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Ikeda Y, Fujii J. The Emerging Roles of γ-Glutamyl Peptides Produced by γ-Glutamyltransferase and the Glutathione Synthesis System. Cells 2023; 12:2831. [PMID: 38132151 PMCID: PMC10741565 DOI: 10.3390/cells12242831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 12/03/2023] [Accepted: 12/06/2023] [Indexed: 12/23/2023] Open
Abstract
L-γ-Glutamyl-L-cysteinyl-glycine is commonly referred to as glutathione (GSH); this ubiquitous thiol plays essential roles in animal life. Conjugation and electron donation to enzymes such as glutathione peroxidase (GPX) are prominent functions of GSH. Cellular glutathione balance is robustly maintained via regulated synthesis, which is catalyzed via the coordination of γ-glutamyl-cysteine synthetase (γ-GCS) and glutathione synthetase, as well as by reductive recycling by glutathione reductase. A prevailing short supply of L-cysteine (Cys) tends to limit glutathione synthesis, which leads to the production of various other γ-glutamyl peptides due to the unique enzymatic properties of γ-GCS. Extracellular degradation of glutathione by γ-glutamyltransferase (GGT) is a dominant source of Cys for some cells. GGT catalyzes the hydrolytic removal of the γ-glutamyl group of glutathione or transfers it to amino acids or to dipeptides outside cells. Such processes depend on an abundance of acceptor substrates. However, the physiological roles of extracellularly preserved γ-glutamyl peptides have long been unclear. The identification of γ-glutamyl peptides, such as glutathione, as allosteric modulators of calcium-sensing receptors (CaSRs) could provide insights into the significance of the preservation of γ-glutamyl peptides. It is conceivable that GGT could generate a new class of intercellular messaging molecules in response to extracellular microenvironments.
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Affiliation(s)
- Yoshitaka Ikeda
- Division of Molecular Cell Biology, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan
| | - Junichi Fujii
- Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, 2-2-2 Iidanishi, Yamagata City 990-9585, Japan
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Fujii J, Osaki T, Soma Y, Matsuda Y. Critical Roles of the Cysteine-Glutathione Axis in the Production of γ-Glutamyl Peptides in the Nervous System. Int J Mol Sci 2023; 24:ijms24098044. [PMID: 37175751 PMCID: PMC10179188 DOI: 10.3390/ijms24098044] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 04/24/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
γ-Glutamyl moiety that is attached to the cysteine (Cys) residue in glutathione (GSH) protects it from peptidase-mediated degradation. The sulfhydryl group of the Cys residue represents most of the functions of GSH, which include electron donation to peroxidases, protection of reactive sulfhydryl in proteins via glutaredoxin, and glutathione conjugation of xenobiotics, whereas Cys-derived sulfur is also a pivotal component of some redox-responsive molecules. The amount of Cys that is available tends to restrict the capacity of GSH synthesis. In in vitro systems, cystine is the major form in the extracellular milieu, and a specific cystine transporter, xCT, is essential for survival in most lines of cells and in many primary cultivated cells as well. A reduction in the supply of Cys causes GPX4 to be inhibited due to insufficient GSH synthesis, which leads to iron-dependent necrotic cell death, ferroptosis. Cells generally cannot take up GSH without the removal of γ-glutamyl moiety by γ-glutamyl transferase (GGT) on the cell surface. Meanwhile, the Cys-GSH axis is essentially common to certain types of cells; primarily, neuronal cells that contain a unique metabolic system for intercellular communication concerning γ-glutamyl peptides. After a general description of metabolic processes concerning the Cys-GSH axis, we provide an overview and discuss the significance of GSH-related compounds in the nervous system.
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Affiliation(s)
- Junichi Fujii
- Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Yamagata 990-9585, Japan
| | - Tsukasa Osaki
- Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Yamagata 990-9585, Japan
| | - Yuya Soma
- Graduate School of Nursing, Yamagata University Faculty of Medicine, Yamagata 990-9585, Japan
| | - Yumi Matsuda
- Graduate School of Nursing, Yamagata University Faculty of Medicine, Yamagata 990-9585, Japan
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3
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Kobayashi S, Homma T, Okumura N, Han J, Nagaoka K, Sato H, Konno H, Yamada S, Takao T, Fujii J. Carnosine dipeptidase II (CNDP2) protects cells under cysteine insufficiency by hydrolyzing glutathione-related peptides. Free Radic Biol Med 2021; 174:12-27. [PMID: 34324979 DOI: 10.1016/j.freeradbiomed.2021.07.036] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 07/06/2021] [Accepted: 07/25/2021] [Indexed: 01/18/2023]
Abstract
The knockout (KO) of the cystine transporter xCT causes ferroptosis, a type of iron-dependent necrotic cell death, in mouse embryonic fibroblasts, but this does not occur in macrophages. In this study, we explored the gene that supports cell survival under a xCT deficiency using a proteomics approach. Analysis of macrophage-derived peptides that were tagged with iTRAQ by liquid chromatography-mass spectrometry revealed a robust elevation in the levels of carnosine dipeptidase II (CNDP2) in xCT KO macrophages. The elevation in the CNDP2 protein levels was confirmed by immunoblot analyses and this elevation was accompanied by an increase in hydrolytic activity towards cysteinylglycine, the intermediate degradation product of glutathione after the removal of the γ-glutamyl group, in xCT KO macrophages. Supplementation of the cystine-free media of Hepa1-6 cells with glutathione or cysteinylglycine extended their survival, whereas the inclusion of bestatin, an inhibitor of CNDP2, counteracted the effects of these compounds. We established CNDP2 KO mice by means of the CRISPR/Cas9 system and found a decrease in dipeptidase activity in the liver, kidney, and brain. An acetaminophen overdose (350 mg/kg) showed not only aggravated hepatic damage but also renal injury in the CNDP2 KO mice, which was not evident in the wild-type mice that were receiving the same dose. The aggravated renal damage in the CNDP2 KO mice was consistent with the presence of abundant levels of CNDP2 in the kidney, the organ prone to developing ferroptosis. These collective data imply that cytosolic CNDP2, in conjugation with the removal of the γ-glutamyl group, recruits Cys from extracellular GSH and supports redox homeostasis of cells, particularly in epithelial cells of proximal tubules that are continuously exposed to oxidative insult from metabolic wastes that are produced in the body.
