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1
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Shin D, Kim Y, Park J, Kim Y. High-throughput proteomics-guided biomarker discovery of hepatocellular carcinoma. Biomed J 2025; 48:100752. [PMID: 38901798 PMCID: PMC11743302 DOI: 10.1016/j.bj.2024.100752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 06/07/2024] [Accepted: 06/12/2024] [Indexed: 06/22/2024] Open
Abstract
Liver cancer stands as the fifth leading cause of cancer-related deaths globally. Hepatocellular carcinoma (HCC) comprises approximately 85%-90% of all primary liver malignancies. However, only 20-30% of HCC patients qualify for curative therapy, primarily due to the absence of reliable tools for early detection and prognosis of HCC. This underscores the critical need for molecular biomarkers for HCC management. Since proteins reflect disease status directly, proteomics has been utilized in biomarker developments for HCC. In particular, proteomics coupled with liquid chromatography-mass spectrometer (LC-MS) methods facilitate the process of discovering biomarker candidates for diagnosis, prognosis, and therapeutic strategies. In this work, we investigated LC-MS-based proteomics methods through recent reference reviews, with a particular focus on sample preparation and LC-MS methods appropriate for the discovery of HCC biomarkers and their clinical applications. We classified proteomics studies of HCC according to sample types, and we examined the coverage of protein biomarker candidates based on LC-MS methods in relation to study scales and goals. Comprehensively, we proposed protein biomarker candidates categorized by sample types and biomarker types for appropriate clinical use. In this review, we summarized recent LC-MS-based proteomics studies on HCC and proposed potential protein biomarkers. Our findings are expected to expand the understanding of HCC pathogenesis and enhance the efficiency of HCC diagnosis and prognosis, thereby contributing to improved patient outcomes.
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Affiliation(s)
- Dongyoon Shin
- Proteomics Research Team, CHA Institute of Future Medicine, Seongnam, South Korea
| | - Yeongshin Kim
- Proteomics Research Team, CHA Institute of Future Medicine, Seongnam, South Korea; Department of Medical Science, School of Medicine, CHA University, Seongnam, South Korea
| | - Junho Park
- Proteomics Research Team, CHA Institute of Future Medicine, Seongnam, South Korea; Department of Pharmacology, School of Medicine, CHA University, Seongnam, South Korea.
| | - Youngsoo Kim
- Proteomics Research Team, CHA Institute of Future Medicine, Seongnam, South Korea; Department of Medical Science, School of Medicine, CHA University, Seongnam, South Korea.
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2
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Deng K, Xing J, Xu G, Jin B, Wan X, Zheng Y, Du S, Sang X. Urinary biomarkers for hepatocellular carcinoma: current knowledge for clinicians. Cancer Cell Int 2023; 23:239. [PMID: 37833757 PMCID: PMC10571477 DOI: 10.1186/s12935-023-03092-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 10/04/2023] [Indexed: 10/15/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most predominant primary liver cancer, causing many illnesses and deaths worldwide. The insidious clinical presentation, difficulty in early diagnosis, and the highly malignant nature make the prognosis of HCC extremely poor. The complex and heterogeneous pathogenesis of HCC poses significant challenges to developing therapies. Urine-based biomarkers for HCC, including diagnostic, prognostic, and monitoring markers, may be valuable supplements to current tools such as serum α-fetoprotein (AFP) and seem promising for progress in precision medicine. Herein, we reviewed the major urinary biomarkers for HCC and assessed their potential for clinical application. Molecular types, testing platforms, and methods for building multimolecule models in the included studies have shown great diversity, thus providing abundant novel tools for future clinical transformation and applications.
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Affiliation(s)
- Kaige Deng
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China
| | - Jiali Xing
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China
| | - Gang Xu
- Department of Liver Surgery and Liver Transplant Center, West China Hospital of Sichuan University, Chengdu, China
| | - Bao Jin
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China
| | - Xueshuai Wan
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China
| | - Yongchang Zheng
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China.
| | - Shunda Du
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China.
| | - Xinting Sang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China.
