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Zeng F, Chen L, Li J, Yu W, Sa N, Zhang K, Qu C, Wen D. A pan-cancer analysis reveals the oncogenic and immunological role of insulin-like growth factor 2 mRNA-binding protein family members. Discov Oncol 2025; 16:323. [PMID: 40088376 PMCID: PMC11910485 DOI: 10.1007/s12672-025-02077-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Accepted: 03/05/2025] [Indexed: 03/17/2025] Open
Abstract
PURPOSE To investigate the expression and clinical significance of insulin-like growth factor 2 mRNA-binding protein family members (IGF2BPs) in pan-cancer and evaluate their potential as targets for tumor immunotherapy. METHODS Based on data from the cancer genome atlas (TCGA) database, pan-cancer analysis was conducted to examine the clinical significance of IGF2BPs expression in twenty-two tumors. RESULTS Differential expression analysis showed high expression of IGF2BPs in most tumor tissues. Survival and mutation analyses suggested that the overexpression of IGF2BPs was associated with poor prognosis and mutation status of certain tumors. Methylation analysis revealed the methylation levels of IGF2BP1/2/3 in certain tumors were intricately linked to their mRNA expression, patient prognosis, and immune cell infiltration. Enrichment analysis indicated that abnormal expression of IGF2BPs was associated with various common tumor-related pathways in different tumors, including AMPK, Hippo, PI3K-Akt, EMT, and p53. In addition, immune correlation analysis revealed that IGF2BPs were closely related to immunotherapy-related indicators (immune cell infiltration, major histocompatibility complex (MHC), immune checkpoints, tumor mutation burden (TMB), and microsatellite instability (MSI)) in some tumors. Drug sensitivity analysis indicated that IGF2BPs were sensitive to some common chemotherapeutic drugs (alvocidib, dasatinib, trametinib, and selumetinib). CONCLUSION IGF2BPs exhibit significantly high expression in most tumors and are associated with prognosis, pathological stage, mutational status, methylation levels, and the relevant indicators of immunotherapy sensitivity in multiple tumors. Moreover, IGF2BPs may play an oncogenic role by activating common signaling pathways. Therefore, IGF2BPs may be potential prognostic markers for tumor therapy and targets for immunotherapy and drug therapy.
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Affiliation(s)
- Fuling Zeng
- Department of Laboratory Medicine, Shenzhen Guangming District People's Hospital, Shenzhen, 518000, Guangdong, China
| | - Liuyan Chen
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, 510632, Guangdong, China
| | - Jing Li
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, 510632, Guangdong, China
| | - Wenna Yu
- College of Pharmacy, Jinan University, Guangzhou, 510632, Guangdong, China
| | - Niya Sa
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, 510632, Guangdong, China
| | - Keke Zhang
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, 510632, Guangdong, China
| | - Chen Qu
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, 510632, Guangdong, China.
| | - Daolin Wen
- Department of Laboratory Medicine, Shenzhen Guangming District People's Hospital, Shenzhen, 518000, Guangdong, China.
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2
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Ma S, Qin Y, Ren W. Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) in hematological diseases. Mol Med 2024; 30:165. [PMID: 39342091 PMCID: PMC11439276 DOI: 10.1186/s10020-024-00936-2] [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: 12/01/2023] [Accepted: 09/13/2024] [Indexed: 10/01/2024] Open
Abstract
The oncofetal mRNA-binding protein IGF2BP1 belongs to a conserved family of RNA-binding proteins. It primarily promotes RNA stability, regulates translation and RNA localization, and mediates gene expression through its downstream effectors. Numerous studies have demonstrated that IGF2BP1 plays crucial roles in embryogenesis and carcinogenesis. IGF2BP1-modulated cell proliferation, invasion, and chemo-resistance in solid tumors have attracted researchers' attention. Additionally, several studies have highlighted the importance of IGF2BP1 in hematologic malignancies and hematological genetic diseases, positioning it as a promising therapeutic target for hematological disorders. However, there is a lack of systematic summaries regarding the IGF2BP1 gene within the hematological field. In this review, we provide a comprehensive overview of the discovery and molecular structure of IGF2BP1, along with recent studies on its role in regulating embryogenesis. We also focus on the mechanisms by which IGF2BP1 regulates hematological malignancies through its interactions with its targeted mRNAs. Furthermore, we systematically elucidate the function and mechanism of IGF2BP1 in promoting fetal hemoglobin expression in adult hematopoietic stem/progenitor cells. Finally, we discuss the limitations and challenges of IGF2BP1 as a therapeutic target, offering insights into its prospects.
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Affiliation(s)
- Shuangping Ma
- Institutes of Health Central Plains, Xinxiang Medical University, Xinxiang, 453003, China.
| | - Yiran Qin
- Institutes of Health Central Plains, Xinxiang Medical University, Xinxiang, 453003, China
| | - Wenjie Ren
- Institutes of Health Central Plains, Xinxiang Medical University, Xinxiang, 453003, China.
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Zorc S, Munoz-Tello P, O’Leary T, Yu X, Giridhar MNK, Hansel-Harris A, Forli S, Griffin PR, Kojetin DJ, Roy RN, Janiszewska M. Structural insights into IMP2 dimerization and RNA binding. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.16.580656. [PMID: 38405706 PMCID: PMC10889000 DOI: 10.1101/2024.02.16.580656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/27/2024]
Abstract
IGF2BP2 (IMP2) is an RNA-binding protein that contributes to cancer tumorigenesis and metabolic disorders. Structural studies focused on individual IMP2 domains have provided important mechanistic insights into IMP2 function; however, structural information on full-length IMP2 is lacking but necessary to understand how to target IMP2 activity in drug discovery. In this study, we investigated the behavior of full-length IMP2 and the influence of RNA binding using biophysical and structural methods including mass photometry, hydrogen-deuterium exchange coupled to mass spectrometry (HDX-MS), and small angle x-ray scattering (SAXS). We found that full-length IMP2 forms multiple oligomeric states but predominantly adopts a dimeric conformation. Molecular models derived from SAXS data suggest the dimer is formed in a head-to-tail orientation by the KH34 and RRM1 domains. Upon RNA binding, IMP2 forms a pseudo-symmetric dimer different from its apo/RNA-free state, with the KH12 domains of each IMP2 molecule forming the dimer interface. We also found that the formation of IMP2 oligomeric species, which includes dimers and higher-order oligomers, is sensitive to ionic strength and RNA binding. Our findings provide the first insight into the structural properties of full-length IMP2, which may lead to novel opportunities for disrupting its function with more effective IMP2 inhibitors.
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Affiliation(s)
- Stephen Zorc
- Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA
- The Skaggs Graduate School of Chemical and Biological Science, The Scripps Research Institute, La Jolla, CA, USA
| | - Paola Munoz-Tello
- Department of Biochemistry and Center for Structural Biology, Vanderbilt University, Nashville, TN, USA
| | - Timothy O’Leary
- The Skaggs Graduate School of Chemical and Biological Science, The Scripps Research Institute, La Jolla, CA, USA
| | - Xiaoyu Yu
- Department of Biochemistry and Center for Structural Biology, Vanderbilt University, Nashville, TN, USA
| | | | - Althea Hansel-Harris
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA
| | - Stefano Forli
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA
| | - Patrick R. Griffin
- The Skaggs Graduate School of Chemical and Biological Science, The Scripps Research Institute, La Jolla, CA, USA
| | - Douglas J. Kojetin
- Department of Biochemistry and Center for Structural Biology, Vanderbilt University, Nashville, TN, USA
| | - Raktim N. Roy
- Department of Integrative Structural and Computational Biology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Michalina Janiszewska
- Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA
- The Skaggs Graduate School of Chemical and Biological Science, The Scripps Research Institute, La Jolla, CA, USA
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Singh D, Biswas D, Tewari M, Kar AG, Ansari MA, Singh S, Narayan G. Clinical Significance of Overexpression of Oct4 in Advanced Stage Gallbladder Carcinoma. J Gastrointest Cancer 2023; 54:1231-1239. [PMID: 36705780 DOI: 10.1007/s12029-023-00913-8] [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] [Accepted: 01/22/2023] [Indexed: 01/28/2023]
Abstract
BACKGROUND Oct4 has critical role in maintaining pluripotency, proliferative potential, and self-renewal capacity in embryonic stem and germ cells. Although Oct4 has been shown to be upregulated in many cancers, its clinical significance in gallbladder carcinoma is poorly understood. METHODS We studied the expression profile of Oct4 in 61 GBC and 30 chronic cholecystitis (as control) using real time RT-PCR, western blotting, and immunohistochemistry. The expression data was correlated with clinico-pathological parameters. The diagnostic utility was assessed through ROC curve, and prognostic value was analyzed by Kaplan-Meier method. RESULTS Oct4 was significantly upregulated at mRNA as well as protein levels. The higher mRNA expression shows significant association with late stage, late T stage, and higher grade of tumor. A significant positive correlation was also observed with stage, T stage, and tumor grade. Sum score analysis of protein expression shows positive correlation with stage and the presence or absence of gallstone in tumor samples. The ROC curve analysis revealed the moderate diagnostic potential of Oct4. Kaplan-Meier analysis showed that patients having higher expression of Oct4 were having low mean survival compared with the patients with lower Oct4 expression. CONCLUSION In conclusion, our data suggests that higher expression of Oct4 may serve as potential biological indicator for tumor aggressiveness and poor prognosis of GBC.
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Affiliation(s)
- Deepika Singh
- Cancer Genetics Laboratory, Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
- Department of Radiation Oncology, The Ohio State University, Columbus, 43210, USA
| | - Dipanjan Biswas
- Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India
- Department of Surgical Oncology, Tata Memorial Hospital, Parel, Mumbai, 400012, India
| | - Mallika Tewari
- Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India
| | - Amrita Ghosh Kar
- Department of Pathology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India
| | - Mumtaz Ahmad Ansari
- Department of General Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India
| | - Sunita Singh
- Department of Zoology, Banaras Hindu University, Mahila Mahavidyalaya, Varanasi, 221005, India
| | - Gopeshwar Narayan
- Cancer Genetics Laboratory, Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, 221005, India.
