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1
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de Paz JL, García-Jiménez MJ, Jafari V, García-Domínguez M, Nieto PM. Synthesis and interaction with growth factors of sulfated oligosaccharides containing an anomeric fluorinated tail. Bioorg Chem 2023; 141:106929. [PMID: 37879181 DOI: 10.1016/j.bioorg.2023.106929] [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: 09/21/2023] [Revised: 10/16/2023] [Accepted: 10/17/2023] [Indexed: 10/27/2023]
Abstract
Compounds that mimic the biological properties of glycosaminoglycans (GAGs) and can be more easily prepared than the native GAG oligosaccharides are highly demanded. Here, we present the synthesis of sulfated oligosaccharides displaying a perfluorinated aliphatic tag at the reducing end as GAG mimetics. The preparation of these molecules was greatly facilitated by the presence of the fluorinated tail since the reaction intermediates were isolated by simple fluorous solid-phase extraction. Fluorescence polarization competition assays indicated that the synthesized oligosaccharides interacted with two heparin-binding growth factors, midkine (MK) and FGF-2, showing higher binding affinities than the natural oligosaccharides, and can be therefore considered as useful GAG mimetics. Moreover, NMR experiments showed that the 3D structure of these compounds is similar to that of the native sequences, in terms of sugar ring and glycosidic linkage conformations. Finally, we also demonstrated that these derivatives are able to block the MK-stimulating effect on NIH3T3 cells growth.
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Affiliation(s)
- José L de Paz
- Glycosystems Laboratory, Instituto de Investigaciones Químicas (IIQ), cicCartuja, CSIC and Universidad de Sevilla, Americo Vespucio, 49, 41092 Sevilla, Spain.
| | - María José García-Jiménez
- Glycosystems Laboratory, Instituto de Investigaciones Químicas (IIQ), cicCartuja, CSIC and Universidad de Sevilla, Americo Vespucio, 49, 41092 Sevilla, Spain
| | - Vahid Jafari
- Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Américo Vespucio, 24, 41092 Sevilla, Spain
| | - Mario García-Domínguez
- Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Américo Vespucio, 24, 41092 Sevilla, Spain
| | - Pedro M Nieto
- Glycosystems Laboratory, Instituto de Investigaciones Químicas (IIQ), cicCartuja, CSIC and Universidad de Sevilla, Americo Vespucio, 49, 41092 Sevilla, Spain.
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2
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Kam NW, Lau CY, Che CM, Lee VHF. Nasopharynx Battlefield: Cellular Immune Responses Mediated by Midkine in Nasopharyngeal Carcinoma and COVID-19. Cancers (Basel) 2023; 15:4850. [PMID: 37835544 PMCID: PMC10571800 DOI: 10.3390/cancers15194850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 09/28/2023] [Accepted: 10/02/2023] [Indexed: 10/15/2023] Open
Abstract
Clinical evidence suggests that the severe respiratory illness coronavirus disease 2019 (COVID-19) is often associated with a cytokine storm that results in dysregulated immune responses. Prolonged COVID-19 positivity is thought to disproportionately affect cancer patients. With COVID-19 disrupting the delivery of cancer care, it is crucial to gain momentum and awareness of the mechanistic intersection between these two diseases. This review discusses the role of the cytokine midkine (MK) as an immunomodulator in patients with COVID-19 and nasopharyngeal carcinoma (NPC), both of which affect the nasal cavity. We conducted a review and analysis of immunocellular similarities and differences based on clinical studies, research articles, and published transcriptomic datasets. We specifically focused on ligand-receptor pairs that could be used to infer intercellular communication, as well as the current medications used for each disease, including NPC patients who have contracted COVID-19. Based on our findings, we recommend close monitoring of the MK axis to maintain the desirable effects of therapeutic regimens in fighting both NPC and COVID-19 infections.
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Affiliation(s)
- Ngar-Woon Kam
- Department of Clinical Oncology, Centre of Cancer Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China; (N.-W.K.); (C.-Y.L.)
- Laboratory for Synthetic Chemistry and Chemical Biology Ltd., Hong Kong Science Park, New Territories, Hong Kong 999077, China;
| | - Cho-Yiu Lau
- Department of Clinical Oncology, Centre of Cancer Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China; (N.-W.K.); (C.-Y.L.)
- Laboratory for Synthetic Chemistry and Chemical Biology Ltd., Hong Kong Science Park, New Territories, Hong Kong 999077, China;
| | - Chi-Ming Che
- Laboratory for Synthetic Chemistry and Chemical Biology Ltd., Hong Kong Science Park, New Territories, Hong Kong 999077, China;
- Department of Chemistry, Faculty of Science, The University of Hong Kong, Hong Kong 999077, China
| | - Victor Ho-Fun Lee
- Department of Clinical Oncology, Centre of Cancer Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China; (N.-W.K.); (C.-Y.L.)
- Clinical Oncology Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China
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Matsunaga W, Gotoh A. Adenovirus as a Vector and Oncolytic Virus. Curr Issues Mol Biol 2023; 45:4826-4840. [PMID: 37367056 DOI: 10.3390/cimb45060307] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 05/30/2023] [Accepted: 05/30/2023] [Indexed: 06/28/2023] Open
Abstract
Adenoviral vectors, both oncolytic viruses and gene delivery vectors, are among the earliest approved and commercialised vectors for gene therapy. Adenoviruses have high cytotoxicity and immunogenicity. Therefore, lentiviruses or adeno-associated viruses as viral vectors and herpes simplex virus as an oncolytic virus have recently drawn attention. Thus, adenoviral vectors are often considered relatively obsolete. However, their high cargo limit and transduction efficiency are significant advantages over newer viral vectors. This review provides an overview of the new-generation adenoviral vectors. In addition, we describe the modification of the fiber knob region that enhances affinity of adenoviral vectors for cancer cells and the utilisation of cancer-cell-specific promoters to suppress expression of unwanted transgenes in non-malignant tissues.
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Affiliation(s)
- Wataru Matsunaga
- Joint-Use Research Facilities, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya 663-8501, Japan
| | - Akinobu Gotoh
- Department of Education for Medical Research Base, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya 663-8501, Japan
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García‐Jiménez MJ, Gil‐Caballero S, Maza S, Corzana F, Juárez‐Vicente F, Miles JR, Sakamoto K, Kadomatsu K, García‐Domínguez M, de Paz JL, Nieto PM. Midkine Interaction with Chondroitin Sulfate Model Synthetic Tetrasaccharides and Their Mimetics: The Role of Aromatic Interactions. Chemistry 2021; 27:12395-12409. [PMID: 34213045 PMCID: PMC8457220 DOI: 10.1002/chem.202101674] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Indexed: 12/29/2022]
Abstract
Midkine (MK) is a neurotrophic factor that participates in the embryonic central nervous system (CNS) development and neural stem cell regulation, interacting with sulfated glycosaminoglycans (GAGs). Chondroitin sulfate (CS) is the natural ligand in the CNS. In this work, we describe the interactions between a library of synthetic models of CS-types and mimics. We did a structural study of this library by NMR and MD (Molecular Dynamics), concluding that the basic shape is controlled by similar geometry of the glycosidic linkages. Their 3D structures are a helix with four residues per turn, almost linear. We have studied the tetrasaccharide-midkine complexes by ligand observed NMR techniques and concluded that the shape of the ligands does not change upon binding. The ligand orientation into the complex is very variable. It is placed inside the central cavity of MK formed by the two structured beta-sheets domains linked by an intrinsically disordered region (IDR). Docking analysis confirmed the participation of aromatics residues from MK completed with electrostatic interactions. Finally, we test the biological activity by increasing the MK expression using CS tetrasaccharides and their capacity in enhancing the growth stimulation effect of MK in NIH3T3 cells.
