH Headings
- Biomarkers, Tumor
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/metabolism
- Carcinoma, Pancreatic Ductal/mortality
- Carcinoma, Pancreatic Ductal/pathology
- Cell Adhesion Molecules/genetics
- Cell Line, Tumor
- CpG Islands
- DNA Methylation
- Drug Resistance, Neoplasm/genetics
- Epithelial-Mesenchymal Transition/genetics
- Fluorouracil/pharmacology
- Gene Expression Regulation, Neoplastic
- Gene Silencing
- Hedgehog Proteins/metabolism
- Humans
- Mixed Function Oxygenases/genetics
- Models, Biological
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/mortality
- Pancreatic Neoplasms/pathology
- Prognosis
- Promoter Regions, Genetic
- Proto-Oncogene Proteins/genetics
- Signal Transduction
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Affiliation(s)
- Hao Li
- Department of Pancreatic Surgery, Shanghai Cancer Centre, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Wang Jiang
- Department of Pancreatic Surgery, Shanghai Cancer Centre, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xue-Ni Liu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li-Yun Yuan
- Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Tian-Jiao Li
- Department of Pancreatic Surgery, Shanghai Cancer Centre, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Shuo Li
- Department of Pancreatic Surgery, Shanghai Cancer Centre, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Shuai-Shuai Xu
- Department of Pancreatic Surgery, Shanghai Cancer Centre, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Wu-Hu Zhang
- Department of Pancreatic Surgery, Shanghai Cancer Centre, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - He-Li Gao
- Department of Pancreatic Surgery, Shanghai Cancer Centre, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xuan Han
- Department of Pancreatic Surgery, Shanghai Cancer Centre, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Wen-Quan Wang
- Department of Pancreatic Surgery, Shanghai Cancer Centre, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Chun-Tao Wu
- Department of Pancreatic Surgery, Shanghai Cancer Centre, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xian-Jun Yu
- Department of Pancreatic Surgery, Shanghai Cancer Centre, Fudan University, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, China.
| | - Hua-Xiang Xu
- Department of Pancreatic Surgery, Shanghai Cancer Centre, Fudan University, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, China.
| | - Liang Liu
- Department of Pancreatic Surgery, Shanghai Cancer Centre, Fudan University, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, China.
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Xu X, Zhou X, Zhang J, Li H, Cao Y, Tan X, Zhu X, Yang J. MicroRNA‐191 modulates cisplatin‐induced DNA damage response by targeting RCC2. FASEB J 2020; 34:13573-13585. [PMID: 32803782 DOI: 10.1096/fj.202000945r] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 07/19/2020] [Accepted: 07/27/2020] [Indexed: 12/16/2022]
Affiliation(s)
- Xianrong Xu
- Department of Preventive Medicine Hangzhou Normal University School of Medicine Hangzhou China
| | - Xiaofeng Zhou
- Department of Radiation Oncology The Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou China
| | - Jianyun Zhang
- Department of Preventive Medicine Hangzhou Normal University School of Medicine Hangzhou China
| | - Hongjuan Li
- Department of Preventive Medicine Hangzhou Normal University School of Medicine Hangzhou China
| | - Yifei Cao
- Department of Preventive Medicine Hangzhou Normal University School of Medicine Hangzhou China
| | - Xiaohua Tan
- Department of Preventive Medicine Hangzhou Normal University School of Medicine Hangzhou China
| | - Xinqiang Zhu
- Laboratory Research Center The Fourth Affiliated Hospital Zhejiang University School of Medicine Yiwu China
| | - Jun Yang
- Department of Preventive Medicine Hangzhou Normal University School of Medicine Hangzhou China
- Zhejiang Provincial Center for Uterine Cancer Diagnosis and Therapy Research The Affiliated Women's Hospital Zhejiang University School of Medicine Hangzhou China
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35
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Luo H, Wang P, Ye H, Shi J, Dai L, Wang X, Song C, Zhang J, Li J. Serum-Derived microRNAs as Prognostic Biomarkers in Osteosarcoma: A Meta-Analysis. Front Genet 2020; 11:789. [PMID: 32849795 PMCID: PMC7431663 DOI: 10.3389/fgene.2020.00789] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 07/02/2020] [Indexed: 12/31/2022] Open
Abstract
Recent reports suggest that microRNAs (miRNAs) may serve as prognostic biomarkers in osteosarcoma. Due to osteosarcoma's early metastasis and poor prognosis, it is very important to find novel prognostic biomarkers for improving osteosarcoma's prognosis. Herein we propose a meta-analysis for serum miRNA's prognostic value in osteosarcoma. In this study, the literature available from PubMed, Web of Science, Embase, and Cochrane Library databases was reviewed. The pooled hazard ratios (HRs) with their 95% confidence intervals (CIs) were calculated to evaluate miRNAs prognostic values. A total of 20 studies investigating serum miRNAs were included in this meta-analysis; the initial terminal point of these reports included overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), and recurrence-free survival (RFS). For prognostic meta-analyses, the pooled HR for terminal events of higher expression of miRNAs and lower expression of miRNAs were 5.68 (95% CI 4.73-6.82, P < 0.05) and 3.78 (95% CI 3.27-4.37, P < 0.05), respectively. Additionally, subgroup analyses were conducted based on the analysis methods applied and clinicopathological features reported. In the pooled analyses, the miRNA expression levels are associated with poor prognosis according to both univariate and multivariate analyses. Furthermore, serum miRNAs (miRNA-195, miRNA-27a, miRNA-191, miRNA-300, miRNA-326, miRNA-497, miRNA-95-3p, miRNA-223, miRNA-491-5p, miRNA-124, miRNA-101, miRNA-139-5p, miRNA-194) were associated with poor OS and found to be closely correlated with clinical stage and distant metastasis in osteosarcoma. The results illustrate that low or high expression of these specific miRNAs are both potentially useful as prognostic serum biomarkers in osteosarcoma, and miRNAs (miRNA-195, miRNA-27a, miRNA-191, miRNA-300, miRNA-326, miRNA-497, miRNA-95-3p, miRNA-223, miRNA-491-5p, miRNA-124, miRNA-101, miRNA-139-5p, miRNA-194) may indicate clinical stage and metastasis in this form of cancer.