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5
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Kendzia S, Franke S, Kröhler T, Golob-Schwarzl N, Schweiger C, Toeglhofer AM, Skofler C, Uranitsch S, El-Heliebi A, Fuchs J, Punschart A, Stiegler P, Keil M, Hoffmann J, Henderson D, Lehrach H, Yaspo ML, Reinhard C, Schäfer R, Keilholz U, Regenbrecht C, Schicho R, Fickert P, Lax SF, Erdmann F, Schulz MH, Kiemer AK, Haybaeck J, Kessler SM. A combined computational and functional approach identifies IGF2BP2 as a driver of chemoresistance in a wide array of pre-clinical models of colorectal cancer. Mol Cancer 2023; 22:89. [PMID: 37248468 PMCID: PMC10227963 DOI: 10.1186/s12943-023-01787-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 05/11/2023] [Indexed: 05/31/2023] Open
Abstract
AIM Chemoresistance is a major cause of treatment failure in colorectal cancer (CRC) therapy. In this study, the impact of the IGF2BP family of RNA-binding proteins on CRC chemoresistance was investigated using in silico, in vitro, and in vivo approaches. METHODS Gene expression data from a well-characterized cohort and publicly available cross-linking immunoprecipitation sequencing (CLIP-Seq) data were collected. Resistance to chemotherapeutics was assessed in patient-derived xenografts (PDXs) and patient-derived organoids (PDOs). Functional studies were performed in 2D and 3D cell culture models, including proliferation, spheroid growth, and mitochondrial respiration analyses. RESULTS We identified IGF2BP2 as the most abundant IGF2BP in primary and metastastatic CRC, correlating with tumor stage in patient samples and tumor growth in PDXs. IGF2BP2 expression in primary tumor tissue was significantly associated with resistance to selumetinib, gefitinib, and regorafenib in PDOs and to 5-fluorouracil and oxaliplatin in PDX in vivo. IGF2BP2 knockout (KO) HCT116 cells were more susceptible to regorafenib in 2D and to oxaliplatin, selumitinib, and nintedanib in 3D cell culture. Further, a bioinformatic analysis using CLIP data suggested stabilization of target transcripts in primary and metastatic tumors. Measurement of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) revealed a decreased basal OCR and an increase in glycolytic ATP production rate in IGF2BP2 KO. In addition, real-time reverse transcriptase polymerase chain reaction (qPCR) analysis confirmed decreased expression of genes of the respiratory chain complex I, complex IV, and the outer mitochondrial membrane in IGF2BP2 KO cells. CONCLUSIONS IGF2BP2 correlates with CRC tumor growth in vivo and promotes chemoresistance by altering mitochondrial respiratory chain metabolism. As a druggable target, IGF2BP2 could be used in future CRC therapy to overcome CRC chemoresistance.
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Affiliation(s)
- Sandra Kendzia
- Institute of Pharmacy, Experimental Pharmacology for Natural Sciences, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Susanne Franke
- Institute of Pharmacy, Experimental Pharmacology for Natural Sciences, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Tarek Kröhler
- Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, Germany
| | - Nicole Golob-Schwarzl
- Diagnostic & Research Center for Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Graz, Austria
- Center for Biomarker Research in Medicine (CBmed), Graz, Austria
- Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria
| | - Caroline Schweiger
- Diagnostic & Research Center for Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Graz, Austria
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Anna M Toeglhofer
- Diagnostic & Research Center for Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Christina Skofler
- Diagnostic & Research Center for Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Graz, Austria
- Center for Biomarker Research in Medicine (CBmed), Graz, Austria
| | - Stefan Uranitsch
- Department of Surgery, Hospital Brothers of Charity Graz, Graz, Austria
| | - Amin El-Heliebi
- Center for Biomarker Research in Medicine (CBmed), Graz, Austria
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
- BioTechMed-Graz, Graz, Austria
| | - Julia Fuchs
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
- Division of Medical Physics and Biophysics, Medical University Graz, Graz, Austria
| | | | - Philipp Stiegler
- Department of Surgery, Medical University of Graz, Graz, Austria
| | - Marlen Keil
- Experimental Pharmacology & Oncology, Berlin GmbH-Berlin-Buch, Germany
| | - Jens Hoffmann
- Experimental Pharmacology & Oncology, Berlin GmbH-Berlin-Buch, Germany
| | | | - Hans Lehrach
- Max Planck Institute for Molecular Genetics, Berlin, Germany
| | | | - Christoph Reinhard
- Eli Lilly & Company, Indianapolis, USA
- CELLphenomics GmbH, Berlin, Germany
| | - Reinhold Schäfer
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Ulrich Keilholz
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Christian Regenbrecht
- CELLphenomics GmbH, Berlin, Germany
- Institute for Pathology, University Hospital Göttingen, Göttingen, Germany
| | - Rudolf Schicho
- Division of Pharmacology, Medical University of Graz, Graz, Austria
| | - Peter Fickert
- Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
| | - Sigurd F Lax
- Department of Pathology, Hospital Graz South-West and School of Medicine, Johannes Kepler University Linz, Linz, Austria
| | - Frank Erdmann
- Institute of Pharmacy, Experimental Pharmacology for Natural Sciences, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Marcel H Schulz
- Institute for Cardiovascular Regeneration, Goethe-University Hospital, Frankfurt, Germany
| | - Alexandra K Kiemer
- Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, Germany
| | - Johannes Haybaeck
- Diagnostic & Research Center for Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Graz, Austria
- Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, Innsbruck, Austria
| | - Sonja M Kessler
- Institute of Pharmacy, Experimental Pharmacology for Natural Sciences, Martin Luther University Halle-Wittenberg, Halle, Germany.
- Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, Germany.
- Diagnostic & Research Center for Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Graz, Austria.
- Halle Research Centre for Drug Therapy (HRCDT), Halle, Germany.
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6
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Wu H, Xu H, Huang S, Tang Y, Tang J, Zhou H, Xie L, Qiao G. m 6A-binding protein IGF2BP1 promotes the malignant phenotypes of lung adenocarcinoma. Front Oncol 2022; 12:989817. [PMID: 36249006 PMCID: PMC9554348 DOI: 10.3389/fonc.2022.989817] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 09/06/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Lung adenocarcinoma (LUAD), the most common type of lung cancer, poses a significant threat to the life of patients. N6-methyladenosine modification is the most abundant epigenetic modification and may play an important role in the lung carcinogenesis. IGF2BP1 is a newly discovered m6A-binding protein, but little is known about its role in LUAD. METHODS Data from TCGA, GEO, Kaplan-Meier Plotter, and GEPIA databases were systematically analyzed to access the expression and prognostic value of IGF2BP1 on LUAD. Real-time polymerase chain reaction, Western blot, and immunohistochemistry were performed to detect the mRNA and protein level of IGF2BP1 in LUAD tissues and para-carcinoma tissues. Functional cell experiments, including Cell Counting Kit-8 assay, Transwell invasion assay, wound healing assay, Annexin V-FITC/PI double-staining assay, and TUNEL assay, were used to investigate the functions of IGF2BP1 on LUAD cell proliferation, invasion, migration, and apoptosis, respectively. The top 50 genes that were positively or negatively related to the expression of IGF2BP1 were identified, and pathway enrichment analysis was performed. m6A modification sites within IGF2BP1-related genes were predicted by SRAMP. RESULT 16 m6A regulators were significantly differentially expressed in LUAD tissues. IGF2BP1 was upregulated in LUAD tissues compared with para-carcinoma tissues. High expression of IGF2PB1 was significantly associated with higher clinical stages and poor prognosis of LUAD patients. Furthermore, our functional experiments indicated that IGF2BP1 facilitated cell proliferation, invasion, and migration and suppressed apoptosis in LUAD. Functional enrichment analysis of IGF2BP1-related genes indicated enrichment in several pathways related to oncogenesis. Additionally, m6A modification sites were detected within IGF2BP1-related genes. CONCLUSIONS Our findings demonstrate that IGF2BP1 plays a contributory role in the development and progression of LUAD. IGF2BP1 has the potential to become a prognostic predictor and therapeutic target for LUAD.