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Affiliation(s)
- María José García‐Jiménez
- Glycosystems LaboratoryInstituto de Investigaciones Químicas (IIQ)cicCartujaCSICUniversidad de SevillaC/ Américo Vespucio, 4941092SevillaSpain
| | - Sergio Gil‐Caballero
- Glycosystems LaboratoryInstituto de Investigaciones Químicas (IIQ)cicCartujaCSICUniversidad de SevillaC/ Américo Vespucio, 4941092SevillaSpain
- Current Address: Universitat de GironaEdifici Jaume Casademont Porta E, Parc CientíficGironaSpain
| | - Susana Maza
- Glycosystems LaboratoryInstituto de Investigaciones Químicas (IIQ)cicCartujaCSICUniversidad de SevillaC/ Américo Vespucio, 4941092SevillaSpain
| | - Francisco Corzana
- Department of ChemistryUniversity of La RiojaLogroño (La Rioja)Spain
| | - Francisco Juárez‐Vicente
- Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMERCSIC-Universidad de Sevilla-Universidad Pablo de OlavideC/ Américo Vespucio, 2441092SevillaSpain
| | - Jonathan R. Miles
- Glycosystems LaboratoryInstituto de Investigaciones Químicas (IIQ)cicCartujaCSICUniversidad de SevillaC/ Américo Vespucio, 4941092SevillaSpain
| | - Kazuma Sakamoto
- Institute for Glyco-core Research (iGCORE)Departments of BiochemistryNagoya University Graduate School of Medicine65 Tsurumai-cho, Showa-kuNagoya466-8550Japan
| | - Kenji Kadomatsu
- Institute for Glyco-core Research (iGCORE)Departments of BiochemistryNagoya University Graduate School of Medicine65 Tsurumai-cho, Showa-kuNagoya466-8550Japan
| | - Mario García‐Domínguez
- Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMERCSIC-Universidad de Sevilla-Universidad Pablo de OlavideC/ Américo Vespucio, 2441092SevillaSpain
| | - José L. de Paz
- Glycosystems LaboratoryInstituto de Investigaciones Químicas (IIQ)cicCartujaCSICUniversidad de SevillaC/ Américo Vespucio, 4941092SevillaSpain
| | - Pedro M. Nieto
- Glycosystems LaboratoryInstituto de Investigaciones Químicas (IIQ)cicCartujaCSICUniversidad de SevillaC/ Américo Vespucio, 4941092SevillaSpain
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Abstract
Pleiotrophin (PTN) is a potent mitogenic cytokine with a high affinity for the polysaccharide glycosaminoglycan (GAG). Although it is most strongly associated with neural development during embryogenesis and the neonatal period, its expression has also been linked to a plethora of other physiological events including cancer metastasis, angiogenesis, bone development, and inflammation. A considerable amount of research has been carried out to understand the mechanisms by which PTN regulates these events. In particular, PTN has now been shown to bind a diverse collection of receptors including many GAG-containing proteoglycans. These interactions lead to the activation of many intracellular kinases and, ultimately, activation and transformation of cells. Structural studies of PTN in complex with both GAG and domains from its non-proteoglycan receptors reveal a binding mechanism that relies on electrostatic interactions and points to PTN-induced receptor oligomerization as one of the possible ways PTN uses to control cellular functions.
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6
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Tian W, Shen J, Chen W. Suppression of midkine gene promotes the antitumoral effect of cisplatin on human gastric cancer cell line AGS in vitro and in vivo via the modulation of Notch signaling pathway. Oncol Rep 2017; 38:745-754. [PMID: 28656262 PMCID: PMC5562011 DOI: 10.3892/or.2017.5743] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2016] [Accepted: 05/30/2017] [Indexed: 12/16/2022] Open
Abstract
Midkine (MK) is reported to be associated with the clinical stages and distant metastases in gastric cancer, and to positively regulate the proliferation of human gastric cancer cells. However, the possible mechanisms of MK in the development of gastric cancer are still not fully clarified. In this study, the therapeutic effect of MK inhibition in gastric cancer in vivo and in vitro was investigated, by knock-down of MK expression with a small interfering RNA (siRNA). MK was expressed in gastric carcinoma tissues and cancer cells. The cytotoxic effect of cisplatin on AGS cells in vitro was attenuated by recombinant human MK, but was promoted by suppressing MK expression via downregulating the Notch signaling pathway-related proteins (Notch 1, Notch 2, Delta-like 1 and Jagged 1). Suppression of MK expression also promoted the inhibitory effect of cisplatin on AGS cells in vivo. In concusion, suppression of midkine gene promoted the antitumoral effect of cisplatin on human gastric cell line AGS in vitro and in vivo via Notch signaling pathway.
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Affiliation(s)
- Wenyan Tian
- The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Jiaqing Shen
- The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Weichang Chen
- The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
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Cheng L, Qiao Z, Xu C, Shen J. Midkine is overexpressed in acute pancreatitis and promotes the pancreatic recovery in L-arginine-induced acute pancreatitis in mice. J Gastroenterol Hepatol 2017; 32:1265-1272. [PMID: 27992669 DOI: 10.1111/jgh.13681] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Revised: 11/20/2016] [Accepted: 12/05/2016] [Indexed: 12/27/2022]
Abstract
BACKGROUND AND AIM Midkine (MK) is involved in the pathogenesis of numerous malignancies, but the expression and effect of MK in acute pancreatitis (AP) have not been well studied and documented. METHODS In this study, the expression of MK was assayed in mice with L-arginine-induced AP. A recombinant human MK (rhMK) was introduced in this study to test the effect of MK on the L-arginine-induced AP. Serum amylase and lipase were assayed. Pancreas tissue samples were also collected for the evaluation of histological injury. Western blot and immunochemical staining of α-amylase and proliferating cell nuclear antigen were applied for the study of acinar regeneration in the pancreas. RESULTS The elevation of MK expression was found in mice with AP induced by L-arginine. After rhMK administration, rhMK did not affect the severity of acute pancreatic injury in acute phase in L-arginine-induced pancreatitis in mice, in accordance with changes of serum amylase and lipase and the histological evaluation. But during the recovery phase, the area of remaining acinar cells was increased and the fibrosis was reduced in rhMK-treated mice. Furthermore, the expression of proliferating cell nuclear antigen and α-amylase was also upregulated after rhMK treatment. CONCLUSION Midkine is over-expressed during AP in the animal model. Recombinant MK could promote the recovery of L-arginine-induced pancreatitis in mice. Therefore, MK may be involved in the regeneration of acinar cells in AP, and rhMK may be a possible therapeutic intervention for the repairment of AP.
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Affiliation(s)
- Li Cheng
- Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenguo Qiao
- Department of Gastroenterology, Affiliated Wujiang Hospital of Nantong University, Suzhou, Jiangsu, 215200, China
| | - Chunfang Xu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China
| | - Jiaqing Shen
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China
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8
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Krzystek-Korpacka M, Gorska S, Diakowska D, Kapturkiewicz B, Podkowik M, Gamian A, Bednarz-Misa I. Midkine is up-regulated in both cancerous and inflamed bowel, reflecting lymph node metastasis in colorectal cancer and clinical activity of ulcerative colitis. Cytokine 2016; 89:68-75. [PMID: 27692729 DOI: 10.1016/j.cyto.2016.09.020] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Revised: 06/29/2016] [Accepted: 09/22/2016] [Indexed: 12/23/2022]
Abstract
Midkine is a multifunctional cytokine and growth factor displaying proinflammatory and pro-tumorigenic activity. Its association with bowel diseases has not been fully elucidated. Our purpose was to delineate midkine expression pattern by RT-qPCR in inflamed/cancerous bowel (n=208) and whole blood (n=150) in colorectal cancer (CRC), Crohn's disease (CD), and ulcerative colitis (UC) and to evaluate midkine dynamics in early postoperative period following colorectal surgery. The expression of midkine was significantly up-regulated in stage III CRC and independently associated with lymph node metastasis. The expression of midkine in whole blood was up-regulated solely in N1 CRC. Midkine expression in cancer-free tissue (CRC) was also elevated and dependent on CRC advancement. In IBD, inflammation increased the bowel expression of midkine solely in UC, in a manner proportional to the disease clinical activity. Large and small bowel differed with respect to the expression of midkine in quiescent tissue (higher in small bowel) and to its correlation pattern with chemokines (in a large bowel) and angiogenic factors and cell cycle regulators (in a small bowel). Circulating midkine and its expression in whole blood dropped directly following colorectal surgery; however, the concentration of midkine in serum was restored on postoperative day three. Midkine is involved in bowel inflammation in UC and lymph node metastasis in CRC, rendering midkine an attractive target for their treatment. Owing to midkine elevation in early postoperative period and its overexpression in tumor-adjacent tissue, targeting midkine might be considered also as a prevention of CRC recurrence following curative tumor resection.