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3
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Jordaens S, Zwaenepoel K, Tjalma W, Deben C, Beyers K, Vankerckhoven V, Pauwels P, Vorsters A. Urine biomarkers in cancer detection: A systematic review of preanalytical parameters and applied methods. Int J Cancer 2023; 152:2186-2205. [PMID: 36647333 DOI: 10.1002/ijc.34434] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/25/2022] [Accepted: 12/29/2022] [Indexed: 01/18/2023]
Abstract
The aim of this review was to explore the status of urine sampling as a liquid biopsy for noninvasive cancer research by reviewing used preanalytical parameters and protocols. We searched two main health sciences databases, PubMed and Web of Science. From all eligible publications (2010-2022), information was extracted regarding: (a) study population characteristics, (b) cancer type, (c) urine preanalytics, (d) analyte class, (e) isolation method, (f) detection method, (g) comparator used, (h) biomarker type, (i) conclusion and (j) sensitivity and specificity. The search query identified 7835 records, of which 924 unique publications remained after screening the title, abstract and full text. Our analysis demonstrated that many publications did not report information about the preanalytical parameters of their urine samples, even though several other studies have shown the importance of standardization of sample handling. Interestingly, it was noted that urine is used for many cancer types and not just cancers originating from the urogenital tract. Many different types of relevant analytes have been shown to be found in urine. Additionally, future considerations and recommendations are discussed: (a) the heterogeneous nature of urine, (b) the need for standardized practice protocols and (c) the road toward the clinic. Urine is an emerging liquid biopsy with broad applicability in different analytes and several cancer types. However, standard practice protocols for sample handling and processing would help to elaborate the clinical utility of urine in cancer research, detection and disease monitoring.
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Affiliation(s)
- Stephanie Jordaens
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Wilrijk, Belgium.,Novosanis NV, Wijnegem, Belgium
| | - Karen Zwaenepoel
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Wilrijk, Belgium.,Laboratory of Pathological Anatomy, Antwerp University Hospital (UZA), Edegem, Belgium
| | - Wiebren Tjalma
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Wilrijk, Belgium.,Multidisciplinary Breast Clinic, Gynecological Oncology Unit, Department of Obstetrics and Gynecology, Antwerp University Hospital (UZA), Edegem, Belgium
| | - Christophe Deben
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Wilrijk, Belgium
| | | | - Vanessa Vankerckhoven
- Novosanis NV, Wijnegem, Belgium.,Center for Evaluation of Vaccination (CEV), Vaccine & Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
| | - Patrick Pauwels
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Wilrijk, Belgium.,Laboratory of Pathological Anatomy, Antwerp University Hospital (UZA), Edegem, Belgium
| | - Alex Vorsters
- Center for Evaluation of Vaccination (CEV), Vaccine & Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
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4
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Noninvasive urinary protein signatures associated with colorectal cancer diagnosis and metastasis. Nat Commun 2022; 13:2757. [PMID: 35589723 PMCID: PMC9119985 DOI: 10.1038/s41467-022-30391-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 04/25/2022] [Indexed: 12/24/2022] Open
Abstract
Currently, imaging, fecal immunochemical tests (FITs) and serum carcinoembryonic antigen (CEA) tests are not adequate for the early detection and evaluation of metastasis and recurrence in colorectal cancer (CRC). To comprehensively identify and validate more accurate noninvasive biomarkers in urine, we implement a staged discovery-verification-validation pipeline in 657 urine and 993 tissue samples from healthy controls and CRC patients with a distinct metastatic risk. The generated diagnostic signature combined with the FIT test reveals a significantly increased sensitivity (+21.2% in the training set, +43.7% in the validation set) compared to FIT alone. Moreover, the generated metastatic signature for risk stratification correctly predicts over 50% of CEA-negative metastatic patients. The tissue validation shows that elevated urinary protein biomarkers reflect their alterations in tissue. Here, we show promising urinary protein signatures and provide potential interventional targets to reliably detect CRC, although further multi-center external validation is needed to generalize the findings. More sensitive and specific non-invasive biomarkers are desired for early detection of cancer. Here, the authors show a protein signature in the urine that increases sensitivity for colorectal cancer detection when combined with fecal immunochemical tests and corrects diagnosis in some fecal immunochemical tests-negative patients.