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Affiliation(s)
- Hansheng Wu
- Department of Thoracic Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Haijie Xu
- Department of Thoracic Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
- Shantou University Medical College, Shantou, China
| | - Shujie Huang
- Shantou University Medical College, Shantou, China
- Department of Thoracic Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yong Tang
- Department of Thoracic Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Jiming Tang
- Department of Thoracic Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Haiyu Zhou
- Department of Thoracic Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Liang Xie
- Department of Thoracic Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Guibin Qiao
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
- Department of Thoracic Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
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7
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Wang J, Li S, Yu H, Gao D. Oxidative stress regulates cardiomyocyte energy metabolism through the IGF2BP2-dynamin2 signaling pathway. Biochem Biophys Res Commun 2022; 624:134-140. [DOI: 10.1016/j.bbrc.2022.07.089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 07/20/2022] [Accepted: 07/23/2022] [Indexed: 11/02/2022]
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Ji J, Li C, Wang J, Wang L, Huang H, Li Y, Fang J. Hsa_circ_0001756 promotes ovarian cancer progression through regulating IGF2BP2-mediated RAB5A expression and the EGFR/MAPK signaling pathway. Cell Cycle 2022; 21:685-696. [PMID: 35113003 PMCID: PMC8973336 DOI: 10.1080/15384101.2021.2010166] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Hsa_circ_0001756 was reported to be upregulated in serum samples of ovarian cancer (OC) patients and may serve as a potential OC biomarker. This study aimed to investigate the role and molecular mechanisms of hsa_circ_0001756 in OC procession. Herein, we detected the expression of hsa_circ_0001756 in OC tissues and cell lines with RT-qPCR assay, which showed that hsa_circ_0001756 was upregulated in OC tissues and cell lines. Then small interfering RNA targeting hsa_circ_0001756 (si-hsa_circ_0001756) was transfected into SKOV3 and A2780 cells, and the proliferation, invasion, and expression of epithelial-mesenchymal transition (EMT) marker proteins were determined with CCK-8, Transwell and Western blotting assays, respectively. We found that hsa_circ_0001756 knockdown inhibited OC cell proliferation, invasion and EMT. Moreover, RNA pull-down assay verified the binding between hsa_circ_0001756 and IGF2 mRNA binding protein 2 (IGF2BP2), and rescue experiments indicated that IGF2BP2 overexpression reversed the effects of has_circ_0001756 knockdown on OC cell functions. Co-IP assay verified IGF2BP2 could interact with RAB GTPase 5A (RAB5A) protein. Then SKOV3 cells were transfected with si-IGF2BP2 alone or together with pcDNA-RAB5A, followed by the detection of SKOV3 cell functions. We found that IGF2BP2 knockdown inhibited OC cell proliferation, invasion, and EMT, while RAB5A overexpression reversed these effects. Finally, SKOV3 cells transfected with si-hsa_circ_0001756 were injected into nude mice through tail vein. Hsa_circ_0001756 knockdown significantly inhibited the xenograft tumor growth of OC in vivo. In conclusion, hsa_circ_0001756 knockdown inhibits OC cell proliferation, invasion, and EMT, and reduces xenograft tumor growth by suppressing IGF2BP2-mediated RAB5A expression and blocking the EGFR/MAPK signaling pathway.
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Affiliation(s)
- Jing Ji
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Chen Li
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Jinfeng Wang
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Lei Wang
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Huifang Huang
- Department of Gynecology, The Northwest Women’s and Children’s Hospital, Xi’an, Shaanxi, China
| | - Ying Li
- Department of Radiology, The First Affiliated Hospital of Xi’an Medical University, Xi’an, Shaanxi, China,CONTACT Ying Li Department of Radiology, The First Affiliated Hospital of Xi’an Medical University, Xi’an, Shaanxi710077, China; Jing Fang Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China
| | - Jing Fang
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
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9
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IGF2BP2 promotes gastric cancer progression by regulating the IGF1R-RhoA-ROCK signaling pathway. Cell Signal 2022; 94:110313. [DOI: 10.1016/j.cellsig.2022.110313] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 03/11/2022] [Accepted: 03/14/2022] [Indexed: 12/12/2022]
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10
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Dahlem C, Abuhaliema A, Kessler SM, Kröhler T, Zoller BGE, Chanda S, Wu Y, Both S, Müller F, Lepikhov K, Kirsch SH, Laggai S, Müller R, Empting M, Kiemer AK. First Small-Molecule Inhibitors Targeting the RNA-Binding Protein IGF2BP2/IMP2 for Cancer Therapy. ACS Chem Biol 2022; 17:361-375. [PMID: 35023719 DOI: 10.1021/acschembio.1c00833] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The RNA-binding protein IGF2BP2/IMP2/VICKZ2/p62 is overexpressed in several tumor entities, promotes tumorigenesis and tumor progression, and has been suggested to worsen the disease outcome. The aim of this study is to (I) validate IMP2 as a potential target for colorectal cancer, (II) set up a screening assay for small-molecule inhibitors of IMP2, and (III) test the biological activity of the obtained hit compounds. Analyses of colorectal and liver cancer gene expression data showed reduced survival in patients with a high IMP2 expression and in patients with a higher IMP2 expression in advanced tumors. In vitro target validation in 2D and 3D cell cultures demonstrated a reduction in cell viability, migration, and proliferation in IMP2 knockout cells. Also, xenotransplant tumor cell growth in vivo was significantly reduced in IMP2 knockouts. Different compound libraries were screened for IMP2 inhibitors using a fluorescence polarization assay, and the results were confirmed by the thermal shift assay and saturation-transfer difference NMR. Ten compounds, which belong to two classes, that is, benzamidobenzoic acid class and ureidothiophene class, were validated in vitro and showed a biological target specificity. The three most active compounds were also tested in vivo and exhibited reduced tumor xenograft growth in zebrafish embryos. In conclusion, our findings support that IMP2 represents a druggable target to reduce tumor cell proliferation.
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Affiliation(s)
- Charlotte Dahlem
- Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken 66123, Germany
| | - Ali Abuhaliema
- Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken 66123, Germany
| | - Sonja M. Kessler
- Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken 66123, Germany
- Institute of Pharmacy, Experimental Pharmacology for Natural Sciences, Martin Luther University Halle-Wittenberg, Halle 06108, Germany
| | - Tarek Kröhler
- Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken 66123, Germany
| | - Ben G. E. Zoller
- Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarland University, Saarbrücken 66123, Germany
| | - Shilpee Chanda
- Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken 66123, Germany
| | - Yingwen Wu
- Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarland University, Saarbrücken 66123, Germany
| | - Simon Both
- Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken 66123, Germany
| | - Fabian Müller
- Center for Bioinformatics, Saarland University, Saarbrücken 66123, Germany
| | | | - Susanne H. Kirsch
- Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, Saarland University, Saarbrücken 66123, Germany
| | - Stephan Laggai
- Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken 66123, Germany
| | - Rolf Müller
- Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, Saarland University, Saarbrücken 66123, Germany
- Department of Pharmacy, Saarland University, Saarbrücken 66123, Germany
| | - Martin Empting
- Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarland University, Saarbrücken 66123, Germany
- Department of Pharmacy, Saarland University, Saarbrücken 66123, Germany
| | - Alexandra K. Kiemer
- Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken 66123, Germany
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11
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Wu J, Wu Y, Guo Q, Wang S, Wu X. RNA-binding proteins in ovarian cancer: a novel avenue of their roles in diagnosis and treatment. J Transl Med 2022; 20:37. [PMID: 35062979 PMCID: PMC8783520 DOI: 10.1186/s12967-022-03245-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 01/11/2022] [Indexed: 12/18/2022] Open
Abstract
Ovarian cancer (OC), an important cause of cancer-related death in women worldwide, is one of the most malignant cancers and is characterized by a poor prognosis. RNA-binding proteins (RBPs), a class of endogenous proteins that can bind to mRNAs and modify (or even determine) the amount of protein they can generate, have attracted great attention in the context of various diseases, especially cancers. Compelling studies have suggested that RBPs are aberrantly expressed in different cancer tissues and cell types, including OC tissues and cells. More specifically, RBPs can regulate proliferation, apoptosis, invasion, metastasis, tumorigenesis and chemosensitivity and serve as potential therapeutic targets in OC. Herein, we summarize what is currently known about the biogenesis, molecular functions and potential roles of human RBPs in OC and their prospects for application in the clinical treatment of OC.
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Affiliation(s)
- Jiangchun Wu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.,Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, People's Republic of China
| | - Yong Wu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.,Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, People's Republic of China
| | - Qinhao Guo
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.,Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, People's Republic of China
| | - Simin Wang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.,Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, People's Republic of China
| | - Xiaohua Wu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. .,Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, People's Republic of China.
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12
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Bosch DE, Salipante SJ, Schmidt RA, Swanson PE, Bryan A, SenGupta DJ, Truong CD, Yeh MM. Neutrophilic inflammation in gallbladder carcinoma correlates with patient survival: A case-control study. Ann Diagn Pathol 2021; 56:151845. [PMID: 34763224 DOI: 10.1016/j.anndiagpath.2021.151845] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 10/17/2021] [Accepted: 10/18/2021] [Indexed: 11/17/2022]
Abstract
Gallbladder carcinoma is an uncommon malignancy with an overall 5-year survival of less than 5%. Gallbladder carcinoma has been strongly linked with cholelithiasis and chronic inflammation. Case reports and series have described cholecystitis with acute (neutrophilic) inflammation in association with gallbladder carcinoma, although a clear relationship to patient outcome has not been established. Our series included 8 cases of gallbladder carcinoma with high tumor-associated neutrophils (>25 per high power field) that were associated with shorter patient survival (Cox regression coefficient 6.2, p = 0.004) than age- and stage-matched controls. High tumor-associated neutrophils were not associated with gallbladder rupture/perforation or increased bacterial load measured by 16S PCR. Neutrophilic inflammation with gallbladder carcinoma correlates to shorter survival, independent of patient age and stage of carcinoma. The findings suggest that the degree of neutrophilic inflammation may have prognostic significance in specimens from patients with gallbladder carcinoma after cholecystectomy. Further studies with larger case numbers are needed to confirm and generalize these findings.
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Affiliation(s)
- Dustin E Bosch
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States of America; Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, United States of America
| | - Stephen J Salipante
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States of America
| | - Rodney A Schmidt
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States of America
| | - Paul E Swanson
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States of America; Department of Medicine, University of Washington, Seattle, WA, United States of America
| | - Andrew Bryan
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States of America
| | - Dhruba J SenGupta
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States of America
| | - Camtu D Truong
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States of America
| | - Matthew M Yeh
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States of America; Department of Medicine, University of Washington, Seattle, WA, United States of America.