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Affiliation(s)
| | - Sabina Gorska
- Laboratory of Medical Microbiology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Dorota Diakowska
- Dept. of Gastrointestinal and General Surgery, Wroclaw Medical University, Wroclaw, Poland
| | - Bartosz Kapturkiewicz
- First Dept. of Oncological Surgery of Lower Silesian Oncology Center, Wroclaw, Poland
| | - Magdalena Podkowik
- Dept. of Food Hygiene and Consumer Health, Wroclaw University of Environmental and Life Sciences, Wroclaw, Poland
| | - Andrzej Gamian
- Dept. of Medical Biochemistry, Wroclaw Medical University, Poland; Wroclaw Research Center EIT+, Wroclaw, Poland
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Yamashita T, Shimada H, Tanaka S, Araki K, Tomifuji M, Mizokami D, Tanaka N, Kamide D, Miyagawa Y, Suzuki H, Tanaka Y, Shiotani A. Serum midkine as a biomarker for malignancy, prognosis, and chemosensitivity in head and neck squamous cell carcinoma. Cancer Med 2016; 5:415-25. [PMID: 26798989 PMCID: PMC4799940 DOI: 10.1002/cam4.600] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Revised: 11/03/2015] [Accepted: 11/08/2015] [Indexed: 12/31/2022] Open
Abstract
Improved therapies for individuals with head and neck squamous cell carcinoma (HNSCC) may be developed by identification of appropriate biomarkers. The aim of this study was to evaluate the usefulness of serum midkine measurement as a biomarker for HNSCC. Pretreatment serum midkine concentrations were measured in 103 patients with HNSCC and 116 control individuals by enzyme‐linked immunosorbent assay. Midkine expression in tumor tissues from 33 patients with HNSCC who underwent definitive surgical resection without preoperative treatment was examined by immunohistochemistry. The cut‐off serum midkine concentrations for predicting the presence of head and neck malignancy and chemosensitivity to induction chemotherapy, as determined using receiver operating characteristic curves, were 482 and 626 pg/mL, respectively. Spearman bivariate correlations showed positive correlations between serum midkine levels and immunohistochemistry staining score (r = 0.612, P < 0.001). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of serum midkine concentration for detection of HNSCC were 57.3, 85.3, 77.6, 69.2, and 72.1%, respectively. However, for predicting the response to induction chemotherapy, the values were 84.6, 60.9, 71.0, 77.8, and 73.5%, respectively. Serum midkine concentration was identified as an independent prognostic factor by multivariate analysis, using Cox's proportional hazards model (P = 0.027). Overexpression of serum midkine yielded a relative risk of death of 3.77, with 95% confidence limits ranging from 1.15 to 17.0. Serum midkine levels in patients with HNSCC were associated with malignancy, chemosensitivity, and prognosis. Serum midkine may be a useful, minimally invasive biomarker for early detection, therapeutic decision‐making, and predicting prognosis.
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Affiliation(s)
- Taku Yamashita
- Department of Otorhinolaryngology-Head and Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, 359-8513, Japan
| | - Hideaki Shimada
- Department of Surgery, School of Medicine, Toho University Omori Medical Center, Tokyo, 143-8541, Japan
| | - Shingo Tanaka
- Department of Otorhinolaryngology-Head and Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, 359-8513, Japan
| | - Koji Araki
- Department of Otorhinolaryngology-Head and Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, 359-8513, Japan
| | - Masayuki Tomifuji
- Department of Otorhinolaryngology-Head and Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, 359-8513, Japan
| | - Daisuke Mizokami
- Department of Otorhinolaryngology-Head and Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, 359-8513, Japan
| | - Nobuaki Tanaka
- Department of Otorhinolaryngology-Head and Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, 359-8513, Japan
| | - Daisuke Kamide
- Department of Otorhinolaryngology-Head and Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, 359-8513, Japan
| | - Yoshihiro Miyagawa
- Department of Otorhinolaryngology-Head and Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, 359-8513, Japan
| | - Hiroshi Suzuki
- Department of Otorhinolaryngology-Head and Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, 359-8513, Japan
| | - Yuya Tanaka
- Department of Otorhinolaryngology-Head and Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, 359-8513, Japan
| | - Akihiro Shiotani
- Department of Otorhinolaryngology-Head and Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, 359-8513, Japan
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10
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Çetin Sorkun H, Akbulut M, Enli Y, Tepeli E, Özkan S, Erdem E. Quantitative comparison of immunohistochemical and PCR analysis of midkine expression in breast cancer types and serum midkine level. Turk J Med Sci 2016; 46:219-27. [PMID: 27511357 DOI: 10.3906/sag-1411-158] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Accepted: 03/07/2015] [Indexed: 11/03/2022] Open
Abstract
BACKGROUND/AIM Midkine (MK), a heparin-binding growth factor, has an important role in cancer progression. The aim of this study was to determine MK expression in breast tissue and the preoperative and postoperative serum levels of patients with breast cancer. MATERIALS AND METHODS Sixty-one patients with breast cancer participated in our study. The MK serum levels were measured pre- and postoperatively for these patients. We also analyzed breast tissues of the 61 patients immunohistochemically. We examined serum midkine levels in 49 healthy volunteers. RESULTS MK expression was observed in 44 (72.1%) of 61 breast cancer patients. In breast cancer patients the serum MK levels (3.68 ± 2.13 ng/mL (mean ± SD)) were significantly higher than in the control group (1.77 ± 0.38 ng/mL) before tumor removal (P = 0.000). After tumor removal, serum MK levels (2.47 ± 1.00 ng/mL) were significantly (P = 0.000) decreased according to preoperative levels. Increased serum levels of MK were related with tumor stages when clinical parameters were analyzed. CONCLUSION We found that increased serum MK levels and protein expressions were associated with the carcinogenesis of breast cancer. MK levels decreased after tumor removal. According to our findings, MK might be a useful tumor marker for patients with breast cancer.
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Affiliation(s)
- Hülya Çetin Sorkun
- Denizli Health Services Vocational School, Pamukkale University, Denizli, Turkey
| | - Metin Akbulut
- Department of Pathology, Faculty of Medicine, Pamukkale University, Denizli, Turkey
| | - Yaşar Enli
- Department of Biochemistry, Faculty of Medicine, Pamukkale University, Denizli, Turkey
| | - Emre Tepeli
- Department of Medical Biology, Faculty of Medicine, Pamukkale University, Denizli, Turkey
| | - Sevgi Özkan
- School of Health, Pamukkale University, Denizli, Turkey
| | - Ergün Erdem
- Department of General Surgery, Faculty of Medicine, Pamukkale University, Denizli, Turkey
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11
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Kuzu F, Arpaci D, Unal M, Altas A, Haytaoglu G, Can M, Barut F, Kokturk F, Ilikhan SU, Bayraktaroglu T. Midkine: A Novel Biomarker to Predict Malignancy in Patients with Nodular Thyroid Disease. Int J Endocrinol 2016; 2016:6035024. [PMID: 27446208 PMCID: PMC4944023 DOI: 10.1155/2016/6035024] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 05/03/2016] [Indexed: 11/17/2022] Open
Abstract
Background. Midkine (MK), a new heparin-binding growth factor, plays important roles in a variety of biological phenomena such as carcinogenesis, inflammation, and angiogenesis. In this study, we aimed to evaluate serum midkine (SMK) and nodular midkine (NMK) levels in patients with thyroid nodules to predict malignancy and whether there was any association between. Methods. A total of 105 patients (74 women, 31 men) with thyroid nodules were enrolled. The levels of SMK and NMK were measured. Any possible correlation between SMK, NMK, and biochemical, cytopathological, or radiological variables was investigated. Results. Both SMK and NMK were found to be higher in hypoechoic nodules with an irregular border and without a halo (p < 0.05). Serum MK levels were significantly higher in nodules with microcalcifications than nodules with macrocalcification or without calcification (p = 0.001). SMK levels were found to be correlated with NMK levels (SMK 0.63 ng/ml versus 1.04 ng/mL and NMK 0.55 ng/mL versus 0.55 ng/mL, r (2) = 0.54, p < 0.001). Conclusion. Both SMK and NMK can predict tumorigenesis of highly malignant/suspicious thyroid cytopathology and also well correlated with sonographic features of thyroid nodules. We suggest that MK levels may serve as an alternative biomarker, in conjunction with the cytopathological results in preoperative assessment of thyroid nodules.