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Affiliation(s)
- Sho Kobayashi
- Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, 2-2-2 Iidanishi, Yamagata, Yamagata, 990-9585, Japan
| | - Takujiro Homma
- Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, 2-2-2 Iidanishi, Yamagata, Yamagata, 990-9585, Japan
| | - Nobuaki Okumura
- Laboratory of Biomolecular Analysis, Institute for Protein Research, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Jia Han
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, 1-1 Uchinada, Ishikawa, 920-0293, Japan
| | - Keita Nagaoka
- Department of Biological Engineering, Graduate School of Science and Engineering, Yamagata University, Yonezawa, Yamagata, 992-8510, Japan
| | - Hideyo Sato
- Laboratory of Biochemistry and Molecular Biology, Department of Medical Technology, Faculty of Medicine, Niigata University, 746-2 Asahimachi-dori, Chuo-ku, Niigata, 951-8518, Japan
| | - Hiroyuki Konno
- Department of Biological Engineering, Graduate School of Science and Engineering, Yamagata University, Yonezawa, Yamagata, 992-8510, Japan
| | - Sohsuke Yamada
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, 1-1 Uchinada, Ishikawa, 920-0293, Japan
| | - Toshifumi Takao
- Laboratory of Protein Profiling and Functional Proteomics, Institute for Protein Research, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Junichi Fujii
- Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, 2-2-2 Iidanishi, Yamagata, Yamagata, 990-9585, Japan.
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Functional and structural features of proteins associated with alternative splicing. Int J Biol Macromol 2020; 147:513-520. [PMID: 31931065 DOI: 10.1016/j.ijbiomac.2019.09.241] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 09/16/2019] [Accepted: 09/21/2019] [Indexed: 12/16/2022]
Abstract
The alternative splicing is a mechanism increasing the number of expressed proteins and a variety of these functions. We uncovered the protein domains most frequently lacked or occurred in the splice variants. Proteins presented by several isoforms participate in such processes as transcription regulation, immune response, etc. Our results displayed the association of alternative splicing with branched regulatory pathways. By considering the published data on the protein proteins encoded by the 18th human chromosome, we noted that alternative products display the differences in several functional features, such as phosphorylation, subcellular location, ligand specificity, protein-protein interactions, etc. The investigation of alternative variants referred to the protein kinase domain was performed by comparing the alternative sequences with 3D structures. It was shown that large enough insertions/deletions could be compatible with the kinase fold if they match between the conserved secondary structures. Using the 3D data on human proteins, we showed that conformational flexibility could accommodate fold alterations in splice variants. The investigations of structural and functional differences in splice isoforms are required to understand how to distinguish the isoforms expressed as functioning proteins from the non-realized transcripts. These studies allow filling the gap between genomic and proteomic data.
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Zhang LQ, Yang HQ, Yang SQ, Wang Y, Chen XJ, Lu HS, Zhao LP. CNDP2 Acts as an Activator for Human Ovarian Cancer Growth and Metastasis via the PI3K/AKT Pathway. Technol Cancer Res Treat 2020; 18:1533033819874773. [PMID: 31537175 PMCID: PMC6755628 DOI: 10.1177/1533033819874773] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Introduction: The mechanism of tumorigenesis and metastasis of ovarian cancer has not yet been
elucidated. This study aimed to investigate the role and molecular mechanism of
cytosolic nonspecific dipeptidase 2 in tumorigenesis and metastasis. Methods: Cytosolic nonspecific dipeptidase 2 expression in human ovarian cancer tissues and cell
lines was assessed with methyl thiazolyl tetrazolium (MTT), clone formation, and
transwell assays performed to evaluate the ability of ovarian cancer cells to
proliferate and migrate. Nude mice tumor formation experiments were also performed by
subcutaneously injecting cells with stable cytosolic nonspecific dipeptidase 2 knockdown
and control SKOV3 cells into BALB/c female nude mice to detect changes in PI3K/AKT
pathway-related proteins by Western blotting. Results: Cytosolic nonspecific dipeptidase 2 was highly expressed in human ovarian cancer
tissues, with its expression associated with pathological data, including ovarian cancer
metastasis. A cytosolic nonspecific dipeptidase 2 stable knockdown or ectopic expression
ovarian cancer cell model was established and demonstrated that cytosolic nonspecific
dipeptidase 2 could promote the proliferation of ovarian cancer cells. Transwell cell
migration and invasion assays confirmed that cytosolic nonspecific dipeptidase 2
enhanced cell metastasis in ovarian cancer. Furthermore, in vivo
xenograft experiments demonstrated that cytosolic nonspecific dipeptidase 2 can promote
the development and progression of ovarian cancer, increasing the expression of
phosphorylated PI3K and AKT. Conclusions: Cytosolic nonspecific dipeptidase 2 promotes the occurrence and development of ovarian
cancer through the PI3K/AKT signaling pathway.