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13
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Li J, Gao X, Zhang Z, Lai Y, Lin X, Lin B, Ma M, Liang X, Li X, Lv W, Lin Y, Zhang N. CircCD44 plays oncogenic roles in triple-negative breast cancer by modulating the miR-502-5p/KRAS and IGF2BP2/Myc axes. Mol Cancer 2021; 20:138. [PMID: 34696797 PMCID: PMC8543802 DOI: 10.1186/s12943-021-01444-1] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 10/08/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Emerging studies have revealed the potent functions of circRNAs in breast cancer tumorigenesis. However, the biogenesis, biofunction and mechanism of circRNAs in triple-negative breast cancer (TNBC) are largely unknown. METHODS High-throughput RNA sequencing was applied to identify dysregulated circRNAs in TNBCs and paired normal tissues. RNA pulldown and luciferase assays were performed to investigate the interaction between circular CD44 (circCD44, also annotated as hsa_circ_0021735) and miR-502-5p. RNA pulldown and RIP assays were used to investigate the interaction between circCD44 and IGF2BP2. Cell viability, colony formation, migration/invasion assays and in vivo tumorigenesis were used to investigate circCD44 biological functions. RESULTS CircCD44 is an uncharacterized circRNA, which is highly expressed in TNBC, and its expression is negatively correlated with the prognosis of TNBC patients. CircCD44 promotes TNBC proliferation, migration, invasion and tumorigenesis at least partially by sponging miR-502-5p and interacting with IGF2BP2. CONCLUSION Our data suggested that overexpressed circCD44 promotes TNBC progression. CircCD44 is potentially a novel diagnostic and therapeutic marker for TNBC patients.
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Affiliation(s)
- Jie Li
- Department of Thyroid and Breast Surgery, The First Affiliate Hospital, Sun Yat-sen University, No 58, Zhongshan 2 Road, Guangzhou, 510080, Guangdong Province, China
| | - Xinya Gao
- Department of Neurosurgery, The First Affiliate Hospital, Sun Yat-sen University, No 58, Zhongshan 2 Road, Guangzhou, 510080, Guangdong Province, China
| | - Zhanqiang Zhang
- Department of Thyroid and Breast Surgery, The First Affiliate Hospital, Sun Yat-sen University, No 58, Zhongshan 2 Road, Guangzhou, 510080, Guangdong Province, China
| | - Yuanhui Lai
- Department of Thyroid and Breast Surgery, The First Affiliate Hospital, Sun Yat-sen University, No 58, Zhongshan 2 Road, Guangzhou, 510080, Guangdong Province, China
| | - Xunxun Lin
- Department of Plastic Surgery, The First Affiliate Hospital, Sun Yat-sen University, Guangzhou, China
| | - Bo Lin
- Department of Thyroid and Breast Surgery, The First Affiliate Hospital, Sun Yat-sen University, No 58, Zhongshan 2 Road, Guangzhou, 510080, Guangdong Province, China
| | - Maoguang Ma
- Department of Thyroid and Breast Surgery, The First Affiliate Hospital, Sun Yat-sen University, No 58, Zhongshan 2 Road, Guangzhou, 510080, Guangdong Province, China
| | - Xiaoli Liang
- Department of Thyroid and Breast Surgery, The First Affiliate Hospital, Sun Yat-sen University, No 58, Zhongshan 2 Road, Guangzhou, 510080, Guangdong Province, China
| | - Xixi Li
- Department of Neurosurgery, The First Affiliate Hospital, Sun Yat-sen University, No 58, Zhongshan 2 Road, Guangzhou, 510080, Guangdong Province, China
| | - Weiming Lv
- Department of Thyroid and Breast Surgery, The First Affiliate Hospital, Sun Yat-sen University, No 58, Zhongshan 2 Road, Guangzhou, 510080, Guangdong Province, China
| | - Ying Lin
- Department of Thyroid and Breast Surgery, The First Affiliate Hospital, Sun Yat-sen University, No 58, Zhongshan 2 Road, Guangzhou, 510080, Guangdong Province, China.
| | - Nu Zhang
- Department of Neurosurgery, The First Affiliate Hospital, Sun Yat-sen University, No 58, Zhongshan 2 Road, Guangzhou, 510080, Guangdong Province, China.
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14
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Blizard S, Park D, O’Toole N, Norooz S, Dela Torre M, Son Y, Holstein A, Austin S, Harman J, Haraszti S, Fared D, Xu M. Neuron-Specific IMP2 Overexpression by Synapsin Promoter-Driven AAV9: A Tool to Study Its Role in Axon Regeneration. Cells 2021; 10:2654. [PMID: 34685634 PMCID: PMC8534607 DOI: 10.3390/cells10102654] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 08/30/2021] [Accepted: 10/02/2021] [Indexed: 11/17/2022] Open
Abstract
Insulin-like growth factor II mRNA-binding protein (IMP) 2 is one of the three homologues (IMP1-3) that belong to a conserved family of mRNA-binding proteins. Its alternative splice product is aberrantly expressed in human hepatocellular carcinoma, and it is therefore identified as HCC. Previous works have indicated that IMP1/ZBP1 (zipcode binding protein) is critical in axon guidance and regeneration by regulating localization and translation of specific mRNAs. However, the role of IMP2 in the nervous system is largely unknown. We used the synapsin promoter-driven adeno-associated viral (AAV) 9 constructs for transgene expression both in vitro and in vivo. These viral vectors have proven to be effective to transduce the neuron-specific overexpression of IMP2 and HCC. Applying this viral vector in the injury-conditioned dorsal root ganglion (DRG) culture demonstrates that overexpression of IMP2 significantly inhibits axons regenerating from the neurons, whereas overexpression of HCC barely interrupts the process. Quantitative analysis of binding affinities of IMPs to β-actin mRNA reveals that it is closely associated with their roles in axon regeneration. Although IMPs share significant structural homology, the distinctive functions imply their different ability to localize specific mRNAs and to regulate the axonal translation.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Mei Xu
- Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, 4170 City Avenue, Philadelphia, PA 19131, USA; (S.B.); (D.P.); (N.O.); (S.N.); (M.D.T.); (Y.S.); (A.H.); (S.A.); (J.H.); (S.H.); (D.F.)
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15
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Cong P, Wu T, Huang X, Liang H, Gao X, Tian L, Li W, Chen A, Wan H, He M, Dai D, Li Z, Xiong L. Identification of the Role and Clinical Prognostic Value of Target Genes of m6A RNA Methylation Regulators in Glioma. Front Cell Dev Biol 2021; 9:709022. [PMID: 34589481 PMCID: PMC8473691 DOI: 10.3389/fcell.2021.709022] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 08/16/2021] [Indexed: 12/23/2022] Open
Abstract
m6A RNA methylation regulators can regulate the growth, progression, and invasion of glioma cells by regulating their target genes, which provides a reliable support for the m6A regulator–target axes as the novel therapeutic targets and clinical prognostic signature in glioma. This study aimed to explore the role and prognostic value of m6A RNA methylation regulators and their targets. Expression profiles and clinicopathological data were obtained from the Chinese Glioma Genome Atlas (CGGA), The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Clinical Proteome Tumor Analysis Consortium (CPTAC) datasets. Differential expression and correlation analyses were performed between normal and glioma tissues at mRNA and protein levels. Univariate Cox regression, survival, and Lasso Cox regression analyses were conducted to identify and establish the prognostic gene signature. Kaplan–Meier curve, multivariate Cox regression analysis, and ROC were utilized to evaluate the prognostic capacity of the prognostic gene signature. The correlation analysis, systematic bioinformatics analysis, and cell experiment were performed to further understand the potential underlying molecular mechanisms and drug sensitivity. Our results suggested that IGF2BP2, KIAA1429, METTL16, and METTL3, as well as 208 targets are involved in the occurrence of glioma, GBM, and LGG. YTHDF1 and 78 targets involved the occurrence of glioma and GBM, not LGG, among which 181 genes were associated with overall survival. From other findings and our cell experiment results, we demonstrated that METTL3 can activate Notch pathway and facilitate glioma occurrence through regulating its direct targets NOTCH3, DLL3, and HES1, and Notch pathway genes may serve as the potential treatment targets for glioma. Our study established and validated a seven-gene signature comprising METTL3, COL18A1, NASP, PHLPP2, TIMP1, U2AF2, and VEGFA, with a good capability for predicting glioma survival, which may guide therapeutic customization and clinical decision-making. These genes were identified to influence 81 anticancer drug responses, which further contributes to the early phase clinical trials of drug development.
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Affiliation(s)
- Peilin Cong
- Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Tingmei Wu
- Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xinwei Huang
- Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Huazheng Liang
- Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xiaofei Gao
- Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Li Tian
- Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Wanrong Li
- Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Aiwen Chen
- Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Hanxi Wan
- Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Mengfan He
- Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Danqing Dai
- Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Zhen Li
- Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Lize Xiong
- Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China
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16
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The biological function of IGF2BPs and their role in tumorigenesis. Invest New Drugs 2021; 39:1682-1693. [PMID: 34251559 DOI: 10.1007/s10637-021-01148-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 06/30/2021] [Indexed: 01/09/2023]
Abstract
The insulin-like growth factor-2 mRNA-binding proteins (IGF2BPs) pertain to a highly conservative RNA-binding family that works as a post-transcriptional fine-tuner for target transcripts. Emerging evidence suggests that IGF2BPs regulate RNA processing and metabolism, including stability, translation, and localization, and are involved in various cellular functions and pathophysiologies. In this review, we summarize the roles and molecular mechanisms of IGF2BPs in cancer development and progression. We mainly discuss the functional relevance of IGF2BPs in embryo development, neurogenesis, metabolism, RNA processing, and tumorigenesis. Understanding IGF2BPs role in tumor progression will provide new insight into cancer pathophysiology.
