|
1
|
Ciccarone F, Ciriolo MR. Reprogrammed mitochondria: a central hub of cancer cell metabolism. Biochem Soc Trans 2024; 52:1305-1315. [PMID: 38716960 DOI: 10.1042/bst20231090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 04/22/2024] [Accepted: 04/26/2024] [Indexed: 06/27/2024]
Abstract
Mitochondria represent the metabolic hub of normal cells and play this role also in cancer but with different functional purposes. While cells in differentiated tissues have the prerogative of maintaining basal metabolism and support the biosynthesis of specialized products, cancer cells have to rewire the metabolic constraints imposed by the differentiation process. They need to balance the bioenergetic supply with the anabolic requirements that entail the intense proliferation rate, including nucleotide and membrane lipid biosynthesis. For this aim, mitochondrial metabolism is reprogrammed following the activation of specific oncogenic pathways or due to specific mutations of mitochondrial proteins. The main process leading to mitochondrial metabolic rewiring is the alteration of the tricarboxylic acid cycle favoring the appropriate orchestration of anaplerotic and cataplerotic reactions. According to the tumor type or the microenvironmental conditions, mitochondria may decouple glucose catabolism from mitochondrial oxidation in favor of glutaminolysis or disable oxidative phosphorylation for avoiding harmful production of free radicals. These and other metabolic settings can be also determined by the neo-production of oncometabolites that are not specific for the tissue of origin or the accumulation of metabolic intermediates able to boost pro-proliferative metabolism also impacting epigenetic/transcriptional programs. The full characterization of tumor-specific mitochondrial signatures may provide the identification of new biomarkers and therapeutic opportunities based on metabolic approaches.
Collapse
Affiliation(s)
- Fabio Ciccarone
- Department of Biology, University of Rome 'Tor Vergata', 00133 Rome, Italy
- IRCCS San Raffaele Roma, 00166 Rome, Italy
| | - Maria Rosa Ciriolo
- Department of Biology, University of Rome 'Tor Vergata', 00133 Rome, Italy
- IRCCS San Raffaele Roma, 00166 Rome, Italy
| |
Collapse
|
|
2
|
Shin D, Kim Y, Park J, Kim Y. High-throughput proteomics-guided biomarker discovery of hepatocellular carcinoma. Biomed J 2024; 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] [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.
Collapse
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.
| |
Collapse
|
|
3
|
Xiao QH, Li ZZ, Ren L, Wang SY, Li XQ, Bai HX, Qiao RZ, Tang N, Liu WJ, Wang JM, Ma GY, Dong DC, Wu KH, Cao W. α-Glucan derivatives as selective blockers of aldolase A: Computer-aided structure optimization and the effects on HCC. Carbohydr Polym 2024; 325:121566. [PMID: 38008473 DOI: 10.1016/j.carbpol.2023.121566] [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: 08/01/2023] [Revised: 10/16/2023] [Accepted: 11/04/2023] [Indexed: 11/28/2023]
Abstract
Aldolase A (ALDOA) promotes hepatocellular carcinoma (HCC) growth and is a potential therapeutic target. A previous study found an α-D-glucan (α-D-(1,6)-Glcp-α-D-(1,4)-Glcp, 10.0:1.0), named HDPS-4II, that could specifically inhibit ALDOA but its activity was not high enough. In this study, the derivatives of α-D-glucan binding to ALDOA were optimized using molecular docking, and its sulfated modification demonstrated the highest affinity with ALDOA among sulfated, carboxylated, and aminated derivatives. Sulfated HDPS-4II and dextrans with different molecular weights (1000 Da, 3000 Da, and 4000 Da) were prepared. Using MST assay, 3-O-sulfated HDPS-4II (SHDPS-4II) and 1000 Da dextran (SDextran1) showed higher affinities to ALDOA with Kd of 1.83 μM and 85.04 μM, respectively. Furthermore, SHDPS-4II and SDextran1 markedly inhibited the proliferation of HCC cells both in vitro and in vivo by blocking ALDOA. These results demonstrate that sulfated modification of α-D-glucans could enhance their affinities with ALDOA and anti-HCC effects.
Collapse
Affiliation(s)
- Qian-Han Xiao
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China
| | - Ze-Zhi Li
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China
| | - Li Ren
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China
| | - Shu-Yao Wang
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China
| | - Xiao-Qiang Li
- Department of Pharmacology, Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, School of Pharmacy, Air Force Medical University, Xi'an, China
| | - Hong-Xin Bai
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China
| | - Rui-Zhi Qiao
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China
| | - Na Tang
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China
| | - Wen-Juan Liu
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China
| | - Jing-Mei Wang
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China
| | - Guang-Yuan Ma
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China
| | - Dian-Chao Dong
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China
| | - Ke-Han Wu
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China
| | - Wei Cao
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China; Department of Pharmacology, Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, School of Pharmacy, Air Force Medical University, Xi'an, China.
| |
Collapse
|
|
4
|
Wang K, Luo L, Fu S, Wang M, Wang Z, Dong L, Wu X, Dai L, Peng Y, Shen G, Chen HN, Nice EC, Wei X, Huang C. PHGDH arginine methylation by PRMT1 promotes serine synthesis and represents a therapeutic vulnerability in hepatocellular carcinoma. Nat Commun 2023; 14:1011. [PMID: 36823188 PMCID: PMC9950448 DOI: 10.1038/s41467-023-36708-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 02/14/2023] [Indexed: 02/25/2023] Open
Abstract
Serine synthesis is crucial for tumor growth and survival, but its regulatory mechanism in cancer remains elusive. Here, using integrative metabolomics and transcriptomics analyses, we show a heterogeneity between metabolite and transcript profiles. Specifically, the level of serine in hepatocellular carcinoma (HCC) tissues is increased, whereas the expression of phosphoglycerate dehydrogenase (PHGDH), the first rate-limiting enzyme in serine biosynthesis pathway, is markedly downregulated. Interestingly, the increased serine level is obtained by enhanced PHGDH catalytic activity due to protein arginine methyltransferase 1 (PRMT1)-mediated methylation of PHGDH at arginine 236. PRMT1-mediated PHGDH methylation and activation potentiates serine synthesis, ameliorates oxidative stress, and promotes HCC growth in vitro and in vivo. Furthermore, PRMT1-mediated PHGDH methylation correlates with PHGDH hyperactivation and serine accumulation in human HCC tissues, and is predictive of poor prognosis of HCC patients. Notably, blocking PHGDH methylation with a TAT-tagged nonmethylated peptide inhibits serine synthesis and restrains HCC growth in an HCC patient-derived xenograft (PDX) model and subcutaneous HCC cell-derived xenograft model. Overall, our findings reveal a regulatory mechanism of PHGDH activity and serine synthesis, and suggest PHGDH methylation as a potential therapeutic vulnerability in HCC.
Collapse
Affiliation(s)
- Kui Wang
- West China School of Basic Medical Sciences & Forensic Medicine, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China
| | - Li Luo
- Center for Reproductive Medicine, Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, 610041, PR China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610041, PR China
| | - Shuyue Fu
- West China School of Basic Medical Sciences & Forensic Medicine, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China
| | - Mao Wang
- West China School of Basic Medical Sciences & Forensic Medicine, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China
| | - Zihao Wang
- Department of Gastrointestinal Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China
| | - Lixia Dong
- West China School of Basic Medical Sciences & Forensic Medicine, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China
| | - Xingyun Wu
- West China School of Basic Medical Sciences & Forensic Medicine, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China
| | - Lunzhi Dai
- West China School of Basic Medical Sciences & Forensic Medicine, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China
| | - Yong Peng
- West China School of Basic Medical Sciences & Forensic Medicine, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China
| | - Guobo Shen
- West China School of Basic Medical Sciences & Forensic Medicine, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China
| | - Hai-Ning Chen
- Department of Gastrointestinal Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China
| | - Edouard Collins Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, 3800, Australia
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, PR China.
| | - Canhua Huang
- West China School of Basic Medical Sciences & Forensic Medicine, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China.
| |
Collapse
|
|
5
|
Dai W, Shen J, Yan J, Bott AJ, Maimouni S, Daguplo HQ, Wang Y, Khayati K, Guo JY, Zhang L, Wang Y, Valvezan A, Ding WX, Chen X, Su X, Gao S, Zong WX. Glutamine synthetase limits β-catenin-mutated liver cancer growth by maintaining nitrogen homeostasis and suppressing mTORC1. J Clin Invest 2022; 132:e161408. [PMID: 36256480 PMCID: PMC9754002 DOI: 10.1172/jci161408] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 10/13/2022] [Indexed: 12/24/2022] Open
Abstract
Glutamine synthetase (GS) catalyzes de novo synthesis of glutamine that facilitates cancer cell growth. In the liver, GS functions next to the urea cycle to remove ammonia waste. As a dysregulated urea cycle is implicated in cancer development, the impact of GS's ammonia clearance function has not been explored in cancer. Here, we show that oncogenic activation of β-catenin (encoded by CTNNB1) led to a decreased urea cycle and elevated ammonia waste burden. While β-catenin induced the expression of GS, which is thought to be cancer promoting, surprisingly, genetic ablation of hepatic GS accelerated the onset of liver tumors in several mouse models that involved β-catenin activation. Mechanistically, GS ablation exacerbated hyperammonemia and facilitated the production of glutamate-derived nonessential amino acids, which subsequently stimulated mechanistic target of rapamycin complex 1 (mTORC1). Pharmacological and genetic inhibition of mTORC1 and glutamic transaminases suppressed tumorigenesis facilitated by GS ablation. While patients with hepatocellular carcinoma, especially those with CTNNB1 mutations, have an overall defective urea cycle and increased expression of GS, there exists a subset of patients with low GS expression that is associated with mTORC1 hyperactivation. Therefore, GS-mediated ammonia clearance serves as a tumor-suppressing mechanism in livers that harbor β-catenin activation mutations and a compromised urea cycle.
Collapse
Affiliation(s)
- Weiwei Dai
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, Piscataway, New Jersey, USA
| | - Jianliang Shen
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, Piscataway, New Jersey, USA
| | - Junrong Yan
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, Piscataway, New Jersey, USA
| | - Alex J. Bott
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, Piscataway, New Jersey, USA
| | - Sara Maimouni
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, Piscataway, New Jersey, USA
| | - Heineken Q. Daguplo
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, Piscataway, New Jersey, USA
| | - Yujue Wang
- Rutgers Cancer Institute of New Jersey, Rutgers-The State University of New Jersey, New Brunswick, New Jersey, USA
| | - Khoosheh Khayati
- Rutgers Cancer Institute of New Jersey, Rutgers-The State University of New Jersey, New Brunswick, New Jersey, USA
| | - Jessie Yanxiang Guo
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, Piscataway, New Jersey, USA
- Rutgers Cancer Institute of New Jersey, Rutgers-The State University of New Jersey, New Brunswick, New Jersey, USA
| | - Lanjing Zhang
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, Piscataway, New Jersey, USA
| | - Yongbo Wang
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Alexander Valvezan
- Rutgers Cancer Institute of New Jersey, Rutgers-The State University of New Jersey, New Brunswick, New Jersey, USA
- Center for Advanced Biotechnology and Medicine, Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers-The State University of New Jersey, Piscataway, New Jersey, USA
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences and Liver Center, UCSF, San Francisco, California, USA
| | - Xiaoyang Su
- Rutgers Cancer Institute of New Jersey, Rutgers-The State University of New Jersey, New Brunswick, New Jersey, USA
| | - Shenglan Gao
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Wei-Xing Zong
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, Piscataway, New Jersey, USA
- Rutgers Cancer Institute of New Jersey, Rutgers-The State University of New Jersey, New Brunswick, New Jersey, USA
| |
Collapse
|
|
6
|
Wu B, Shang H, Liu J, Liang X, Yuan Y, Chen Y, Wang C, Jing H, Cheng W. Quantitative Proteomics Analysis of FFPE Tumor Samples Reveals the Influences of NET-1 siRNA Nanoparticles and Sonodynamic Therapy on Tetraspanin Protein Involved in HCC. Front Mol Biosci 2021; 8:678444. [PMID: 34041269 PMCID: PMC8141748 DOI: 10.3389/fmolb.2021.678444] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 04/26/2021] [Indexed: 12/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) poses a severe threat to human health. The NET-1 protein has been proved to be strongly associated with HCC proliferation and metastasis in our previous study. Here, we established and validated the NET-1 siRNA nanoparticles system to conduct targeted gene therapy of HCC xenograft in vivo with the aid of sonodynamic therapy. Then, we conducted a label-free proteome mass spectrometry workflow to analyze formalin-fixed and paraffin-embedded HCC xenograft samples collected in this study. The result showed that 78 proteins were differentially expressed after NET-1 protein inhibited. Among them, the expression of 17 proteins upregulated and the expression of 61 proteins were significantly downregulated. Of the protein abundance, the vast majority of Gene Ontology enrichment terms belong to the biological process. The KEGG pathway enrichment analysis showed that the 78 differentially expressed proteins significantly enriched in 45 pathways. We concluded that the function of the NET-1 gene is not only to regulate HCC but also to participate in a variety of biochemical metabolic pathways in the human body. Furthermore, the protein–protein interaction analysis indicated that the interactions of differentially expressed proteins are incredibly sophisticated. All the protein–protein interactions happened after the NET-1 gene has been silenced. Finally, our study also provides a useful proposal for targeted therapy based on tetraspanin proteins to treat HCC, and further mechanism investigations are needed to reveal a more detailed mechanism of action for NET-1 protein regulation of HCC.