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Affiliation(s)
- Fatih Kuzu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Bulent Ecevit University, 67600 Zonguldak, Turkey
| | - Dilek Arpaci
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Bulent Ecevit University, 67600 Zonguldak, Turkey
| | - Mustafa Unal
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Bulent Ecevit University, 67600 Zonguldak, Turkey
- *Mustafa Unal:
| | - Ayfer Altas
- Department of Internal Medicine, Faculty of Medicine, Bulent Ecevit University, 67600 Zonguldak, Turkey
| | - Gürkan Haytaoglu
- Department of Internal Medicine, Faculty of Medicine, Bulent Ecevit University, 67600 Zonguldak, Turkey
| | - Murat Can
- Department of Biochemistry, Faculty of Medicine, Bulent Ecevit University, 67600 Zonguldak, Turkey
| | - Figen Barut
- Department of Pathology, Faculty of Medicine, Bulent Ecevit University, 67600 Zonguldak, Turkey
| | - Furuzan Kokturk
- Department of Biostatistics, Faculty of Medicine, Bulent Ecevit University, 67600 Zonguldak, Turkey
| | - Sevil Uygun Ilikhan
- Department of Internal Medicine, Faculty of Medicine, Bulent Ecevit University, 67600 Zonguldak, Turkey
| | - Taner Bayraktaroglu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Bulent Ecevit University, 67600 Zonguldak, Turkey
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Jia M, Zhao HZ, Cheng YP, Luo ZB, Zhang JY, Li SS, Xu XJ, Tang YM. High expression of Midkine (MK) indicates poor prognosis in childhood acute lymphoblastic leukemia. ACTA ACUST UNITED AC 2015; 21:69-77. [PMID: 26352402 DOI: 10.1179/1607845415y.0000000050] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVES Midkine (MK) expression has been reported to be correlated with the poor prognosis of patients with various tumors. However, there are no data available about the prognostic value of MK expression in childhood acute lymphoblastic leukemia (ALL). METHODS In this study, MK mRNA expression was determined by real-time polymerase chain reaction in 120 childhood ALL and 30 healthy volunteers. Patients were dichotomized at the median value and divided into two groups: MK(low) group and MK(high) group. RESULTS MK(high) patients had higher white blood cell counts, higher peripheral blood blasts percentages, and higher minimal residual disease levels than MK(low) patients. Moreover, the MK gene was expressed significantly higher in patients with relapsed ALL than in patients who maintained complete remission or at diagnosis. MK(high) patients harbored inferior relapse-free survival (RFS, P = 0.047) and overall survival (OS, P = 0.022) than MK(low) patients, and high expression of MK was found to be independently predictive of inferior OS (P = 0.032) but not RFS (P = 0.077) in the overall cohort. CONCLUSION AND DISCUSSION MK high expression is an independent adverse prognostic factor in childhood ALL. Its level may be incorporated into an improved risk classification system for ALL and suggest the need of alternative regimens.
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Affiliation(s)
- Ming Jia
- a Division of Hematology-Oncology , Children's Hospital of Zhejiang University School of Medicine, Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education , Hangzhou 310003 , PR China
| | - Hai-Zhao Zhao
- a Division of Hematology-Oncology , Children's Hospital of Zhejiang University School of Medicine, Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education , Hangzhou 310003 , PR China
| | - Yu-Ping Cheng
- a Division of Hematology-Oncology , Children's Hospital of Zhejiang University School of Medicine, Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education , Hangzhou 310003 , PR China
| | - Ze-Bin Luo
- a Division of Hematology-Oncology , Children's Hospital of Zhejiang University School of Medicine, Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education , Hangzhou 310003 , PR China
| | - Jing-Ying Zhang
- a Division of Hematology-Oncology , Children's Hospital of Zhejiang University School of Medicine, Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education , Hangzhou 310003 , PR China
| | - Si-Si Li
- a Division of Hematology-Oncology , Children's Hospital of Zhejiang University School of Medicine, Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education , Hangzhou 310003 , PR China
| | - Xiao-Jun Xu
- a Division of Hematology-Oncology , Children's Hospital of Zhejiang University School of Medicine, Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education , Hangzhou 310003 , PR China
| | - Yong-Min Tang
- a Division of Hematology-Oncology , Children's Hospital of Zhejiang University School of Medicine, Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education , Hangzhou 310003 , PR China
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Li F, Tian P, Zhang J, Kou C. The clinical and prognostic significance of midkine in breast cancer patients. Tumour Biol 2015; 36:9789-94. [PMID: 26159850 DOI: 10.1007/s13277-015-3710-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2015] [Accepted: 06/23/2015] [Indexed: 02/03/2023] Open
Abstract
Midkine overexpression has been shown to be a tumor biomarker in several types of human cancer, but little is known about the clinical significance of midkine in breast cancer patients. The aim of this study was to analyze the expression of midkine in breast cancer and its correlation with clinicopathological characteristics, including breast cancer patient's survival. The expression status of midkine in breast cancer from Gene Expression Omnibus (GEO accession number: GDS3853) was observed initially. Furthermore, the expression of midkine messenger RNA (mRNA) and protein was examined in breast cancer and normal mammary tissues through real-time PCR and immunohistochemistry. Moreover, the relationship of midkine protein expression with clinical characteristics of 170 breast cancer patients was analyzed by immunohistochemistry. In our results, midkine was up-expressed in breast cancer tissues compared with normal mammary tissues in microarray data (GDS3853). Midkine mRNA and protein expression was significantly increased in breast cancer tissues than in normal mammary tissues. By immunohistochemistry, high levels of midkine protein were positively associated with the status of clinical stage, T classification, N classification, and M classification in breast cancer patients. Furthermore, midkine overexpression was an independent poor prognostic indicator for the survival of patients with breast cancer. In conclusion, overexpression of midkine protein serves as an unfavorable prognostic biomarker in breast cancer patients.
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Affiliation(s)
- Fuguang Li
- Department of General Surgery, The Central Hospital of Ankang City, Ankang, Shanxi, 725000, China
| | - Peijun Tian
- Department of Hematology, The Central Hospital of Ankang City, Ankang, Shanxi, 725000, China
| | - Jun Zhang
- Department of General Surgery, The Central Hospital of Ankang City, Ankang, Shanxi, 725000, China
| | - Changyuan Kou
- Department of Oncology, The Central Hospital of Ankang City, Ankang, Shanxi, 725000, China.
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Huang HL, Shen JF, Min LS, Ping JL, Lu YL, Dai LC. Inhibitory effect of midkine-binding peptide on tumor proliferation and migration. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:5387-5394. [PMID: 26191241 PMCID: PMC4503112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 02/08/2015] [Accepted: 04/10/2015] [Indexed: 06/04/2023]
Abstract
BACKGROUND To investigate the inhibitory effect of midkine-binding peptides on human umbilical vein endothelial cells (HUVECs) proliferation and angiogenesis of xenograft tumor. METHODS The midkine-binding peptides were panned by Ph.D.-7(™) Phage Display Peptide Library Kit, and the specific binding activities of positive clones to target protein were examined by phage ELISA. The effect of midkine-binding peptides on proliferation of HUVECs was confirmed by MTT test. The xenograft tumor model was formed in BALB/c mice with the murine hepatocarcinoma cells H22 (H22). Microvessel density (MVD) was analyzed by immunohistochemistry of factor VIII staining. RESULTS Midkine-binding peptides have the inhibitory effects on tumor angiogenesis, a proliferation assay using human umbilical vein endothelial cells (HUVECs) indicated that particular midkine-binding peptides significantly inhibited the proliferation of the HUVECs. Midkine-binding peptides were also observed to efficiently suppress angiogenesis induced by murine hepatocarcinoma H22 cells in BALB/c nude mice. CONCLUSION The midkine-binding peptides can inhibit solid tumor growth by retarding the formation of new blood vessels. The results indicate that midkine-binding peptides may represent potent anti-angiogenesis agents in vivo.