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17
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Liu H, Qin G, Ji Y, Wang X, Bao H, Guan X, Wei A, Cai Z. Potential role of m6A RNA methylation regulators in osteosarcoma and its clinical prognostic value. J Orthop Surg Res 2021; 16:294. [PMID: 33952279 PMCID: PMC8097785 DOI: 10.1186/s13018-021-02422-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 04/14/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Osteosarcoma is a disease with high mortality in children and adolescents, and metastasis is one of the important clinical features of osteosarcoma. N6-Methyladenosine (m6A) is the most abundant methylation modification in mRNA, which is regulated by m6A regulators. It is reported that it is related to the occurrence and development of tumors. However, the mechanism of its action in osteosarcoma is rarely known. The purpose of this study was to identify the potential role of m6A regulatory factor in osteosarcoma and its clinical prognostic value. METHODS Here, we used The Cancer Genome Atlas (TCGA) to comprehensively analyze the relationship between m6A regulatory factors and osteosarcoma (metastasis group and non-metastasis group). We analyzed their survival relationship and analyzed all the m6A regulatory factors in TCGA tumor data set by using the univariate Cox proportional hazard regression model. Finally, we selected two survival-related methylation regulators (FTO and IGF2BP2) as risk gene signature. RESULTS According to the median risk, patients were divided into low-risk group and high-risk group. Multivariate Cox regression analysis showed that these two risk genes were considered to be the key factors independently predicting the prognosis of patients with osteosarcoma. In addition, we verified their characteristics with gene expression omnibus (GEO) DataSets and confirmed that they are related to tumor and immune-related signaling pathways through gene set enrichment analysis (GESA) and immune infiltration analysis. CONCLUSIONS In conclusion, m6A regulators might play an important role in the metastasis of osteosarcoma and have potential important value for the prognosis and treatment strategy of osteosarcoma patients.
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Affiliation(s)
- Hua Liu
- Department of Orthopedics, Haian Hospital of Traditional Chinese Medicine, 55 Ninghai Middle Road, Haian, Nantong, Jiangsu Province, 226600, People's Republic of China
| | - Guangzhen Qin
- Department of Orthopedics, Haian Hospital of Traditional Chinese Medicine, 55 Ninghai Middle Road, Haian, Nantong, Jiangsu Province, 226600, People's Republic of China
| | - Yanan Ji
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong, Jiangsu Province, 226001, People's Republic of China
| | - Xiaojian Wang
- Department of Orthopedics, Haian Hospital of Traditional Chinese Medicine, 55 Ninghai Middle Road, Haian, Nantong, Jiangsu Province, 226600, People's Republic of China
| | - Hailin Bao
- Clinical Laboratory, Haian Hospital of Traditional Chinese Medicine, Haian, Nantong, Jiangsu Province, 226600, People's Republic of China
| | - Xiaojun Guan
- Department of Orthopedics, Haian Hospital of Traditional Chinese Medicine, 55 Ninghai Middle Road, Haian, Nantong, Jiangsu Province, 226600, People's Republic of China
| | - Aichun Wei
- Department of Orthopedics, Haian Hospital of Traditional Chinese Medicine, 55 Ninghai Middle Road, Haian, Nantong, Jiangsu Province, 226600, People's Republic of China
| | - Zhigang Cai
- Department of Orthopedics, Haian Hospital of Traditional Chinese Medicine, 55 Ninghai Middle Road, Haian, Nantong, Jiangsu Province, 226600, People's Republic of China.
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18
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Wang J, Chen L, Qiang P. The role of IGF2BP2, an m6A reader gene, in human metabolic diseases and cancers. Cancer Cell Int 2021; 21:99. [PMID: 33568150 PMCID: PMC7876817 DOI: 10.1186/s12935-021-01799-x] [Citation(s) in RCA: 129] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 02/03/2021] [Indexed: 02/07/2023] Open
Abstract
The human insulin-like growth factor 2 (IGF2) mRNA binding proteins 2 (IGF2BP2/IMP2) is an RNA-binding protein that regulates multiple biological processes. Previously, IGF2BP2 was thought to be a type 2 diabetes (T2D)-associated gene. Indeed IGF2BP2 modulates cellular metabolism in human metabolic diseases such as diabetes, obesity and fatty liver through post-transcriptional regulation of numerous genes in multiple cell types. Emerging evidence shows that IGF2BP2 is an N6-methyladenosine (m6A) reader that participates in the development and progression of cancers by communicating with different RNAs such as microRNAs (miRNAs), messenger RNAs (mRNAs) and long non-coding RNAs (lncRNAs). Additionally, IGF2BP2 is an independent prognostic factor for multiple cancer types. In this review, we summarize the current knowledge on IGF2BP2 with regard to diverse human metabolic diseases and its potential for cancer prognosis.
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Affiliation(s)
- Jinyan Wang
- Department of Oncology, Zhangjiagang First People's Hospital, Zhangjiagang Affiliated Hospital of Soochow University, Zhangjiagang, China.,The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China
| | - Lijuan Chen
- Department of Gynecology, Zhangjiagang First People's Hospital, Zhangjiagang Affiliated Hospital of Soochow University, Zhangjiagang, 215600, Jiangsu, People's Republic of China.
| | - Ping Qiang
- Department of Gynecology, Zhangjiagang First People's Hospital, Zhangjiagang Affiliated Hospital of Soochow University, Zhangjiagang, 215600, Jiangsu, People's Republic of China.
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19
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Zhang Y, Wang H, Chen T, Wang H, Liang X, Zhang Y, Duan J, Qian S, Qiao K, Zhang L, Liu Y, Wang J. C24-Ceramide Drives Gallbladder Cancer Progression Through Directly Targeting Phosphatidylinositol 5-Phosphate 4-Kinase Type-2 Gamma to Facilitate Mammalian Target of Rapamycin Signaling Activation. Hepatology 2021; 73:692-712. [PMID: 32374916 DOI: 10.1002/hep.31304] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 03/05/2020] [Accepted: 04/08/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND AIMS The wide prevalence of chemoresistance and compromised early diagnosis of gallbladder cancer (GBC) has led to poor patient prognosis, requiring sustained efforts for the identification of effective biomarkers and therapeutic intervention. Ceramides have emerged as intracellular signaling molecules linked to tumorigenesis and therapeutic response in cancers. However, the clinical relevance of ceramides with GBC has not been investigated. APPROACH AND RESULTS In the present study, we revealed aberrant gene expressions (e.g., serine palmitoyltransferase 1 [SPTLC1] and ceramide synthase 2 [CERS2]) of de novo ceramide biosynthesis and length-specific ceramide production in GBC tissues. Analyses of serum ceramide pattern in healthy controls, gallbladder stone, and GBC patients identified C24-Ceramide as a potential diagnostic biomarker for patients with GBC. Importantly, elevation of SPTLC1, CERS2, and its product, C24-Ceramide, was associated with tumor staging, distal metastasis, and worse prognosis. In line with this, C24 -Ceramide promoted GBC cell proliferation and migration in vitro and in vivo. Mechanistically, C24-Ceramide directly bound to phosphatidylinositol 5-phosphate 4-kinase type-2 gamma (PIP4K2C), a regulator of mammalian target of rapamycin (mTOR), to facilitate mTOR complex formation and activation. C6-Ceramide, an analogue of natural ceramide, competed with C24-Ceramide for PIP4K2C binding, thereby abrogating C24-Ceramide-mediated mTOR signaling activation and oncogenic activity. Furthermore, stimulation with C6-Ceramide significantly suppressed the proliferative and metastatic capacity of GBC cells in vitro and in vivo, which was dependent on PIP4K2C. CONCLUSIONS Our findings highlight the clinical relevance of ceramide metabolism with GBC progression and identify C24-Ceramide as a diagnostic biomarker for GBC. We propose that PIP4K2C is indispensable for C6-Ceramide as a potential therapeutic intervention for GBC through a direct competition with C24-Ceramide.
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Affiliation(s)
- Yonglong Zhang
- Department of Biliary-Pancreatic SurgeryRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Hui Wang
- Department of Biliary-Pancreatic SurgeryRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Tao Chen
- Department of Biliary-Pancreatic SurgeryRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Haolu Wang
- The University of Queensland Diamantina InstituteThe University of QueenslandBrisbaneQueenslandAustralia
- Gallipoli Medical Research InstituteGreenslopes Private HospitalBrisbaneQueenslandAustralia
| | - Xiaowen Liang
- The University of Queensland Diamantina InstituteThe University of QueenslandBrisbaneQueenslandAustralia
- Gallipoli Medical Research InstituteGreenslopes Private HospitalBrisbaneQueenslandAustralia
| | - Yuchen Zhang
- Department of Biliary-Pancreatic SurgeryRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Jinlin Duan
- Department of Pathology Affiliated Tongren HospitalSchool of MedicineShanghai Jiaotong UniversityShanghaiChina
| | - Shenjiao Qian
- Department of Biliary-Pancreatic SurgeryRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Ke Qiao
- Key Laboratory of Medical Molecular Virology (MOE & MOH)Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Lei Zhang
- Institutes of Biomedical Sciences of Shanghai Medical SchoolFudan UniversityShanghaiChina
| | - Yanfeng Liu
- Clinical Stem Cell CenterRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Jian Wang
- Department of Biliary-Pancreatic SurgeryRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
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Fabbiano F, Corsi J, Gurrieri E, Trevisan C, Notarangelo M, D'Agostino VG. RNA packaging into extracellular vesicles: An orchestra of RNA-binding proteins? J Extracell Vesicles 2020; 10:e12043. [PMID: 33391635 PMCID: PMC7769857 DOI: 10.1002/jev2.12043] [Citation(s) in RCA: 169] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 11/17/2020] [Accepted: 12/03/2020] [Indexed: 12/11/2022] Open
Abstract
Extracellular vesicles (EVs) are heterogeneous membranous particles released from the cells through different biogenetic and secretory mechanisms. We now conceive EVs as shuttles mediating cellular communication, carrying a variety of molecules resulting from intracellular homeostatic mechanisms. The RNA is a widely detected cargo and, impressively, a recognized functional intermediate that elects EVs as modulators of cancer cell phenotypes, determinants of disease spreading, cell surrogates in regenerative medicine, and a source for non-invasive molecular diagnostics. The mechanistic elucidation of the intracellular events responsible for the engagement of RNA into EVs will significantly improve the comprehension and possibly the prediction of EV "quality" in association with cell physiology. Interestingly, the application of multidisciplinary approaches, including biochemical as well as cell-based and computational strategies, is increasingly revealing an active RNA-packaging process implicating RNA-binding proteins (RBPs) in the sorting of coding and non-coding RNAs. In this review, we provide a comprehensive view of RBPs recently emerging as part of the EV biology, considering the scenarios where: (i) individual RBPs were detected in EVs along with their RNA substrates, (ii) RBPs were detected in EVs with inferred RNA targets, and (iii) EV-transcripts were found to harbour sequence motifs mirroring the activity of RBPs. Proteins so far identified are members of the hnRNP family (hnRNPA2B1, hnRNPC1, hnRNPG, hnRNPH1, hnRNPK, and hnRNPQ), as well as YBX1, HuR, AGO2, IGF2BP1, MEX3C, ANXA2, ALIX, NCL, FUS, TDP-43, MVP, LIN28, SRP9/14, QKI, and TERT. We describe the RBPs based on protein domain features, current knowledge on the association with human diseases, recognition of RNA consensus motifs, and the need to clarify the functional significance in different cellular contexts. We also summarize data on previously identified RBP inhibitor small molecules that could also be introduced in EV research as potential modulators of vesicular RNA sorting.