Collapse
Affiliation(s)
- Bolin Wu
- Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, China.,Department of Interventional Ultrasound, Harbin Medical University Cancer Hospital, Harbin, China.,Institute of Cancer Prevention and Treatment, Heilongjiang Academy of Medical Science, Harbin Medical University, Harbin, China
| | - Haitao Shang
- Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, China
| | - Jiayin Liu
- Institute of Cancer Prevention and Treatment, Heilongjiang Academy of Medical Science, Harbin Medical University, Harbin, China.,Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xitian Liang
- Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yanchi Yuan
- Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, China.,Institute of Cancer Prevention and Treatment, Heilongjiang Academy of Medical Science, Harbin Medical University, Harbin, China
| | - Yichi Chen
- Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, China.,Institute of Cancer Prevention and Treatment, Heilongjiang Academy of Medical Science, Harbin Medical University, Harbin, China
| | - Chunyue Wang
- Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, China.,Institute of Cancer Prevention and Treatment, Heilongjiang Academy of Medical Science, Harbin Medical University, Harbin, China
| | - Hui Jing
- Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, China
| | - Wen Cheng
- Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, China.,Department of Interventional Ultrasound, Harbin Medical University Cancer Hospital, Harbin, China
| |
Collapse
|
|
7
|
Kuhara K, Kitagawa T, Baron B, Tokuda K, Sakamoto K, Nagano H, Nakamura K, Kobayashi M, Nagayasu H, Kuramitsu Y. Proteomic Analysis of Hepatocellular Carcinoma Tissues With Encapsulation Shows Up-regulation of Leucine Aminopeptidase 3 and Phosphoenolpyruvate Carboxykinase 2. Cancer Genomics Proteomics 2021; 18:307-316. [PMID: 33893083 DOI: 10.21873/cgp.20261] [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: 02/16/2021] [Revised: 03/05/2021] [Accepted: 03/08/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND/AIM Cancer is the most fatal disease worldwide whose most lethal characteristics are invasion and metastasis. Hepatocellular carcinoma (HCC) is one of the most fatal cancers worldwide. HCC often shows encapsulation, which is related to better prognosis. In this study, proteomic analysis of HCC tissues with and without encapsulation was performed, in order to elucidate the factors which play important roles in encapsulation. MATERIALS AND METHODS Five HCC tissues surrounded by a capsule and five HCC tissues which broke the capsule were obtained from patients diagnosed with HCC who underwent surgical liver resection. Protein samples from these tissues were separated by two-dimensional gel electrophoresis (2-DE), and the protein spots whose expression was different between encapsulated and non-encapsulated HCC tissues were identified through gel imaging analysis software. The selected protein spots were analyzed and identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS Two-DE analysis showed 14 spots whose expression was different between encapsulated and non-encapsulated HCC tissues. Of these, 9 were up-regulated and 5 were down-regulated in HCC tissues without encapsulation. The validation by Western blot confirmed that leucine aminopeptidase 3 (LAP3) and phosphoenolpyruvate carboxykinase mitochondrial (PCK2) were up-regulated significantly in HCC tissues with a capsule, compared to HCC tissues that broke the capsule. CONCLUSION These findings suggest that LAP3 and PCK2 could be factors responsible for the maintenance of encapsulation in HCC tissues.
Collapse
Affiliation(s)
- Keisuke Kuhara
- Advanced Research Promotion Centre, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan.,Division of Oral and Maxillofacial Surgery, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan
| | - Takao Kitagawa
- Advanced Research Promotion Centre, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan
| | - Byron Baron
- Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta
| | - Kazuhiro Tokuda
- Graduate School of Health and Welfare, Yamaguchi Prefectural University, Yamaguchi, Japan
| | - Kazuhiko Sakamoto
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Hiroaki Nagano
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Kazuyuki Nakamura
- Centre of Clinical Laboratories in Tokuyama Medical Association Hospital, Shunan, Japan
| | - Masanobu Kobayashi
- Advanced Research Promotion Centre, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan
| | - Hiroki Nagayasu
- Division of Oral and Maxillofacial Surgery, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan
| | - Yasuhiro Kuramitsu
- Advanced Research Promotion Centre, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan;
| |
Collapse
|
|
8
|
Zhang Q, Zhang Y, Sun S, Wang K, Qian J, Cui Z, Tao T, Zhou J. ACOX2 is a prognostic marker and impedes the progression of hepatocellular carcinoma via PPARα pathway. Cell Death Dis 2021; 12:15. [PMID: 33414412 PMCID: PMC7791021 DOI: 10.1038/s41419-020-03291-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 11/24/2020] [Accepted: 11/27/2020] [Indexed: 02/08/2023]
Abstract
Hepatocellular carcinoma (HCC) has been extensively studied as one of the most aggressive tumors worldwide. However, its mortality rate remains high due to ideal diagnosis and treatment strategies. Uncovering novel genes with prognostic significance would shed light on improving the HCC patient's outcome. In our study, we applied data-independent acquisition (DIA) quantitative proteomics to investigate the expression landscape of 24 paired HCC patients. A total of 1029 differentially expressed proteins (DEPs) were screened. Then, we compared DEPs in our cohort with the differentially expressed genes (DEGs) in The Cancer Genome Atlas, and investigated their prognostic significance, and found 183 prognosis-related genes (PRGs). By conducting protein-protein interaction topological analysis, we identified four subnetworks with prognostic significance. Acyl-CoA oxidase 2 (ACOX2) is a novel gene in subnetwork1, encodes a peroxisomal enzyme, and its function in HCC was investigated in vivo and in vitro. The lower expression of ACOX2 was validated by real-time quantitative PCR, immunohistochemistry, and Western blot. Cell Counting Kit-8 assay, wound healing, and transwell migration assay were applied to evaluate the impact of ACOX2 overexpression on the proliferation and migration abilities in two liver cancer cell lines. ACOX2 overexpression, using a subcutaneous xenograft tumor model, indicated a tumor suppressor role in HCC. To uncover the underlying mechanism, gene set enrichment analysis was conducted, and peroxisome proliferator-activated receptor-α (PPARα) was proposed to be a potential target. In conclusion, we demonstrated a PRG ACOX2, and its overexpression reduced the proliferation and metastasis of liver cancer in vitro and in vivo through PPARα pathway.
Collapse
Affiliation(s)
- Qifan Zhang
- Department of General Surgery, Division of Hepatobiliopancreatic Surgery, Nanfang Hospital, Southern Medical University, 1838 North of Guangzhou Avenue, Guangzhou, Guangdong, 510515, China
| | - Yunbin Zhang
- Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Shibo Sun
- Department of General Surgery, Division of Hepatobiliopancreatic Surgery, Nanfang Hospital, Southern Medical University, 1838 North of Guangzhou Avenue, Guangzhou, Guangdong, 510515, China
| | - Kai Wang
- Department of General Surgery, Division of Hepatobiliopancreatic Surgery, Nanfang Hospital, Southern Medical University, 1838 North of Guangzhou Avenue, Guangzhou, Guangdong, 510515, China
| | - Jianping Qian
- Department of General Surgery, Division of Hepatobiliopancreatic Surgery, Nanfang Hospital, Southern Medical University, 1838 North of Guangzhou Avenue, Guangzhou, Guangdong, 510515, China
| | - Zhonglin Cui
- Department of General Surgery, Division of Hepatobiliopancreatic Surgery, Nanfang Hospital, Southern Medical University, 1838 North of Guangzhou Avenue, Guangzhou, Guangdong, 510515, China
| | - Tao Tao
- Department of Anesthesiology, Central People's Hospital of Zhanjiang, 236 Yuanzhu Road, Zhanjiang, Guangdong, 524045, China.
| | - Jie Zhou
- Department of General Surgery, Division of Hepatobiliopancreatic Surgery, Nanfang Hospital, Southern Medical University, 1838 North of Guangzhou Avenue, Guangzhou, Guangdong, 510515, China.
| |
Collapse
|
|
9
|
Tenen DG, Chai L, Tan JL. Metabolic alterations and vulnerabilities in hepatocellular carcinoma. Gastroenterol Rep (Oxf) 2021; 9:1-13. [PMID: 33747521 PMCID: PMC7962738 DOI: 10.1093/gastro/goaa066] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 07/06/2020] [Accepted: 08/28/2020] [Indexed: 12/13/2022] Open
Abstract
Liver cancer is a serious disease. It is ranked as the cancer with the second highest number of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC), which arises from transformed hepatocytes, is the major subtype of liver cancer. It accounts for 85% of total liver-cancer cases. An important aspect of HCC that has been actively studied is its metabolism. With the liver as the primary site of numerous metabolic processes in the body, it has been shown that the metabolism of HCC cells is highly dysregulated compared to that of normal hepatocytes. It is therefore crucial to understand the metabolic alterations caused by HCC and the underlying mechanisms for these alterations. This deeper understanding will allow diagnostic and therapeutic advancements in the treatment of HCC. In this review, we will summarize the current literature in HCC metabolic alterations, induced vulnerabilities, and potential therapeutic interventions.
Collapse
Affiliation(s)
- Daniel G Tenen
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
- Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA
| | - Li Chai
- Department of Pathology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Justin L Tan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
- Experimental Drug Development Centre, Agency for Science, Technology and Research (A*STAR), Singapore
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore
| |
Collapse
|
|
10
|
Saito Y, Takasawa A, Takasawa K, Aoyama T, Akimoto T, Ota M, Magara K, Murata M, Hirohashi Y, Hasegawa T, Sawada N, Saito T, Osanai M. Aldolase A promotes epithelial-mesenchymal transition to increase malignant potentials of cervical adenocarcinoma. Cancer Sci 2020; 111:3071-3081. [PMID: 32530543 PMCID: PMC7419050 DOI: 10.1111/cas.14524] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 05/30/2020] [Accepted: 06/08/2020] [Indexed: 12/29/2022] Open
Abstract
Recent studies have revealed that metabolic reprogramming is closely associated with epithelial-mesenchymal transition (EMT) during cancer progression. Aldolase A (ALDOA) is a key glycolytic enzyme that is highly expressed in several types of cancer. In this study, we found that ALDOA is highly expressed in uterine cervical adenocarcinoma and that high ALDOA expression promotes EMT to increase malignant potentials, such as metastasis and invasiveness, in cervical adenocarcinoma cells. In human surgical specimens, ALDOA was highly expressed in cervical adenocarcinoma and high ALDOA expression was correlated with lymph node metastasis, lymphovascular infiltration, and short overall survival. Suppression of ALDOA expression significantly reduced cell growth, migration, and invasiveness of cervical cancer cells. Aldolase A expression was partially regulated by hypoxia-inducible factor-1α (HIF-1α). Shotgun proteome analysis revealed that cell-cell adhesion-related proteins were significantly increased in ALDOA-overexpressing cells. Interestingly, overexpression of ALDOA caused severe morphological changes, including a cuboidal-to-spindle shape shift and reduced microvilli formation, coincident with modulation of the expression of typical EMT-related proteins. Overexpression of ALDOA increased migration and invasion in vitro. Furthermore, overexpression of ALDOA induced HIF-1α, suggesting a positive feedback loop between ALDOA and HIF-1α. In conclusion, ALDOA is overexpressed in cervical adenocarcinoma and contributes to malignant potentials of tumor cells through modulation of HIF-1α signaling. The feedback loop between ALDOA and HIF-1α could become a therapeutic target to improve the prognosis of this malignancy.
Collapse
Affiliation(s)
- Yuki Saito
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Akira Takasawa
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kumi Takasawa
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tomoyuki Aoyama
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Taishi Akimoto
- Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Misaki Ota
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kazufumi Magara
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masaki Murata
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yoshihiko Hirohashi
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tadashi Hasegawa
- Department of Surgical Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Norimasa Sawada
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tsuyoshi Saito
- Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Makoto Osanai
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| |
Collapse
|
|
11
|
Energy Metabolism in Cancer: The Roles of STAT3 and STAT5 in the Regulation of Metabolism-Related Genes. Cancers (Basel) 2020; 12:cancers12010124. [PMID: 31947710 PMCID: PMC7016889 DOI: 10.3390/cancers12010124] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 12/03/2019] [Accepted: 12/12/2019] [Indexed: 12/21/2022] Open
Abstract
A central characteristic of many types of cancer is altered energy metabolism processes such as enhanced glucose uptake and glycolysis and decreased oxidative metabolism. The regulation of energy metabolism is an elaborate process involving regulatory proteins such as HIF (pro-metastatic protein), which reduces oxidative metabolism, and some other proteins such as tumour suppressors that promote oxidative phosphorylation. In recent years, it has been demonstrated that signal transducer and activator of transcription (STAT) proteins play a pivotal role in metabolism regulation. STAT3 and STAT5 are essential regulators of cytokine- or growth factor-induced cell survival and proliferation, as well as the crosstalk between STAT signalling and oxidative metabolism. Several reports suggest that the constitutive activation of STAT proteins promotes glycolysis through the transcriptional activation of hypoxia-inducible factors and therefore, the alteration of mitochondrial activity. It seems that STAT proteins function as an integrative centre for different growth and survival signals for energy and respiratory metabolism. This review summarises the functions of STAT3 and STAT5 in the regulation of some metabolism-related genes and the importance of oxygen in the tumour microenvironment to regulate cell metabolism, particularly in the metabolic pathways that are involved in energy production in cancer cells.