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Affiliation(s)
- Huan Luo
- College of Public Health, Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Tumor Epidemiology, Zhengzhou University, Zhengzhou, China
| | - Peng Wang
- College of Public Health, Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Tumor Epidemiology, Zhengzhou University, Zhengzhou, China
| | - Hua Ye
- College of Public Health, Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Tumor Epidemiology, Zhengzhou University, Zhengzhou, China
| | - Jianxiang Shi
- Henan Key Laboratory of Tumor Epidemiology, Zhengzhou University, Zhengzhou, China.,Zhengzhou University, Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou, China
| | - Liping Dai
- Henan Key Laboratory of Tumor Epidemiology, Zhengzhou University, Zhengzhou, China.,Zhengzhou University, Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou, China
| | - Xiao Wang
- Henan Key Laboratory of Tumor Epidemiology, Zhengzhou University, Zhengzhou, China.,Zhengzhou University, Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou, China
| | - Chunhua Song
- College of Public Health, Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Tumor Epidemiology, Zhengzhou University, Zhengzhou, China
| | - Jianying Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Tumor Epidemiology, Zhengzhou University, Zhengzhou, China.,Zhengzhou University, Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou, China
| | - Jitian Li
- Laboratory of Molecular Biology, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou, China
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36
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Karimzadeh MR, Pourdavoud P, Ehtesham N, Qadbeigi M, Asl MM, Alani B, Mosallaei M, Pakzad B. Regulation of DNA methylation machinery by epi-miRNAs in human cancer: emerging new targets in cancer therapy. Cancer Gene Ther 2020; 28:157-174. [PMID: 32773776 DOI: 10.1038/s41417-020-00210-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Revised: 07/24/2020] [Accepted: 07/29/2020] [Indexed: 12/13/2022]
Abstract
Disruption in DNA methylation processes can lead to alteration in gene expression and function that would ultimately result in malignant transformation. In this way, studies have shown that, in cancers, methylation-associated silencing inactivates tumor suppressor genes, as effectively as mutations. DNA methylation machinery is composed of several genes, including those with DNA methyltransferases activity, proteins that bind to methylated cytosine in the promoter region, and enzymes with demethylase activity. Based on a prominent body of evidence, DNA methylation machinery could be regulated by microRNAs (miRNAs) called epi-miRNAs. Numerous studies demonstrated that dysregulation in DNA methylation regulators like upstream epi-miRNAs is indispensable for carcinogenesis; consequently, the malignant capacity of these cells could be reversed by restoring of this regulatory system in cancer. Conceivably, recognition of these epi-miRNAs in cancer cells could not only reveal novel molecular entities in carcinogenesis, but also render promising targets for cancer therapy. In this review, at first, we have an overview of the methylation alteration in cancers, and the effect of this phenomenon in miRNAs expression and after that, we conduct an in-depth discussion about the regulation of DNA methylation regulators by epi-miRNAs in cancer cells.
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Affiliation(s)
- Mohammad Reza Karimzadeh
- Department of medical Genetics, School of Medicine, Bam University of Medical Sciences, Bam, Iran
| | | | - Naeim Ehtesham
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Masood Movahedi Asl
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Behrang Alani
- Department of Applied Cell Sciences, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Meysam Mosallaei
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Bahram Pakzad
- Department of Internal Medicine, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran.
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37
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Gao YX, Yang TW, Yin JM, Yang PX, Kou BX, Chai MY, Liu XN, Chen DX. Progress and prospects of biomarkers in primary liver cancer (Review). Int J Oncol 2020; 57:54-66. [PMID: 32236573 DOI: 10.3892/ijo.2020.5035] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 02/17/2020] [Indexed: 12/24/2022] Open
Abstract
Tumor biomarkers are important in the early screening, diagnosis, therapeutic evaluation, recurrence and prognosis prediction of tumors. Primary liver cancer is one of the most common malignant tumors; it has high incidence and mortality rates and seriously endangers human health. The main pathological types of primary liver cancer include hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and combined HCC‑cholangiocarcinoma (cHCC‑CC). In the present review, a systematic outline of the current biomarkers of primary liver cancer is presented, from conventional blood biomarkers, histochemical biomarkers and potential biomarkers to resistance‑associated biomarkers. The important relationships are deeply elucidated between biomarkers and diagnosis, prognosis, clinicopathological features and resistance, as well as their clinical significance, in patients with the three main types of primary liver cancer. Moreover, a summary of several important biomarker signaling pathways is provided, which is helpful for studying the biological mechanism of liver cancer. The purpose of this review is to provide help for clinical or medical researchers in the early diagnosis, differential diagnosis, prognosis and treatment of HCC.