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Affiliation(s)
- Fabrizio Fabbiano
- Department of CellularComputational and Integrative Biology (CIBIO)University of TrentoTrentoItaly
| | - Jessica Corsi
- Department of CellularComputational and Integrative Biology (CIBIO)University of TrentoTrentoItaly
| | - Elena Gurrieri
- Department of CellularComputational and Integrative Biology (CIBIO)University of TrentoTrentoItaly
| | - Caterina Trevisan
- Department of CellularComputational and Integrative Biology (CIBIO)University of TrentoTrentoItaly
| | - Michela Notarangelo
- Department of CellularComputational and Integrative Biology (CIBIO)University of TrentoTrentoItaly
| | - Vito G. D'Agostino
- Department of CellularComputational and Integrative Biology (CIBIO)University of TrentoTrentoItaly
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21
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Dai N. The Diverse Functions of IMP2/IGF2BP2 in Metabolism. Trends Endocrinol Metab 2020; 31:670-679. [PMID: 32586768 DOI: 10.1016/j.tem.2020.05.007] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 04/28/2020] [Accepted: 05/26/2020] [Indexed: 12/13/2022]
Abstract
The human insulin-like growth factor 2 (IGF2) mRNA binding protein family (IMPs/IGF2BPs) is involved in a spectrum of biological processes, including development, tumorigenesis, and stemness. IMPs play a major role in post-transcriptional regulation of RNAs through the ribonucleoprotein complex (RNP). They have emerged as direct mammalian target of rapamycin (mTOR) substrates that coordinate nutrient stimulation and RNA life cycle control. IMP2 is a human type 2 diabetes (T2D) gene associated with impaired insulin secretion. Recently, using murine models, the substantial progress in understanding disease mechanisms has highlighted the significance of IMP2 in metabolism. This new knowledge may have the potential for therapeutic benefit.
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Affiliation(s)
- Ning Dai
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.
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Sachan A, Saluja SS, Nekarakanti PK, Nimisha, Mahajan B, Nag HH, Mishra PK. Raised CA19-9 and CEA have prognostic relevance in gallbladder carcinoma. BMC Cancer 2020; 20:826. [PMID: 32867709 PMCID: PMC7457344 DOI: 10.1186/s12885-020-07334-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Accepted: 08/24/2020] [Indexed: 02/08/2023] Open
Abstract
Background Role of tumor markers in gall bladder carcinoma (GBC) is not well established. We evaluated the prognostic value of carbohydrate antigen 19–9 (CA19–9) and carcinoma embryonic antigen (CEA) in patients with GBC. Methods Of the 225 patients of GBC enrolled,176 patients were included in the study (excluded 49 patients with jaundice). Patients were divided into 3 groups; resectable n = 92, unresectable n = 17, metastatic n = 67. The clinico-pathological characteristics, tumor markers and survival data were analysed. The cutoff values of CA19–9 & CEA for predicting metastases were computed using receiver operating characteristic curve. Kaplan Meir survival and Cox regression analysis were done for factors predicting survival and recurrence. Results The median value of Ca19–9 was significantly higher in metastatic group [resectable: 21.3, unresectable: 53.9 and metastatic: 79; p < 0.001] but not for CEA [3.5, 7.8 and 5 ng/ml (p = 0.20)]. A cutoff value of 72 IU/ml for CA19–9, 5 ng/ml for CEA had a sensitivity and specificity of 52 and 80%, 51 and 72% respectively for detection of metastatic disease. Median, 3-year & 5-year survival were significantly lower in patients with CEA > 4 (p = 0.041), Ca19.9 > 37 (p = 0.019), T3/T4 (p = 0.001), node positive (p = 0.001) and presence of perineural invasion (p = 0.001). However, on multivariate analysis, only Ca19.9 > 37 predicted recurrence (p = 0.002, HR 5.8). Conclusions Raised CA19.9 and CEA predict metastatic disease in patients with GBC without jaundice with a high specificity and may help in prognostication of the patient. CA19–9 was better than CEA in prediction of tumor burden and in predicting recurrence.
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Affiliation(s)
- Ashish Sachan
- Department of Gastrointestinal Surgery, Govind Ballabh Pant Institute of Post Graduate Medical Education and Research, Room no 218, Jawahar Lal Nehru Marg, New Delhi, 110002, India
| | - Sundeep Singh Saluja
- Department of Gastrointestinal Surgery, Govind Ballabh Pant Institute of Post Graduate Medical Education and Research, Room no 218, Jawahar Lal Nehru Marg, New Delhi, 110002, India.
| | - Phani Kumar Nekarakanti
- Department of Gastrointestinal Surgery, Govind Ballabh Pant Institute of Post Graduate Medical Education and Research, Room no 218, Jawahar Lal Nehru Marg, New Delhi, 110002, India
| | - Nimisha
- Department of Gastrointestinal Surgery, Govind Ballabh Pant Institute of Post Graduate Medical Education and Research, Room no 218, Jawahar Lal Nehru Marg, New Delhi, 110002, India
| | - Bhawna Mahajan
- Department of Biochemistry, Govind Ballabh Pant Institute of Post Graduate Medical Education and Research, New Delhi, India
| | - Hirdaya H Nag
- Department of Gastrointestinal Surgery, Govind Ballabh Pant Institute of Post Graduate Medical Education and Research, Room no 218, Jawahar Lal Nehru Marg, New Delhi, 110002, India
| | - Pramod K Mishra
- Department of Gastrointestinal Surgery, Govind Ballabh Pant Institute of Post Graduate Medical Education and Research, Room no 218, Jawahar Lal Nehru Marg, New Delhi, 110002, India
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Valbuena Perez JV, Linnenberger R, Dembek A, Bruscoli S, Riccardi C, Schulz MH, Meyer MR, Kiemer AK, Hoppstädter J. Altered glucocorticoid metabolism represents a feature of macroph-aging. Aging Cell 2020; 19:e13156. [PMID: 32463582 PMCID: PMC7294787 DOI: 10.1111/acel.13156] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 03/20/2020] [Accepted: 04/05/2020] [Indexed: 12/23/2022] Open
Abstract
The aging process is characterized by a chronic, low‐grade inflammatory state, termed “inflammaging.” It has been suggested that macrophage activation plays a key role in the induction and maintenance of this state. In the present study, we aimed to elucidate the mechanisms responsible for aging‐associated changes in the myeloid compartment of mice. The aging phenotype, characterized by elevated cytokine production, was associated with a dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis and diminished serum corticosteroid levels. In particular, the concentration of corticosterone, the major active glucocorticoid in rodents, was decreased. This could be explained by an impaired expression and activity of 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1), an enzyme that determines the extent of cellular glucocorticoid responses by reducing the corticosteroids cortisone/11‐dehydrocorticosterone to their active forms cortisol/corticosterone, in aged macrophages and peripheral leukocytes. These changes were accompanied by a downregulation of the glucocorticoid receptor target gene glucocorticoid‐induced leucine zipper (GILZ) in vitro and in vivo. Since GILZ plays a central role in macrophage activation, we hypothesized that the loss of GILZ contributed to the process of macroph‐aging. The phenotype of macrophages from aged mice was indeed mimicked in young GILZ knockout mice. In summary, the current study provides insight into the role of glucocorticoid metabolism and GILZ regulation during aging.
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Affiliation(s)
| | - Rebecca Linnenberger
- Pharmaceutical Biology Department of Pharmacy Saarland University Saarbrücken Germany
| | - Anna Dembek
- Pharmaceutical Biology Department of Pharmacy Saarland University Saarbrücken Germany
| | - Stefano Bruscoli
- Pharmacology Department of Medicine Perugia University Perugia Italy
| | - Carlo Riccardi
- Pharmacology Department of Medicine Perugia University Perugia Italy
| | - Marcel H. Schulz
- Institute for Cardiovascular Regeneration Goethe University Frankfurt am Main Germany
- German Center for Cardiovascular Research (DZHK) Partner Site RheinMain Frankfurt am Main Germany
| | - Markus R. Meyer
- Department of Experimental and Clinical Toxicology Institute of Experimental and Clinical Pharmacology and Toxicology Center for Molecular Signaling (PZMS) Saarland University Homburg Germany
| | - Alexandra K. Kiemer
- Pharmaceutical Biology Department of Pharmacy Saarland University Saarbrücken Germany
| | - Jessica Hoppstädter
- Pharmaceutical Biology Department of Pharmacy Saarland University Saarbrücken Germany
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Bekric D, Neureiter D, Ritter M, Jakab M, Gaisberger M, Pichler M, Kiesslich T, Mayr C. Long Non-Coding RNAs in Biliary Tract Cancer-An Up-to-Date Review. J Clin Med 2020; 9:jcm9041200. [PMID: 32331331 PMCID: PMC7231154 DOI: 10.3390/jcm9041200] [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: 03/03/2020] [Revised: 03/31/2020] [Accepted: 04/07/2020] [Indexed: 02/07/2023] Open
Abstract
The term long non-coding RNA (lncRNA) describes non protein-coding transcripts with a length greater than 200 base pairs. The ongoing discovery, characterization and functional categorization of lncRNAs has led to a better understanding of the involvement of lncRNAs in diverse biological and pathological processes including cancer. Aberrant expression of specific lncRNA species was demonstrated in various cancer types and associated with unfavorable clinical characteristics. Recent studies suggest that lncRNAs are also involved in the development and progression of biliary tract cancer, a rare disease with high mortality and limited therapeutic options. In this review, we summarize current findings regarding the manifold roles of lncRNAs in biliary tract cancer and give an overview of the clinical and molecular consequences of aberrant lncRNA expression as well as of underlying regulatory functions of selected lncRNA species in the context of biliary tract cancer.