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Affiliation(s)
- Hui-Lian Huang
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital Huzhou 313000, China
| | | | - Li-Shan Min
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital Huzhou 313000, China
| | - Jin-Liang Ping
- Department of Pathology, Huzhou Central Hospital Huzhou 313000, Zhejiang Province, China
| | - Yong-Liang Lu
- Huzhou Teacher's Collage Huzhou 31300, Zhejiang Province, China
| | - Li-Cheng Dai
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital Huzhou 313000, China
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15
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Güngör C, Hofmann BT, Wolters-Eisfeld G, Bockhorn M. Pancreatic cancer. Br J Pharmacol 2014; 171:849-58. [PMID: 24024905 DOI: 10.1111/bph.12401] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2013] [Revised: 08/16/2013] [Accepted: 09/03/2013] [Indexed: 12/17/2022] Open
Abstract
UNLABELLED In recent years, it has become clear that the current standard therapeutic options for pancreatic cancer are not adequate and still do not meet the criteria to cure patients suffering from this lethal disease. Although research over the past decade has shown very interesting and promising new therapeutic options for these patients, only minor clinical success was achieved. Therefore, there is still an urgent need for new approaches that deal with early detection and new therapeutic options in pancreatic cancer. To provide optimal care for patients with pancreatic cancer, we need to understand better its complex molecular biology and thus to identify new target molecules that promote the proliferation and resistance to chemotherapy of pancreatic cancer cells. In spite of significant progress in curing cancers with chemotherapy, pancreatic cancer remains one of the most resistant solid tumour cancers and many studies suggest that drug-resistant cancer cells are the most aggressive with the highest relapse and metastatic rates. In this context, activated Notch signalling is strongly linked with chemoresistance and therefore reflects a rational new target to circumvent resistance to chemotherapy in pancreatic cancer. Here, we have focused our discussion on the latest research, current therapy options and recently identified target molecules such as Notch-2 and the heparin-binding growth factor midkine, which exhibit a wide range of cancer-relevant functions and therefore provide attractive new therapeutic target molecules, in terms of pancreatic cancer and other cancers also. LINKED ARTICLES This article is part of a themed section on Midkine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-4.
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Affiliation(s)
- C Güngör
- Department of General, Visceral and Thoracic Surgery, Experimental Oncology, Campus Research, University Hospital Hamburg-Eppendorf, Hamburg, Germany
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16
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Kishida S, Kadomatsu K. Involvement of midkine in neuroblastoma tumourigenesis. Br J Pharmacol 2014; 171:896-904. [PMID: 24116381 DOI: 10.1111/bph.12442] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2013] [Revised: 09/09/2013] [Accepted: 09/16/2013] [Indexed: 12/16/2022] Open
Abstract
UNLABELLED Midkine is highly expressed in various cancers, including neuroblastoma, one of the most malignant paediatric solid tumours known. Also, it has been shown to be useful as a tumour marker, a prognosis factor and a target of molecular therapy. Several molecular tools (e.g. siRNA, antibodies and RNA aptamer) have been used to establish a midkine-targeted therapy. The involvement of midkine in tumourigenesis has been demonstrated in vivo in a mouse neuroblastoma model, where targeting it with an RNA aptamer was shown to be an effective treatment for xenografted tumours. Chemoresistance is one of the notable phenotypes regulated by midkine in various cancer cell types. In pancreatic tumours and glioma cells, midkine is expressed in chemoresistant cells and is involved in the survival of these cells in the presence of anticancer drugs. In contrast to these tumours, midkine was found to be expressed in every neuroblastoma cell line tested and the knockdown of midkine alone was sufficient to suppress their growth. These results indicate that neuroblastoma cells are highly dependent on midkine and that a midkine-targeted therapy could exert a significant effect in these cells. However, to achieve a midkine-targeted therapy for high-risk neuroblastoma patients, the further refinement of the RNA aptamer or antibody as tools and the elucidation of midkine signalling are immediate issues that need to be resolved. Regarding the latter, although it has been shown that Notch2 functions as a receptor in neuroblastoma cells, it is likely that other receptors (e.g. anaplastic lymphoma kinase) are also involved in midkine signalling. LINKED ARTICLES This article is part of a themed section on Midkine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-4.
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Affiliation(s)
- S Kishida
- Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Aguirre Palma LM, Gehrke I, Kreuzer KA. Angiogenic factors in chronic lymphocytic leukaemia (CLL): Where do we stand? Crit Rev Oncol Hematol 2014; 93:225-36. [PMID: 25459668 DOI: 10.1016/j.critrevonc.2014.10.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Revised: 07/23/2014] [Accepted: 10/01/2014] [Indexed: 01/09/2023] Open
Abstract
The role of angiogenesis in haematological malignancies such as chronic lymphocytic leukaemia (CLL) is difficult to envision, because leukaemia cells are not dependent on a network of blood vessels to support basic physiological requirements. Regardless, CLL cells secrete high levels of major angiogenic factors, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and platelet derived growth factor (PDGF). Nonetheless, it remains unclear how most angiogenic factors regulate accumulation and delayed apoptosis of CLL cells. Angiogenic factors such as leptin, granulocyte colony-stimulating factor (G-CSF), follistatin, angiopoietin-1 (Ang1), angiogenin (ANG), midkine (MK), pleiotrophin (PTN), progranulin (PGRN), proliferin (PLF), placental growth factor (PIGF), and endothelial locus-1 (Del-1), represent novel therapeutic targets of future CLL research but have remained widely overlooked. This review aims to outline our current understanding of angiogenic growth factors and their relationship with CLL, a still uncured haematopoietic malignancy.
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Affiliation(s)
| | - Iris Gehrke
- Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, MB, Canada.
| | - Karl-Anton Kreuzer
- Department I of Internal Medicine, University of Cologne, Cologne, Germany.
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OVA66, a tumor associated protein, induces oncogenic transformation of NIH3T3 cells. PLoS One 2014; 9:e85705. [PMID: 24633332 PMCID: PMC3954546 DOI: 10.1371/journal.pone.0085705] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Accepted: 11/29/2013] [Indexed: 11/19/2022] Open
Abstract
The tumor associated antigen OVA66 has been demonstrated to be highly expressed in malignant tumors and implicated in various cellular processes. To further elucidate its oncogenic character, we established an OVA66 stably overexpressed NIH3T3 cell line and a vector transfected control, named NIH3T3-flagOVA66 and NIH3T3-mock, respectively. NIH3T3-flagOVA66 cells showed faster cell cycling, proliferation, cell migration and more resistance to 5-fluorouracil-induced apoptosis. When NIH3T3-flagOVA66 and NIH3T3-mock cells were injected into nude mice for xenograft tumorigenicity assays, the NIH3T3-flagOVA66 cells formed tumors whereas no tumors were observed in mice inoculated with NIH3T3-mock cells. Analysis of PI3K/AKT and ERK1/2 MAPK signaling pathways by serum stimulation indicated hyperactivation of AKT and ERK1/2 in NIH3T3-flagOVA66 cells compared with NIH3T3-mock cells, while a decreased level of p-AKT and p-ERK1/2 were observed in OVA66 knocked down HeLa cells. To further validate if the p-AKT or p-ERK1/2 is essential for OVA66 induced oncogenic transformation, we treated the cells with the PI3K/AKT specific inhibitor LY294002 and the ERK1/2 MAPK specific inhibitor PD98059 and found either inhibitor can attenuate the cell colony forming ability in soft agar and the cell viability of NIH3T3-flagOVA66 cells, suggesting aberrantly activated AKT and ERK1/2 signaling be indispensible of the tumorigenic role of OVA66. Our results indicate that OVA66 is important in oncogenic transformation, promoting proliferation, cell migration and reducing apoptosis via hyperactivating PI3K/AKT and ERK1/2 MAPK signaling pathway. Thus, OVA66 might be a novel target for early detection, prevention and treatment of tumors in the future.
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19
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Oncolytic virotherapy for osteosarcoma using midkine promoter-regulated adenoviruses. Cancer Gene Ther 2014; 21:126-32. [DOI: 10.1038/cgt.2014.7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Accepted: 02/05/2014] [Indexed: 01/08/2023]
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Fan N, Sun H, Wang Y, Zhang L, Xia Z, Peng L, Hou Y, Shen W, Liu R, Peng Y. Midkine, a potential link between obesity and insulin resistance. PLoS One 2014; 9:e88299. [PMID: 24516630 PMCID: PMC3917881 DOI: 10.1371/journal.pone.0088299] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2013] [Accepted: 01/06/2014] [Indexed: 12/16/2022] Open
Abstract
Obesity is associated with increased production of inflammatory mediators in adipose tissue, which contributes to chronic inflammation and insulin resistance. Midkine (MK) is a heparin-binding growth factor with potent proinflammatory activities. We aimed to test whether MK is associated with obesity and has a role in insulin resistance. It was found that MK was expressed in adipocytes and regulated by inflammatory modulators (TNF-α and rosiglitazone). In addition, a significant increase in MK levels was observed in adipose tissue of obese ob/ob mice as well as in serum of overweight/obese subjects when compared with their respective controls. In vitro studies further revealed that MK impaired insulin signaling in 3T3-L1 adipocytes, as indicated by reduced phosphorylation of Akt and IRS-1 and decreased translocation of glucose transporter 4 (GLUT4) to the plasma membrane in response to insulin stimulation. Moreover, MK activated the STAT3-suppressor of cytokine signaling 3 (SOCS3) pathway in adipocytes. Thus, MK is a novel adipocyte-secreted factor associated with obesity and inhibition of insulin signaling in adipocytes. It may provide a potential link between obesity and insulin resistance.