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Affiliation(s)
- Yu-Xue Gao
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Tong-Wang Yang
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Ji-Ming Yin
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Peng-Xiang Yang
- Organ Transplantation Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Bu-Xin Kou
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Meng-Yin Chai
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Xiao-Ni Liu
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - De-Xi Chen
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
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38
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Huang Y, Huang CX, Wang WF, Liu H, Wang HL. Zebrafish miR-462-731 is required for digestive organ development. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY D-GENOMICS & PROTEOMICS 2020; 34:100679. [PMID: 32200130 DOI: 10.1016/j.cbd.2020.100679] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 02/24/2020] [Accepted: 02/26/2020] [Indexed: 02/06/2023]
Abstract
MicroRNAs (miRNAs), as important regulators of post-transcriptional gene expression, play important roles in the occurrence and function of organs. In this study, morpholino (MO) knockdown of miR-462/miR-731 was used to investigate the potential mechanisms of the miR-462-731 cluster during zebrafish liver development. The results showed significant reduction of digestive organs, especially liver and exocrine pancreas after the miR-462/miR-731 knockdown, and those phenotypes could be partially rescued by corresponding miRNA duplex. Acinar cells of the exocrine pancreas were also severely affected with pancreatic insufficiency. In particular, knockdown of miR-462 caused pancreas morphogenesis abnormity with specific bilateral exocrine pancreas. Additionally, it was found that miR-731 played a role in liver and exocrine pancreas development by directly targeting dkk3b, instead of the down-regulation of Wnt/β-catenin signaling. These findings contribute significantly to our understanding of molecular mechanisms of miR-462-731 cluster in development of digestive organs.
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Affiliation(s)
- Yan Huang
- Key Lab of Freshwater Animal Breeding, Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, College of Fishery, Huazhong Agricultural University, Wuhan, Hubei, PR China
| | - Chun-Xiao Huang
- Key Lab of Freshwater Animal Breeding, Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, College of Fishery, Huazhong Agricultural University, Wuhan, Hubei, PR China
| | - Wei-Feng Wang
- Key Lab of Freshwater Animal Breeding, Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, College of Fishery, Huazhong Agricultural University, Wuhan, Hubei, PR China
| | - Hong Liu
- Key Lab of Freshwater Animal Breeding, Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, College of Fishery, Huazhong Agricultural University, Wuhan, Hubei, PR China
| | - Huan-Ling Wang
- Key Lab of Freshwater Animal Breeding, Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, College of Fishery, Huazhong Agricultural University, Wuhan, Hubei, PR China.
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Tiemin P, Peng X, Qingfu L, Yan W, Junlin X, Zhefeng H, Ming Z, Desen L, Qinghui M. Dysregulation of the miR-148a-GLUT1 axis promotes the progression and chemoresistance of human intrahepatic cholangiocarcinoma. Oncogenesis 2020; 9:19. [PMID: 32054829 PMCID: PMC7018977 DOI: 10.1038/s41389-020-0207-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 01/30/2020] [Accepted: 02/04/2020] [Indexed: 11/09/2022] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a highly fatal malignant cancer worldwide. Elucidating the underlying molecular mechanism of iCCA progression is critical for the identification of new therapeutic targets. The present study explored the role of the miR-148a-GLUT1 axis in the progression of iCCA. The expression of GLUT1 was detected by using immunohistochemistry, western blot assays, and real-time polymerase chain reaction. The effects of GLUT1 on cell proliferation, invasion, and chemoresistance were investigated both in vitro and in vivo. A luciferase reporter assay was used to explore the effect of miR-148a on GLUT1 expression. GLUT1 was overexpressed in iCCA tissues. GLUT1 overexpression was associated with shorter overall and disease-free survival. Knockdown of GLUT1 reduced, while overexpression of GLUT1 promoted, the proliferation, motility, and invasiveness of iCCA cells in vitro and in vivo. Silencing GLUT1 significantly sensitized iCCA cells to gemcitabine in vitro and in vivo. GLUT1 was directly regulated by miR-148a, whose downregulation was associated with the proliferation, migration, and invasion of iCCA cells. WZB117, a GLUT1 inhibitor, inhibited tumor growth in an iCCA patient-derived xenograft model. These results indicate that downregulation of miR-148a levels results in GLUT1 overexpression in iCCA, leading to iCCA progression and gemcitabine resistance.
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Affiliation(s)
- Pei Tiemin
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiao Peng
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Lang Qingfu
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wang Yan
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xue Junlin
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - He Zhefeng
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhao Ming
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Liang Desen
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Meng Qinghui
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
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Zhou LY, Zhang FW, Tong J, Liu F. MiR-191-5p inhibits lung adenocarcinoma by repressing SATB1 to inhibit Wnt pathway. Mol Genet Genomic Med 2019; 8:e1043. [PMID: 31724324 PMCID: PMC6978255 DOI: 10.1002/mgg3.1043] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Revised: 10/08/2019] [Accepted: 10/11/2019] [Indexed: 12/19/2022] Open
Abstract
Background To investigate the function of miR‐191‐5p in lung adenocarcinoma and its possible mechanism. Methods QRT‐PCR was adopted for the detection of the expression levels of miR‐191‐5p and SATB1 (HGNC: 10541). The effects of miR‐191‐5p and SATB1 on cell proliferation and migration were examined through the CCK‐8 and Transwell assays. Subsequently, the binding relationships between miR‐191‐5p and SATB1 were confirmed by dual‐luciferase reporter gene assay. Finally, the potential mechanisms of action of miR‐191‐5p were explored through a serious of in vivo and in vitro experiments. Results Lung adenocarcinoma patients had a notably lower expression level of miR‐191‐5p than controls, patients with metastasis had a lower level than those without metastasis, and the level in patients with lung adenocarcinoma in stage III‐IV was lower than that in patients with lung adenocarcinoma in stage I‐II. Overexpression of miR‐191‐5p repressed the migration and proliferation of lung cancer A549/H1650 cells. According to the reporter gene assay, miR‐191‐5p could bind to SATB1. Besides, SATB1 was significantly overexpressed in cancer tissues of patients with lung adenocarcinoma, and SATB1 overexpression accelerated the migration and proliferation of A549/H1650 cells and reversed inhibition on cell migration and proliferation by miR‐191‐5p. Conclusion Overexpression of miR‐191‐5p is capable of blocking the migration and proliferation of lung cancer cells, and its mechanism may be through targeting SATB1 thus downregulating Wnt signaling.