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Affiliation(s)
- Dino Bekric
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; (D.B.); (M.R.); (M.J.); (M.G.); (T.K.)
| | - Daniel Neureiter
- Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria;
- Cancer Cluster Salzburg, 5020 Salzburg, Austria
| | - Markus Ritter
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; (D.B.); (M.R.); (M.J.); (M.G.); (T.K.)
- Ludwig Boltzmann Institute for Arthritis and Rehabilitation, Paracelsus Medical University, 5020 Salzburg, Austria
- Gastein Research Institute, Paracelsus Medical University, 5020 Salzburg, Austria
| | - Martin Jakab
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; (D.B.); (M.R.); (M.J.); (M.G.); (T.K.)
| | - Martin Gaisberger
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; (D.B.); (M.R.); (M.J.); (M.G.); (T.K.)
- Ludwig Boltzmann Institute for Arthritis and Rehabilitation, Paracelsus Medical University, 5020 Salzburg, Austria
- Gastein Research Institute, Paracelsus Medical University, 5020 Salzburg, Austria
| | - Martin Pichler
- Research Unit of Non-Coding RNAs and Genome Editing, Division of Clinical Oncology, Department of Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, 8036 Graz, Austria;
| | - Tobias Kiesslich
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; (D.B.); (M.R.); (M.J.); (M.G.); (T.K.)
- Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria
| | - Christian Mayr
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; (D.B.); (M.R.); (M.J.); (M.G.); (T.K.)
- Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria
- Correspondence:
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Zhu D, Gu X, Lin Z, Yu D, Wang J, Li L. HASPIN is involved in the progression of gallbladder carcinoma. Exp Cell Res 2020; 390:111863. [PMID: 31987787 DOI: 10.1016/j.yexcr.2020.111863] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 01/19/2020] [Accepted: 01/22/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gallbladder carcinoma (GBC) is a common malignant tumor of the biliary system, but the current treatment of GBC is unsatisfactory. Therefore, new treatment targets and strategies are urgently needed. METHODS The expression of HASPIN in GBC was detected by immunohistochemical staining. HASPIN knockdown cell model was constructed by lentivirus infection, and the infection efficiency of lentivirus and knockdown efficiency of shHASPIN were verified by fluorescence immunoassay, qRT-PCR and Western blot. The effects of HASPIN knockdown on cell proliferation, clone-formation ability and apoptosis were determined by MTT, clone formation assay, flow cytometry and Human Apoptosis Antibody Array in vitro. Besides, the effect of HASPIN knockdown on the growth of GBC solid tumors was demonstrated in vivo. RESULTS The expression of HASPIN in GBC was up-regulated and positively correlated with the pathological grade of GBC. ShHASPIN significantly down-regulated the mRNA and protein levels of HASPIN, suggesting that HASPIN knockdown cell model was successfully constructed in vitro. After HASPIN knockdown, the proliferation and clone-formation ability of GBC cells were observably inhibited, the apoptotic levels were markedly increased, and the expression of Caspase 3, IGFBP-5, p21 and sTNF-R1 related to apoptotic pathway was up-regulated. Furthermore, HASPIN knockdown inhibited the growth of GBC in vivo. CONCLUSION HASPIN was up-regulated in GBC and played an important role in promoting the progress of GBC.
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MESH Headings
- Aged
- Animals
- Apoptosis
- Carcinoma/genetics
- Carcinoma/metabolism
- Carcinoma/pathology
- Carcinoma/therapy
- Caspase 3/genetics
- Caspase 3/metabolism
- Cell Line, Tumor
- Cell Proliferation
- Clone Cells
- Cyclin-Dependent Kinase Inhibitor p21/genetics
- Cyclin-Dependent Kinase Inhibitor p21/metabolism
- Female
- Gallbladder Neoplasms/genetics
- Gallbladder Neoplasms/metabolism
- Gallbladder Neoplasms/pathology
- Gallbladder Neoplasms/therapy
- Gene Expression Regulation, Neoplastic
- Humans
- Insulin-Like Growth Factor Binding Protein 5/genetics
- Insulin-Like Growth Factor Binding Protein 5/metabolism
- Intracellular Signaling Peptides and Proteins/antagonists & inhibitors
- Intracellular Signaling Peptides and Proteins/genetics
- Intracellular Signaling Peptides and Proteins/metabolism
- Male
- Mice
- Mice, Nude
- Middle Aged
- Protein Array Analysis
- Protein Serine-Threonine Kinases/antagonists & inhibitors
- Protein Serine-Threonine Kinases/genetics
- Protein Serine-Threonine Kinases/metabolism
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- RNA, Small Interfering/genetics
- RNA, Small Interfering/metabolism
- Receptors, Tumor Necrosis Factor, Type I/genetics
- Receptors, Tumor Necrosis Factor, Type I/metabolism
- Signal Transduction
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Dawei Zhu
- Department of Gynaecology and Obstetrics, Daping Hospital, Army Medical University, China
| | - Xing Gu
- Department of Gynaecology and Obstetrics, Daping Hospital, Army Medical University, China
| | - Zhenyu Lin
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
| | - Dandan Yu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
| | - Jing Wang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
| | - Li Li
- Department of Gynaecology and Obstetrics, Daping Hospital, Army Medical University, China.
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Xu X, Yu Y, Zong K, Lv P, Gu Y. Up-regulation of IGF2BP2 by multiple mechanisms in pancreatic cancer promotes cancer proliferation by activating the PI3K/Akt signaling pathway. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:497. [PMID: 31852504 PMCID: PMC6921559 DOI: 10.1186/s13046-019-1470-y] [Citation(s) in RCA: 134] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Accepted: 10/28/2019] [Indexed: 02/08/2023]
Abstract
Background The survival of pancreatic cancer patients remains poor. However, the underlying molecular mechanism and new therapeutic target of pancreatic cancer are still needed to be found. Many studies have shown that the IGF2 mRNA-binding protein 2 (IGF2BP2) plays oncogenic roles in cancers. However, the clinical significance, role and molecular mechanisms of IGF2BP2 in pancreatic cancer remain unclear. Methods The expression of IGF2BP2 and miR-141 was detected in pancreatic cancer, and clinical significances were analyzed by statistical analysis. The function of IGF2BP2 and miR-141 was determined in vitro and in vivo, and the underlying mechanism was investigated. The gene copy number variation (CNV) of IGF2BP2 was analyzed based on The Cancer Genome Atlas (TCGA) dataset. microRNAs (miRNAs) regulating IGF2BP2 were predicted by online tools and confirmed by experiments. Results IGF2BP2 is overexpressed in pancreatic cancer tissues compared with control tissues. Upregulation of IGF2BP2 predicts shorter overall survival (OS) in pancreatic cancer patients by statistical analysis. IGF2BP2 overexpression is partially due to genomic amplification. Bioinformatics analyses and validation experiments showed that IGF2BP2 is a direct target of miR-141. A negative correlation between IGF2BP2 mRNA expression and the expression of miR-141 was observed in pancreatic cancer tissues and more importantly, reexpression of miR-141 rescued the oncogenic role of IGF2BP2. Moreover, upregulating IGF2BP2 expression promotes pancreatic cancer cell growth by activating the PI3K/Akt signaling pathway in vitro and in vivo. Conclusions We comprehensively reveal the oncogenic role of IGF2BP2 in pancreatic cancer carcinogenesis and confirm that genomic amplification and the silencing of miR-141 contribute to its activation. Our findings highlight that IGF2BP2 may be a promising molecular target for the treatment of pancreatic cancer.
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Affiliation(s)
- Xiaodong Xu
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe east Road, Zhengzhou, 450000, China
| | - Yan Yu
- Department of Infection Disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Ke Zong
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Pengwei Lv
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe east Road, Zhengzhou, 450000, China.
| | - Yuantin Gu
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe east Road, Zhengzhou, 450000, China.
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Wan BS, Cheng M, Zhang L. Insulin-like growth factor 2 mRNA-binding protein 1 promotes cell proliferation via activation of AKT and is directly targeted by microRNA-494 in pancreatic cancer. World J Gastroenterol 2019; 25:6063-6076. [PMID: 31686763 PMCID: PMC6824281 DOI: 10.3748/wjg.v25.i40.6063] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Revised: 09/03/2019] [Accepted: 09/28/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Studies have shown that insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) plays critical roles in the genesis and development of human cancers.
AIM To investigate the clinical significance and role of IGF2BP1 in pancreatic cancer.