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Affiliation(s)
- Li Q Zhang
- Department of Gynecology, Taizhou Central Hospital, Taizhou, China
| | - Hua Q Yang
- Department of Gynecology, Taizhou Central Hospital, Taizhou, China
| | - Su Q Yang
- Department of Gynecology, Taizhou Central Hospital, Taizhou, China
| | - Ying Wang
- Department of Gynecology, Taizhou Central Hospital, Taizhou, China
| | - Xian J Chen
- Department of Clinical Laboratory, Taizhou Central Hospital, Taizhou, China
| | - Hong S Lu
- Department of Pathology, Taizhou Central Hospital, Taizhou, China
| | - Ling P Zhao
- Department of Gynecology, Taizhou Central Hospital, Taizhou, China
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Andreyeva EN, Ogienko AA, Dubatolova TD, Oshchepkova AL, Kozhevnikova EN, Ivankin AV, Pavlova GA, Kopyl SA, Pindyurin AV. A toolset to study functions of Cytosolic non-specific dipeptidase 2 (CNDP2) using Drosophila as a model organism. BMC Genet 2019; 20:31. [PMID: 30885138 PMCID: PMC6421639 DOI: 10.1186/s12863-019-0726-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Background Expression of the CNDP2 gene is frequently up- or down-regulated in different types of human cancers. However, how the product of this gene is involved in cell growth and proliferation is poorly understood. Moreover, our knowledge of the functions of the CNDP2 orthologs in well-established model organisms is scarce. In particular, the function of the D. melanogaster ortholog of CNDP2, encoded by the CG17337 gene (hereafter referred to as dCNDP2), is still unknown. Results This study was aimed at developing a set of genetic and molecular tools to study the roles of dCNDP2. We generated a dCNDP2 null mutation (hereafter ∆dCNDP2) using CRISPR/Cas9-mediated homologous recombination (HR) and found that the ∆dCNDP2 mutants are homozygous viable, morphologically normal and fertile. We also generated transgenic fly lines expressing eGFP-tagged and non-tagged dCNDP2 protein, all under the control of the UAS promoter, as well as polyclonal antibodies specific to dCNDP2. Using these tools, we demonstrate that only one of the two predicted dCNDP2 isoforms is expressed throughout the different tissues tested. dCNDP2 was detected in both the cytoplasm and the nucleus, and was found to be associated with multiple sites in the salivary gland polytene chromosomes. Conclusions The dCNDP2 gene is not essential for fly viability under standard laboratory conditions. The subcellular localization pattern of dCNDP2 suggests that this protein might have roles in both the cytoplasm and the nucleus. The genetic and molecular tools developed in this study will allow further functional characterization of the conserved CNDP2 protein using D. melanogaster as a model system. Electronic supplementary material The online version of this article (10.1186/s12863-019-0726-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Evgeniya N Andreyeva
- Institute of Molecular and Cellular Biology, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia.
| | - Anna A Ogienko
- Institute of Molecular and Cellular Biology, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia.,Novosibirsk State University, Novosibirsk, 630090, Russia
| | - Tatiana D Dubatolova
- Institute of Molecular and Cellular Biology, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia
| | - Anastasiya L Oshchepkova
- Institute of Molecular and Cellular Biology, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia.,Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia
| | - Elena N Kozhevnikova
- Institute of Molecular and Cellular Biology, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia
| | - Anton V Ivankin
- Institute of Molecular and Cellular Biology, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia
| | - Gera A Pavlova
- Institute of Molecular and Cellular Biology, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia
| | - Sergei A Kopyl
- Institute of Molecular and Cellular Biology, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia
| | - Alexey V Pindyurin
- Institute of Molecular and Cellular Biology, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia. .,Novosibirsk State University, Novosibirsk, 630090, Russia.
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Liang CM, Chen L, Hu H, Ma HY, Gao LL, Qin J, Zhong CP. Chemokines and their receptors play important roles in the development of hepatocellular carcinoma. World J Hepatol 2015; 7:1390-1402. [PMID: 26052384 PMCID: PMC4450202 DOI: 10.4254/wjh.v7.i10.1390] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 11/08/2014] [Accepted: 04/07/2015] [Indexed: 02/06/2023] Open
Abstract
The chemokine system consists of four different subclasses with over 50 chemokines and 19 receptors. Their functions in the immune system have been well elucidated and research during the last decades unveils their new roles in hepatocellular carcinoma (HCC). The chemokines and their receptors in the microenvironment influence the development of HCC by several aspects including: inflammation, effects on immune cells, angiogenesis, and direct effects on HCC cells. Regarding these aspects, pre-clinical research by targeting the chemokine system has yielded promising data, and these findings bring us new clues in the chemokine-based therapies for HCC.
