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Lachiondo-Ortega S, Rejano-Gordillo CM, Simon J, Lopitz-Otsoa F, C Delgado T, Mazan-Mamczarz K, Goikoetxea-Usandizaga N, Zapata-Pavas LE, García-Del Río A, Guerra P, Peña-Sanfélix P, Hermán-Sánchez N, Al-Abdulla R, Fernandez-Rodríguez C, Azkargorta M, Velázquez-Cruz A, Guyon J, Martín C, Zalamea JD, Egia-Mendikute L, Sanz-Parra A, Serrano-Maciá M, González-Recio I, Gonzalez-Lopez M, Martínez-Cruz LA, Pontisso P, Aransay AM, Barrio R, Sutherland JD, Abrescia NGA, Elortza F, Lujambio A, Banales JM, Luque RM, Gahete MD, Palazón A, Avila MA, G Marin JJ, De S, Daubon T, Díaz-Quintana A, Díaz-Moreno I, Gorospe M, Rodríguez MS, Martínez-Chantar ML. SUMOylation controls Hu antigen R posttranscriptional activity in liver cancer. Cell Rep 2024; 43:113924. [PMID: 38507413 PMCID: PMC11025316 DOI: 10.1016/j.celrep.2024.113924] [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: 09/30/2022] [Revised: 08/08/2023] [Accepted: 02/21/2024] [Indexed: 03/22/2024] Open
Abstract
The posttranslational modification of proteins critically influences many biological processes and is a key mechanism that regulates the function of the RNA-binding protein Hu antigen R (HuR), a hub in liver cancer. Here, we show that HuR is SUMOylated in the tumor sections of patients with hepatocellular carcinoma in contrast to the surrounding tissue, as well as in human cell line and mouse models of the disease. SUMOylation of HuR promotes major cancer hallmarks, namely proliferation and invasion, whereas the absence of HuR SUMOylation results in a senescent phenotype with dysfunctional mitochondria and endoplasmic reticulum. Mechanistically, SUMOylation induces a structural rearrangement of the RNA recognition motifs that modulates HuR binding affinity to its target RNAs, further modifying the transcriptomic profile toward hepatic tumor progression. Overall, SUMOylation constitutes a mechanism of HuR regulation that could be potentially exploited as a therapeutic strategy for liver cancer.
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Affiliation(s)
- Sofia Lachiondo-Ortega
- Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
| | - Claudia M Rejano-Gordillo
- Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain; Department of Biochemistry and Molecular Biology, Faculty of Sciences, University of Extremadura, University Institute of Biosanitary Research of Extremadura (INUBE), 06071 Badajoz, Spain; Biofisika Institute, Consejo Superior de Investigaciones Científicas (CSIC), Departamento Bioquímica y Biología Molecular, Facultad de Ciencia y Tecnología, Universidad del País Vasco (UPV/EHU), Leioa, Spain
| | - Jorge Simon
- Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, Madrid, Spain
| | - Fernando Lopitz-Otsoa
- Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
| | - Teresa C Delgado
- Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
| | - Krystyna Mazan-Mamczarz
- Laboratory of Genetics and Genomics, National Institute on Aging (NIA), Intramural Research Program (IRP), National Institutes of Health (NIH), Baltimore, MD, USA
| | - Naroa Goikoetxea-Usandizaga
- Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
| | - L Estefanía Zapata-Pavas
- Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
| | - Ana García-Del Río
- Cancer Immunology and Immunotherapy Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
| | - Pietro Guerra
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, 35128 Padua, Italy
| | - Patricia Peña-Sanfélix
- Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
| | - Natalia Hermán-Sánchez
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Department of Cell Biology, Physiology and Immunology of University of Córdoba, Reina Sofia University Hospital, CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), 14004 Córdoba, Spain
| | - Ruba Al-Abdulla
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Elche, Spain; Institute of Medical Biochemistry and Molecular Biology, University Medicine of Greifswald, 17475 Greifswald, Germany
| | - Carmen Fernandez-Rodríguez
- Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
| | - Mikel Azkargorta
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, Madrid, Spain; Proteomics Platform, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Carlos III Networked Proteomics Platform (ProteoRed-ISCIII), 48160 Derio, Bizkaia, Spain
| | - Alejandro Velázquez-Cruz
- Instituto de Investigaciones Químicas (IIQ), Centro de Investigaciones Científicas Isla de la Cartuja (cicCartuja), Universidad de Sevilla, Consejo Superior de Investigaciones Científicas (CSIC), Sevilla, Spain