Collapse
|
|
12
|
Satriano L, Lewinska M, Rodrigues PM, Banales JM, Andersen JB. Metabolic rearrangements in primary liver cancers: cause and consequences. Nat Rev Gastroenterol Hepatol 2019; 16:748-766. [PMID: 31666728 DOI: 10.1038/s41575-019-0217-8] [Citation(s) in RCA: 157] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/19/2019] [Indexed: 02/07/2023]
Abstract
Primary liver cancer (PLC) is the fourth most frequent cause of cancer-related death. The high mortality rates arise from late diagnosis and the limited accuracy of diagnostic and prognostic biomarkers. The liver is a major regulator, orchestrating the clearance of toxins, balancing glucose, lipid and amino acid uptake, managing whole-body metabolism and maintaining metabolic homeostasis. Tumour onset and progression is frequently accompanied by rearrangements of metabolic pathways, leading to dysregulation of metabolism. The limitation of current therapies targeting PLCs, such as hepatocellular carcinoma and cholangiocarcinoma, points towards the importance of deciphering this metabolic complexity. In this Review, we discuss the role of metabolic liver disruptions and the implications of these processes in PLCs, emphasizing their clinical relevance and value in early diagnosis and prognosis and as putative therapeutic targets. We also describe system biology approaches able to reconstruct the metabolic complexity of liver diseases. We also discuss whether metabolic rearrangements are a cause or consequence of PLCs, emphasizing the opportunity to clinically exploit the rewired metabolism. In line with this idea, we discuss circulating metabolites as promising biomarkers for PLCs.
Collapse
Affiliation(s)
- Letizia Satriano
- Biotech Research and Innovation Centre (BRIC) Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Monika Lewinska
- Biotech Research and Innovation Centre (BRIC) Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Pedro M Rodrigues
- Biodonostia Health Research Institute, Donostia University Hospital, San Sebastian, Spain
| | - Jesus M Banales
- Biodonostia Health Research Institute, Donostia University Hospital, San Sebastian, Spain.,National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain.,IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Jesper B Andersen
- Biotech Research and Innovation Centre (BRIC) Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
| |
Collapse
|
|
13
|
Cho A, Eskandari R, Granlund KL, Keshari KR. Hyperpolarized [6- 13C, 15N 3]-Arginine as a Probe for in Vivo Arginase Activity. ACS Chem Biol 2019; 14:665-673. [PMID: 30893552 DOI: 10.1021/acschembio.8b01044] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Alterations in arginase enzyme expression are linked with various diseases and have been shown to support disease progression, thus motivating the development of an imaging probe for this enzymatic target. 13C-enriched arginine can be used as a hyperpolarized (HP) magnetic resonance (MR) probe for arginase flux since the arginine carbon-6 resonance (157 ppm) is converted to urea (163 ppm) following arginase-catalyzed hydrolysis. However, scalar relaxation from adjacent 14N-nuclei shortens cabon-6 T 1 and T 2 times, yielding poor spectral properties. To address these limitations, we report the synthesis of [6-13C,15N3]-arginine and demonstrate that 15N-enrichment increases carbon-6 relaxation times, thereby improving signal-to-noise ratio and spectral resolution. By overcoming these limitations with this novel isotope-labeling scheme, we were able to perform in vitro and in vivo arginase activity measurements with HP MR. We present HP [6-13C,15N3]-arginine as a noninvasive arginase imaging agent for preclinical studies, with the potential for future clinical diagnostic use.
Collapse
Affiliation(s)
- Andrew Cho
- Department of Biochemistry and Structural Biology, Weill Cornell Graduate School, New York, New York 10065, United States
- Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, New York 10065, United States
| | - Roozbeh Eskandari
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States
| | - Kristin L. Granlund
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States
| | - Kayvan R. Keshari
- Department of Biochemistry and Structural Biology, Weill Cornell Graduate School, New York, New York 10065, United States
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States
| |
Collapse
|
|
14
|
Prevention of hepatic stellate cell activation using JQ1- and atorvastatin-loaded chitosan nanoparticles as a promising approach in therapy of liver fibrosis. Eur J Pharm Biopharm 2019; 134:96-106. [DOI: 10.1016/j.ejpb.2018.11.018] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 10/09/2018] [Accepted: 11/20/2018] [Indexed: 01/14/2023]
|
|
15
|
Heron PW, Abellán-Flos M, Salmon L, Sygusch J. Bisphosphonate Inhibitors of Mammalian Glycolytic Aldolase. J Med Chem 2018; 61:10558-10572. [PMID: 30418024 DOI: 10.1021/acs.jmedchem.8b01000] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The glycolytic enzyme aldolase is an emerging drug target in diseases such as cancer and protozoan infections which are dependent on a hyperglycolytic phenotype to synthesize adenosine 5'-triphosphate and metabolic precursors for biomass production. To date, structural information for the enzyme in complex with phosphate-derived inhibitors has been lacking. Thus, we determined the crystal structure of mammalian aldolase in complex with naphthalene 2,6-bisphosphate (1) that served as a template for the design of bisphosphonate-based inhibitors, namely, 2-phosphate-naphthalene 6-bisphosphonate (2), 2-naphthol 6-bisphosphonate (3), and 1-phosphate-benzene 4-bisphosphonate (4). All inhibitors targeted the active site, and the most promising lead, 2, exhibited slow-binding inhibition with an overall inhibition constant of ∼38 nM. Compound 2 inhibited proliferation of HeLa cancer cells, whereas HEK293 cells expressing a normal phenotype were not inhibited. The crystal structures delineated the essential features of high-affinity phosphate-derived inhibitors and provide a template for the development of inhibitors with prophylaxis potential.
Collapse
Affiliation(s)
- Paul W Heron
- Département de Biochimie et Médecine Moléculaire , Université de Montréal , CP 6128, Succursale Centre-Ville, Montréal , Québec H3C 3J7 , Canada
| | - Marta Abellán-Flos
- Equipe de Chimie Bioorganique et Bioinorganique, Institut de Chimie Moléculaire et des Matériaux D'Orsay (ICMMO) , Univ Paris-Saclay, Univ Paris-Sud, CNRS UMR8182, LabEx LERMIT , rue du doyen Georges Poitou , F-91405 Orsay , France
| | - Laurent Salmon
- Equipe de Chimie Bioorganique et Bioinorganique, Institut de Chimie Moléculaire et des Matériaux D'Orsay (ICMMO) , Univ Paris-Saclay, Univ Paris-Sud, CNRS UMR8182, LabEx LERMIT , rue du doyen Georges Poitou , F-91405 Orsay , France
| | - Jurgen Sygusch
- Département de Biochimie et Médecine Moléculaire , Université de Montréal , CP 6128, Succursale Centre-Ville, Montréal , Québec H3C 3J7 , Canada
| |
Collapse
|
|
16
|
Conway JR, Kofman E, Mo SS, Elmarakeby H, Van Allen E. Genomics of response to immune checkpoint therapies for cancer: implications for precision medicine. Genome Med 2018; 10:93. [PMID: 30497521 PMCID: PMC6264032 DOI: 10.1186/s13073-018-0605-7] [Citation(s) in RCA: 114] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Immune checkpoint blockade (ICB) therapies, which potentiate the body's natural immune response against tumor cells, have shown immense promise in the treatment of various cancers. Currently, tumor mutational burden (TMB) and programmed death ligand 1 (PD-L1) expression are the primary biomarkers evaluated for clinical management of cancer patients across histologies. However, the wide range of responses has demonstrated that the specific molecular and genetic characteristics of each patient's tumor and immune system must be considered to maximize treatment efficacy. Here, we review the various biological pathways and emerging biomarkers implicated in response to PD-(L)1 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) therapies, including oncogenic signaling pathways, human leukocyte antigen (HLA) variability, mutation and neoantigen burden, microbiome composition, endogenous retroviruses (ERV), and deficiencies in chromatin remodeling and DNA damage repair (DDR) machinery. We also discuss several mechanisms that have been observed to confer resistance to ICB, such as loss of phosphatase and tensin homolog (PTEN), loss of major histocompatibility complex (MHC) I/II expression, and activation of the indoleamine 2,3-dioxygenase 1 (IDO1) and transforming growth factor beta (TGFβ) pathways. Clinical trials testing the combination of PD-(L)1 or CTLA-4 blockade with molecular mediators of these pathways are becoming more common and may hold promise for improving treatment efficacy and response. Ultimately, some of the genes and molecular mechanisms highlighted in this review may serve as novel biological targets or therapeutic vulnerabilities to improve clinical outcomes in patients.
Collapse
Affiliation(s)
- Jake R Conway
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, 02142, USA
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, 02215, USA
| | - Eric Kofman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, 02142, USA
| | - Shirley S Mo
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, 02142, USA
| | - Haitham Elmarakeby
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, 02142, USA
- Department of System and Computer Engineering, Al-Azhar University, Cairo, 11751, Egypt
| | - Eliezer Van Allen
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, 02142, USA.
| |
Collapse
|
|
17
|
Abstract
Cancer cells reprogramme metabolism to maximize the use of nitrogen and carbon for the anabolic synthesis of macromolecules that are required during tumour proliferation and growth. To achieve this aim, one strategy is to reduce catabolism and nitrogen disposal. The urea cycle (UC) in the liver is the main metabolic pathway to convert excess nitrogen into disposable urea. Outside the liver, UC enzymes are differentially expressed, enabling the use of nitrogen for the synthesis of UC intermediates that are required to accommodate cellular needs. Interestingly, the expression of UC enzymes is altered in cancer, revealing a revolutionary mechanism to maximize nitrogen incorporation into biomass. In this Review, we discuss the metabolic benefits underlying UC deregulation in cancer and the relevance of these alterations for cancer diagnosis and therapy.
Collapse
Affiliation(s)
- Rom Keshet
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Peter Szlosarek
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, London, UK
- Barts Health NHS Trust, St Bartholomew's Hospital, London, UK
| | - Arkaitz Carracedo
- CIC bioGUNE, Bizkaia, Spain
- CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
- Biochemistry and Molecular Biology Department, University of the Basque Country, Bilbao, Spain
| | - Ayelet Erez
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
| |
Collapse
|
|
18
|
Lee JS, Adler L, Karathia H, Carmel N, Rabinovich S, Auslander N, Keshet R, Stettner N, Silberman A, Agemy L, Helbling D, Eilam R, Sun Q, Brandis A, Malitsky S, Itkin M, Weiss H, Pinto S, Kalaora S, Levy R, Barnea E, Admon A, Dimmock D, Stern-Ginossar N, Scherz A, Nagamani SCS, Unda M, Wilson DM, Elhasid R, Carracedo A, Samuels Y, Hannenhalli S, Ruppin E, Erez A. Urea Cycle Dysregulation Generates Clinically Relevant Genomic and Biochemical Signatures. Cell 2018; 174:1559-1570.e22. [PMID: 30100185 PMCID: PMC6225773 DOI: 10.1016/j.cell.2018.07.019] [Citation(s) in RCA: 203] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Revised: 05/21/2018] [Accepted: 07/12/2018] [Indexed: 01/02/2023]
Abstract
The urea cycle (UC) is the main pathway by which mammals dispose of waste nitrogen. We find that specific alterations in the expression of most UC enzymes occur in many tumors, leading to a general metabolic hallmark termed "UC dysregulation" (UCD). UCD elicits nitrogen diversion toward carbamoyl-phosphate synthetase2, aspartate transcarbamylase, and dihydrooratase (CAD) activation and enhances pyrimidine synthesis, resulting in detectable changes in nitrogen metabolites in both patient tumors and their bio-fluids. The accompanying excess of pyrimidine versus purine nucleotides results in a genomic signature consisting of transversion mutations at the DNA, RNA, and protein levels. This mutational bias is associated with increased numbers of hydrophobic tumor antigens and a better response to immune checkpoint inhibitors independent of mutational load. Taken together, our findings demonstrate that UCD is a common feature of tumors that profoundly affects carcinogenesis, mutagenesis, and immunotherapy response.