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8
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N-lactoyl-amino acids are ubiquitous metabolites that originate from CNDP2-mediated reverse proteolysis of lactate and amino acids. Proc Natl Acad Sci U S A 2015; 112:6601-6. [PMID: 25964343 DOI: 10.1073/pnas.1424638112] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Despite technological advances in metabolomics, large parts of the human metabolome are still unexplored. In an untargeted metabolomics screen aiming to identify substrates of the orphan transporter ATP-binding cassette subfamily C member 5 (ABCC5), we identified a class of mammalian metabolites, N-lactoyl-amino acids. Using parallel protein fractionation in conjunction with shotgun proteomics on fractions containing N-lactoyl-Phe-forming activity, we unexpectedly found that a protease, cytosolic nonspecific dipeptidase 2 (CNDP2), catalyzes their formation. N-lactoyl-amino acids are ubiquitous pseudodipeptides of lactic acid and amino acids that are rapidly formed by reverse proteolysis, a process previously considered to be negligible in vivo. The plasma levels of these metabolites strongly correlate with plasma levels of lactate and amino acid, as shown by increased levels after physical exercise and in patients with phenylketonuria who suffer from elevated Phe levels. Our approach to identify unknown metabolites and their biosynthesis has general applicability in the further exploration of the human metabolome.
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Xue C, Zhang Z, Yu H, Yu M, Yuan K, Yang T, Miao M, Shi H. Up-regulation of CNDP2 facilitates the proliferation of colon cancer. BMC Gastroenterol 2014; 14:96. [PMID: 24885395 PMCID: PMC4035726 DOI: 10.1186/1471-230x-14-96] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2013] [Accepted: 05/14/2014] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Cytosolic nonspecific dipetidase (CN2) belongs to the family of M20 metallopeptidases. It was stated in previous articles that higher expression levels of CN2 were observed in renal cell carcinoma and breast cancer. Our study explored the correlation between CN2 and colon carcinogenesis. METHODS We analysed the relationship between 183 patients clinicopathological characteristics and its CN2 expression. To detect the levels of CN2 in colon cancer cell lines and colon cancer tissues by western blot. To verify cell proliferation in colon cancer cells with knockdown of CNDP2 and explore the causes of these phenomena. RESULTS The expression levels of CN2 in clinical colon tumors and colon cancer cell lines were significantly higher than that in normal colon mucosa and colon cell lines. The difference in CN2 levels was associated with tumor location (right- and left-sided colon cancer), but there was no significant association with age, gender, tumor size, tumor grade, tumor stage or serum carcinoembryonic antigen (CEA). Knockdown of CNDP2 inhibited cell proliferation, blocked cell cycle progression and retarded carcinogenesis in an animal model. The signaling pathway through which knockdown of CNDP2 inhibited cell proliferation and tumorigenesis involved in EGFR, cyclin B1 and cyclin E. CONCLUSIONS Knockdown of CNDP2 can inhibit the proliferation of colon cancer in vitro and retarded carcinogenesis in vivo.
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Affiliation(s)
| | | | | | | | | | | | - Mingyong Miao
- Department of Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan II Road, Guangzhou, Guangdong 510080, China.
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Zhang Z, Miao L, Xin X, Zhang J, Yang S, Miao M, Kong X, Jiao B. Underexpressed CNDP2 participates in gastric cancer growth inhibition through activating the MAPK signaling pathway. Mol Med 2014; 20:17-28. [PMID: 24395568 DOI: 10.2119/molmed.2013.00102] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2013] [Accepted: 12/17/2013] [Indexed: 12/27/2022] Open
Abstract
Increasing evidence suggests that cytosolic non-specific dipeptidase 2 (CNDP2) appears to do more than just perform an enzymatic activity; it is functionally important in cancers as well. Here, we show that the expression of CNDP2 is commonly down-regulated in gastric cancer tissues. The ectopic expression of CNDP2 resulted in significant inhibition of cell proliferation, induction of cell apoptosis and cell cycle arrest, and suppressed gastric tumor growth in nude mice. We further revealed that the reintroduction of CNDP2 transcriptionally upregulated p38 and activated c-Jun NH2-terminal kinase (JNK), whereas the loss of CNDP2 increased the phosphorylation of extracellular signal-related kinase (ERK). These results suggest that CNDP2 acts as a functional tumor suppressor in gastric cancer via activation of the mitogen-activated protein kinase (MAPK) pathway.