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Affiliation(s)
- Lai-Yong Zhou
- Department of Cardiothoracic surgery, The People's Hospital of Bao'an Shenzhen, The Affiliated Bao'an Hospital of Southern Medical University, Shenzhen, China
| | - Fu-Wei Zhang
- Department of Cardiothoracic surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jian Tong
- Department of Cardiothoracic surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Fang Liu
- Department of Pathology, The People's Hospital of Bao'an Shenzhen, The Affiliated Bao'an Hospital of Southern Medical University, Shenzhen, China
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Shi G, Liu C, Yang Y, Song L, Liu X, Wang C, Peng Z, Li H, Zhong L. Panx1 promotes invasion-metastasis cascade in hepatocellular carcinoma. J Cancer 2019; 10:5681-5688. [PMID: 31737105 PMCID: PMC6843873 DOI: 10.7150/jca.32986] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 08/03/2019] [Indexed: 01/14/2023] Open
Abstract
Background: The molecular function of pannexin1 (Panx1) in different tumor types has been remained equivocal. Until now, there is no study focused on the function of panx1 in hepatocellular carcinoma (HCC). This study aimed to explore the role of Panx1 in the invasion and metastasis of HCC. Methods: The expressions of Panx1 in 126 cases of HCC were analyzed by immunohistochemistry (IHC). The effects of Panx1 on HCC cell metastasis and invasion were observed by transwell. The expression levels of Panx1 and epithelial-mesenchymal transition (EMT) related proteins in HCC cells and tissues were detected by western blot and IHC. The tumor metastatic abilities were compared between Panx1 knockout mice and nude mice. Results: The higher expression of Panx1 in HCC was positively correlated with tumor lymph node metastasis, TNM (tumor, node, metastasis) classification and poor prognosis (overall survival, hazard ratio [HR] 2.769, 95% confidence interval [95%CI] 1.528-5.017, P=0.001; disease-free survival, HR=2.344, 95%CI 1.473-3.730, P<0.001). Overexpression of Panx1 promoted invasion and migration of HCC cells through modulation of EMT in vitro and in vivo. Conclusions: Our results suggest that the high expression of Panx1 is associated with poor HCC prognosis, providing a new clue for effective intervention for HCC metastasis.
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Affiliation(s)
- Guangjun Shi
- Department of Hepatobiliary Surgery, The Affiliated Qingdao Municipal Hospital of Qingdao University, Qingdao, China
| | - Chuanliang Liu
- Department of General Surgery, The Third People's Hospital of LinYi, Linyi, China
| | - Yiming Yang
- School of Life Science, Shanghai University, Shanghai, China
| | - Liwei Song
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xueni Liu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chuanxu Wang
- Department of Hepatobiliary Surgery, The Affiliated Qingdao Municipal Hospital of Qingdao University, Qingdao, China
| | - Zhihai Peng
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hao Li
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lin Zhong
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Zaccari P, Cardinale V, Severi C, Pedica F, Carpino G, Gaudio E, Doglioni C, Petrone MC, Alvaro D, Arcidiacono PG, Capurso G. Common features between neoplastic and preneoplastic lesions of the biliary tract and the pancreas. World J Gastroenterol 2019; 25:4343-4359. [PMID: 31496617 PMCID: PMC6710182 DOI: 10.3748/wjg.v25.i31.4343] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 07/13/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
the bile duct system and pancreas show many similarities due to their anatomical proximity and common embryological origin. Consequently, preneoplastic and neoplastic lesions of the bile duct and pancreas share analogies in terms of molecular, histological and pathophysiological features. Intraepithelial neoplasms are reported in biliary tract, as biliary intraepithelial neoplasm (BilIN), and in pancreas, as pancreatic intraepithelial neoplasm (PanIN). Both can evolve to invasive carcinomas, respectively cholangiocarcinoma (CCA) and pancreatic ductal adenocarcinoma (PDAC). Intraductal papillary neoplasms arise in biliary tract and pancreas. Intraductal papillary neoplasm of the biliary tract (IPNB) share common histologic and phenotypic features such as pancreatobiliary, gastric, intestinal and oncocytic types, and biological behavior with the pancreatic counterpart, the intraductal papillary mucinous neoplasm of the pancreas (IPMN). All these neoplastic lesions exhibit similar immunohistochemical phenotypes, suggesting a common carcinogenic process. Indeed, CCA and PDAC display similar clinic-pathological features as growth pattern, poor response to conventional chemotherapy and radiotherapy and, as a consequence, an unfavorable prognosis. The objective of this review is to discuss similarities and differences between the neoplastic lesions of the pancreas and biliary tract with potential implications on a common origin from similar stem/progenitor cells.