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5
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Moving beyond the Tip of the Iceberg: DJ-1 Implications in Cancer Metabolism. Cells 2022; 11:cells11091432. [PMID: 35563738 PMCID: PMC9103122 DOI: 10.3390/cells11091432] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 04/10/2022] [Accepted: 04/20/2022] [Indexed: 12/13/2022] Open
Abstract
DJ-1, also called Parkinson’s protein 7 (PARK7), is ubiquitously expressed and plays multiple actions in different physiological and, especially, pathophysiological processes, as evidenced by its identification in neurodegenerative diseases and its high expression in different types of cancer. To date, the exact activity of DJ-1 in carcinogenesis has not been fully elucidated, however several recent studies disclosed its involvement in regulating fundamental pathways involved in cancer onset, development, and metastatization. At this purpose, we have dissected the role of DJ-1 in maintaining the transformed phenotype, survival, drug resistance, metastasis formation, and differentiation in cancer cells. Moreover, we have discussed the role of DJ-1 in controlling the redox status in cancer cells, along with the ability to attenuate reactive oxygen species (ROS)-dependent cell death, as well as to mediate ferropotosis. Finally, a mention to the development of therapeutic strategies targeting DJ-1 has been done. We have reported the most recent studies, aiming to shed light on the role played by DJ-1 in different cancer aspects and create the foundation for moving beyond the tip of the iceberg.
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Singh P, Kumari M, Bal A, Srinivasan R, Ghosh S. Heat shock protein 60 is a disease-associated sialoglycoprotein in human non-small cell lung cancer. Biol Chem 2021; 401:969-983. [PMID: 32049642 DOI: 10.1515/hsz-2019-0352] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 02/03/2020] [Indexed: 01/23/2023]
Abstract
The diagnostic and therapeutic potential of Maackia amurensis agglutinin (MAA) have been reported in various malignancies. Earlier, we have found that MAA specifically interacted with human non-small cell lung-cancer (NSCLC) cells and induced apoptosis in these cells. The present study was designed to identify M. amurensis leukoagglutinin (MAL-I, one of the components of MAA, having the same carbohydrate specificity as MAA) interacting membrane sialoglycoprotein(s) of two subtypes of human NSCLC cell lines. Nine proteins were identified using two-dimensional (2D)-polyacrylamide gel electrophoresis (PAGE) followed by MAL-I-overlay transblotting and matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS). Among these proteins, HSP60 was selected for further characterization. The sialoglycoprotein nature of membrane-HSP60 of NSCLC cell lines was confirmed by its reduced reactivity with MAL-I in Western blots in the presence of GM2 and by dual staining of the cell lines with MAL-I and HSP60-antibody. These findings were further substantiated by enzymatic analysis of membrane-HSP60 as well as in-silico evidence regarding this protein. Our observations were validated by immunohistochemical analysis of both subtypes of NSCLC tissue sections. Membrane-HSP60 was found to be involved in the inhibition of MAL-I-induced morphological alteration of NSCLC cells and also in the proliferation and migration of these cells, indicating the probable role of sialylated membrane-HSP60 in this disease.
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Affiliation(s)
- Praveen Singh
- Department of Experimental Medicine and Biotechnology, PGIMER, Chandigarh 160012, India
| | - Munmun Kumari
- Department of Experimental Medicine and Biotechnology, PGIMER, Chandigarh 160012, India
| | - Amanjit Bal
- Department of Histopathology, PGIMER, Chandigarh 160012, India
| | - Radhika Srinivasan
- Department of Cytology and Gynecological Pathology, PGIMER, Chandigarh 160012, India
| | - Sujata Ghosh
- Department of Experimental Medicine and Biotechnology, PGIMER, Chandigarh 160012, India
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7
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Guan MC, Ouyang W, Wang MD, Liang L, Li N, Fu TT, Shen F, Lau WY, Xu QR, Huang DS, Zhu H, Yang T. Biomarkers for hepatocellular carcinoma based on body fluids and feces. World J Gastrointest Oncol 2021; 13:351-365. [PMID: 34040698 PMCID: PMC8131906 DOI: 10.4251/wjgo.v13.i5.351] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/18/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Novel non-/minimally-invasive and effective approaches are urgently needed to supplement and improve current strategies for diagnosis and management of hepatocellular carcinoma (HCC). Overwhelming evidence from published studies on HCC has documented that multiple molecular biomarkers detected in body fluids and feces can be utilized in early-diagnosis, predicting responses to specific therapies, evaluating prognosis before or after therapy, as well as serving as novel therapeutic targets. Detection and analysis of proteins, metabolites, circulating nucleic acids, circulating tumor cells, and extracellular vesicles in body fluids (e.g., blood and urine) and gut microbiota (e.g., in feces) have excellent capabilities to improve different aspects of management of HCC. Numerous studies have been devoted in identifying more promising candidate biomarkers and therapeutic targets for diagnosis, treatment, and monitoring responses of HCC to conventional therapies, most of which may improve diagnosis and management of HCC in the future. This review aimed to summarize recent advances in utilizing these biomarkers in HCC and discuss their clinical significance.