METHODS Expression levels of IGF2BP1 and microRNA-494 (miR-494) were mined based on Gene Expression Omnibus datasets and validated in both clinical samples and cell lines by quantitative real-time polymerase chain reaction and Western blot. The relationship between IGF2BP1 expression and clinicopathological factors of pancreatic cancer patients was analyzed. The effect and mechanism of IGF2BP1 on pancreatic cancer cell proliferation were investigated in vitro and in vivo. Analyses were performed to explore underlying mechanisms of IGF2BP1 upregulation in pancreatic cancer and assays were carried out to verify the post-transcriptional regulation of IGF2BP1 by miR-494.
RESULTS We found that IGF2BP1 was upregulated and associated with a poor prognosis in pancreatic cancer patients. We showed that downregulation of IGF2BP1 inhibited pancreatic cancer cell growth in vitro and in vivo via the AKT signaling pathway. Mechanistically, we showed that the frequent upregulation of IGF2BP1 was attributed to the downregulation of miR-494 expression in pancreatic cancer. Furthermore, we discovered that reexpression of miR-494 could partially abrogate the oncogenic role of IGF2BP1.
CONCLUSION Our results revealed that upregulated IGF2BP1 promotes the proliferation of pancreatic cancer cells via the AKT signaling pathway and confirmed that the activation of IGF2BP1 is partly due to the silencing of miR-494.
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Affiliation(s)
- Bai-Shun Wan
- Department of Hepatobiliary and Pancreatic Surgery, the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, Henan Province, China
| | - Ming Cheng
- Department of Information, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan Province, China
| | - Ling Zhang
- Department of Hepatobiliary and Pancreatic Surgery, the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, Henan Province, China
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Dahlem C, Barghash A, Puchas P, Haybaeck J, Kessler SM. The Insulin-Like Growth Factor 2 mRNA Binding Protein IMP2/IGF2BP2 is Overexpressed and Correlates with Poor Survival in Pancreatic Cancer. Int J Mol Sci 2019; 20:ijms20133204. [PMID: 31261900 PMCID: PMC6651604 DOI: 10.3390/ijms20133204] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 06/23/2019] [Accepted: 06/27/2019] [Indexed: 01/23/2023] Open
Abstract
The insulin-like growth factor 2 (IGF2) mRNA binding protein IMP2 (IGF2BP2) is an oncogenic protein known to be overexpressed in different tumor types. Pancreatic cancer is a very lethal cancer that requires early diagnosis and new treatment options. The aim of our study was to investigate the role of IMP2 in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC). IMP2 was significantly overexpressed in a human precursor (PanIN) lesions suggesting IMP2 as a marker for early stages of PDAC. In a PDAC cohort of matched normal and tumor samples IMP2 showed overexpression in tumor tissues compared with normal pancreatic tissue. Strict correlation analysis (threshold R2 > 0.75) revealed 22 genes highly positively and 9 genes highly negatively correlating with IMP2. Besides genes involved in the inhibition of apoptosis (Bcl-XL), especially factors involved in ubiquitination were strongly correlated with IMP2 expression: SMURF1 and FBXO45. Moreover, protein kinase C (PKC) signaling pathway was distinctly affected: DXS1179E encoding PKC iota, PKC substrate PLEK2, and inositol triphosphate receptor IP3R3 were positively correlated with IMP2 expression. Besides tumor initiation, IMP2 also seemed to have an impact on tumor progression. TGF-β treatment of Panc-1 pancreatic cancer cells to induce epithelial-mesenchymal transition (EMT) was accompanied by increased IMP2 expression. EMT is important for cancer cells to gain migratory and invasive potential, which is essential for metastasis. Concordantly, circulating tumor cells showed higher IMP2 levels as compared with normal tissue from tumor origin and with normal hematological cells. Accordingly, IMP2 protein levels correlated with poor survival. In conclusion, as IMP2 seems to promote tumor progression of PDAC, it might be an interesting diagnostic and prognostic marker as well as a novel target for the treatment of PDAC.
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Affiliation(s)
- Charlotte Dahlem
- Department of Pharmacy, Pharmaceutical Biology, Saarland University, 66123 Saarbrücken, Germany
| | - Ahmad Barghash
- Department of Computer Science, German Jordanian University, Amman 11180, Jordan
| | - Philip Puchas
- Institute of Pathology, Medical University of Graz, 8010 Graz, Austria
| | - Johannes Haybaeck
- Institute of Pathology, Medical University of Graz, 8010 Graz, Austria.
- Department of Pathology, Medical Faculty, Otto von Guericke University Magdeburg, 39120 Magdeburg, Germany.
- Department of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
| | - Sonja M Kessler
- Department of Pharmacy, Pharmaceutical Biology, Saarland University, 66123 Saarbrücken, Germany.
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Zhu S, Yang J, Cui X, Zhao Y, Tao Z, Xia F, Chen L, Huang J, Ma X. Preoperative platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio as predictors of clinical outcome in patients with gallbladder cancer. Sci Rep 2019; 9:1823. [PMID: 30755649 PMCID: PMC6372648 DOI: 10.1038/s41598-018-38396-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 12/20/2018] [Indexed: 02/06/2023] Open
Abstract
Some inflammatory biomarkers are associated with the post-surgical prognosis in cancer patients. However, their clinical importance in gallbladder cancer has rarely been explored. The aim of this study is to assess the efficacy of surgical intervention and the effectiveness of preoperative test on neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and monocyte-to-lymphocyte ratio (MLR) for predicting the prognosis in gallbladder cancer patients. In this study, a total of 255 gallbladder cancer patients were retrospectively selected. For each patient, we recorded his/her treatment algorithm (with or without surgery) and their preoperative inflammatory biomarkers, as well as their detailed survival information for 5 years. A total of 216 patients received surgical intervention and the other 39 chose conservative treatment. The median survival time was 4.6 months for non-surgical group (P < 0.001), and 12.2 months for surgical intervention group. Among the surgical group, ROC analysis showed the AUC of NLR, PLR and MLR were 0.675 (95% CI: 0.600 to 0.751, P < 0.001), 0.599 (95% CI: 0.520 to 0.677, P = 0.017) and 0.607 (95% CI: 0.529 to 0.686, P = 0.009), respectively. In conclusion, surgical intervention did improve the overall survival, and elevated NLR and MLR before surgery are associated with shorter OS of GBC patients.
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Affiliation(s)
- Sha Zhu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.,West China School of Medicine, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China
| | - Jing Yang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Xiwei Cui
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.,West China School of Medicine, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China
| | - Yunuo Zhao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Zhihang Tao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.,West China School of Medicine, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China
| | - Fan Xia
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.,West China School of Medicine, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China
| | - Linyan Chen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.,West China School of Medicine, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China
| | - Juan Huang
- Department of Hematology, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610031, Sichuan, China.
| | - Xuelei Ma
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
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30
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Kleinegger F, Hofer E, Wodlej C, Golob-Schwarzl N, Birkl-Toeglhofer AM, Stallinger A, Petzold J, Orlova A, Krassnig S, Reihs R, Niedrist T, Mangge H, Park YN, Thalhammer M, Aigelsreiter A, Lax S, Garbers C, Fickert P, Rose-John S, Moriggl R, Rinner B, Haybaeck J. Pharmacologic IL-6Rα inhibition in cholangiocarcinoma promotes cancer cell growth and survival. Biochim Biophys Acta Mol Basis Dis 2019; 1865:308-321. [DOI: 10.1016/j.bbadis.2018.11.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Revised: 10/25/2018] [Accepted: 11/07/2018] [Indexed: 02/08/2023]
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31
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Huang X, Zhang H, Guo X, Zhu Z, Cai H, Kong X. Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) in cancer. J Hematol Oncol 2018; 11:88. [PMID: 29954406 PMCID: PMC6025799 DOI: 10.1186/s13045-018-0628-y] [Citation(s) in RCA: 204] [Impact Index Per Article: 29.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 06/06/2018] [Indexed: 12/20/2022] Open
Abstract
The insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1) plays essential roles in embryogenesis and carcinogenesis. IGF2BP1 serves as a post-transcriptional fine-tuner regulating the expression of some essential mRNA targets required for the control of tumor cell proliferation and growth, invasion, and chemo-resistance, associating with a poor overall survival and metastasis in various types of human cancers. Therefore, IGF2BP1 has been traditionally regarded as an oncogene and potential therapeutic target for cancers. Nevertheless, a few studies have also demonstrated its tumor-suppressive role. However, the details about the contradictory functions of IGF2BP1 are unclear. The growing numbers of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) have been identified as its direct regulators, during tumor cell proliferation, growth, and invasion in multiple cancers. Thus, the mechanisms of post-transcriptional modulation of gene expression mediated by IGF2BP1, miRNAs, and lncRNAs in determining the fate of the development of tissues and organs, as well as tumorigenesis, need to be elucidated. In this review, we summarized the tissue distribution, expression, and roles of IGF2BP1 in embryogenesis and tumorigenesis, and focused on modulation of the interconnectivity between IGF2BP1 and its targeted mRNAs or non-coding RNAs (ncRNAs). The potential use of inhibitors of IGF2BP1 and its related pathways in cancer therapy was also discussed.
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Affiliation(s)
- Xinwei Huang
- Faculty of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming City, 650504, Yunnan Province, China
- Medical School, Kunming University of Science and Technology, Kunming City, 650504, Yunnan Province, China
| | - Hong Zhang
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu City, 610500, Sichuan Province, China
| | - Xiaoran Guo
- Medical School, Kunming University of Science and Technology, Kunming City, 650504, Yunnan Province, China
| | - Zongxin Zhu
- Medical School, Kunming University of Science and Technology, Kunming City, 650504, Yunnan Province, China
| | - Haibo Cai
- Department of Oncology, Yunfeng Hospital, Xuanwei City, 655400, Yunnan Province, China.
| | - Xiangyang Kong
- Medical School, Kunming University of Science and Technology, Kunming City, 650504, Yunnan Province, China.
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