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Affiliation(s)
- Zhenwei Zhang
- Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai, China Key Laboratory of Liver Disease, Center of Infectious Diseases, Guangzhou 458 Hospital, Guangzhou, China
| | - Lei Miao
- Department of Pharmacology, School of Pharmacy and Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Xiaoming Xin
- Department of Pharmacology, School of Pharmacy and Institute of Biomedical Sciences, Fudan University, Shanghai, China Department of Pharmacology, Taishan Medical University, Shandong Province, China
| | - Jianpeng Zhang
- Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai, China
| | - Shengsheng Yang
- Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai, China
| | - Mingyong Miao
- Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai, China
| | - Xiangping Kong
- Key Laboratory of Liver Disease, Center of Infectious Diseases, Guangzhou 458 Hospital, Guangzhou, China
| | - Binghua Jiao
- Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai, China
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11
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Li L, Zhang Z, Wang C, Miao L, Zhang J, Wang J, Jiao B, Zhao S. Quantitative proteomics approach to screening of potential diagnostic and therapeutic targets for laryngeal carcinoma. PLoS One 2014; 9:e90181. [PMID: 24587265 PMCID: PMC3937387 DOI: 10.1371/journal.pone.0090181] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Accepted: 01/28/2014] [Indexed: 12/31/2022] Open
Abstract
To discover candidate biomarkers for diagnosis and detection of human laryngeal carcinoma and explore possible mechanisms of this cancer carcinogenesis, two-dimensional strong cation-exchange/reversed-phase nano-scale liquid chromatography/mass spectrometry analysis was used to identify differentially expressed proteins between the laryngeal carcinoma tissue and the adjacent normal tissue. As a result, 281 proteins with significant difference in expression were identified, and four differential proteins, Profilin-1 (PFN1), Nucleolin (NCL), Cytosolic non-specific dipeptidase (CNDP2) and Mimecan (OGN) with different subcellular localization were selectively validated. Semiquantitative RT-PCR and Western blotting were performed to detect the expression of the four proteins employing a large collection of human laryngeal carcinoma tissues, and the results validated the differentially expressed proteins identified by the proteomics. Furthermore, we knocked down PFN1 in immortalized human laryngeal squamous cell line Hep-2 cells and then the proliferation and metastasis of these transfected cells were measured. The results showed that PFN1 silencing inhibited the proliferation and affected the migration ability of Hep-2 cells, providing some new insights into the pathogenesis of PFN1 in laryngeal carcinoma. Altogether, our present data first time show that PFN1, NCL, CNDP2 and OGN are novel potential biomarkers for diagnosis and therapeutic targets for laryngeal carcinoma, and PFN1 is involved in the metastasis of laryngeal carcinoma.
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Affiliation(s)
- Li Li
- Department of Otolaryngology-Head and Neck Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Zhenwei Zhang
- Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai, China
- Key Laboratory of Liver Disease, Center of Infectious Diseases, Guangzhou 458 Hospital, Guangzhou, China
| | - Chengyu Wang
- Department of Otolaryngology-Head and Neck Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Lei Miao
- Department of Pharmacology, School of Pharmacy and Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jianpeng Zhang
- Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai, China
- * E-mail: (BJ); (SZ); (JZ)
| | - Jiasen Wang
- Department of Otolaryngology-Head and Neck Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Binghua Jiao
- Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai, China
- * E-mail: (BJ); (SZ); (JZ)
| | - Shuwei Zhao
- Department of Otolaryngology-Head and Neck Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
- * E-mail: (BJ); (SZ); (JZ)
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12
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Giovannetti E, Wang Q, Avan A, Funel N, Lagerweij T, Lee JH, Caretti V, van der Velde A, Boggi U, Wang Y, Vasile E, Peters GJ, Wurdinger T, Giaccone G. Role of CYB5A in pancreatic cancer prognosis and autophagy modulation. J Natl Cancer Inst 2013; 106:djt346. [PMID: 24301457 DOI: 10.1093/jnci/djt346] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Loss of 18q22.3 is a prognostic marker in pancreatic ductal adenocarcinoma (PDAC). This study investigated genes encoded by this cytoband. METHODS We studied mRNA/protein expression in radically resected (n = 130) and metastatic patients (n = 50). The role of CYB5A was tested in 11 PDAC cell lines and five primary cultures through retrovirus-mediated upregulation and small interfering RNA using wound-healing, invasion, annexin-V, electron microscopy, and autophagic assays, as well as autophagy genes and kinases arrays. CYB5A+ orthotopic models (n = 6 mice/group) were monitored by Firefly and Gaussia-luciferase bioluminescence, magnetic resonance imaging, and high-frequency ultrasound. Data were analyzed by t test, Fisher exact-test, log-rank test and Cox proportional hazards models. All statistical tests were two-sided. RESULTS Both resected and metastatic patients with low mRNA or protein expression of CYB5A had statistically significantly shorter survival (eg, median = 16.7 months, 95% confidence interval [CI] = 13.5 to 19.9; vs median = 24.8 months, 95% CI = 12.8 to 36.9; P = .02, two-sided log-rank test; n = 82 radically resected PDACs), and multivariable analyses confirmed prognostic relevance. Moreover, we characterized a novel function to CYB5A, autophagy induction, concomitant with reduced proliferation and migration/invasion of PDAC cells. Network analysis of proautophagic pathways suggested CYB5A interaction with TRAF6, which was confirmed by TRAF6 downregulation after CYB5A reconstitution (-69% in SU.86.86-CYB5A+; P = .005, two-sided t test). CYB5A silencing had opposite effects, restoring TRAF6 expression and wound healing. In vivo studies showed that CYB5A induced autophagy while inhibiting tumor growth/metastasis and increasing survival (median = 57 days, 95% CI = 52 to 61; vs median = 44 days, 95% CI = 21 to 57; P = .03, two-sided log-rank test). CONCLUSIONS These results define CYB5A as a novel prognostic factor for PDAC that exerts its tumor-suppressor function through autophagy induction and TRAF6 modulation.