| | - Joris Guyon
- University of Bordeaux, INSERM, BPH, U1219, 33000 Bordeaux, France; CHU de Bordeaux, Service de Pharmacologie Médicale, 33000 Bordeaux, France
| | - César Martín
- Biofisika Institute, Consejo Superior de Investigaciones Científicas (CSIC), Departamento Bioquímica y Biología Molecular, Facultad de Ciencia y Tecnología, Universidad del País Vasco (UPV/EHU), Leioa, Spain
| | - Juan Diego Zalamea
- Structure and Cell Biology of Viruses Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
| | - Leire Egia-Mendikute
- Cancer Immunology and Immunotherapy Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
| | - Arantza Sanz-Parra
- Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
| | - Marina Serrano-Maciá
- Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
| | - Irene González-Recio
- Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
| | - Monika Gonzalez-Lopez
- Genome Analysis Platform, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
| | - Luis Alfonso Martínez-Cruz
- Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
| | - Patrizia Pontisso
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, 35128 Padua, Italy
| | - Ana M Aransay
- Genome Analysis Platform, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
| | - Rosa Barrio
- Ubiquitin-likes and Development Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
| | - James D Sutherland
- Ubiquitin-likes and Development Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
| | - Nicola G A Abrescia
- Structure and Cell Biology of Viruses Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain
| | - Félix Elortza
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, Madrid, Spain; Proteomics Platform, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Carlos III Networked Proteomics Platform (ProteoRed-ISCIII), 48160 Derio, Bizkaia, Spain
| | - Amaia Lujambio
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jesus M Banales
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, Madrid, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain; Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, San Sebastian, Spain; Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain
| | - Raúl M Luque
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Department of Cell Biology, Physiology and Immunology of University of Córdoba, Reina Sofia University Hospital, CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), 14004 Córdoba, Spain
| | - Manuel D Gahete
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Department of Cell Biology, Physiology and Immunology of University of Córdoba, Reina Sofia University Hospital, CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), 14004 Córdoba, Spain
| | - Asís Palazón
- Cancer Immunology and Immunotherapy Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain
| | - Matias A Avila
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, Madrid, Spain; Hepatology Program, Centro de Investigación Médica Aplicada (CIMA), University of Navarra, Pamplona, Spain; Instituto de Investigaciones Sanitarias de Navarra (IdiSNA), Pamplona, Spain
| | - Jose J G Marin
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, Madrid, Spain; Experimental Hepatology and Drug Targeting (HEVEPHARM), Instituto de Investigación Biomédica de Salamanca (IBSAL), University of Salamanca, Salamanca, Spain
| | - Supriyo De
- Laboratory of Genetics and Genomics, National Institute on Aging (NIA), Intramural Research Program (IRP), National Institutes of Health (NIH), Baltimore, MD, USA
| | - Thomas Daubon
- University of Bordeaux, CNRS, IBGC, UMR 5095, Bordeaux, France
| | - Antonio Díaz-Quintana
- Instituto de Investigaciones Químicas (IIQ), Centro de Investigaciones Científicas Isla de la Cartuja (cicCartuja), Universidad de Sevilla, Consejo Superior de Investigaciones Científicas (CSIC), Sevilla, Spain
| | - Irene Díaz-Moreno
- Instituto de Investigaciones Químicas (IIQ), Centro de Investigaciones Científicas Isla de la Cartuja (cicCartuja), Universidad de Sevilla, Consejo Superior de Investigaciones Científicas (CSIC), Sevilla, Spain
| | - Myriam Gorospe
- Laboratory of Genetics and Genomics, National Institute on Aging (NIA), Intramural Research Program (IRP), National Institutes of Health (NIH), Baltimore, MD, USA
| | - Manuel S Rodríguez
- Laboratoire de Chimie de Coordination (LCC), UPR 8241, CNRS; IPBS-University of Toulouse III-Paul Sabatier, Toulouse, France
| | - María Luz Martínez-Chantar
- Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, Madrid, Spain.