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Affiliation(s)
- Ming-Cheng Guan
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Wei Ouyang
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Ming-Da Wang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital (Navy Medical University), Second Military Medical University, Shanghai 200438, China
| | - Lei Liang
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medical College), Hangzhou 310000, Zhejiang Province, China
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
| | - Na Li
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Ting-Ting Fu
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Feng Shen
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital (Navy Medical University), Second Military Medical University, Shanghai 200438, China
| | - Wan-Yee Lau
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital (Navy Medical University), Second Military Medical University, Shanghai 200438, China
- Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Qiu-Ran Xu
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medical College), Hangzhou 310000, Zhejiang Province, China
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
| | - Dong-Sheng Huang
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medical College), Hangzhou 310000, Zhejiang Province, China
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
| | - Hong Zhu
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Tian Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital (Navy Medical University), Second Military Medical University, Shanghai 200438, China
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medical College), Hangzhou 310000, Zhejiang Province, China
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
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8
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miR-618 rs2682818 C>A polymorphism decreases Hirschsprung disease risk in Chinese children. Biosci Rep 2020; 40:223573. [PMID: 32364585 PMCID: PMC7214396 DOI: 10.1042/bsr20193989] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 04/27/2020] [Accepted: 04/30/2020] [Indexed: 12/02/2022] Open
Abstract
MicroRNAs (miRNAs) are endogenous non-coding small RNAs that play an important role in the development of many malignant tumors. In addition, recent studies have reported that single nucleotide polymorphisms (SNPs) located in the miRNA functional region was inextricably linked to tumor susceptibility. In the present study, we investigated the susceptibility between miR-618 rs2682818 C>A and Hirschsprung disease (HSCR) in the Southern Chinese population (1470 patients and 1473 controls). Odds ratios (ORs) and 95% confidence intervals (CIs) were used for estimating the strength of interrelation between them. We found that the CA/AA genotypes of miR-618 rs2682818 were associated with a decreased risk of HSCR when compared with the CC genotype (OR = 0.84, 95% CI = 0.72–0.99, P=0.032). Based on the stratified analysis of HSCR subtypes, the rs2682818 CA/AA genotypes were able to significantly lessen the risk of HSCR compared with CC genotype in patients with long-segment HSCR (adjusted OR = 0.70, 95% CI = 0.52–0.93, P=0.013). In conclusion, our results indicated that the miR-618 rs2682818 C>A polymorphism was associated with a reduced risk of HSCR in Chinese children, especially in patients with long-segment HSCR (L-HSCR) subtype.
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Jin W. Novel Insights into PARK7 (DJ-1), a Potential Anti-Cancer Therapeutic Target, and Implications for Cancer Progression. J Clin Med 2020; 9:jcm9051256. [PMID: 32357493 PMCID: PMC7288009 DOI: 10.3390/jcm9051256] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 04/23/2020] [Accepted: 04/24/2020] [Indexed: 12/28/2022] Open
Abstract
The expression of PARK7 is upregulated in various types of cancer, suggesting its potential role as a critical regulator of the pathogenesis of cancer and in the treatment of cancer and neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, and Huntington disease. PARK7 activates various intracellular signaling pathways that have been implicated in the induction of tumor progression, which subsequently enhances tumor initiation, continued proliferation, metastasis, recurrence, and resistance to chemotherapy. Additionally, secreted PARK7 has been identified as a high-risk factor for the pathogenesis and survival of various cancers. This review summarizes the current understanding of the correlation between the expression of PARK7 and tumor progression.