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Affiliation(s)
- Elisa Giovannetti
- Affiliations of authors: Department of Medical Oncology (EG, AA, GJP) and Department of Neurosurgery (TL, VC, TW), VU University Medical Center, and Centre for Integrative Bioinformatics (AvdV), VU University, Amsterdam, the Netherlands; Department of Ricerca Traslazionale e delle Nuove Tecnologie in Medicina e Chirurgia, University of Pisa, Pisa, Italy (NF, UB, EV); Department of Neurology, Stanford University, Stanford, CA (VC); Department of Neurology, Massachusetts General Hospital and Neuroscience Program, Harvard Medical School, Boston, MA (TW); Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD (QW, J-HL, YW, GG)
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Liu M, Wu R, Yang F, Wang T, Zhang P, Gu J, Wan D, Yang S. Identification of FN1BP1 as a novel cell cycle regulator through modulating G1 checkpoint in human hepatocarcinoma Hep3B cells. PLoS One 2013; 8:e57574. [PMID: 23469028 PMCID: PMC3585200 DOI: 10.1371/journal.pone.0057574] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2012] [Accepted: 01/22/2013] [Indexed: 01/05/2023] Open
Abstract
A novel human gene, FN1BP1 (fibronectin 1 binding protein 1), was identified using the human placenta cDNA library. Northern blotting showed a transcript of ∼2.8 kb in human placenta, liver, and skeletal muscle tissues. This mRNA transcript length was similar to the full FN1BP1 sequence obtained previously. We established a conditionally induced stable cell line of Hep3B-Tet-on-FN1BP1 to investigate the preliminary function and mechanism of the secretory FN1BP1 protein. Cell-proliferation and colony-conformation assays demonstrated that FN1BP1 protein suppressed Hep3B cell growth and colonization in vitro. Analysis of Atlas human cDNA expression indicated that after FN1BP1 Dox-inducing expression for 24 h, 19 genes were up-regulated and 22 genes were down-regulated more than two-fold. Most of these gene changes were related to cell-cycle-arrest proteins (p21cip1, p15, and cyclin E1), transcription factors (general transcription factors, zinc finger proteins, transcriptional enhancer factors), SWI/SNF (SWItch/Sucrose NonFermentable) complex units, early-response proteins, and nerve growth or neurotrophic factors. Down-regulated genes were subject to colony-stimulating factors (e.g., GMSFs), and many repair genes were involved in DNA damage (RAD, ERCC, DNA topoisomerase, polymerase, and ligase). Some interesting genes (p21cip1, ID2, GMSF, ERCC5, and RPA1), which changed in the cDNA microarray analysis, were confirmed by semi-qRT-PCR, and similar changes in expression were observed. FCM cell-cycle analysis indicated that FN1BP1 over-expression could result in G1 phase arrest. FN1BP1 might inhibit cell growth and/or colony conformation through G1 phase arrest of the Hep3B cell cycle. These results indicate the potential role of FN1BP1 as a treatment target for hepatocellular carcinoma.
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Affiliation(s)
- Mei Liu
- The Jingsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiaotong University, Shanghai, China
| | - Ronghua Wu
- The Jingsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu, China
| | - Fuye Yang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiaotong University, Shanghai, China
| | - Tao Wang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiaotong University, Shanghai, China
| | - Pingping Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiaotong University, Shanghai, China
| | - Jianren Gu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiaotong University, Shanghai, China
| | - Dafang Wan
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiaotong University, Shanghai, China
| | - Shengli Yang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiaotong University, Shanghai, China
- * E-mail:
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Interactive cellular proteins related to classical swine fever virus non-structure protein 2 by yeast two-hybrid analysis. Mol Biol Rep 2012; 39:10515-24. [PMID: 23076522 DOI: 10.1007/s11033-012-1936-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2012] [Accepted: 10/01/2012] [Indexed: 10/27/2022]
Abstract
Classical swine fever is caused by the classical swine fever virus (CSFV), which has a special affinity to endothelial cells. This fever is characterized by hemorrhage and necrosis of vascular injury. Very little information is available on the interaction between vascular endothelial cells and CSFV. In the current report, the cDNA library of swine umbilical vein endothelial cell (SUVEC) was constructed by the switching mechanism at 5' end of the RNA transcript approach. The yeast two-hybrid (Y2H) system was adopted to screen non-structure 2 protein (NS2) interactive proteins in the SUVEC line. Alignment with the NCBI database revealed 11 interactive proteins: GOPC, HNRNPH1, DNAJA1, ATP6, CSDE1, CNDP2, FANCL, TMED4, DNAJA4, MOAP1, and PNMA1. These proteins were mostly related to apoptosis, stress response and oxidation reduction, or metabolism. In the protein interaction network constructed based on proteins with NS2, the more important proteins were MOAP1, DNAJA1, GOPC, FANCL, TMED4, and CSDE1. The interactions detected by the Y2H should be regarded only as preliminary indications. However, the CSFV NS2 interactive proteins in the SUVEC cDNA library obtained in the current study provides valuable information for gaining a better understanding of the host protein-virus interactions of the CSFV NS2 protein.