Collapse
Affiliation(s)
- Joo Sang Lee
- Cancer Data Science Lab, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Center for Bioinformatics and Computational Biology, University of Maryland Institute for Advanced Computer Studies, Department of Computer Science, University of Maryland, College Park, MD 20742, USA
| | - Lital Adler
- Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Hiren Karathia
- Center for Bioinformatics and Computational Biology, University of Maryland Institute for Advanced Computer Studies, Department of Computer Science, University of Maryland, College Park, MD 20742, USA
| | - Narin Carmel
- Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Shiran Rabinovich
- Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Noam Auslander
- Cancer Data Science Lab, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Center for Bioinformatics and Computational Biology, University of Maryland Institute for Advanced Computer Studies, Department of Computer Science, University of Maryland, College Park, MD 20742, USA
| | - Rom Keshet
- Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Noa Stettner
- Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel; Department of Veterinary Resources, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Alon Silberman
- Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Lilach Agemy
- Department of Plant and Environmental Science, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | | | - Raya Eilam
- Department of Veterinary Resources, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Qin Sun
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Alexander Brandis
- Life Sciences Core Facilities, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Sergey Malitsky
- Life Sciences Core Facilities, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Maxim Itkin
- Life Sciences Core Facilities, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Hila Weiss
- Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Sivan Pinto
- Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Shelly Kalaora
- Department of Molecular Cell Biology, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Ronen Levy
- Department of Molecular Cell Biology, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Eilon Barnea
- Faculty of Biology, Technion - Israel Institute of Technology, 3200003 Haifa, Israel
| | - Arie Admon
- Faculty of Biology, Technion - Israel Institute of Technology, 3200003 Haifa, Israel
| | - David Dimmock
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA
| | - Noam Stern-Ginossar
- Department of Molecular Genetics, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Avigdor Scherz
- Department of Veterinary Resources, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Sandesh C S Nagamani
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA
| | - Miguel Unda
- Department of Urology, Basurto University Hospital, 48013 Bilbao, Spain; CIBERONC, Madrid, Spain
| | - David M Wilson
- Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program, NIH, 251 Bayview Blvd., Baltimore, MD 21224, USA
| | - Ronit Elhasid
- Sackler Faculty of Medicine, Department of Pediatric Hemato Oncology, Sourasky Medical Center, Tel Aviv University, 6997801 Tel Aviv, Israel
| | - Arkaitz Carracedo
- CIBERONC, Madrid, Spain; CIC bioGUNE, Bizkaia Technology Park, 801 Building, 48160 Derio, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain; Biochemistry and Molecular Biology Department, University of the Basque Country (UPV/EHU), Bilbao, Spain
| | - Yardena Samuels
- Department of Molecular Cell Biology, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Sridhar Hannenhalli
- Center for Bioinformatics and Computational Biology, University of Maryland Institute for Advanced Computer Studies, Department of Computer Science, University of Maryland, College Park, MD 20742, USA
| | - Eytan Ruppin
- Cancer Data Science Lab, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Center for Bioinformatics and Computational Biology, University of Maryland Institute for Advanced Computer Studies, Department of Computer Science, University of Maryland, College Park, MD 20742, USA; Schools of Medicine and Computer Science, Tel Aviv University, 6997801 Tel Aviv, Israel.
| | - Ayelet Erez
- Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel.
| |
Collapse
|
|
19
|
Retrospective Proteomic Screening of 100 Breast Cancer Tissues. Proteomes 2017; 5:proteomes5030015. [PMID: 28686225 PMCID: PMC5620532 DOI: 10.3390/proteomes5030015] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 06/20/2017] [Accepted: 07/04/2017] [Indexed: 12/18/2022] Open
Abstract
The present investigation has been conducted on one hundred tissue fragments of breast cancer, collected and immediately cryopreserved following the surgical resection. The specimens were selected from patients with invasive ductal carcinoma of the breast, the most frequent and potentially aggressive type of mammary cancer, with the objective to increase the knowledge of breast cancer molecular markers potentially useful for clinical applications. The proteomic screening; by 2D-IPG and mass spectrometry; allowed us to identify two main classes of protein clusters: proteins expressed ubiquitously at high levels in all patients; and proteins expressed sporadically among the same patients. Within the group of ubiquitous proteins, glycolytic enzymes and proteins with anti-apoptotic activity were predominant. Among the sporadic ones, proteins involved in cell motility, molecular chaperones and proteins involved in the detoxification appeared prevalent. The data of the present study indicates that the primary tumor growth is reasonably supported by concurrent events: the inhibition of apoptosis and stimulation of cellular proliferation, and the increased expression of glycolytic enzymes with multiple functions. The second phase of the evolution of the tumor can be prematurely scheduled by the occasional presence of proteins involved in cell motility and in the defenses of the oxidative stress. We suggest that this approach on large-scale 2D-IPG proteomics of breast cancer is currently a valid tool that offers the opportunity to evaluate on the same assay the presence and recurrence of individual proteins, their isoforms and short forms, to be proposed as prognostic indicators and susceptibility to metastasis in patients operated on for invasive ductal carcinoma of the breast.
Collapse
|
|
20
|
Identification of CD14 as a potential biomarker of hepatocellular carcinoma using iTRAQ quantitative proteomics. Oncotarget 2017; 8:62011-62028. [PMID: 28977922 PMCID: PMC5617482 DOI: 10.18632/oncotarget.18782] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2017] [Accepted: 05/14/2017] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors without effective diagnostic biomarkers. This study intended to dynamically analyze serum proteomics in different pathological stages of liver diseases, and discover potential diagnostic biomarkers for early HCC. Patients with hepatitis B virus (HBV) infection, liver cirrhosis (LC), or HCC together with healthy controls (HC) were enrolled. Proteins differentially expressed between groups were screened using isobaric tagging for relative and absolute quantitation (iTRAQ), and promising HCC biomarker candidates were subjected to bioinformatics analysis, including K-means clustering, gene ontology (GO) and string network analysis. Potential biomarkers were validated by Western blotting and enzyme-linked immunosorbent assay (ELISA), and their diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis. Finally, 93 differentially expressed proteins were identified, of which 43 differed between HBV and HC, 70 between LC and HC, and 51 between HCC and HC. Expression levels of gelsolin (GELS) and sulfhydryl oxidase 1 (QSOX1) varied with disease state as follows: HC < HBV < LC < HCC. The reverse trend was observed with CD14. These iTRAQ results were confirmed by Western blotting and ELISA. Logistic regression and ROC curve analysis identified the optimal cut-off for alpha-fetoprotein (AFP), CD14 and AFP/CD14 was 191.4 ng/mL (AUC 0.646, 95%CI 0.467-0.825, sensitivity 31.6%, specificity 94.4%), 3.16 ng/mL (AUC 0.760, 95%CI 0.604-0.917, sensitivity 94.7%, specificity 50%) and 0.197 ng/mL (AUC 0.889, 95%CI 0.785-0.993, sensitivity 84.2%, specificity 83.3%) respectively. In conclusion, Assaying CD14 levels may complement AFP measurement for early detection of HCC.
Collapse
|
|
21
|
El-Mesery M, El-Mowafy M, Elgaml A, Youssef LF, Abed SY. Correlation of Serum Soluble Fibrinogen-Like Protein 2 with Soluble FAS Ligand and Interferon Gamma in Egyptian Hepatitis C Virus-Infected Patients and Hepatocellular Carcinoma Patients. J Interferon Cytokine Res 2017; 37:342-347. [PMID: 28609212 DOI: 10.1089/jir.2016.0128] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Infection with hepatitis C virus (HCV) remains one of the serious human diseases worldwide, especially in Egypt, which can lead to cirrhosis or hepatocellular carcinoma (HCC). However, the exact molecular mechanism of HCC progress in HCV-infected patients remains unclear. Soluble fibrinogen-like protein 2 (sFGL2) is a modulator of the immune response that is secreted by T cells and inhibits maturation of dendritic cells and T cell proliferation. In the current study, serum sFGL2 levels were analyzed by enzyme-linked immunosorbent assay (ELISA) technique in 30 chronic HCV-infected patients (HCV group), 30 chronic HCV-infected patients with HCC (HCC group), and 12 healthy individuals (control group). Moreover, serum levels of soluble FAS ligand (sFASL) and interferon gamma (IFN-γ) were analyzed and correlated with sFGL2 levels. According to our results, serum sFGL2 levels were significantly elevated in all patients with chronic HCV infection. However, HCC patients showed lower sFGL2 levels than HCV-infected patients without HCC incidence. In addition, serum sFASL levels were significantly elevated in both HCV and HCC groups, whereas serum IFN-γ levels were only elevated in the HCC group. Interestingly, sFGL2 correlated positively with serum total bilirubin level and negatively with serum levels of sFASL, IFN-γ, and albumin in HCV and HCC groups. Thus, conclusively, sFGL2 level increases in Egyptian HCV-infected and HCC patients. Taken together, the current work may open future possibility of designing new treatment strategies for HCV infection targeting sFGL2 and its immunosuppressive effect.
Collapse
Affiliation(s)
- Mohamed El-Mesery
- 1 Department of Biochemistry, Faculty of Pharmacy, Mansoura University , Mansoura, Egypt
| | - Mohammed El-Mowafy
- 2 Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University , Mansoura, Egypt
| | - Abdelaziz Elgaml
- 2 Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University , Mansoura, Egypt
| | - Laila F Youssef
- 1 Department of Biochemistry, Faculty of Pharmacy, Mansoura University , Mansoura, Egypt
| | - Sally Y Abed
- 3 Department of Tropical Medicine, Faculty of Medicine, Mansoura University , Mansoura, Egypt
| |
Collapse
|
|
22
|
Morais M, Dias F, Teixeira AL, Medeiros R. MicroRNAs and altered metabolism of clear cell renal cell carcinoma: Potential role as aerobic glycolysis biomarkers. Biochim Biophys Acta Gen Subj 2017; 1861:2175-2185. [PMID: 28579513 DOI: 10.1016/j.bbagen.2017.05.028] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 05/09/2017] [Accepted: 05/30/2017] [Indexed: 12/16/2022]
Abstract
BACKGROUND Warburg Effect is a metabolic switch that occurs in most of cancer cells but its advantages are not fully understood. This switch is known to happen in renal cell carcinoma (RCC), which is the most common solid cancer of the adult kidney. RCC carcinogenesis is related to pVHL loss and Hypoxia Inducible Factor (HIF) activation, ultimately leading to the activation of several genes related to glycolysis. MicroRNAs (miRNAs) regulate gene expression at a post-transcriptional level and are also deregulated in several cancers, including RCC. SCOPE OF REVIEW This review focuses in the miRNAs that direct target enzymes involved in glycolysis and that are deregulated in several cancers. It also reviews the possible application of miRNAs in the improvement of clinical patients' management. MAJOR CONCLUSIONS Several miRNAs that direct target enzymes involved in glycolysis are downregulated in cancer, strongly influencing the Warburg Effect. Due to this strong influence, FDG-PET can possibly benefit from measurement of these miRNAs. Restoring their levels can also bring an improvement to the current therapies. GENERAL SIGNIFICANCE Despite being known for almost a hundred years, the Warburg Effect is not fully understood. MiRNAs are now known to be intrinsically connected with this effect and present an opportunity to understand it. They also open a new door to improve current diagnosis and prognosis tests as well as to complement current therapies. This is urgent for cancers like RCC, mostly due to the lack of an efficient screening test for early relapse detection and follow-up and the development of resistance to current therapies.
Collapse
Affiliation(s)
- Mariana Morais
- Molecular Oncology and Viral Pathology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal; ICBAS, Abel Salazar Institute for the Biomedical Sciences, University of Porto, Portugal
| | - Francisca Dias
- Molecular Oncology and Viral Pathology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal; ICBAS, Abel Salazar Institute for the Biomedical Sciences, University of Porto, Portugal; Research Department, LPCC-Portuguese League, Against Cancer (NRNorte), Porto, Portugal
| | - Ana L Teixeira
- Molecular Oncology and Viral Pathology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal; Research Department, LPCC-Portuguese League, Against Cancer (NRNorte), Porto, Portugal.
| | - Rui Medeiros
- Molecular Oncology and Viral Pathology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal; Research Department, LPCC-Portuguese League, Against Cancer (NRNorte), Porto, Portugal; CEBIMED, Faculty of Health Sciences, Fernando Pessoa University, Porto, Portugal; FMUP, Faculty of Medicine, University of Porto, Portugal.
| |
Collapse
|
|
23
|
Poezevara G, Lozano S, Cuissart B, Bureau R, Bureau P, Croixmarie V, Vayer P, Lepailleur A. A Computational Selection of Metabolite Biomarkers Using Emerging Pattern Mining: A Case Study in Human Hepatocellular Carcinoma. J Proteome Res 2017; 16:2240-2249. [PMID: 28447453 DOI: 10.1021/acs.jproteome.7b00054] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The biomarker development in metabolomics aims at discriminating diseased from normal subjects and at creating a predictive model that can be used to diagnose new subjects. From a case study on human hepatocellular carcinoma (HCC), we studied for the first time the potential usefulness of the emerging patterns (EPs) that come from the data mining domain. When applied to a metabolomics data set labeled with two classes (e.g., HCC patients vs healthy subjects), EP mining can capture differentiating combinations of metabolites between the two classes. We observed that the so-called jumping emerging patterns (JEPs), which correspond to the combinations of metabolites that occur in only one of the two classes, achieved better performance than individual biomarkers. Particularly, the implementation of the JEPs in a rules-based diagnostic tool drastically reduced the false positive rate, i.e., the rate of healthy subjects predicted as HCC patients.