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Affiliation(s)
- Wook Jin
- Laboratory of Molecular Disease and Cell Regulation, Department of Biochemistry, School of Medicine, Gachon University, Incheon 406-840, Korea
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10
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Heat Shock Protein 60 (HSP60) Serves as a Potential Target for the Sensitization of Chemoresistant Ovarian Cancer Cells. Reprod Sci 2020; 27:1030-1036. [DOI: 10.1007/s43032-019-00089-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 08/13/2019] [Indexed: 10/24/2022]
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11
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Pan WY, Zeng JH, Wen DY, Wang JY, Wang PP, Chen G, Feng ZB. Oncogenic value of microRNA-15b-5p in hepatocellular carcinoma and a bioinformatics investigation. Oncol Lett 2018; 17:1695-1713. [PMID: 30675229 PMCID: PMC6341845 DOI: 10.3892/ol.2018.9748] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 10/12/2018] [Indexed: 02/07/2023] Open
Abstract
miR-15b-5p has frequently been reported to function as a biomarker in some malignancies; however, the function of miR-15b-5p in hepatocellular carcinoma (HCC) and its molecular mechanism are still not well understood. The present study was designed to confirm the clinical value of miR-15b-5p and further explore its underlying molecular mechanism. A comprehensive investigation of the clinical value of miR-15b-5p in HCC was investigated by data mining The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets as well as literature. In addition, intersected target genes of miR-15b-5p were predicted using the miRWalk database and differentially expressed genes of HCC from TCGA. Furthermore, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were carried out. Then, a protein-protein interaction network (PPI) was constructed to reveal the interactions between some hub target genes of miR-15b-5p. The miR-15b-5p expression level in HCC was predominantly overexpressed compared with non-HCC tissues samples (SMD=0.618, 95% CI: 0.207, 1.029; P<0.0001) based on 991 HCC and 456 adjacent non-HCC tissue samples. The pooled summary receiver operator characteristic (SROC) of miR-15b-5p was 0.81 (Q*=0.74), and the pooled sensitivity and specificity of miR-15b-5p in HCC were 72% (95% CI: 69–75%) and 68% (95% CI: 65–72%), respectively. Bioinformatically, 225 overlapping genes were selected as prospective target genes of miR-15b-5p in HCC, and profoundly enriched GO terms and KEGG pathway investigation in silico demonstrated that the target genes were associated with prostate cancer, proximal tubule bicarbonate reclamation, heart trabecula formation, extracellular space, and interleukin-1 receptor activity. Five genes (ACACB, RIPK4, MAP2K1, TLR4 and IGF1) were defined as hub genes from the PPI network. The high expression of miR-15b-5p could play an essential part in hepatocarcinogenesis through diverse regulation approaches.
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Affiliation(s)
- Wen-Ya Pan
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Jiang-Hui Zeng
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Dong-Yue Wen
- Department of Ultrasonography, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Jie-Yu Wang
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Peng-Peng Wang
- Department of Nursing, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Gang Chen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Zhen-Bo Feng
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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12
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Zhu Y, Zhu J, Lu C, Zhang Q, Xie W, Sun P, Dong X, Yue L, Sun Y, Yi X, Zhu T, Ruan G, Aebersold R, Huang S, Guo T. Identification of Protein Abundance Changes in Hepatocellular Carcinoma Tissues Using PCT-SWATH. Proteomics Clin Appl 2018; 13:e1700179. [PMID: 30365225 DOI: 10.1002/prca.201700179] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 10/16/2018] [Indexed: 12/16/2022]
Abstract
PURPOSE To rapidly identify protein abundance changes in biopsy-level fresh-frozen hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN The pressure-cycling technology (PCT) is applied and sequential window acquisition of all theoretical mass spectra (SWATH-MS) workflow is optimized to analyze 38 biopsy-level tissue samples from 19 HCC patients. Each proteome is analyzed with 45 min LC gradient. MCM7 is validated using immunohistochemistry (IHC). RESULTS A total of 11 787 proteotypic peptides from 2579 SwissProt proteins are quantified with high confidence. The coefficient of variation (CV) of peptide yield using PCT is 32.9%, and the R2 of peptide quantification is 0.9729. Five hundred forty-one proteins showed significant abundance change between the tumor area and its adjacent benign area. From 24 upregulated pathways and 13 suppressed ones, enhanced biomolecule synthesis and suppressed small molecular metabolism in liver tumor tissues are observed. Protein changes based on α-fetoprotein expression and hepatitis B virus infection are further analyzed. The data altogether highlight 16 promising tumor marker candidates. The upregulation of minichromosome maintenance complex component 7 (MCM7) is further observed in multiple HCC tumor tissues by IHC. CONCLUSIONS AND CLINICAL RELEVANCE The practicality of rapid proteomic analysis of biopsy-level fresh-frozen HCC tissue samples with PCT-SWATH has been demonstrated and promising tumor marker candidates including MCM7 are identified.