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Turajlic S, Furney SJ, Lambros MB, Mitsopoulos C, Kozarewa I, Geyer FC, MacKay A, Hakas J, Zvelebil M, Lord CJ, Ashworth A, Thomas M, Stamp G, Larkin J, Reis-Filho JS, Marais R. Whole genome sequencing of matched primary and metastatic acral melanomas. Genome Res 2012; 22:196-207. [PMID: 22183965 PMCID: PMC3266028 DOI: 10.1101/gr.125591.111] [Citation(s) in RCA: 125] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2011] [Accepted: 11/29/2011] [Indexed: 12/25/2022]
Abstract
Next generation sequencing has enabled systematic discovery of mutational spectra in cancer samples. Here, we used whole genome sequencing to characterize somatic mutations and structural variation in a primary acral melanoma and its lymph node metastasis. Our data show that the somatic mutational rates in this acral melanoma sample pair were more comparable to the rates reported in cancer genomes not associated with mutagenic exposure than in the genome of a melanoma cell line or the transcriptome of melanoma short-term cultures. Despite the perception that acral skin is sun-protected, the dominant mutational signature in these samples is compatible with damage due to ultraviolet light exposure. A nonsense mutation in ERCC5 discovered in both the primary and metastatic tumors could also have contributed to the mutational signature through accumulation of unrepaired dipyrimidine lesions. However, evidence of transcription-coupled repair was suggested by the lower mutational rate in the transcribed regions and expressed genes. The primary and the metastasis are highly similar at the level of global gene copy number alterations, loss of heterozygosity and single nucleotide variation (SNV). Furthermore, the majority of the SNVs in the primary tumor were propagated in the metastasis and one nonsynonymous coding SNV and one splice site mutation appeared to arise de novo in the metastatic lesion.
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Affiliation(s)
- Samra Turajlic
- Signal Transduction Team, Division of Cancer Biology, Institute of Cancer Research, London SW3 6JB, United Kingdom
| | - Simon J. Furney
- Signal Transduction Team, Division of Cancer Biology, Institute of Cancer Research, London SW3 6JB, United Kingdom
| | - Maryou B. Lambros
- Molecular Pathology Team, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, United Kingdom
| | - Costas Mitsopoulos
- Cancer Informatics, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, United Kingdom
| | - Iwanka Kozarewa
- Division of Breast Cancer Research, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, United Kingdom
| | - Felipe C. Geyer
- Molecular Pathology Team, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, United Kingdom
| | - Alan MacKay
- Molecular Pathology Team, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, United Kingdom
| | - Jarle Hakas
- Cancer Informatics, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, United Kingdom
| | - Marketa Zvelebil
- Cancer Informatics, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, United Kingdom
| | - Christopher J. Lord
- Division of Breast Cancer Research, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, United Kingdom
| | - Alan Ashworth
- Division of Breast Cancer Research, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, United Kingdom
| | - Meirion Thomas
- Department of Surgery, Royal Marsden Hospital, London SW3 6JJ, United Kingdom
| | - Gordon Stamp
- Department of Histopathology, Royal Marsden Hospital, London SW3 6JJ, United Kingdom
| | - James Larkin
- Melanoma Unit, Royal Marsden Hospital, London SW3 6JJ, United Kingdom
| | - Jorge S. Reis-Filho
- Molecular Pathology Team, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, United Kingdom
| | - Richard Marais
- Signal Transduction Team, Division of Cancer Biology, Institute of Cancer Research, London SW3 6JB, United Kingdom
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Lee JH, Giovannetti E, Hwang JH, Petrini I, Wang Q, Voortman J, Wang Y, Steinberg SM, Funel N, Meltzer PS, Wang Y, Giaccone G. Loss of 18q22.3 involving the carboxypeptidase of glutamate-like gene is associated with poor prognosis in resected pancreatic cancer. Clin Cancer Res 2011; 18:524-33. [PMID: 22128300 DOI: 10.1158/1078-0432.ccr-11-1903] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PURPOSES Pancreatic cancer is the fourth leading cause of cancer-related death, and studies on the clinical relevance of its genomic imbalances are warranted. EXPERIMENTAL DESIGN Recurrent copy number alterations of cytobands and genes were analyzed by array comparative genomic hybridization (aCGH) in 44 resected pancreatic cancer specimens. Prognostic markers identified by aCGH were validated by PCR gene copy number assay in an independent validation cohort of 61 resected pancreatic cancers. The functions of gene identified were evaluated by proliferation, cell cycle, and migration assays in pancreatic cancer cells. RESULTS We showed recurrent copy number gains and losses in the first cohort. Loss of 18q22.3 was significantly associated with short-term overall survival in the first cohort (P = 0.019). This cytoband includes the carboxypeptidase of glutamate-like (CPGL) gene. CPGL gene deletion was associated with shorter overall survival in the validation cohort (P = 0.003). CPGL deletion and mutations of TP53 or Kras seem to be independent events. A Cox model analysis of the two cohorts combined showed that loss of 18q22.3/deletion of the CPGL gene was an independent poor prognostic factor for overall survival (HR = 2.72, P = 0.0007). Reconstitution of CPGL or its splicing variant CPGL-B into CPGL-negative pancreatic cancer cells attenuated cell growth, migration, and induced G(1) accumulation. CONCLUSION Loss of 18q22.3/deletion of the CPGL gene is a poor prognostic marker in resected pancreatic cancer, and functional studies suggest the CPGL gene as growth suppressor gene in pancreatic cancer.