Collapse
Affiliation(s)
- Guillaume Poezevara
- Centre d'Etudes et de Recherche sur le Médicament de Normandie, Normandie Univ, UNICAEN, CERMN , 14000 Caen, France.,Groupe de Recherche en Informatique, Image, Automatique et Instrumentation de Caen, Normandie Univ, UNICAEN, ENSICAEN, CNRS, GREYC , 14000 Caen, France.,QUIID SAS , 17 rue Claude Bloch, 14000 Caen, France
| | - Sylvain Lozano
- Technologie Servier , 27 rue Eugène Vignat, 45000 Orléans, France
| | - Bertrand Cuissart
- Groupe de Recherche en Informatique, Image, Automatique et Instrumentation de Caen, Normandie Univ, UNICAEN, ENSICAEN, CNRS, GREYC , 14000 Caen, France
| | - Ronan Bureau
- Centre d'Etudes et de Recherche sur le Médicament de Normandie, Normandie Univ, UNICAEN, CERMN , 14000 Caen, France
| | - Pierre Bureau
- Centre d'Etudes et de Recherche sur le Médicament de Normandie, Normandie Univ, UNICAEN, CERMN , 14000 Caen, France
| | | | - Philippe Vayer
- Technologie Servier , 27 rue Eugène Vignat, 45000 Orléans, France
| | - Alban Lepailleur
- Centre d'Etudes et de Recherche sur le Médicament de Normandie, Normandie Univ, UNICAEN, CERMN , 14000 Caen, France
| |
Collapse
|
|
24
|
Quantitative proteomics by SWATH-MS reveals sophisticated metabolic reprogramming in hepatocellular carcinoma tissues. Sci Rep 2017; 7:45913. [PMID: 28378759 PMCID: PMC5381110 DOI: 10.1038/srep45913] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Accepted: 02/15/2017] [Indexed: 12/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and understanding its molecular pathogenesis is pivotal to managing this disease. Sequential window acquisition of all theoretical mass spectra (SWATH-MS) is an optimal proteomic strategy to seek crucial proteins involved in HCC development and progression. In this study, a quantitative proteomic study of tumour and adjacent non-tumour liver tissues was performed using a SWATH-MS strategy. In total, 4,216 proteins were reliably quantified, and 338 were differentially expressed, with 191 proteins up-regulated and 147 down-regulated in HCC tissues compared with adjacent non-tumourous tissues. Functional analysis revealed distinct pathway enrichment of up- and down-regulated proteins. The most significantly down-regulated proteins were involved in metabolic pathways. Notably, our study revealed sophisticated metabolic reprogramming in HCC, including alteration of the pentose phosphate pathway; serine, glycine and sarcosine biosynthesis/metabolism; glycolysis; gluconeogenesis; fatty acid biosynthesis; and fatty acid β-oxidation. Twenty-seven metabolic enzymes, including PCK2, PDH and G6PD, were significantly changed in this study. To our knowledge, this study presents the most complete view of tissue-specific metabolic reprogramming in HCC, identifying hundreds of differentially expressed proteins, which together form a rich resource for novel drug targets or diagnostic biomarker discovery.
Collapse
|
|
25
|
Morandi A, Taddei ML, Chiarugi P, Giannoni E. Targeting the Metabolic Reprogramming That Controls Epithelial-to-Mesenchymal Transition in Aggressive Tumors. Front Oncol 2017; 7:40. [PMID: 28352611 PMCID: PMC5348536 DOI: 10.3389/fonc.2017.00040] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 02/28/2017] [Indexed: 01/06/2023] Open
Abstract
The epithelial-to-mesenchymal transition (EMT) process allows the trans-differentiation of a cell with epithelial features into a cell with mesenchymal characteristics. This process has been reported to be a key priming event for tumor development and therefore EMT activation is now considered an established trait of malignancy. The transcriptional and epigenetic reprogramming that governs EMT has been extensively characterized and reviewed in the last decade. However, increasing evidence demonstrates a correlation between metabolic reprogramming and EMT execution. The aim of the current review is to gather the recent findings that illustrate this correlation to help deciphering whether metabolic changes are causative or just a bystander effect of EMT activation. The review is divided accordingly to the catabolic and anabolic pathways that characterize carbohydrate, aminoacid, and lipid metabolism. Moreover, at the end of each part, we have discussed a series of potential metabolic targets involved in EMT promotion and execution for which drugs are either available or that could be further investigated for therapeutic intervention.
Collapse
Affiliation(s)
- Andrea Morandi
- Department of Experimental and Clinical Biomedical Sciences, University of Florence , Florence , Italy
| | - Maria Letizia Taddei
- Department of Experimental and Clinical Medicine, University of Florence , Florence , Italy
| | - Paola Chiarugi
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy; Excellence Centre for Research, Transfer and High Education DenoTHE, University of Florence, Florence, Italy
| | - Elisa Giannoni
- Department of Experimental and Clinical Biomedical Sciences, University of Florence , Florence , Italy
| |
Collapse
|
|
26
|
Ophiobolin A Induces Autophagy and Activates the Mitochondrial Pathway of Apoptosis in Human Melanoma Cells. PLoS One 2016; 11:e0167672. [PMID: 27936075 PMCID: PMC5147944 DOI: 10.1371/journal.pone.0167672] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Accepted: 11/20/2016] [Indexed: 12/31/2022] Open
Abstract
Ophiobolin A, a fungal toxin from Bipolaris species known to affect different cellular processes in plants, has recently been shown to have anti-cancer activity in mammalian cells. In the present study, we investigated the anti-proliferative effect of Ophiobolin A on human melanoma A375 and CHL-1 cell lines. This cellular model was chosen because of the incidence of melanoma malignant tumor on human population and its resistance to chemical treatments. Ophyobolin A strongly reduced cell viability of melanoma cells by affecting mitochondrial functionality. The toxin induced depolarization of mitochondrial membrane potential, reactive oxygen species production and mitochondrial network fragmentation, leading to autophagy induction and ultimately resulting in cell death by activation of the mitochondrial pathway of apoptosis. Finally, a comparative proteomic investigation on A375 cells allowed to identify several Ophiobolin A down-regulated proteins, which are involved in fundamental processes for cell homeostasis and viability.
Collapse
|
|
27
|
Gupta MK, Behara SK, Vadde R. In silico analysis of differential gene expressions in biliary stricture and hepatic carcinoma. Gene 2016; 597:49-58. [PMID: 27777109 DOI: 10.1016/j.gene.2016.10.032] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Revised: 10/15/2016] [Accepted: 10/19/2016] [Indexed: 12/16/2022]
Abstract
In-silico attempt was made to identify the key hub genes which get differentially expressed in biliary stricture and hepatic carcinoma. Gene expression data, GSE34166, was downloaded from the GEO database, which contains 10 biliary stricture samples (4 benign control and 6 malignant carcinoma), for screening of key hub genes associated with the disease. R packages scripts were identified 85 differentially expressed genes. Further these genes were uploaded in WebGestalt database and identified nine key genes. Using STRING database and Gephi software, the protein-protein interaction networks were constructed and also studied gene ontology through WebGestalt. Finally, we identified four key genes (CXCR4, ADH1C, ABCB1 and ADH1A) are associated with liver carcinoma and further cross-validated with Liverome, Protein Atlas database and bibliography. In addition, transcription factors and their binding sites also studied. These identified hub genes and their transcription factors are the probable potential targets for possible future drug design.
Collapse
Affiliation(s)
- Manoj Kumar Gupta
- Department of Biotechnology & Bioinformatics, Yogi Vemana University, Kadapa 516003, Andhra Pradesh, India.
| | - Santosh Kumar Behara
- Biomedical Informatics Centre, Regional Medical Research Centre (ICMR), Bhubaneswar 751023, Odisha, India.
| | - Ramakrishna Vadde
- Department of Biotechnology & Bioinformatics, Yogi Vemana University, Kadapa 516003, Andhra Pradesh, India.
| |
Collapse
|
|
28
|
Deng J, Wang L, Ni J, Beretov J, Wasinger V, Wu D, Duan W, Graham P, Li Y. Proteomics discovery of chemoresistant biomarkers for ovarian cancer therapy. Expert Rev Proteomics 2016; 13:905-915. [DOI: 10.1080/14789450.2016.1233065] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Affiliation(s)
- Junli Deng
- Cancer Care Centre, St George Hospital, Kogarah, Australia
- St George and Sutherland Clinical School, University of New South Wales (UNSW), Kensington, Australia
- Department of Gynecological Oncology, Henan Cancer Hospital, Zhengzhou, China
- Zhengzhou University, Zhengzhou, China
| | - Li Wang
- Department of Gynecological Oncology, Henan Cancer Hospital, Zhengzhou, China
- Zhengzhou University, Zhengzhou, China
| | - Jie Ni
- Cancer Care Centre, St George Hospital, Kogarah, Australia
- St George and Sutherland Clinical School, University of New South Wales (UNSW), Kensington, Australia
| | - Julia Beretov
- Cancer Care Centre, St George Hospital, Kogarah, Australia
- St George and Sutherland Clinical School, University of New South Wales (UNSW), Kensington, Australia
| | - Valerie Wasinger
- Mark Wainwright Analytical Centre, Bioanalytical Mass Spectrometry Facility, University of New South Wales (UNSW), Kensington, Australia
- School of Medical Sciences, University of New South Wales (UNSW), Kensington, Australia
| | - Duojia Wu
- Cancer Care Centre, St George Hospital, Kogarah, Australia
- St George and Sutherland Clinical School, University of New South Wales (UNSW), Kensington, Australia
| | - Wei Duan
- School of Medicine, Deakin University, Waurn Ponds, Australia
| | - Peter Graham
- Cancer Care Centre, St George Hospital, Kogarah, Australia
- St George and Sutherland Clinical School, University of New South Wales (UNSW), Kensington, Australia
| | - Yong Li
- Cancer Care Centre, St George Hospital, Kogarah, Australia
- St George and Sutherland Clinical School, University of New South Wales (UNSW), Kensington, Australia
| |
Collapse
|
|
29
|
Xing X, Liang D, Huang Y, Zeng Y, Han X, Liu X, Liu J. The application of proteomics in different aspects of hepatocellular carcinoma research. J Proteomics 2016; 145:70-80. [PMID: 27072111 DOI: 10.1016/j.jprot.2016.03.050] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2015] [Revised: 03/23/2016] [Accepted: 03/29/2016] [Indexed: 12/12/2022]
|
|
30
|
Megger DA, Rosowski K, Ahrens M, Bracht T, Eisenacher M, Schlaak JF, Weber F, Hoffmann AC, Meyer HE, Baba HA, Sitek B. Tissue-based quantitative proteome analysis of human hepatocellular carcinoma using tandem mass tags. Biomarkers 2016; 22:113-122. [DOI: 10.1080/1354750x.2016.1210678] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Affiliation(s)
| | | | - Maike Ahrens
- Medizinisches Proteom-Center, Ruhr-Universität Bochum, Germany
| | - Thilo Bracht
- Medizinisches Proteom-Center, Ruhr-Universität Bochum, Germany
| | | | - Jörg F. Schlaak
- Department of Gastroenterology and Hepatology, University Hospital of Essen, Germany
| | - Frank Weber
- Department of General, Visceral and Transplantation Surgery, University Hospital of Essen, Germany
| | - Andreas-Claudius Hoffmann
- Department of Medicine (Cancer Research), Molecular Oncology Risk-Profile Evaluation, University Hospital of Essen, Germany
| | - Helmut E. Meyer
- Medizinisches Proteom-Center, Ruhr-Universität Bochum, Germany
| | - Hideo A. Baba
- Department of Pathology, University Hospital of Essen, Germany
| | - Barbara Sitek
- Medizinisches Proteom-Center, Ruhr-Universität Bochum, Germany
| |
Collapse
|
|
31
|
Likhitrattanapisal S, Tipanee J, Janvilisri T. Meta-analysis of gene expression profiles identifies differential biomarkers for hepatocellular carcinoma and cholangiocarcinoma. Tumour Biol 2016; 37:12755-12766. [PMID: 27448818 DOI: 10.1007/s13277-016-5186-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 07/13/2016] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the members of hepatobiliary diseases. Both types of cancer often exert high levels of similarity in terms of phenotypic characteristics, thus leading to difficulties in HCC and CCA differential diagnoses. In this study, a transcriptome meta-analysis was performed on HCC and CCA microarray data to identify differential transcriptome networks and potential biomarkers for HCC and CCA. Raw data from nine gene expression profiling datasets, consisting of 1,185 samples in total, were methodologically compiled and analyzed. To evaluate differentially expressed (DE) genes in HCC and CCA, the levels of gene expression were compared between cancer and its normal counterparts (i.e., HCC versus normal liver and CCA versus normal bile duct) using t test (P < 0.05) and k-fold validation. A total of 226 DE genes were specific to HCC, 249 DE genes specific to CCA, and 41 DE genes in both HCC and CCA. Gene ontology and pathway enrichment analyses revealed different patterns between functional transcriptome networks of HCC and CCA. Cell cycle and glycolysis/gluconeogenesis pathways were exclusively dysregulated in HCC whereas complement and coagulation cascades as well as glycine, serine, and threonine metabolism were prodominantly differentially expressed in CCA. Our meta-analysis revealed distinct dysregulation in transcriptome networks between HCC and CCA. Certain genes in these networks were discussed in the context of HCC and CCA transition, unique characteristics of HCC and CCA, and their potentials as HCC and CCA differential biomarkers.
Collapse
Affiliation(s)
| | - Jaitip Tipanee
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand
| | - Tavan Janvilisri
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand.
| |
Collapse
|
|
32
|
Jiang ZH, Chen QY, Harrison TJ, Li GJ, Wang XY, Li H, Hu LP, Li KW, Yang QL, Tan C, Fang ZL. Hepatitis B Virus Core Promoter Double Mutations (A1762T, G1764A) Are Associated with Lower Levels of Serum Dihydrolipoyl Dehydrogenase. Intervirology 2016; 59:1-7. [PMID: 27303803 PMCID: PMC5079069 DOI: 10.1159/000445319] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 03/08/2016] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVES The aim of this study was to identify serum proteins with differential concentrations between hepatocellular carcinoma (HCC) patients and HBsAg asymptomatic carriers among individuals infected with hepatitis B virus (HBV) with basal core promoter (BCP) double mutations (A1762T, G1764A). METHODS iTRAQ and liquid chromatography-tandem mass spectrometry were used to identify differentially expressed protein, and an ELISA test was used for the validation test. RESULTS The total number of proteins identified was 1,125, of which 239 showed statistically significant differences in their expression. The relative concentrations of serum dihydrolipoyl dehydrogenase (DLD), which showed the most significant correlation with liver diseases and infection, were significantly lower in HCC patients than asymptomatic HBsAg carriers and individuals negative for HBsAg. However, only the difference between HCC patients with BCP double mutations and HBsAg-negative individuals could be confirmed by ELISA. Meanwhile, we found that the concentrations of serum DLD in those infected with HBV with BCP double mutations were significantly lower than in individuals with the wild-type BCP. However, the difference in the concentrations of serum DLD between individuals with wild-type BCP and those negative for HBsAg was not significant. CONCLUSIONS HBV with BCP double mutations are associated with lower concentrations of serum DLD.