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Affiliation(s)
- Yi Zhu
- Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang, P. R. China.,Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule (ETH) Zurich, Zurich, Switzerland
| | - Jiang Zhu
- Center for Stem Cell Research and Application, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China
| | - Cong Lu
- Center for Stem Cell Research and Application, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China
| | - Qiushi Zhang
- Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang, P. R. China
| | - Wei Xie
- Center for Stem Cell Research and Application, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China
| | - Ping Sun
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China
| | - Xiaochuan Dong
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China
| | - Liang Yue
- Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang, P. R. China
| | - Yaoting Sun
- Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang, P. R. China
| | - Xiao Yi
- Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang, P. R. China
| | - Tiansheng Zhu
- Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang, P. R. China
| | - Guan Ruan
- Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang, P. R. China
| | - Ruedi Aebersold
- Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule (ETH) Zurich, Zurich, Switzerland.,Faculty of Science, University of Zürich, Zürich, Switzerland
| | - Shi'ang Huang
- Center for Stem Cell Research and Application, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China
| | - Tiannan Guo
- Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang, P. R. China.,Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule (ETH) Zurich, Zurich, Switzerland
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13
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Targeting Heat Shock Proteins in Cancer: A Promising Therapeutic Approach. Int J Mol Sci 2017; 18:ijms18091978. [PMID: 28914774 PMCID: PMC5618627 DOI: 10.3390/ijms18091978] [Citation(s) in RCA: 325] [Impact Index Per Article: 40.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Revised: 09/01/2017] [Accepted: 09/05/2017] [Indexed: 12/12/2022] Open
Abstract
Heat shock proteins (HSPs) are a large family of chaperones that are involved in protein folding and maturation of a variety of "client" proteins protecting them from degradation, oxidative stress, hypoxia, and thermal stress. Hence, they are significant regulators of cellular proliferation, differentiation and strongly implicated in the molecular orchestration of cancer development and progression as many of their clients are well established oncoproteins in multiple tumor types. Interestingly, tumor cells are more HSP chaperonage-dependent than normal cells for proliferation and survival because the oncoproteins in cancer cells are often misfolded and require augmented chaperonage activity for correction. This led to the development of several inhibitors of HSP90 and other HSPs that have shown promise both preclinically and clinically in the treatment of cancer. In this article, we comprehensively review the roles of some of the important HSPs in cancer, and how targeting them could be efficacious, especially when traditional cancer therapies fail.
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14
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Chen S, Chen H, Gao S, Qiu S, Zhou H, Yu M, Tu J. Differential expression of plasma microRNA-125b in hepatitis B virus-related liver diseases and diagnostic potential for hepatitis B virus-induced hepatocellular carcinoma. Hepatol Res 2017; 47:312-320. [PMID: 27152955 DOI: 10.1111/hepr.12739] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Revised: 04/08/2016] [Accepted: 05/02/2016] [Indexed: 12/18/2022]
Abstract
AIM Acting as a tumor suppressor, microRNA (miR)-125b shows aberrant low expression in hepatocellular carcinoma (HCC), and researchers have found that its dysregulation has a close relationship with hepatitis B virus (HBV) infection. Here, we investigated the expression profile of this miRNA in the plasma of healthy subjects and patients with chronic HBV-related liver diseases in order to confirm the feasibility of this circulating miRNA as a differential diagnostic biomarker for HBV-induced HCC (HBV-HCC). METHODS A total of 242 individuals were enrolled in this study. The expression levels of plasma miR-125b were examined using quantitative real-time polymerase chain reaction technology. RESULTS The levels of plasma miR-125b were remarkably decreased in HBV-HCC patients compared to healthy controls and HBV subjects without HCC (all P < 0.001), and the low plasma miR-125b levels in HBV-HCC patients were associated with higher prevalence of metastasis (P = 0.021). The receiver-operating characteristic curve analyses indicated that plasma miR-125b presented a high accuracy (area under the curve = 0.891, 0.958, 0.958) for diagnosing HBV-HCC cases from healthy controls and patients with chronic hepatitis B and HBV-related liver cirrhosis, respectively. In addition, our study found that the expression levels of plasma miR-125b in HBV patients without HCC were higher than those in healthy subjects (P < 0.001); it yielded an area under the curve of 0.691 in discriminating patients with chronic HBV infection who were negative for HCC from healthy controls. CONCLUSION The measurement of plasma-based miR-125b holds promise as a diagnostic marker for HBV-HCC differential diagnosis and for chronic HBV viral infection. Those HBV-infected individuals with increased risk of HCC would be detected early through monitoring the changes in this circulating miRNA.