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Affiliation(s)
- Piera Zaccari
- Department of Internal Medicine and Medical Specialties, Gastroenterology Unit, Sapienza University of Rome, Rome 00161, Italy
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 00161 Rome, Italy
| | - Carola Severi
- Department of Internal Medicine and Medical Specialties, Gastroenterology Unit, Sapienza University of Rome, Rome 00161, Italy
| | - Federica Pedica
- Pathology Department, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Milan 20132, Italy
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico", Rome 00161, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Division of Human Anatomy, Sapienza University of Rome, Rome 00161, Italy
| | - Claudio Doglioni
- Pathology Department, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Milan 20132, Italy
| | - Maria Chiara Petrone
- PancreatoBiliary Endoscopy and EUS Division, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Milan 20132, Italy
| | - Domenico Alvaro
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome 00161, Italy
| | - Paolo Giorgio Arcidiacono
- PancreatoBiliary Endoscopy and EUS Division, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Milan 20132, Italy
| | - Gabriele Capurso
- PancreatoBiliary Endoscopy and EUS Division, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Milan 20132, Italy
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Moro A, Paredes AZ, Farooq A, Sahara K, Tsilimigras DI, Mehta R, Endo I, Guglielmi A, Aldrighetti L, Alexandrescu S, Marques HP, Shen F, Koerkamp BG, Sasaki K, Pawlik TM. Discordance in prediction of prognosis among patients with intrahepatic cholangiocarcinoma: A preoperative vs postoperative perspective. J Surg Oncol 2019; 120:946-955. [DOI: 10.1002/jso.25671] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Accepted: 08/04/2019] [Indexed: 12/25/2022]
Affiliation(s)
- Amika Moro
- Department of Surgery, Division of Surgical OncologyThe Ohio State University Wexner Medical Center and James Comprehensive Cancer Center Columbus Ohio
| | - Anghela Z. Paredes
- Department of Surgery, Division of Surgical OncologyThe Ohio State University Wexner Medical Center and James Comprehensive Cancer Center Columbus Ohio
| | - Ayesha Farooq
- Department of Surgery, Division of Surgical OncologyThe Ohio State University Wexner Medical Center and James Comprehensive Cancer Center Columbus Ohio
| | - Kota Sahara
- Department of Surgery, Division of Surgical OncologyThe Ohio State University Wexner Medical Center and James Comprehensive Cancer Center Columbus Ohio
- Department of Gastroenterological SurgeryYokohama City University School of Medicine Yokohama Japan
| | - Diamantis I. Tsilimigras
- Department of Surgery, Division of Surgical OncologyThe Ohio State University Wexner Medical Center and James Comprehensive Cancer Center Columbus Ohio
| | - Rittal Mehta
- Department of Surgery, Division of Surgical OncologyThe Ohio State University Wexner Medical Center and James Comprehensive Cancer Center Columbus Ohio
| | - Itaru Endo
- Department of Gastroenterological SurgeryYokohama City University School of Medicine Yokohama Japan
| | | | | | | | | | - Feng Shen
- Department of SurgeryEastern Hepatobiliary Surgery Hospital Shanghai China
| | - Bas G. Koerkamp
- Department of SurgeryErasmus University Medical Centre Rotterdam Netherlands
| | - Kazunari Sasaki
- Department of General SurgeryCleveland Clinic Foundation Cleveland Ohio
| | - Timothy M. Pawlik
- Department of Surgery, Division of Surgical OncologyThe Ohio State University Wexner Medical Center and James Comprehensive Cancer Center Columbus Ohio
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MicroRNAs as Potential Biomarkers for Chemoresistance in Adenocarcinomas of the Esophagogastric Junction. JOURNAL OF ONCOLOGY 2019; 2019:4903152. [PMID: 31467538 PMCID: PMC6701342 DOI: 10.1155/2019/4903152] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 07/15/2019] [Indexed: 12/11/2022]
Abstract
Concerning adenocarcinomas of the esophagogastric junction, neoadjuvant chemotherapy is regularly implemented, but patients' response varies greatly, with some cases showing no therapeutic effect, being deemed as chemoresistant. Small, noncoding RNAs (miRNAs) have evolved as key players in biological processes, including malignant diseases, often promoting tumor growth and expansion. In addition, specific miRNAs have been implicated in the development of chemoresistance through evasion of apoptosis, cell cycle alterations, and drug target modification. We performed a retrospective study of 33 patients receiving neoadjuvant chemotherapy by measuring their miRNA expression profiles. Histologic tumor regression was evaluated using resection specimens, while miRNA profiles were prepared using preoperative biopsies without prior therapy. A preselected panel of 96 miRNAs, known to be of importance in various malignancies, was used to test for significant differences between responsive (chemosensitive) and nonresponsive (chemoresistant) cases. The cohort consisted of 12 nonresponsive and 21 responsive cases with the following 4 miRNAs differentially expressed between both the groups: hsa-let-7f-5p, hsa-miRNA-221-3p, hsa-miRNA-31-5p, and hsa-miRNA-191-5p. The former 3 showed upregulation in chemoresistant cases, while the latter showed upregulation in chemosensitive cases. In addition, significant correlation between high expression of hsa-miRNA-194-5p and prolonged survival could be demonstrated (p value <0.0001). In conclusion, we identified a panel of 3 miRNAs predicting chemoresistance and a single miRNA contributing to chemosensitivity. These miRNAs might function as prognostic biomarkers and enable clinicians to better predict the effect of one or more reliably select patients benefitting from (neoadjuvant) chemotherapy.