Collapse
Affiliation(s)
- Zhi-Hua Jiang
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi, PR China
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
33
|
Teng YC, Shen ZQ, Kao CH, Tsai TF. Hepatocellular carcinoma mouse models: Hepatitis B virus-associated hepatocarcinogenesis and haploinsufficient tumor suppressor genes. World J Gastroenterol 2016; 22:300-325. [PMID: 26755878 PMCID: PMC4698494 DOI: 10.3748/wjg.v22.i1.300] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Revised: 10/14/2015] [Accepted: 11/24/2015] [Indexed: 02/06/2023] Open
Abstract
The multifactorial and multistage pathogenesis of hepatocellular carcinoma (HCC) has fascinated a wide spectrum of scientists for decades. While a number of major risk factors have been identified, their mechanistic roles in hepatocarcinogenesis still need to be elucidated. Many tumor suppressor genes (TSGs) have been identified as being involved in HCC. These TSGs can be classified into two groups depending on the situation with respect to allelic mutation/loss in the tumors: the recessive TSGs with two required mutated alleles and the haploinsufficient TSGs with one required mutated allele. Hepatitis B virus (HBV) is one of the most important risk factors associated with HCC. Although mice cannot be infected with HBV due to the narrow host range of HBV and the lack of a proper receptor, one advantage of mouse models for HBV/HCC research is the numerous and powerful genetic tools that help investigate the phenotypic effects of viral proteins and allow the dissection of the dose-dependent action of TSGs. Here, we mainly focus on the application of mouse models in relation to HBV-associated HCC and on TSGs that act either in a recessive or in a haploinsufficient manner. Discoveries obtained using mouse models will have a great impact on HCC translational medicine.
Collapse
|
|
34
|
Naboulsi W, Megger DA, Bracht T, Kohl M, Turewicz M, Eisenacher M, Voss DM, Schlaak JF, Hoffmann AC, Weber F, Baba HA, Meyer HE, Sitek B. Quantitative Tissue Proteomics Analysis Reveals Versican as Potential Biomarker for Early-Stage Hepatocellular Carcinoma. J Proteome Res 2015; 15:38-47. [DOI: 10.1021/acs.jproteome.5b00420] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Affiliation(s)
- Wael Naboulsi
- Medizinisches
Proteom-Center, Ruhr-Universität Bochum, 44801 Bochum, Germany
| | - Dominik A. Megger
- Medizinisches
Proteom-Center, Ruhr-Universität Bochum, 44801 Bochum, Germany
| | - Thilo Bracht
- Medizinisches
Proteom-Center, Ruhr-Universität Bochum, 44801 Bochum, Germany
| | - Michael Kohl
- Medizinisches
Proteom-Center, Ruhr-Universität Bochum, 44801 Bochum, Germany
| | - Michael Turewicz
- Medizinisches
Proteom-Center, Ruhr-Universität Bochum, 44801 Bochum, Germany
| | - Martin Eisenacher
- Medizinisches
Proteom-Center, Ruhr-Universität Bochum, 44801 Bochum, Germany
| | - Don Marvin Voss
- Medizinisches
Proteom-Center, Ruhr-Universität Bochum, 44801 Bochum, Germany
| | | | | | | | | | - Helmut E. Meyer
- Medizinisches
Proteom-Center, Ruhr-Universität Bochum, 44801 Bochum, Germany
| | - Barbara Sitek
- Medizinisches
Proteom-Center, Ruhr-Universität Bochum, 44801 Bochum, Germany
| |
Collapse
|
|
35
|
Subbannayya Y, Syed N, Barbhuiya MA, Raja R, Marimuthu A, Sahasrabuddhe N, Pinto SM, Manda SS, Renuse S, Manju HC, Zameer MAL, Sharma J, Brait M, Srikumar K, Roa JC, Vijaya Kumar M, Kumar KVV, Prasad TSK, Ramaswamy G, Kumar RV, Pandey A, Gowda H, Chatterjee A. Calcium calmodulin dependent kinase kinase 2 - a novel therapeutic target for gastric adenocarcinoma. Cancer Biol Ther 2015; 16:336-45. [PMID: 25756516 DOI: 10.4161/15384047.2014.972264] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer is one of the most common gastrointestinal malignancies and is associated with poor prognosis. Exploring alterations in the proteomic landscape of gastric cancer is likely to provide potential biomarkers for early detection and molecules for targeted therapeutic intervention. Using iTRAQ-based quantitative proteomic analysis, we identified 22 proteins that were overexpressed and 17 proteins that were downregulated in gastric tumor tissues as compared to the adjacent normal tissue. Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) was found to be 7-fold overexpressed in gastric tumor tissues. Immunohistochemical labeling of tumor tissue microarrays for validation of CAMKK2 overexpression revealed that it was indeed overexpressed in 94% (92 of 98) of gastric cancer cases. Silencing of CAMKK2 using siRNA significantly reduced cell proliferation, colony formation and invasion of gastric cancer cells. Our results demonstrate that CAMKK2 signals in gastric cancer through AMPK activation and suggest that CAMKK2 could be a novel therapeutic target in gastric cancer.
Collapse
|
|
36
|
Subbannayya T, Leal-Rojas P, Barbhuiya MA, Raja R, Renuse S, Sathe G, Pinto SM, Syed N, Nanjappa V, Patil AH, Garcia P, Sahasrabuddhe NA, Nair B, Guerrero-Preston R, Navani S, Tiwari PK, Santosh V, Sidransky D, Prasad TSK, Gowda H, Roa JC, Pandey A, Chatterjee A. Macrophage migration inhibitory factor - a therapeutic target in gallbladder cancer. BMC Cancer 2015; 15:843. [PMID: 26530123 PMCID: PMC4632274 DOI: 10.1186/s12885-015-1855-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Accepted: 10/27/2015] [Indexed: 12/20/2022] Open
Abstract
Background Poor prognosis in gallbladder cancer is due to late presentation of the disease, lack of reliable biomarkers for early diagnosis and limited targeted therapies. Early diagnostic markers and novel therapeutic targets can significantly improve clinical management of gallbladder cancer. Methods Proteomic analysis of four gallbladder cancer cell lines based on the invasive property (non-invasive to highly invasive) was carried out using the isobaric tags for relative and absolute quantitation labeling-based quantitative proteomic approach. The expression of macrophage migration inhibitory factor was analysed in gallbladder adenocarcinoma tissues using immunohistochemistry. In vitro cellular assays were carried out in a panel of gallbladder cancer cell lines using MIF inhibitors, ISO-1 and 4-IPP or its specific siRNA. Results The quantitative proteomic experiment led to the identification of 3,653 proteins, among which 654 were found to be overexpressed and 387 were downregulated in the invasive cell lines (OCUG-1, NOZ and GB-d1) compared to the non-invasive cell line, TGBC24TKB. Among these, macrophage migration inhibitory factor (MIF) was observed to be highly overexpressed in two of the invasive cell lines. MIF is a pleiotropic proinflammatory cytokine that plays a causative role in multiple diseases, including cancer. MIF has been reported to play a central role in tumor cell proliferation and invasion in several cancers. Immunohistochemical labeling of tumor tissue microarrays for MIF expression revealed that it was overexpressed in 21 of 29 gallbladder adenocarcinoma cases. Silencing/inhibition of MIF using siRNA and/or MIF antagonists resulted in a significant decrease in cell viability, colony forming ability and invasive property of the gallbladder cancer cells. Conclusions Our findings support the role of MIF in tumor aggressiveness and suggest its potential application as a therapeutic target for gallbladder cancer. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1855-z) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Tejaswini Subbannayya
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India. .,Amrita School of Biotechnology, Amrita University, Kollam, 690525, India.
| | - Pamela Leal-Rojas
- Department of Pathology, Center of Genetic and Immunological Studies (CEGIN) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco, Chile. .,McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
| | - Mustafa A Barbhuiya
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. .,Adrienne Helis Malvin Research Foundation, New Orleans, LA, 70130, USA.
| | - Remya Raja
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India.
| | - Santosh Renuse
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India. .,Amrita School of Biotechnology, Amrita University, Kollam, 690525, India.
| | - Gajanan Sathe
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India. .,Manipal University, Madhav Nagar, Manipal, 576104, India.
| | - Sneha M Pinto
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India. .,YU-IOB Center for Systems Biology and Molecular Medicine, Yenepoya University, Mangalore, 575018, India.
| | - Nazia Syed
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India. .,Department of Biochemistry and Molecular Biology, School of Life Sciences, Pondicherry University, Puducherry, 605014, India.
| | - Vishalakshi Nanjappa
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India. .,Amrita School of Biotechnology, Amrita University, Kollam, 690525, India.
| | - Arun H Patil
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India. .,School of Biotechnology, KIIT University, Bhubaneswar, Odisha, 751024, India.
| | - Patricia Garcia
- Department of Pathology, Advanced Center for Chronic Diseases (ACCDiS), CITO, Pontificia Universidad Católica de Chile, Santiago, Chile.
| | | | - Bipin Nair
- Amrita School of Biotechnology, Amrita University, Kollam, 690525, India.
| | - Rafael Guerrero-Preston
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.
| | | | - Pramod K Tiwari
- Centre for Genomics, Molecular and Human Genetics, Jiwaji University, Gwalior, 474011, India. .,School of Studies in Zoology, Jiwaji University, Gwalior, India.
| | - Vani Santosh
- Department of Pathology, National Institute of Mental Health and Neurosciences, Bangalore, 560029, India.
| | - David Sidransky
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.
| | - T S Keshava Prasad
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India. .,Amrita School of Biotechnology, Amrita University, Kollam, 690525, India. .,YU-IOB Center for Systems Biology and Molecular Medicine, Yenepoya University, Mangalore, 575018, India. .,NIMHANS-IOB Proteomics and Bioinformatics Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences, Bangalore, 560029, India.
| | - Harsha Gowda
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India. .,YU-IOB Center for Systems Biology and Molecular Medicine, Yenepoya University, Mangalore, 575018, India.
| | - Juan Carlos Roa
- Department of Pathology, Advanced Center for Chronic Diseases (ACCDiS), CITO, Pontificia Universidad Católica de Chile, Santiago, Chile.
| | - Akhilesh Pandey
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. .,Departments of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. .,Departments of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. .,Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
| | - Aditi Chatterjee
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India. .,Manipal University, Madhav Nagar, Manipal, 576104, India. .,YU-IOB Center for Systems Biology and Molecular Medicine, Yenepoya University, Mangalore, 575018, India.
| |
Collapse
|
|
37
|
Xing X, Huang Y, Wang S, Chi M, Zeng Y, Chen L, Li L, Zeng J, Lin M, Han X, Liu X, Liu J. Comparative analysis of primary hepatocellular carcinoma with single and multiple lesions by iTRAQ-based quantitative proteomics. J Proteomics 2015; 128:262-71. [PMID: 26300425 DOI: 10.1016/j.jprot.2015.08.007] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Revised: 07/16/2015] [Accepted: 08/12/2015] [Indexed: 02/07/2023]
|
|
38
|
Syed N, Barbhuiya MA, Pinto SM, Nirujogi RS, Renuse S, Datta KK, Khan AA, Srikumar K, Prasad TSK, Kumar MV, Kumar RV, Chatterjee A, Pandey A, Gowda H. Phosphotyrosine profiling identifies ephrin receptor A2 as a potential therapeutic target in esophageal squamous-cell carcinoma. Proteomics 2015; 15:374-82. [PMID: 25366905 PMCID: PMC4309511 DOI: 10.1002/pmic.201400379] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Revised: 10/01/2014] [Accepted: 10/28/2014] [Indexed: 01/17/2023]
Abstract
Esophageal squamous‐cell carcinoma (ESCC) is one of the most common malignancies in Asia. Currently, surgical resection of early‐stage tumor is the best available treatment. However, most patients present late when surgery is not an option. Data suggest that chemotherapy regimens are inadequate for clinical management of advanced cancer. Targeted therapy has emerged as one of the most promising approaches to treat several malignancies. A prerequisite for developing targeted therapy is prior knowledge of proteins and pathways that drive proliferation in malignancies. We carried out phosphotyrosine profiling across four different ESCC cell lines and compared it to non‐neoplastic Het‐1A cell line to identify activated tyrosine kinase signaling pathways in ESCC. A total of 278 unique phosphopeptides were identified across these cell lines. This included several tyrosine kinases and their substrates that were hyperphosphorylated in ESCC. Ephrin receptor A2 (EPHA2), a receptor tyrosine kinase, was hyperphosphorylated in all the ESCC cell lines used in the study. EPHA2 is reported to be oncogenic in several cancers and is also known to promote metastasis. Immunohistochemistry‐based studies have revealed EPHA2 is overexpressed in nearly 50% of ESCC. We demonstrated EPHA2 as a potential therapeutic target in ESCC by carrying out siRNA‐based knockdown studies. Knockdown of EPHA2 in ESCC cell line TE8 resulted in significant decrease in cell proliferation and invasion, suggesting it is a promising therapeutic target in ESCC that warrants further evaluation.