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Affiliation(s)
- Shanshan Chen
- Department of Clinical Laboratory Medicine and Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Hao Chen
- Department of Clinical Laboratory Medicine and Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Shanshan Gao
- Department of Clinical Laboratory Medicine and Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Shili Qiu
- Department of Clinical Laboratory Medicine and Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Hu Zhou
- Department of Clinical Laboratory Medicine and Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Mingxia Yu
- Department of Clinical Laboratory Medicine and Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Jiancheng Tu
- Department of Clinical Laboratory Medicine and Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China
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15
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Wu J, Liu T, Rios Z, Mei Q, Lin X, Cao S. Heat Shock Proteins and Cancer. Trends Pharmacol Sci 2016; 38:226-256. [PMID: 28012700 DOI: 10.1016/j.tips.2016.11.009] [Citation(s) in RCA: 457] [Impact Index Per Article: 50.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 10/23/2016] [Accepted: 11/11/2016] [Indexed: 12/21/2022]
Abstract
Heat shock proteins (HSPs) constitute a large family of proteins involved in protein folding and maturation whose expression is induced by heat shock or other stressors. The major groups are classified based on their molecular weights and include HSP27, HSP40, HSP60, HSP70, HSP90, and large HSPs. HSPs play a significant role in cellular proliferation, differentiation, and carcinogenesis. In this article we comprehensively review the roles of major HSPs in cancer biology and pharmacology. HSPs are thought to play significant roles in the molecular mechanisms leading to cancer development and metastasis. HSPs may also have potential clinical uses as biomarkers for cancer diagnosis, for assessing disease progression, or as therapeutic targets for cancer therapy.
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Affiliation(s)
- Jianming Wu
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Tuoen Liu
- Department of Biomedical Sciences, West Virginia School of Osteopathic Medicine, Lewisburg, WV 24901, USA.
| | - Zechary Rios
- University of Illinois College of Medicine at Chicago, Chicago, IL 60612, USA
| | - Qibing Mei
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Xiukun Lin
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Shousong Cao
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China.
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16
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Nie W, Yan L, Lee YH, Guha C, Kurland IJ, Lu H. Advanced mass spectrometry-based multi-omics technologies for exploring the pathogenesis of hepatocellular carcinoma. MASS SPECTROMETRY REVIEWS 2016; 35:331-349. [PMID: 24890331 DOI: 10.1002/mas.21439] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/13/2013] [Revised: 04/17/2014] [Accepted: 04/17/2014] [Indexed: 06/03/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the primary hepatic malignancies and is the third most common cause of cancer related death worldwide. Although a wealth of knowledge has been gained concerning the initiation and progression of HCC over the last half century, efforts to improve our understanding of its pathogenesis at a molecular level are still greatly needed, to enable clinicians to enhance the standards of the current diagnosis and treatment of HCC. In the post-genome era, advanced mass spectrometry driven multi-omics technologies (e.g., profiling of DNA damage adducts, RNA modification profiling, proteomics, and metabolomics) stand at the interface between chemistry and biology, and have yielded valuable outcomes from the study of a diversity of complicated diseases. Particularly, these technologies are being broadly used to dissect various biological aspects of HCC with the purpose of biomarker discovery, interrogating pathogenesis as well as for therapeutic discovery. This proof of knowledge-based critical review aims at exploring the selected applications of those defined omics technologies in the HCC niche with an emphasis on translational applications driven by advanced mass spectrometry, toward the specific clinical use for HCC patients. This approach will enable the biomedical community, through both basic research and the clinical sciences, to enhance the applicability of mass spectrometry-based omics technologies in dissecting the pathogenesis of HCC and could lead to novel therapeutic discoveries for HCC.