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Affiliation(s)
- Jih-Hsiang Lee
- Medical Oncology Branch, Genetic Branch, and Biostatistics and Data Management Section, National Cancer Institute, NIH, Bethesda, MD 20892, USA
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Ryu HS, Park SH, Lee KB, Shin E, Jang JJ. Expression of the Transmembrane Glycoprotein CD44s Is Potentially an Independent Predictor of Recurrence in Hepatocellular Carcinoma. Gut Liver 2011; 5:204-9. [PMID: 21814602 PMCID: PMC3140667 DOI: 10.5009/gnl.2011.5.2.204] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2010] [Accepted: 12/13/2010] [Indexed: 02/06/2023] Open
Abstract
Background/Aims Cluster differentiation 44 standard isoform (CD44s) is a transmembrane glycoprotein. CD44s is a known prognostic factor in various cancers, due to its involvement in tumor cell growth, invasion and metastasis. Its prognostic role, however, is debated because it can be a positive or negative prognostic factor depending on tumor type and is still an ambiguous prognostic indicator in other cancers, especially hepatocellular carcinoma (HCC). We investigated the relationship between CD44s expression and survival in HCC patients. Methods A total of 260 HCC samples were collected to generate a tissue microarray. Staining of the arrays with a primary mouse CD44s monoclonal antibody was followed by evaluation of the relationship between CD44s expression and tumor differentiation. The effect of CD44s expression on patient survival was analyzed. Results CD44s protein expression correlated with histological grade (most and worst Edmondson grade) of the HCC (p=0.029 and p=0.039, respectively) and adversely affected the disease free survival period based on univariate and multivariate analyses (p=0.038 and p=0.077, respectively). Conclusions High CD44s protein expression correlates with shorter disease free survival and poorly differentiated HCC. CD44s-targeted therapy may be efficacious for HCC treatment in the future.
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Affiliation(s)
- Han Suk Ryu
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
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Midorikawa Y, Sugiyama Y, Aburatani H. Molecular targets for liver cancer therapy: From screening of target genes to clinical trials. Hepatol Res 2010; 40:49-60. [PMID: 19788683 DOI: 10.1111/j.1872-034x.2009.00583.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Cancer arises from the accumulation of genetic alterations, and the inactivation of oncogenes, or recovery of suppressor genes, are promising strategies for cancer treatment. Genome-based drug research starts with identification of target genes and is accomplished by exploitation of target-based drugs such as monoclonal antibodies, small molecules and antisense drugs. Recently, clinical trials for treatment of advanced hepatocellular carcinoma (HCC) have been performed, and the effectiveness of sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor and Ras kinase, has been demonstrated. In addition to known target genes, microarray technology has enabled us to constitute novel therapeutic targets, and many researchers have applied this technology in studies of HCC and have identified candidate target genes, validated to affect cell growth. In addition, promoter arrays for whole-genome epigenetic aberration analysis, ChIP-chip analysis using tiling arrays, and high-throughput sequencing systems have been applied to drug discovery. To elucidate the status of therapeutic target genes in vivo, development of diagnostic markers for stratification of patients is a pressing need. Here, we review recent advances in microarray technology for liver cancer, discuss the innovations and approaches to therapeutic target discovery, and present data regarding the outcome of gene target therapy using monoclonal antibodies and molecular diagnostic markers in our laboratory.
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Affiliation(s)
- Yutaka Midorikawa
- Department of Surgery, Teikyo University School of Medicine University Hospital, Mizonokuchi, Kawasaki
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Okamura N, Masuda T, Gotoh A, Shirakawa T, Terao S, Kaneko N, Suganuma K, Watanabe M, Matsubara T, Seto R, Matsumoto J, Kawakami M, Yamamori M, Nakamura T, Yagami T, Sakaeda T, Fujisawa M, Nishimura O, Okumura K. Quantitative proteomic analysis to discover potential diagnostic markers and therapeutic targets in human renal cell carcinoma. Proteomics 2008; 8:3194-203. [DOI: 10.1002/pmic.200700619] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Midorikawa Y, Sugiyama Y, Aburatani H. Screening of liver-targeted drugs. Expert Opin Drug Discov 2008; 3:643-54. [DOI: 10.1517/17460441.3.6.643] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Abstract
Proteases have long been associated with cancer progression because of their ability to degrade extracellular matrices, which facilitates invasion and metastasis. However, recent studies have shown that these enzymes target a diversity of substrates and favour all steps of tumour evolution. Unexpectedly, the post-trial studies have also revealed proteases with tumour-suppressive effects. These effects are associated with more than 30 different enzymes that belong to three distinct protease classes. What are the clinical implications of these findings?
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Affiliation(s)
- Carlos López-Otín
- Carlos López-Otín is at the Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.
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