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Rodriguez-Ayllon M, Plaza-Florido A, Mendez-Gutierrez A, Altmäe S, Solis-Urra P, Aguilera CM, Catena A, Ortega FB, Esteban-Cornejo I. The effects of a 20-week exercise program on blood-circulating biomarkers related to brain health in overweight or obese children: The ActiveBrains project. JOURNAL OF SPORT AND HEALTH SCIENCE 2023; 12:175-185. [PMID: 36529369 PMCID: PMC10105026 DOI: 10.1016/j.jshs.2022.12.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 09/30/2022] [Accepted: 10/25/2022] [Indexed: 05/28/2023]
Abstract
BACKGROUND Emerging research supports the idea that exercise positively affects neurodevelopment. However, the mechanisms linking exercise with brain health are largely unknown. We aimed to investigate the effect of exercise on (a) blood biomarkers selected based on previous evidence (brain-derived neurotrophic factor, β-hydroxybutyrate (BHB), cathepsin B (CTSB), kynurenine, fibroblast growth factor 21 (FGF21), soluble vascular cell adhesion molecule-1 (sVCAM-1)); and (b) a panel of 92 neurology-related proteins (discovery analysis). We also investigated whether changes in these biomarkers mediate the effects of exercise on brain health (hippocampal structure and function, cognitive performance, and mental health). METHODS We randomized 81 overweight/obese children (10.1 ± 1.1 years, 41% girls) into 2 groups: either 20 weeks of aerobic plus resistance exercise or control. Candidate biomarkers were assessed using enzyme-linked immunosorbent assay (ELISA) for kynurenine, FGF21, and CTSB; colorimetry for β-hydroxybutyrate; and XMap for brain-derived neurotrophic factor and soluble vascular cell adhesion molecule-1. The 92 neurology-related proteins were analyzed by an antibody-based proteomic analysis. RESULTS Our intervention had no significant effect on candidate biomarkers (all p > 0.05). In the discovery analysis, a reduction in circulating macrophage scavenger receptor type-I was observed (standardized differences between groups = -0.3, p = 0.001). This effect was validated using ELISA methods (standardized difference = -0.3, p = 0.01). None of the biomarkers mediated the effects of exercise on brain health. CONCLUSIONS Our study does not support a chronic effect of exercise on candidate biomarkers. We observed that while chronic exercise reduced the levels of macrophage scavenger receptor type-I, it did not mediate the effects of exercise on brain health. Future studies should explore the implications of this novel biomarker for overall health.
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Affiliation(s)
- María Rodriguez-Ayllon
- PROFITH "PROmoting FITness and Health through physical activity" research group, Sport and Health University Research Institute (iMUDS), Department of Physical and Sports Education, Faculty of Sport Sciences, University of Granada, Granada 18071, Spain; Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3015 GD, the Netherlands
| | - Abel Plaza-Florido
- PROFITH "PROmoting FITness and Health through physical activity" research group, Sport and Health University Research Institute (iMUDS), Department of Physical and Sports Education, Faculty of Sport Sciences, University of Granada, Granada 18071, Spain
| | - Andrea Mendez-Gutierrez
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, Granada 18071, Spain
| | - Signe Altmäe
- Department of Biochemistry and Molecular Biology, Faculty of Sciences, University of Granada, Granada 18071, Spain
| | - Patricio Solis-Urra
- PROFITH "PROmoting FITness and Health through physical activity" research group, Sport and Health University Research Institute (iMUDS), Department of Physical and Sports Education, Faculty of Sport Sciences, University of Granada, Granada 18071, Spain; Nuclear Medicine Services, Virgen de Las Nieves University Hospital, Granada 18014, Spain; Faculty of Education and Social Sciences, Universidad Andres Bello, Viña del Mar 2531015, Chile
| | - Concepción M Aguilera
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, Granada 18071, Spain
| | - Andrés Catena
- Department of Experimental Psychology, School of Psychology, University of Granada, Granada 18011, Spain
| | - Francisco B Ortega
- PROFITH "PROmoting FITness and Health through physical activity" research group, Sport and Health University Research Institute (iMUDS), Department of Physical and Sports Education, Faculty of Sport Sciences, University of Granada, Granada 18071, Spain; Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä 40014, Finland; Department of Bioscience and Nutrition, Karolinska Institutet, Huddinge, SE 141 57, Sweden.
| | - Irene Esteban-Cornejo
- PROFITH "PROmoting FITness and Health through physical activity" research group, Sport and Health University Research Institute (iMUDS), Department of Physical and Sports Education, Faculty of Sport Sciences, University of Granada, Granada 18071, Spain
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Natu A, Singh A, Gupta S. Hepatocellular carcinoma: Understanding molecular mechanisms for defining potential clinical modalities. World J Hepatol 2021; 13:1568-1583. [PMID: 34904030 PMCID: PMC8637668 DOI: 10.4254/wjh.v13.i11.1568] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 05/12/2021] [Accepted: 09/08/2021] [Indexed: 02/06/2023] Open
Abstract
Liver cancer is the sixth most commonly occurring cancer and costs millions of lives per year. The diagnosis of hepatocellular carcinoma (HCC) has relied on scanning techniques and serum-based markers such as α-fetoprotein. These measures have limitations due to their detection limits and asymptomatic conditions during the early stages, resulting in late-stage cancer diagnosis where targeted chemotherapy or systemic treatment with sorafenib is offered. However, the aid of conventional therapy for patients in the advanced stage of HCC has limited outcomes. Thus, it is essential to seek a new treatment strategy and improve the diagnostic techniques to manage the disease. Researchers have used the omics profile of HCC patients for sub-classification of tissues into different groups, which has helped us with prognosis. Despite these efforts, a promising target for treatment has not been identified. The hurdle in this situation is genetic and epigenetic variations in the tumor, leading to disparities in response to treatment. Understanding reversible epigenetic changes along with clinical traits help to define new markers for patient categorization and design personalized therapy. Many clinical trials of inhibitors of epigenetic modifiers (also known as epi-drugs) are in progress. Epi-drugs like azacytidine or belinostat are already approved for other cancer treatments. Furthermore, epigenetic changes have also been observed in drug-resistant HCC tumors. In such cases, combinatorial treatment of epi-drugs with systemic therapy or trans-arterial chemoembolization might re-sensitize resistant cells.