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Li F, Wen J, Shi J, Wang Y, Yang F, Liu C. MicroRNA-191 targets CCAAT/enhanced binding protein β and functions as an oncogenic molecule in human non-small cell lung carcinoma cells. Exp Ther Med 2019; 18:1175-1183. [PMID: 31316611 PMCID: PMC6601399 DOI: 10.3892/etm.2019.7668] [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: 11/28/2017] [Accepted: 10/26/2018] [Indexed: 12/24/2022] Open
Abstract
The aberrant expression of microRNAs (miRs) may be involved in tumor growth and progression in human non-small cell lung carcinoma (NSCLC). The present study aimed to investigate the potential roles of miR-191 in NSCLC. Western blotting and reverse transcription-quantitative polymerase chain reaction were performed to assess protein and/or mRNA levels. Scratch wound healing and transwell assays were performed to determine the NSCLC cell migration and invasion. A luciferase demonstrated that CCAAT/enhanced binding protein β (C/EBPβ) was a target of miR-191. Previously, miR-191 has been reported to act as an oncogenic player in multiple human cancers. C/EBPβ has been identified as a target gene of miR-191; however, the roles and underlying mechanisms of miR-191 associated with the regulation of tumor invasion in NSCLC remain unknown. In the present study, it was demonstrated that miR-191 expression levels were higher in human NSCLC tumors compared with in normal adjacent tissue and elevated miR-191 expression levels were closely associated with tumor node metastasis stage in patients with NSCLC. Furthermore, transfection with miR-191 mimic inhibited C/EBPβ expression at the mRNA and protein levels and promoted A549 cell migration and invasion. C/EBPβ was reported to be the direct target gene of miR-191 using a dual luciferase reporter assay. Finally, C/EBPβ siRNA can mimic the effects of miR-191. These findings indicated that miR-191 may function as an oncogene in NSCLC, at least partially due to its negative regulatory on C/EBPβ.
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Affiliation(s)
- Fuliang Li
- Department of Pathology, Anqiu People's Hospital, Anqiu, Shandong 262100, P.R. China
| | - Jingjing Wen
- Department of Pathology, Weifang Yidu Central Hospital, Weifang, Shandong 262500, P.R. China
| | - Jinsheng Shi
- Department of Pathology, Weifang Yidu Central Hospital, Weifang, Shandong 262500, P.R. China
| | - Yun Wang
- Department of Pathology, Anqiu People's Hospital, Anqiu, Shandong 262100, P.R. China
| | - Feifei Yang
- Department of Pathology, Anqiu People's Hospital, Anqiu, Shandong 262100, P.R. China
| | - Chunying Liu
- Department of B-ultrasound, Anqiu People's Hospital, Anqiu, Shandong 262100, P.R. China
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Liu M, Yu J, Wang D, Niu Y, Chen S, Gao P, Yang Z, Wang H, Zhang J, Zhang C, Zhao Y, Hu W, Sun G. Epigenetically Upregulated MicroRNA-602 Is Involved in a Negative Feedback Loop with FOXK2 in Esophageal Squamous Cell Carcinoma. Mol Ther 2019; 27:1796-1809. [PMID: 31401147 DOI: 10.1016/j.ymthe.2019.07.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Revised: 06/23/2019] [Accepted: 07/08/2019] [Indexed: 12/17/2022] Open
Abstract
MicroRNA is an endogenous, small RNA controlling multiple target genes and playing roles in various tumorigenesis processes. In this study, our results revealed that miR-602 expression levels in tumor tissues and preoperative serum from esophageal squamous cell carcinoma (ESCC) patients were higher than those in non-tumorous tissues and healthy volunteers. miR-602 overexpression was closely related to lymph node metastasis and TNM stages and correlated short overall, and it acted as an independent prognostic marker of ESCC. The methylation status of the miR-602 gene indicated more frequent hypomethylation of the CpG sites located upstream of the miR-602 gene in the ESCC tissues than in the adjacent normal tissues, and the methylation status of miR-602 correlated inversely with its expression levels. Subsequently, miR-602 overexpression promoted ESCC proliferation and metastasis and regulated cell cycles in vitro and in vivo. Mechanistically, a dual-luciferase experiment validated that Fork head box (FOX)K2 (FOXK2) was a direct target of miR-602. More importantly, systemic delivery of formulated miR-602 antagomir could reduce tumor growth and increased FOXK2 protein expression in nude mice. This work provides novel insight into the molecular pathogenesis of ESCC.
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Affiliation(s)
- Meiyue Liu
- Department of Radiation Oncology, North China University of Science and Technology Affiliated People's Hospital, Tangshan 063000, China
| | - Jiarui Yu
- Department of Radiation Oncology, North China University of Science and Technology Affiliated People's Hospital, Tangshan 063000, China
| | - Dan Wang
- Department of Radiation Oncology, North China University of Science and Technology Affiliated People's Hospital, Tangshan 063000, China
| | - Yi Niu
- Department of Radiation Oncology, North China University of Science and Technology Affiliated People's Hospital, Tangshan 063000, China
| | - Siyuan Chen
- Department of Radiation Oncology, North China University of Science and Technology Affiliated People's Hospital, Tangshan 063000, China
| | - Peng Gao
- Department of Radiation Oncology, North China University of Science and Technology Affiliated People's Hospital, Tangshan 063000, China
| | - Zhao Yang
- Department of Radiation Oncology, North China University of Science and Technology Affiliated People's Hospital, Tangshan 063000, China
| | - Huan Wang
- Department of Radiation Oncology, North China University of Science and Technology Affiliated People's Hospital, Tangshan 063000, China
| | - Jie Zhang
- Department of Pathology, North China University of Science and Technology Affiliated People's Hospital, Tangshan 063000, China
| | - Chao Zhang
- Department of Radiation Oncology, North China University of Science and Technology Affiliated People's Hospital, Tangshan 063000, China
| | - Yue Zhao
- Zhejiang Cancer Research Institute, Zhejiang Cancer Hospital, Hangzhou 310022, China.