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Affiliation(s)
- Nengguang Fan
- Department of Endocrinology, Shanghai First People’s Hospital, Shanghai Jiao Tong University, Shanghai, China
- Department of Endocrinology, Shanghai Songjiang Center Hospital, Shanghai, China
| | - Haiyan Sun
- Department of Endocrinology, Shanghai First People’s Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yifei Wang
- Department of Endocrinology, Shanghai First People’s Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Lijuan Zhang
- Department of Endocrinology, Shanghai Songjiang Center Hospital, Shanghai, China
| | - Zhenhua Xia
- Department of Endocrinology, Shanghai Songjiang Center Hospital, Shanghai, China
| | - Liang Peng
- Department of Laboratory Medicine, Shanghai Songjiang Center Hospital, Shanghai, China
| | - Yanqiang Hou
- Department of Laboratory Medicine, Shanghai Songjiang Center Hospital, Shanghai, China
| | - Weiqin Shen
- Department of Laboratory Medicine, Shanghai Songjiang Center Hospital, Shanghai, China
| | - Rui Liu
- Department of Endocrinology, Shanghai First People’s Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yongde Peng
- Department of Endocrinology, Shanghai First People’s Hospital, Shanghai Jiao Tong University, Shanghai, China
- * E-mail:
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Takagi-Kimura M, Yamano T, Tamamoto A, Okamura N, Okamura H, Hashimoto-Tamaoki T, Tagawa M, Kasahara N, Kubo S. Enhanced antitumor efficacy of fiber-modified, midkine promoter-regulated oncolytic adenovirus in human malignant mesothelioma. Cancer Sci 2013; 104:1433-9. [PMID: 23962292 DOI: 10.1111/cas.12267] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2013] [Revised: 08/09/2013] [Accepted: 08/15/2013] [Indexed: 01/28/2023] Open
Abstract
Oncolytic virotherapy using adenoviruses has potential for therapeutic benefits in malignant mesothelioma. However, the downregulation of coxsackie virus/adenovirus receptor (CAR) expression is frequently a critical rate-limiting factor that impedes the effectiveness of adenovirus serotype 5 (Ad5)-based vectors in many cancer types. We evaluated CAR (Ad5 receptor) and CD46 (adenovirus serotype 35 [Ad35] receptor) expression in six human malignant mesothelioma cell lines. Very low CAR expression was observed in MSTO-211H and NCI-H2052 cells, whereas the other cell lines showed strong expression. In contrast, CD46 was highly expressed in all mesothelioma cell lines. On this basis, we replaced the CAR binding sequence of Ad5 with the CD46 binding sequence of Ad35 in the replication-defective adenoviruses and the tumor-specific midkine promoter-regulated oncolytic adenoviruses. By this fiber modification, the infectivity, virus progeny production, and in vitro cytocidal effects of the adenoviruses were significantly enhanced in low CAR-expressing MSTO-211H and NCI-H2052 cells, also resulting in similar or even higher levels in high CAR-expressing mesothelioma cell lines. In MSTO-211H xenograft models, the fiber-modified oncolytic adenovirus significantly enhanced antitumor effect compared to its equivalent Ad5-based vector. Our data demonstrate that Ad35 fiber modification of binding tropism in a midkine promoter-regulated oncolytic Ad5 vector confers transductional targeting to oncolytic adenoviruses, thereby facilitating more effective treatment of malignant mesothelioma.
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Midkine overcomes neurite outgrowth inhibition of chondroitin sulfate proteoglycan without glial activation and promotes functional recovery after spinal cord injury. Neurosci Lett 2013; 550:150-5. [PMID: 23811026 DOI: 10.1016/j.neulet.2013.06.025] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2013] [Revised: 06/11/2013] [Accepted: 06/13/2013] [Indexed: 02/04/2023]
Abstract
Injuries in the mammalian central nervous system induce a variety of factors which promote or inhibit neuronal axon regeneration/sprouting. However, the inhibitory activities are much stronger, and indeed are the major obstacle to functional recovery. Chondroitin sulfate proteoglycans (CSPGs) are produced by activated glial cells, and are among the strongest inhibitors. Here, we investigated the role of the growth factor midkine (MK), which binds to CSPGs, in neuronal injury. MK expression was induced by spinal cord injury, and was mainly produced by activated astrocytes. A prolonged culture of neurons also produced MK. MK not only enhanced neurite outgrowth on the substratum coated with poly-l-lysine, but also overcame the neurite growth inhibition by the CSPG substratum. Moreover, we found that MK activated neither astrocytes nor microglia as evaluated by morphological changes and cell proliferation or nitric oxide production. These properties would be advantageous for the treatment of neuronal injuries in vivo. Therefore, we next explored the therapeutic effect of MK in a rat spinal cord injury model. MK or vehicle was administered intrathecally for 2 weeks using an osmotic pump after spinal cord contusion injury. Rats treated with MK showed significantly better functional recovery after 5 weeks. These results suggest that MK may offer a potent alternative for the treatment of neuronal injuries without activating glial cells.
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Nordin A, Wang W, Welén K, Damber JE. Midkine is associated with neuroendocrine differentiation in castration-resistant prostate cancer. Prostate 2013; 73:657-67. [PMID: 23129424 DOI: 10.1002/pros.22607] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2012] [Accepted: 10/05/2012] [Indexed: 12/26/2022]
Abstract
BACKGROUND Castration-resistant prostate cancer (CRPC) is an incurable disease and both androgen-deprivation therapy (ADT) and neuroendocrine differentiation (NED) are closely related to CRPC transition. More knowledge concerning neuroendocrine (NE)-transformed PC cells, the NED process and its association with CRPC, is needed. Expression of growth factor midkine (MDK) is correlated with poor clinical outcomes in various human cancers, including PC. In the present study, we have evaluated MDK expression and NED in two separate tumor groups: early and advanced PC. METHODS Immunohistochemical analysis of MDK, the neuronal marker tubulin-beta III (TUBB3) and the NE-marker chromogranin A (CGA) in a human archival material consisting of hormone naive (HN)/stage T1b (n = 29) and CRPC (n = 24) tumors. Triple immunofluorescent imaging was performed on a selection of specimens. RESULTS MDK, TUBB3, and CGA were upregulated in CRPC compared to HN tumors. MDK was highly associated to the expression of both CGA and TUBB3, and identified MDK-positive NE-like looking cells found to co-express CGA or, more commonly, CGA together with TUBB3. CGA and TUBB3 staining displayed a partial expression overlap, an overlap almost exclusively displaying also MDK expression. CONCLUSIONS MDK upregulation in CRPC is associated with NED (shown by its relation to CGA and TUBB3). The results suggest that MDK represents an over-bridging marker between different populations of NE-like tumor cells, possibly as part of the NED process and associated CRPC transition, something that needs to be evaluated experimentally as does the applicability of MDK as a future target.
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Affiliation(s)
- Anna Nordin
- Department of Urology, Sahlgrenska Cancer Center, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden
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Regulation of CLL survival by hypoxia-inducible factor and its target genes. FEBS Lett 2012; 586:2906-10. [PMID: 22841548 DOI: 10.1016/j.febslet.2012.07.016] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2012] [Revised: 07/10/2012] [Accepted: 07/10/2012] [Indexed: 02/02/2023]
Abstract
Chronic lymphocytic leukemia (CLL), the most common adult leukemia in the Western world, is characterized by the progressive accumulation of small mature CD5(+)B lymphocytes in the peripheral blood, lymphoid organs, and bone marrow (BM). The main feature of the disease is decreased apoptosis, resulting in the pathologic accumulation of these malignant cells. Appropriate cellular responses to changes in oxygen tension during normal development or pathological processes, such as cardiovascular disease and cancer, are ultimately regulated by the transcription factor, hypoxia-inducible factor (HIF). Unlike their normal counterparts, CLL cells express HIF-1α even under normoxia. In addition, overexpression of HIF-1α has been observed in leukemic cells in BM specimens from CLL patients. The HIF transcription factor has been implicated in controlling the expression of a wide variety of genes implicated in apoptosis, angiogenesis, invasion, and metastasis. This review describes pathways regulating CLL survival with a focus on HIF-1α and its target genes, MIF and Midkine (MK), and the potential cross-talk between these factors.