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Affiliation(s)
- Abhiram Natu
- Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400085, Maharashtra, India
| | - Anjali Singh
- Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400085, Maharashtra, India
| | - Sanjay Gupta
- Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400085, Maharashtra, India
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Wu Y, Li X, Chen M, Liu Z, Zhang X, Zheng S, Xu X. Phosphorylation of PED/PEA-15 at Ser116 and phosphorylation of p27 at Thr187 indicates a poor prognosis in hepatocellular carcinoma. Oncol Lett 2021; 21:177. [PMID: 33574916 PMCID: PMC7816284 DOI: 10.3892/ol.2021.12438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Accepted: 11/24/2020] [Indexed: 11/06/2022] Open
Abstract
Hepatocellular carcinoma (HCC) constitutes a deadly cancer with a high rate of recurrence and metastasis. Phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes-15 (PED/PEA-15) is a protein involved in the metabolism of glucose that regulates numerous cellular processes, including cell division, apoptosis and migration in numerous types of cancer. However, PED/PEA-15 may act as a tumor-promotor or a tumor-suppressor depending on its phosphorylation status. In the present study, the association between the phosphorylation of PED/PEA-15 at Ser116 [PED/PEA-15(S116)], the phosphorylation of P27 at Thr187 [P-p27(T187)] and the clinicopathological features and prognosis of patients with HCC was assessed. The levels of PED/PEA-15(S116) and P-p27(T187) were determined using immunohistochemistry and western blotting analysis in resected liver tumor tissues and adjacent non-cancerous tissues obtained from 60 patients with HCC as well as normal liver tissues from 12 patients with benign lesions. The association between the expression levels of these two markers and the clinicopathological features of patients with HCC was explored. Using the Kaplan-Meier method, the prognostic value of PED/PEA-15(S116) and P-p27(T187) expression levels was determined. The results demonstrated that the levels of PED/PEA-15(S116) and P-p27(T187) proteins were remarkably higher in the HCC group compared with those in the adjacent and normal tissue groups (both P<0.05). In addition, a moderate positive correlation was observed between the levels of PED/PEA-15(S116) and P-p27(T187) (r=0.434; P<0.05). The levels of these two proteins were associated with the Edmondson grade, Tumor-Node-Metastasis (TNM) stage, vascular invasion and tumor multiplicity (all P<0.05). Furthermore, the Kaplan-Meier analysis results demonstrated that patients with HCC that presented with positive expression of PED/PEA-15(S116) and P-p27(T187) exhibited a dismal prognosis compared with that in patients with negative expression regarding the overall survival (OS), as well as disease-free survival (both P<0.05). Multivariate Cox analysis revealed that the TNM stage (P<0.05), vascular invasion (P<0.05), PED/PEA-15(S116) levels (P<0.001) and P-p27(T187) levels (P<0.05) were independent prognostic factors for OS in patients with HCC. In conclusion the results of the present study demonstrated that PED/PEA-15(S116) and P-p27(T187) levels were upregulated in HCC tissues compared with those in the adjacent and normal tissues; PED/PEA-15(S116) and P-p27(T187) expression may serve as an indicator of a poor prognosis in patients with HCC, suggesting that these proteins may be prospective therapeutic targets for HCC.
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Affiliation(s)
- Yifeng Wu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China.,Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang 310006, P.R. China.,Division of Hepatobiliary and Pancreatic Surgery, Yinzhou Hospital Affiliated to Medical School of Ningbo University, Ningbo, Zhejiang 315040, P.R. China
| | - Xianpeng Li
- Division of Hepatobiliary and Pancreatic Surgery, Yinzhou Hospital Affiliated to Medical School of Ningbo University, Ningbo, Zhejiang 315040, P.R. China
| | - Mingliang Chen
- Division of Hepatobiliary and Pancreatic Surgery, Yinzhou Hospital Affiliated to Medical School of Ningbo University, Ningbo, Zhejiang 315040, P.R. China
| | - Zhikun Liu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China.,Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang 310006, P.R. China
| | - Xuanyu Zhang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China.,Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang 310006, P.R. China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China.,Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang 310006, P.R. China
| | - Xiao Xu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China.,Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang 310006, P.R. China
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