| | - Wanning Hu
- Department of Radiation Oncology, North China University of Science and Technology Affiliated People's Hospital, Tangshan 063000, China.
| | - Guogui Sun
- Department of Radiation Oncology, North China University of Science and Technology Affiliated People's Hospital, Tangshan 063000, China.
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Chang W, Wang Y, Li W, Shi L, Geng Z. MicroRNA-551b-3p inhibits tumour growth of human cholangiocarcinoma by targeting Cyclin D1. J Cell Mol Med 2019; 23:4945-4954. [PMID: 31199052 PMCID: PMC6653057 DOI: 10.1111/jcmm.14312] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Revised: 03/01/2019] [Accepted: 03/11/2019] [Indexed: 12/14/2022] Open
Abstract
MicroRNAs (miRNAs) are powerful regulators in the tumorigenesis of cholangiocarcinoma (CCA). Previous studies report that miR‐551b‐3p acts as an oncogenic factor in ovarian cancer, but plays a tumour suppressive role in gastric cancer. However, the expression pattern and potential function of miR‐551b‐3p were still unclear in CCA. Therefore, this study aimed to explore the expression of miR‐551b‐3p and its role as well as molecular mechanism in CCA. Analysis of TCGA dataset suggested that miR‐551b‐3p was under‐expressed in CCA tissues compared to normal bile duct tissues. Furthermore, our data confirmed the decreased levels of miR‐551b‐3p in CCA samples and cell lines. Interestingly, TCGA data suggested that low miR‐551b‐3p level indicated reduced overall survival of CCA patients. Gain‐ and loss‐of‐function experiments found that miR‐551b‐3p inhibited the proliferation, G1‐S phase transition and induced apoptosis of CCA cells. In vivo experiments revealed that ectopic expression of miR‐551b‐3p inhibited tumour growth of CCA in mice. Further investigation demonstrated that miR‐551b‐3p directly bond to the 3′‐UTR of Cyclin D1 (CCND1) mRNA and negatively regulated the abundance of CCND1 in CCA cells. An inverse correlation between miR‐551b‐3p expression and the level of CCND1 mRNA was detected in CCA tissues from TCGA dataset. Notably, CCND1 knockdown showed similar effects to miR‐551b‐3p overexpression in HuCCT‐1 cells. CCND1 restoration rescued miR‐551b‐3p‐induced inhibition of proliferation, G1 phase arrest and apoptosis in HuCCT‐1 cells. In summary, miR‐551b‐3p inhibits the expression of CCND1 to suppress CCA cell proliferation and induce apoptosis, which may provide a theoretical basis for improving CCA treatment.
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Affiliation(s)
- Weiping Chang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,Department of General Surgery, The First Affiliated Hospital of Xi'an Medical University, Xi'an, China
| | - Yuan Wang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - WenZhi Li
- Chang'an District Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Lei Shi
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Zhimin Geng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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Li H, Zhang SR, Xu HX, Wang WQ, Li S, Li TJ, Ni QX, Yu XJ, Liu L, Wu CT. SRPX2 and RAB31 are effective prognostic biomarkers in pancreatic cancer. J Cancer 2019; 10:2670-2678. [PMID: 31258775 PMCID: PMC6584922 DOI: 10.7150/jca.32072] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 05/01/2019] [Indexed: 12/13/2022] Open
Abstract
Introduction: SRPX2 and RAB31 play important roles in tumorigenesis and metastasis; however, their prognostic value in pancreatic cancer remains unclear. This study aimed to investigate the potential interactions and effects of SRPX2 and RAB31 on the diagnosis and prognosis of pancreatic cancer. Methods: The expression of SRPX2 and RAB31 in pancreatic tumor tissues and cells was evaluated through database mining of the Oncomine, Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases, and validated the results through immunohistochemistry (IHC) and Western blot in our clinical database. Protein-protein interactions were explored by immunofluorescence and Co-immunoprecipitation (Co-IP). Two hundred tissue microarray specimens from patients (79 training and 121 validation), who underwent curative pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) were used. Additionally, the association between the SRPX2 and RAB31 and prognosis of PDAC patients after surgery was analyzed. Results: The expression of SRPX2 and RAB31 was highly increased in pancreatic cancer, and there was a significant positive correlation between these two proteins. Co-IP showed the direct interaction between SRPX2 and RAB31. Kaplan-Meier analysis showed that positive expression of SRPX2 and RAB31 was associated with reduced disease-free survival (DFS) and overall survival (OS) of PDAC patients in the training set and the validation sets. Furthermore, multivariate analysis indicated that the 8th edition TNM stage and combination of SRPX2 and RAB31 were independent prognostic factors that associated with OS and DFS in the training, and the validation sets, respectively. Conclusions: The combination of SRPX2 and RAB31 can be important markers for the prognosis of pancreatic cancer.