Collapse
Affiliation(s)
- Nazia Syed
- Institute of Bioinformatics, International Technology Park, Bangalore, India; Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry, India
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
39
|
Wei W, Huang XH, Liang D, Zeng YY, Ma C, Wu YB, Li YT, Zhang X, Zeng JH, Liu JF. A proteomic analysis of transplanted liver in a rat model of chronic rejection. Clin Res Hepatol Gastroenterol 2015; 39:340-50. [PMID: 25468549 DOI: 10.1016/j.clinre.2014.10.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Revised: 07/29/2014] [Accepted: 10/03/2014] [Indexed: 02/04/2023]
Abstract
BACKGROUND Chronic rejection (CR) is an important cause of liver allograft failure. In the latter condition, re-transplantation of the liver (ReLT) is the only option for survival. Unfortunately, with the current state of knowledge, it is difficult to diagnose and treat early CR. OBJECTIVE To explore the biomarkers of the chronic rejection in orthotopic liver transplantation (OLT). METHODS A rat model of chronic liver allograft rejection was established, and the differential protein expression in chronic allograft rejection (CR) was analyzed by iTRAQ-MALDI-TOF/TOF. RESULTS Expression of sixty-two proteins was found to be significantly changed in CR rats. In the present study, CLU, Lcn2 and Krt19 were identified and quantified as early and reliable biomarkers for chronic rejection. CONCLUSION Analysis of differential protein expression by iTRAQ-MALDI-TOF/TOF is a potentially effective method to help understand the mechanism of CR in orthotopic liver transplantation. The proteins CLU, Lcn2 and Krt19 might be potential prognostic markers for predicting chronic rejection after liver transplantation.
Collapse
Affiliation(s)
- Wei Wei
- The First Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
| | - Xin-Hui Huang
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Dong Liang
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Yong-Yi Zeng
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Chuang Ma
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Yan-Bin Wu
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Yun-Tong Li
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Xiang Zhang
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Jin-Hua Zeng
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Jing-Feng Liu
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China.
| |
Collapse
|
|
40
|
Murthy KR, Rajagopalan P, Pinto SM, Advani J, Murthy PR, Goel R, Subbannayya Y, Balakrishnan L, Dash M, Anil AK, Manda SS, Nirujogi RS, Kelkar DS, Sathe GJ, Dey G, Chatterjee A, Gowda H, Chakravarti S, Shankar S, Sahasrabuddhe NA, Nair B, Somani BL, Prasad TSK, Pandey A. Proteomics of Human Aqueous Humor. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2015; 19:283-93. [PMID: 25933257 DOI: 10.1089/omi.2015.0029] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
- Krishna R. Murthy
- Institute of Bioinformatics, International Tech Park, Bangalore, India
- Department of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam, India
- Vittala International Institute of Ophthalmology, Bangalore, India
| | - Pavithra Rajagopalan
- Institute of Bioinformatics, International Tech Park, Bangalore, India
- School of Biotechnology, KIIT University, Bhubaneswar, India
| | - Sneha M. Pinto
- Institute of Bioinformatics, International Tech Park, Bangalore, India
- Manipal University, Madhav Nagar, Manipal, Karnataka, India
| | - Jayshree Advani
- Institute of Bioinformatics, International Tech Park, Bangalore, India
- Manipal University, Madhav Nagar, Manipal, Karnataka, India
| | | | - Renu Goel
- Institute of Bioinformatics, International Tech Park, Bangalore, India
| | - Yashwanth Subbannayya
- Institute of Bioinformatics, International Tech Park, Bangalore, India
- Rajiv Gandhi University of Health Sciences, Bangalore, India
| | - Lavanya Balakrishnan
- Institute of Bioinformatics, International Tech Park, Bangalore, India
- Department of Biotechnology, Kuvempu University, Shankaraghatta, India
| | - Mahashweta Dash
- Department of Internal Medicine, Armed Forces Medical College, Pune, India
| | - Abhijith K. Anil
- Department of Internal Medicine, Armed Forces Medical College, Pune, India
| | - Srikanth S. Manda
- Institute of Bioinformatics, International Tech Park, Bangalore, India
- Centre of Excellence in Bioinformatics, School of Life Sciences, Pondicherry University, Puducherry, India
| | - Raja Sekhar Nirujogi
- Institute of Bioinformatics, International Tech Park, Bangalore, India
- Centre of Excellence in Bioinformatics, School of Life Sciences, Pondicherry University, Puducherry, India
| | | | - Gajanan J. Sathe
- Institute of Bioinformatics, International Tech Park, Bangalore, India
- Manipal University, Madhav Nagar, Manipal, Karnataka, India
| | - Gourav Dey
- Institute of Bioinformatics, International Tech Park, Bangalore, India
- Manipal University, Madhav Nagar, Manipal, Karnataka, India
| | - Aditi Chatterjee
- Institute of Bioinformatics, International Tech Park, Bangalore, India
- School of Biotechnology, KIIT University, Bhubaneswar, India
| | - Harsha Gowda
- Institute of Bioinformatics, International Tech Park, Bangalore, India
| | - Shukti Chakravarti
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Subramanian Shankar
- Department of Rheumatology, Medical Division, Command Hospital (Air Force), Bangalore, India
| | | | - Bipin Nair
- Department of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam, India
| | - Babu Lal Somani
- Institute of Bioinformatics, International Tech Park, Bangalore, India
| | - T. S. Keshava Prasad
- Institute of Bioinformatics, International Tech Park, Bangalore, India
- Department of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam, India
- Manipal University, Madhav Nagar, Manipal, Karnataka, India
- Centre of Excellence in Bioinformatics, School of Life Sciences, Pondicherry University, Puducherry, India
| | - Akhilesh Pandey
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| |
Collapse
|
|
41
|
Puangpila C, El Rassi Z. Capturing and identification of differentially expressed fucome by a gel free and label free approach. J Chromatogr B Analyt Technol Biomed Life Sci 2015; 989:112-21. [PMID: 25817263 PMCID: PMC4385428 DOI: 10.1016/j.jchromb.2015.03.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2014] [Revised: 02/28/2015] [Accepted: 03/06/2015] [Indexed: 12/12/2022]
Abstract
This research reports a proof-of-concept that describes an instrumental approach that is gel free and label free at both the separation and mass spectrometry ends for the capturing and identification of differentially expressed proteins (DEPs) in diseases, e.g., cancers. The research consists of subjecting/processing equalized and non-equalized (i.e., untreated) disease-free and hepatocellular carcinoma (HCC) human sera via a multicolumn platform for capturing/fractionating human serum fucome. The equalization was performed via the combinatorial peptide ligand library (CPLL) beads technology that ensured narrowing the protein concentration range, thus allowing the detection of low abundance proteins. The equalized and non-equalized disease-free and HCC sera were first fractionated online onto two lectin columns specific to fucose, namely Aleuria aurantia lectin (AAL) and Lotus tetragonolobus agglutinin (LTA) followed by the online fractionation of the lectin captured fucome by reversed phase chromatography. The online desalted fractions were first subjected to trypsinolysis and then to liquid chromatography-mass spectrometry (LC-MS/MS) analysis. In comparison with untreated serum, the CPLL treated serum is superior in terms of the total number of identified DEPs, which reflected an increased number of DEPs in a wide abundance range. The DEPs in HCC serum were found to be 70 and 40 in both LTA and AAL fractions for the serum treated by CPLL and untreated serum, respectively. In addition, the platform combined with the CPLL treatment was accomplished with virtually no sample loss and dilution as well as with no experimental biases and sample labeling when comparing the diseased-free and cancer sera using LC-MS/MS.
Collapse
Affiliation(s)
- Chanida Puangpila
- Department of Chemistry, Oklahoma State University, Stillwater, OK 74078-3071, United States
| | - Ziad El Rassi
- Department of Chemistry, Oklahoma State University, Stillwater, OK 74078-3071, United States.
| |
Collapse
|
|
42
|
Tsai TH, Song E, Zhu R, Di Poto C, Wang M, Luo Y, Varghese RS, Tadesse MG, Ziada DH, Desai CS, Shetty K, Mechref Y, Ressom HW. LC-MS/MS-based serum proteomics for identification of candidate biomarkers for hepatocellular carcinoma. Proteomics 2015; 15:2369-81. [PMID: 25778709 DOI: 10.1002/pmic.201400364] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Revised: 01/28/2015] [Accepted: 03/11/2015] [Indexed: 12/21/2022]
Abstract
Associating changes in protein levels with the onset of cancer has been widely investigated to identify clinically relevant diagnostic biomarkers. In the present study, we analyzed sera from 205 patients recruited in the United States and Egypt for biomarker discovery using label-free proteomic analysis by LC-MS/MS. We performed untargeted proteomic analysis of sera to identify candidate proteins with statistically significant differences between hepatocellular carcinoma (HCC) and patients with liver cirrhosis. We further evaluated the significance of 101 proteins in sera from the same 205 patients through targeted quantitation by MRM on a triple quadrupole mass spectrometer. This led to the identification of 21 candidate protein biomarkers that were significantly altered in both the United States and Egyptian cohorts. Among the 21 candidates, ten were previously reported as HCC-associated proteins (eight exhibiting consistent trends with our observation), whereas 11 are new candidates discovered by this study. Pathway analysis based on the significant proteins reveals upregulation of the complement and coagulation cascades pathway and downregulation of the antigen processing and presentation pathway in HCC cases versus patients with liver cirrhosis. The results of this study demonstrate the power of combining untargeted and targeted quantitation methods for a comprehensive serum proteomic analysis, to evaluate changes in protein levels and discover novel diagnostic biomarkers. All MS data have been deposited in the ProteomeXchange with identifier PXD001171 (http://proteomecentral.proteomexchange.org/dataset/PXD001171).
Collapse
Affiliation(s)
- Tsung-Heng Tsai
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Ehwang Song
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, USA
| | - Rui Zhu
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, USA
| | - Cristina Di Poto
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Minkun Wang
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Yue Luo
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Rency S Varghese
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Mahlet G Tadesse
- Department of Mathematics and Statistics, Georgetown University, Washington, DC, USA
| | - Dina Hazem Ziada
- Department of Tropical Medicine and Infectious Diseases, Tanta University, Tanta, Egypt
| | - Chirag S Desai
- MedStar Georgetown University Hospital and Georgetown University Medical Center, Washington, DC, USA
| | - Kirti Shetty
- Johns Hopkins University, Gastroenterology & Hepatology at Sibley, Washington, DC, USA
| | - Yehia Mechref
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, USA
| | - Habtom W Ressom
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| |
Collapse
|
|
43
|
Bertram K, Valcu CM, Weitnauer M, Linne U, Görlach A. NOX1 supports the metabolic remodeling of HepG2 cells. PLoS One 2015; 10:e0122002. [PMID: 25806803 PMCID: PMC4373763 DOI: 10.1371/journal.pone.0122002] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 02/09/2015] [Indexed: 12/31/2022] Open
Abstract
NADPH oxidases are important sources of reactive oxygen species (ROS) which act as signaling molecules in the regulation of protein expression, cell proliferation, differentiation, migration and cell death. The NOX1 subunit is over-expressed in several cancers and NOX1 derived ROS have been repeatedly linked with tumorigenesis and tumor progression although underlying pathways are ill defined. We engineered NOX1-depleted HepG2 hepatoblastoma cells and employed differential display 2DE experiments in order to investigate changes in NOX1-dependent protein expression profiles. A total of 17 protein functions were identified to be dysregulated in NOX1-depleted cells. The proteomic results support a connection between NOX1 and the Warburg effect and a role for NOX in the regulation of glucose and glutamine metabolism as well as of lipid, protein and nucleotide synthesis in hepatic tumor cells. Metabolic remodeling is a common feature of tumor cells and understanding the underlying mechanisms is essential for the development of new cancer treatments. Our results reveal a manifold involvement of NOX1 in the metabolic remodeling of hepatoblastoma cells towards a sustained production of building blocks required to maintain a high proliferative rate, thus rendering NOX1 a potential target for cancer therapy.