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Cohen S, Shachar I. Cytokines as regulators of proliferation and survival of healthy and malignant peripheral B cells. Cytokine 2012; 60:13-22. [PMID: 22784632 DOI: 10.1016/j.cyto.2012.06.019] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2012] [Revised: 05/21/2012] [Accepted: 06/04/2012] [Indexed: 12/31/2022]
Abstract
Adaptive immunity depends on the production and maintenance of a pool of mature peripheral lymphocytes throughout life. The signals regulating the survival of mature splenic B cells have become a major focus in recent studies of B cell immunology. Lasting B cell persistence in the periphery is dependent on survival signals that are transduced by cell surface receptors. Cytokines have been shown to play a critical role in maintaining lymphocyte homeostasis. This review focuses on the role of cytokines and their receptors in the regulation of peripheral B cell survival, with an emphasis on those that have received relatively less attention in the literature.
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Affiliation(s)
- Sivan Cohen
- Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel
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Abstract
Midkine (MK) is a heparin-binding growth factor involved in various cellular processes such as cellular proliferation, survival, and migration. In addition to these typical growth factor activities, MK exhibits several other activities related to fibrinolysis, blood pressure, host defense and other processes. Many cell-surface receptors have been identified to account for the multiple biological activities of MK. The expression of MK is frequently upregulated in many types of human carcinoma. Moreover, blood MK levels are closely correlated with patient outcome. Knockdown and blockade of MK suppress tumorigenesis and tumor development. Thus, MK serves as a tumor marker and a molecular target for cancer therapy. Furthermore, there is growing evidence that MK plays pivotal roles in neural and inflammatory diseases. Understanding of the mechanisms of action of MK is expected to create new therapeutic options for several human diseases.
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Affiliation(s)
- Kazuma Sakamoto
- Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Colombo C, Creighton CJ, Ghadimi MP, Bolshakov S, Warneke CL, Zhang Y, Lusby K, Zhu S, Lazar AJ, West RB, van de Rijn M, Lev D. Increased midkine expression correlates with desmoid tumour recurrence: a potential biomarker and therapeutic target. J Pathol 2011; 225:574-82. [PMID: 21826666 DOI: 10.1002/path.2951] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2011] [Revised: 05/17/2011] [Accepted: 06/05/2011] [Indexed: 12/18/2022]
Abstract
Desmoid tumours (DTs) are soft tissue monoclonal neoplasms exhibiting a unique phenotype, consisting of aggressive local invasiveness without metastatic capacity. While DTs can infrequently occur as part of familial adenomatosis polyposis, most cases arise sporadically. Sporadic DTs harbour a high prevalence of CTNNB1 mutations and hence increased β-catenin signalling. However, β-catenin downstream transcriptional targets and other molecular deregulations operative in DT inception and progression are currently not well defined, contributing to the lack of sensitive molecular prognosticators and efficacious targeted therapeutic strategies. We compared the gene expression profiles of 14 sporadic DTs to those of five corresponding normal tissues and six solitary fibrous tumour specimens. A DT expression signature consisting of 636 up- and 119 down-regulated genes highly enriched for extracellular matrix, cell adhesion and wound healing-related proteins was generated. Furthermore, 98 (15%) of the over-expressed genes were demonstrated to contain a TCF/LEF consensus binding site in their promoters, possibly heralding direct β-catenin downstream targets relevant to DT. The protein products of three of the up-regulated DT genes: ADAM12, MMP2 and midkine, were found to be commonly expressed in a large cohort of human DT samples assembled on a tissue microarray. Interestingly, enhanced midkine expression significantly correlated with a higher propensity and decreased time for primary DT recurrence (log-rank p = 0.0025). Finally, midkine was found to enhance the migration and invasion of primary DT cell cultures. Taken together, these studies provide insights into potential DT molecular aberrations and novel β-catenin transcriptional targets. Further studies to confirm the utility of midkine as a clinical DT molecular prognosticator and a potential therapeutic target are therefore warranted. Raw gene array data can be found at: http://smd.stanford.edu/
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Affiliation(s)
- Chiara Colombo
- Department of Surgical Oncology, University of Texas MD Anderson Cancer Center (MDACC), Houston, TX 77054, USA
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Kato N, Kosugi T, Sato W, Ishimoto T, Kojima H, Sato Y, Sakamoto K, Maruyama S, Yuzawa Y, Matsuo S, Kadomatsu K. Basigin/CD147 promotes renal fibrosis after unilateral ureteral obstruction. THE AMERICAN JOURNAL OF PATHOLOGY 2011; 178:572-9. [PMID: 21281789 DOI: 10.1016/j.ajpath.2010.10.009] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2010] [Revised: 09/03/2010] [Accepted: 10/01/2010] [Indexed: 12/20/2022]
Abstract
Regardless of their primary causes, progressive renal fibrosis and tubular atrophy are the main predictors of progression to end-stage renal disease. Basigin/CD147 is a multifunctional molecule-it induces matrix metalloproteinases and hyaluronan, for example-and has been implicated in organ fibrosis. However, the relationship between basigin and organ fibrosis has been poorly studied. We investigated basigin's role in renal fibrosis using a unilateral ureteral obstruction model. Basigin-deficient mice (Bsg(-/-)) demonstrated significantly less fibrosis after surgery than Bsg(+/+) mice. Fewer macrophages had infiltrated in Bsg(-/-) kidneys. Consistent with these in vivo data, primary cultured tubular epithelial cells from Bsg(-/-) mice produced less matrix metalloproteinase and exhibited less motility on stimulation with transforming growth factor β. Furthermore, Bsg(-/-) embryonic fibro blasts produced less hyaluronan and α-smooth muscle actin after transforming growth factor β stimulation. Together, these results demonstrate for the first time that basigin is a key regulator of renal fibrosis. Basigin could be a candidate target molecule for the prevention of organ fibrosis.
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Affiliation(s)
- Noritoshi Kato
- Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Krust B, El Khoury D, Soundaramourty C, Nondier I, Hovanessian AG. Suppression of tumorigenicity of rhabdoid tumor derived G401 cells by the multivalent HB-19 pseudopeptide that targets surface nucleolin. Biochimie 2011; 93:426-33. [PMID: 21040752 DOI: 10.1016/j.biochi.2010.10.015] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2010] [Accepted: 10/21/2010] [Indexed: 02/02/2023]
Abstract
Several studies have indicated that the cell-surface expressed nucleolin is implicated in tumorigenesis and angiogenesis, and represents an important target for cancer therapy. Here we show that treatment of rhabdoid tumor derived G401 cells with a nucleolin antagonist, the HB-19 pseudopeptide, could restore contact inhibition, impair anchorage-independent growth, and suppress tumor development in nude mice. G401 cells grow without contact inhibition, which is an in vitro characteristic property of malignant tumor cells. At concentrations of HB-19 that does not affect cell viability and multiplication index, there is restoration of contact inhibition thus suggesting that HB-19 treatment causes reversion of the malignant phenotype. Accordingly, HB-19 pretreated G401 cells lose the capacity to form colonies in soft agar. When assayed for tumorigenicity in nude mice, only 50% of mice injected with HB-19 pretreated G401 cells developed tumors with the mean tumor weight of 0.32 g, compared to 100% of mice injected with control G401 cells with the mean tumor weight of 2.36 g. Interestingly, the restoration of contact inhibition in HB-19 treated G401 cells is concomitant with marked reduction of transcripts coding the Wilms' tumor 1 gene, matrix metalloproteinase-2, epithelial isoform of CD44, and vascular endothelial growth factor, whereas no apparent modification is detected for transcripts coding the proto-oncogene c-Myc, anti-apoptotic Bcl-2, pro-apoptotic Bax, tissue inhibitor of metalloproteinase TIMP-1, angiogenesis inhibitor TSP-1, and growth factor Midkine. These findings indicate that the molecular mechanism of action of HB-19 on such highly malignant rhabdoid tumor cells is associated with a selective inhibitory effect on the expression of genes implicated in tumorigenesis and angiogenesis.