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Affiliation(s)
- Hao Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 20032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Shi-Rong Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 20032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Hua-Xiang Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 20032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Wen-Quan Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 20032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Shuo Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 20032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Tian-Jiao Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 20032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Quan-Xing Ni
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 20032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Xian-Jun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 20032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Liang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 20032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Chun-Tao Wu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 20032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
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Zhang PF, Wei CY, Huang XY, Peng R, Yang X, Lu JC, Zhang C, Gao C, Cai JB, Gao PT, Gao DM, Shi GM, Ke AW, Fan J. Circular RNA circTRIM33-12 acts as the sponge of MicroRNA-191 to suppress hepatocellular carcinoma progression. Mol Cancer 2019; 18:105. [PMID: 31153371 PMCID: PMC6545035 DOI: 10.1186/s12943-019-1031-1] [Citation(s) in RCA: 167] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 05/15/2019] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Recently, the dysregulation of circular RNA (circRNA) have been shown to have important regulatory roles in cancer development and progression, including hepatocellular carcinoma (HCC). However, the roles of most circRNAs in HCC are still unknown. METHODS The expression of circular tripartite motif containing 33-12 (circTRIM33-12) in HCC tissues and cell lines was detected by qRT-PCR. The role of circTRIM33-12 in HCC progression was assessed by western blotting, CCK-8, flow cytometry, transwell and a subcutaneous tumor mouse assays both in vitro and in vivo. In vivo circRNA precipitation, RNA immunoprecipitation, luciferase reporter assays were performed to evaluate the interaction between circTRIM33-12 and miR-191. RESULTS Here, we found that circTRIM33-12, is downregulated in HCC tissues and cell lines. The downregulation of circTRIM33-12 in HCC was significantly correlated with malignant characteristics and served as an independent risk factor for the overall survival (OS) and recurrence-free survival (RFS) of patients with HCC after surgery. The reduced expression of circTRIM33-12 in HCC cells increases tumor proliferation, migration, invasion and immune evasion. Mechanistically, we demonstrated that circTRIM33-12 upregulated TET1 expression by sponging miR-191, resulting in significantly reduced 5-hydroxymethylcytosine (5hmC) levels in HCC cells. CONCLUSIONS These results reveal the important role of circTRIM33-12 in the proliferation, migration, invasion and immune evasion abilities of HCC cells and provide a new perspective on circRNAs in HCC progression.
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Affiliation(s)
- Peng-Fei Zhang
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Chuan-Yuan Wei
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Xiao-Yong Huang
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Rui Peng
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Xuan Yang
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Jia-Cheng Lu
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Chi Zhang
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Chao Gao
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Jia-Bin Cai
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Ping-Ting Gao
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Dong-Mei Gao
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Guo-Ming Shi
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.
| | - Ai-Wu Ke
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.
| | - Jia Fan
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.
- Cancer Center, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200031, People's Republic of China.
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50
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Kong L, Wu Q, Zhao L, Ye J, Li N, Yang H. Upregulated lncRNA-UCA1 contributes to metastasis of bile duct carcinoma through regulation of miR-122/ CLIC1 and activation of the ERK/MAPK signaling pathway. Cell Cycle 2019; 18:1212-1228. [PMID: 31106658 DOI: 10.1080/15384101.2019.1593647] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
In the present study, we aimed to identify specific lncRNAs and miRNAs, as well as mRNAs, involved in bile duct carcinoma (BDC) and to further explore the way in which lncRNA UCA1 regulates cell metastasis ability. Differentially expressed RNAs were screened out from the TCGA database. In in vitro experiments, qRT-PCR was used to measure lncRNA UCA1, miR-122 and CLIC1 expression. We performed a dual luciferase assay to validate the target relationships among UCA1, CLIC1 and miR-122. The cell migration ability was measured by a wound healing assay, and Transwell assays were applied to detect cell invasive ability. Western blot analysis was employed to detect the expression of related proteins in the MAPK signaling pathway. According to the bioinformatics analysis, lncRNA UCA1 and CLIC1 were both significantly upregulated in BDC, while the expression of miR-122 declined compared with the normal group. The target relationship among UCA1, CLIC1 and miR-122 was verified. UCA1 promoted BDC cell migration and invasiveness, while miR-122 inhibited their progression. CLIC1 served as the downstream target gene of miR-122 and had opposite effects. The ERK/MAPK signaling pathway was activated after upregulating UCA1. LncRNA-UCA1 promoted the metastasis of BDC cells by regulating the expression of miR-122 and its downstream gene mRNA CLIC1 and promoted the activation of the ERK/MAPK pathway, which expanded the horizons of targeted therapy of cholangiocarcinoma.
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Affiliation(s)
- Lei Kong
- a Department of General Surgery, Ruijin Hospital North, School of Medicine , Shanghai Jiaotong University , Shanghai , China
| | - Qinghua Wu
- a Department of General Surgery, Ruijin Hospital North, School of Medicine , Shanghai Jiaotong University , Shanghai , China
| | - Liangchao Zhao
- a Department of General Surgery, Ruijin Hospital North, School of Medicine , Shanghai Jiaotong University , Shanghai , China
| | - Jinhua Ye
- a Department of General Surgery, Ruijin Hospital North, School of Medicine , Shanghai Jiaotong University , Shanghai , China
| | - Nengping Li
- a Department of General Surgery, Ruijin Hospital North, School of Medicine , Shanghai Jiaotong University , Shanghai , China
| | - Huali Yang
- b Department of Ultrasound , Shanghai Fourth People's Hospital , Shanghai , China
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