Collapse
Affiliation(s)
- Katharina Bertram
- Experimental and Molecular Paediatric Cardiology, German Heart Centre Munich at the Technical University Munich, Lazarettstr. 36, Munich, Germany
| | - Cristina-Maria Valcu
- Experimental and Molecular Paediatric Cardiology, German Heart Centre Munich at the Technical University Munich, Lazarettstr. 36, Munich, Germany
- * E-mail: (CMV), (AG)
| | - Michael Weitnauer
- Experimental and Molecular Paediatric Cardiology, German Heart Centre Munich at the Technical University Munich, Lazarettstr. 36, Munich, Germany
| | - Uwe Linne
- Chemistry Department—Mass Spectrometry, Philipps-University Marburg, Hans-Meerwein-Strasse, Marburg, Germany
| | - Agnes Görlach
- Experimental and Molecular Paediatric Cardiology, German Heart Centre Munich at the Technical University Munich, Lazarettstr. 36, Munich, Germany
- * E-mail: (CMV), (AG)
| |
Collapse
|
|
44
|
Exosomes released from breast cancer carcinomas stimulate cell movement. PLoS One 2015; 10:e0117495. [PMID: 25798887 PMCID: PMC4370373 DOI: 10.1371/journal.pone.0117495] [Citation(s) in RCA: 122] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2013] [Accepted: 12/24/2014] [Indexed: 12/18/2022] Open
Abstract
For metastasis to occur cells must communicate with to their local environment to initiate growth and invasion. Exosomes have emerged as an important mediator of cell-to-cell signalling through the transfer of molecules such as mRNAs, microRNAs, and proteins between cells. Exosomes have been proposed to act as regulators of cancer progression. Here, we study the effect of exosomes on cell migration, an important step in metastasis. We performed cell migration assays, endocytosis assays, and exosome proteomic profiling on exosomes released from three breast cancer cell lines that model progressive stages of metastasis. Results from these experiments suggest: (1) exosomes promote cell migration and (2) the signal is stronger from exosomes isolated from cells with higher metastatic potentials; (3) exosomes are endocytosed at the same rate regardless of the cell type; (4) exosomes released from cells show differential enrichment of proteins with unique protein signatures of both identity and abundance. We conclude that breast cancer cells of increasing metastatic potential secrete exosomes with distinct protein signatures that proportionally increase cell movement and suggest that released exosomes could play an active role in metastasis.
Collapse
|
|
45
|
Label-free alpha fetoprotein immunosensor established by the facile synthesis of a palladium–graphene nanocomposite. Biosens Bioelectron 2014; 61:245-50. [DOI: 10.1016/j.bios.2014.05.021] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Revised: 05/08/2014] [Accepted: 05/08/2014] [Indexed: 01/28/2023]
|
|
46
|
Lincet H, Icard P. How do glycolytic enzymes favour cancer cell proliferation by nonmetabolic functions? Oncogene 2014; 34:3751-9. [PMID: 25263450 DOI: 10.1038/onc.2014.320] [Citation(s) in RCA: 140] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Revised: 08/23/2014] [Accepted: 08/23/2014] [Indexed: 12/16/2022]
Abstract
Cancer cells enhance their glycolysis, producing lactate, even in the presence of oxygen. Glycolysis is a series of ten metabolic reactions catalysed by enzymes whose expression is most often increased in tumour cells. HKII and phosphoglucose isomerase (PGI) have mainly an antiapoptotic effect; PGI and glyceraldehyde-3-phosphate dehydrogenase activate survival pathways (Akt and so on); phosphofructokinase 1 and triose phosphate isomerase participate in cell cycle activation; aldolase promotes epithelial mesenchymal transition; PKM2 enhances various nuclear effects such as transcription, stabilisation and so on. This review outlines the multiple non-glycolytic roles of glycolytic enzymes, which are essential for promoting cancer cells' survival, proliferation, chemoresistance and dissemination.
Collapse
Affiliation(s)
- H Lincet
- 1] Locally Aggressive Cancer Biology and Therapy Unit (BioTICLA), Caen, France [2] Normandie University, Caen, France [3] François-Baclesse Centre for Cancer, Caen, France
| | - P Icard
- 1] Locally Aggressive Cancer Biology and Therapy Unit (BioTICLA), Caen, France [2] Ecole Polytechnique, Laboratoire d'Informatique, Palaiseau, France
| |
Collapse
|
|
47
|
Murthy KR, Goel R, Subbannayya Y, Jacob HK, Murthy PR, Manda SS, Patil AH, Sharma R, Sahasrabuddhe NA, Parashar A, Nair BG, Krishna V, Prasad TK, Gowda H, Pandey A. Proteomic analysis of human vitreous humor. Clin Proteomics 2014; 11:29. [PMID: 25097467 PMCID: PMC4106660 DOI: 10.1186/1559-0275-11-29] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Accepted: 05/16/2014] [Indexed: 12/11/2022] Open
Abstract
Background The vitreous humor is a transparent, gelatinous mass whose main constituent is water. It plays an important role in providing metabolic nutrient requirements of the lens, coordinating eye growth and providing support to the retina. It is in close proximity to the retina and reflects many of the changes occurring in this tissue. The biochemical changes occurring in the vitreous could provide a better understanding about the pathophysiological processes that occur in vitreoretinopathy. In this study, we investigated the proteome of normal human vitreous humor using high resolution Fourier transform mass spectrometry. Results The vitreous humor was subjected to multiple fractionation techniques followed by LC-MS/MS analysis. We identified 1,205 proteins, 682 of which have not been described previously in the vitreous humor. Most proteins were localized to the extracellular space (24%), cytoplasm (20%) or plasma membrane (14%). Classification based on molecular function showed that 27% had catalytic activity, 10% structural activity, 10% binding activity, 4% cell and 4% transporter activity. Categorization for biological processes showed 28% participate in metabolism, 20% in cell communication and 13% in cell growth. The data have been deposited to the ProteomeXchange with identifier PXD000957. Conclusion This large catalog of vitreous proteins should facilitate biomedical research into pathological conditions of the eye including diabetic retinopathy, retinal detachment and cataract.
Collapse
Affiliation(s)
- Krishna R Murthy
- Institute of Bioinformatics, International Technology Park, Bangalore 560 066, India.,Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam, Kerala 690 525, India.,Vittala International Institute Of Ophthalmology, Bangalore, Karnataka 560085, India
| | - Renu Goel
- Institute of Bioinformatics, International Technology Park, Bangalore 560 066, India.,Department of Biotechnology, Kuvempu University, Shankaraghatta, Karnataka 577 451, India
| | - Yashwanth Subbannayya
- Institute of Bioinformatics, International Technology Park, Bangalore 560 066, India
| | - Harrys Kc Jacob
- Institute of Bioinformatics, International Technology Park, Bangalore 560 066, India
| | - Praveen R Murthy
- Vittala International Institute Of Ophthalmology, Bangalore, Karnataka 560085, India
| | - Srikanth Srinivas Manda
- Institute of Bioinformatics, International Technology Park, Bangalore 560 066, India.,Centre of Excellence in Bioinformatics, Bioinformatics Centre, School of Life Sciences, Pondicherry University, Puducherry 605 014, India
| | - Arun H Patil
- Institute of Bioinformatics, International Technology Park, Bangalore 560 066, India
| | - Rakesh Sharma
- Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bangalore 560 006, India
| | | | | | - Bipin G Nair
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam, Kerala 690 525, India
| | | | - Ts Keshava Prasad
- Institute of Bioinformatics, International Technology Park, Bangalore 560 066, India.,Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam, Kerala 690 525, India.,Centre of Excellence in Bioinformatics, Bioinformatics Centre, School of Life Sciences, Pondicherry University, Puducherry 605 014, India
| | - Harsha Gowda
- Institute of Bioinformatics, International Technology Park, Bangalore 560 066, India
| | - Akhilesh Pandey
- Department of Biological Chemistry, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore 21205 MD, USA.,Department of Oncology and Pathology, Johns Hopkins University School of Medicine, Baltimore 21205 MD, USA
| |
Collapse
|
|
48
|
Kawai M, Zhao J, Ishiguro H, Takeyama H. Carbon dioxide‑pneumoperitoneum in rats reduces ischemia/reperfusion‑induced hepatic apoptosis and inflammatory responses by stimulating sensory neurons. Mol Med Rep 2014; 10:1303-8. [PMID: 24938740 DOI: 10.3892/mmr.2014.2329] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Accepted: 04/16/2014] [Indexed: 11/05/2022] Open
Abstract
Laparoscopic surgery induces a milder inflammatory response than open surgery, however, the precise mechanisms underlying this phenomenon remain to be elucidated. Our previous study demonstrated that stimulation of sensory neurons inhibited hepatic apoptosis and inflammatory responses in rats subjected to hepatic ischemia/reperfusion (I/R). Since carbon dioxide (CO2) has been demonstrated to stimulate sensory neurons, it was hypothesized that CO2‑pneumoperitoneum, as used in laparoscopic surgery, may attenuate inflammatory responses by stimulating sensory neurons. This hypothesis was examined using rats subjected to hepatic I/R. The rats were subjected to partial hepatic ischemia for 60 min followed by reperfusion. Abdominal insufflation with CO2 or air was performed for 30 min prior to hepatic I/R. Hepatic I/R‑induced hepatocellular apoptosis and expression of the neutrophil chemoattractant endothelial monocyte‑activated polypeptide‑II, were inhibited by CO2‑pneumoperitoneum, however, not by air‑pneumoperitoneum. Pretreatment with the transient receptor potential vanilloid 1 antagonist SB366791 reversed the protective effects of CO2‑pneumoperitoneum. The results from the present study demonstrated that CO2‑pneumoperitoneum attenuates hepatic apoptosis and inflammatory responses in rats subjected to hepatic I/R, possibly by stimulating sensory neurons. These findings suggested that CO2‑pneumoperitoneum contributed to the attenuated inflammatory response observed following laparoscopic surgery.
Collapse
Affiliation(s)
- Miho Kawai
- Department of Gastroenterological Surgery, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Aichi 467‑8601, Japan
| | - Juan Zhao
- Department of Translational Medical Science Research, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Aichi 467‑8601, Japan
| | - Hideyuki Ishiguro
- Department of Gastroenterological Surgery, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Aichi 467‑8601, Japan
| | - Hiromitsu Takeyama
- Department of Gastroenterological Surgery, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Aichi 467‑8601, Japan
| |
Collapse
|
|
49
|
Chen S, Zhao H, Deng J, Liao P, Xu Z, Cheng Y. Comparative proteomics of glioma stem cells and differentiated tumor cells identifies S100A9 as a potential therapeutic target. J Cell Biochem 2014; 114:2795-808. [PMID: 23836528 DOI: 10.1002/jcb.24626] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2013] [Accepted: 06/27/2013] [Indexed: 12/25/2022]
Abstract
Recent studies have suggested the existence of a small subset of cancer cells called cancer stem cells (CSCs), which possess the ability to initiate malignancies, promote tumor formation, drive metastasis, and evade conventional chemotherapies. Elucidation of the specific signaling pathway and mechanism underlying the action of CSCs might improve the efficacy of cancer treatments. In this study, we analyzed differentially expressed proteins between glioma stem cells and differentiated tumor cells isolated from the human glioma cell line, U251, via iTRAQ-tagging combined with two dimensional liquid chromatography tandem MS analysis to identify proteins correlated with specific features of CSCs. Out of a total data set of 559 identified proteins, 29 proteins were up-regulated in the glioma stem cells when compared with the differentiated cells. Interestingly, The expression level of S100A9 was fivefold higher in glioma stem cells than differentiated cells. Similar results were also observed in glioma stem cells derived from other glioma cells. More importantly, knockdown of S100A9 by RNA interference suppressed the proliferation of glioma stem cell line and decreased the growth of xenograft tumors in vivo. Taken together, these results indicate that the tumorigenesis potential of CSCs arises from highly expressed S100A9.
Collapse
Affiliation(s)
- Song Chen
- Department of Neurosurgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | | | | | | | | | | |
Collapse
|
|
50
|
Megger DA, Naboulsi W, Meyer HE, Sitek B. Proteome Analyses of Hepatocellular Carcinoma. J Clin Transl Hepatol 2014; 2:23-30. [PMID: 26357614 PMCID: PMC4521250 DOI: 10.14218/jcth.2013.00022] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Revised: 12/06/2013] [Accepted: 12/07/2013] [Indexed: 12/16/2022] Open
Abstract
Proteomics has evolved into a powerful and widely used bioanalytical technique in the study of cancer, especially hepatocellular carcinoma (HCC). In this review, we provide an up to date overview of feasible proteome-analytical techniques for clinical questions. In addition, we present a broad summary of proteomic studies of HCC utilizing various technical approaches for the analysis of samples derived from diverse sources like HCC cell lines, animal models, human tissue and body fluids.
Collapse
Affiliation(s)
- Dominik A. Megger
- Medizinisches Proteom-Center, Ruhr-Universität Bochum, Bochum, Germany
- Contributed equally
- Correspondence to: Dominik A. Megger, Medizinisches Proteom-Center, Ruhr-Universität Bochum, Bochum 44801, Germany. Tel: +49-234/32-26119. E-mail: ; Barbara Sitek, Medizinisches Proteom-Center, Ruhr-Universität Bochum, Bochum 44801, Germany. Tel: +49-234/32-24362. E-mail:
| | - Wael Naboulsi
- Medizinisches Proteom-Center, Ruhr-Universität Bochum, Bochum, Germany
- Contributed equally
| | - Helmut E. Meyer
- Medizinisches Proteom-Center, Ruhr-Universität Bochum, Bochum, Germany
- Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany
| | - Barbara Sitek
- Medizinisches Proteom-Center, Ruhr-Universität Bochum, Bochum, Germany
- Correspondence to: Dominik A. Megger, Medizinisches Proteom-Center, Ruhr-Universität Bochum, Bochum 44801, Germany. Tel: +49-234/32-26119. E-mail: ; Barbara Sitek, Medizinisches Proteom-Center, Ruhr-Universität Bochum, Bochum 44801, Germany. Tel: +49-234/32-24362. E-mail:
| |
Collapse
|