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Affiliation(s)
- Wenna Nie
- Chongqing University Innovative Drug Research Centre, School of Chemistry and Chemical Engineering, Chongqing, 401331, PR China
| | - Leyu Yan
- Chongqing University Innovative Drug Research Centre, School of Chemistry and Chemical Engineering, Chongqing, 401331, PR China
| | - Yie H Lee
- Interdisciplinary Research Group in Infectious Diseases, Singapore-MIT Alliance for Research & Technology, Singapore, 138602, Singapore
| | - Chandan Guha
- Department of Radiation Oncology, Montefiore Medical Center, New York, New York, 10461
- Department of Medicine, Albert Einstein College of Medicine, New York, New York, 10461
| | - Irwin J Kurland
- Stable Isotope and Metabolomics Core Facility, Diabetes Research and Training Center, Department of Medicine, Albert Einstein College of Medicine, New York, New York, 10461
| | - Haitao Lu
- Chongqing University Innovative Drug Research Centre, School of Chemistry and Chemical Engineering, Chongqing, 401331, PR China
- Tissue Repair and Regeneration Program, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, QLD, 4059, Australia
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Falcon-Perez JM, Royo F. Circulating RNA: looking at the liver through a frosted glass. Biomarkers 2015; 20:339-54. [DOI: 10.3109/1354750x.2015.1101785] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- J. M. Falcon-Perez
- Metabolomics Unit, CIC bioGUNE, CIBERehd, Technology Park of Bizkaia, Derio, Bizkaia, Spain and
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - F. Royo
- Metabolomics Unit, CIC bioGUNE, CIBERehd, Technology Park of Bizkaia, Derio, Bizkaia, Spain and
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18
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Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide. Hepatocarcinogenesis is a complex, multistep process. It is now recognized that HCC is a both genetic and epigenetic disease; genetic and epigenetic components cooperate at all stages of hepatocarcinogenesis. Epigenetic changes involve aberrant DNA methylation, posttranslational histone modifications and aberrant expression of microRNAs all of which can affect the expression of oncogenes, tumor suppressor genes and other tumor-related genes and alter the pathways in cancer development. Several risk factors for HCC, including hepatitis B and C virus infections and exposure to the chemical carcinogen aflatoxin B1 have been found to influence epigenetic changes. Their interactions could play an important role in the initiation and progression of HCC. Discovery and detection of biomarkers for epigenetic changes is a promising area for early diagnosis and risk prediction of HCC.
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Affiliation(s)
- Yujing Zhang
- Department of Environmental Health Sciences, Mailman School of Public Health and Cancer Center of Columbia University, Room 1608, 630 West 168th Street, New York, NY, 10032, USA,
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Shadrach KG, Rayborn ME, Hollyfield JG, Bonilha VL. DJ-1-dependent regulation of oxidative stress in the retinal pigment epithelium (RPE). PLoS One 2013; 8:e67983. [PMID: 23844142 PMCID: PMC3699467 DOI: 10.1371/journal.pone.0067983] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Accepted: 05/23/2013] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND DJ-1 is found in many tissues, including the brain, where it has been extensively studied due to its association with Parkinson's disease. DJ-1 functions as a redox-sensitive molecular chaperone and transcription regulator that robustly protects cells from oxidative stress. METHODOLOGY Retinal pigment epithelial (RPE) cultures were treated with H2O2 for various times followed by biochemical and immunohistological analysis. Cells were transfected with adenoviruses carrying the full-length human DJ-1 cDNA and a mutant construct, which has the cysteine residues at amino acid 46, 53 and 106 mutated to serine (C to S) prior to stress experiments. DJ-1 localization, levels of expression and reactive oxygen species (ROS) generation were also analyzed in cells expressing exogenous DJ-1 under baseline and oxidative stress conditions. The presence of DJ-1 and oxidized DJ-1 was evaluated in human RPE total lysates. The distribution of DJ-1 was assessed in AMD and non-AMD cryosectionss and in isolated human Bruch's membrane (BM)/choroid from AMD eyes. PRINCIPAL FINDINGS DJ-1 in RPE cells under baseline conditions, displays a diffuse cytoplasmic and nuclear staining. After oxidative challenge, more DJ-1 was associated with mitochondria. Increasing concentrations of H2O2 resulted in a dose-dependent increase in DJ-1. Overexpression of DJ-1 but not the C to S mutant prior to exposure to oxidative stress led to significant decrease in the generation of ROS. DJ-1 and oxDJ-1 intensity of immunoreactivity was significantly higher in the RPE lysates from AMD eyes. More DJ-1 was localized to RPE cells from AMD donors with geographic atrophy and DJ-1 was also present in isolated human BM/choroid from AMD eyes. CONCLUSIONS/SIGNIFICANCE DJ-1 regulates RPE responses to oxidative stress. Most importantly, increased DJ-1 expression prior to oxidative stress leads to decreased generation of ROS, which will be relevant for future studies of AMD since oxidative stress is a known factor affecting this disease.
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Affiliation(s)
- Karen G. Shadrach
- Department of Ophthalmic Research, The Cole Eye Institute, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America
| | - Mary E. Rayborn
- Department of Ophthalmic Research, The Cole Eye Institute, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America
| | - Joe G. Hollyfield
- Department of Ophthalmic Research, The Cole Eye Institute, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America
| | - Vera L. Bonilha
- Department of Ophthalmic Research, The Cole Eye Institute, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America
- * E-mail:
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