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Affiliation(s)
- Bernard Krust
- CNRS-Université Paris Descartes, Unité Régulation de la Transcription de Maladies Génétique, 45 rue des Saints Pères, Paris Cedex 06, France
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Muramatsu T. Midkine: a promising molecule for drug development to treat diseases of the central nervous system. Curr Pharm Des 2011; 17:410-23. [PMID: 21375488 PMCID: PMC3267162 DOI: 10.2174/138161211795164167] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2011] [Accepted: 03/01/2011] [Indexed: 12/17/2022]
Abstract
Midkine (MK) is a heparin-binding cytokine, and promotes growth, survival, migration and other activities of target cells. After describing the general properties of MK, this review focuses on MK and MK inhibitors as therapeutics for diseases in the central nervous system. MK is strongly expressed during embryogenesis especially at the midgestation period, but is expressed only at restricted sites in adults. MK expression is induced upon tissue injury such as ischemic brain damage. Since exogenously administered MK or the gene transfer of MK suppresses neuronal cell death in experimental systems, MK has the potential to treat cerebral infarction. MK might become important also in the treatment of neurodegenerative diseases such as Alzheimer's disease. MK is involved in inflammatory diseases by enhancing migration of leukocytes, inducing chemokine production and suppressing regulatory T cells. Since an aptamer to MK suppresses experimental autoimmune encephalitis, MK inhibitors are promising for the treatment of multiple sclerosis. MK is overexpressed in most malignant tumors including glioblastoma, and is involved in tumor invasion. MK inhibitors may be of value in the treatment of glioblastoma. Furthermore, an oncolytic adenovirus, whose replication is under the control of the MK promoter, inhibits the growth of glioblastoma xenografts. MK inhibitors under development include antibodies, aptamers, glycosaminoglycans, peptides and low molecular weight compounds. siRNA and antisense oligoDNA have proved effective against malignant tumors and inflammatory diseases in experimental systems. Practical information concerning the development of MK and MK inhibitors as therapeutics is described in the final part of the review.
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Affiliation(s)
- Takashi Muramatsu
- Department of Health Science, Faculty of Psychological and Physical Science, Aichi Gakuin University, 12 Araike, Iwasaki-cho, Nisshin, Aichi 470-0195, Japan.
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Kubo S, Kawasaki Y, Yamaoka N, Tagawa M, Kasahara N, Terada N, Okamura H. Complete regression of human malignant mesothelioma xenografts following local injection of midkine promoter-driven oncolytic adenovirus. J Gene Med 2010; 12:681-92. [PMID: 20635326 DOI: 10.1002/jgm.1486] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Malignant mesothelioma is a highly aggressive tumor with poor prognosis. We hypothesized that the tumor-specific midkine (Mdk) promoter could confer transcriptional targeting to oncolytic adenoviruses for effective treatment of malignant mesothelioma. METHODS We analysed Mdk expression by quantitative reverse transcription-polymerase chain reaction in six human mesothelioma cell lines, and tested Mdk promoter activity by luciferase reporter assay. On the basis of these data, we constructed a replication-selective oncolytic adenovirus designated AdMdk-E1-iresTK. This virus contains a Mdk promoter-driven adenoviral E1 gene and herpes simplex virus-thymidine kinase (TK) suicide gene and cytomagalovirus promoter-driven enhanced green fluorescent protein marker gene. Selectivity of viral replication and cytolysis were characterized in normal versus mesothelioma cells in vitro, and intratumoral spread and antitumor efficacy were investigated in vivo. RESULTS Mdk promoter activity was restricted in normal cells, but highly activated in mesothelioma cell lines. AdMdk-E1-iresTK was seen to efficiently replicate, produce viral progeny and spread in multiple mesothelioma cell lines. Lytic spread of AdMdk-E1-iresTK mediated the efficient killing of these mesothelioma cells, and its in vitro cytocidal effect was significantly enhanced by treatment with the prodrug, ganciclovir. Intratumoral injection of AdMdk-E1-iresTK caused complete regression of MESO4 and MSTO human mesothelioma xenografts in athymic mice. In vivo fluorescence imaging demonstrated intratumoral spread of AdMdk-E1-iresTK-derived signals, which vanished after tumor eradication. CONCLUSIONS These data indicate that transcriptional targeting of viral replication by the Mdk promoter represents a promising general strategy for oncolytic virotherapy of cancers with up-regulated Mdk expression, including malignant mesothelioma.
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Affiliation(s)
- Shuji Kubo
- Laboratory of Host Defenses, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
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Neunaber C, Catala-Lehnen P, Beil FT, Marshall RP, Kanbach V, Baranowsky A, Lehmann W, Streichert T, Ignatius A, Muramatsu T, Schinke T, Amling M. Increased trabecular bone formation in mice lacking the growth factor midkine. J Bone Miner Res 2010; 25:1724-35. [PMID: 20200993 DOI: 10.1002/jbmr.75] [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: 01/18/2023]
Abstract
Midkine (Mdk) and pleiotrophin (Ptn) comprise a family of heparin-binding growth factors known primarily for their effects on neuronal cells. Since transgenic mice overexpressing Ptn have been reported to display increased bone density, we have previously analyzed Ptn-deficient mice but failed to detect any abnormality of skeletal development and remodeling. Together with the finding that Mdk expression increases in the course of primary osteoblast differentiation, we reasoned that Mdk, rather than Ptn, could play a physiologic role in bone formation. Here, we show that Mdk-deficient mice display an increased trabecular bone volume at 12 and 18 months of age, accompanied by cortical porosity. Histomorphometric quantification demonstrated an increased bone-formation rate compared with wild-type littermates, whereas bone resorption was differentially affected in trabecular and cortical bone of Mdk-deficient mice. To understand the effect of Mdk on bone formation at the molecular level, we performed a genome-wide expression analysis of primary osteoblasts and identified Ank and Enpp1 as Mdk-induced genes whose decreased expression in Mdk-deficient osteoblasts may explain, at least in part, the observed skeletal phenotype. Finally, we performed ovariectomy and observed bone loss only in wild-type but not in Mdk-deficient animals. Taken together, our data demonstrate that Mdk deficiency, at least in mice, results in an increased trabecular bone formation, thereby raising the possibility that Mdk-specific antagonists might prove beneficial in osteoporosis therapy.
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Affiliation(s)
- Claudia Neunaber
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Jono H, Ando Y. Midkine: a novel prognostic biomarker for cancer. Cancers (Basel) 2010; 2:624-41. [PMID: 24281085 PMCID: PMC3835095 DOI: 10.3390/cancers2020624] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2010] [Revised: 03/03/2010] [Accepted: 04/19/2010] [Indexed: 01/04/2023] Open
Abstract
Since diagnosis at an early stage still remains a key issue for modern oncology and is crucial for successful cancer therapy, development of sensitive, specific, and non-invasive tumor markers, especially, in serum, is urgently needed. Midkine (MK), a plasma secreted protein, was initially identified in embryonal carcinoma cells at early stages of retinoic acid-induced differentiation. Multiple studies have reported that MK plays important roles in tumor progression, and is highly expressed in various malignant tumors. Because increased serum MK concentrations also have been reported in patients with various tumors, serum MK may have the potential to become a very useful tumor marker. Here, we review and discuss the possibility and usefulness of MK as a novel tumor marker.
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Affiliation(s)
- Hirofumi Jono
- Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan.
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35
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Asano Y, Kishida S, Mu P, Sakamoto K, Murohara T, Kadomatsu K. DRR1 is expressed in the developing nervous system and downregulated during neuroblastoma carcinogenesis. Biochem Biophys Res Commun 2010; 394:829-35. [DOI: 10.1016/j.bbrc.2010.03.085] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2010] [Accepted: 03/12/2010] [Indexed: 12/12/2022]
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Lucas S, Henze G, Schnabel D, Barthlen W, Sakuma S, Kurtz A, Driever PH. Serum levels of Midkine in children and adolescents without malignant disease. Pediatr Int 2010; 52:75-9. [PMID: 19460128 DOI: 10.1111/j.1442-200x.2009.02885.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
BACKGROUND Midkine (MK), a heparin-binding growth factor, is a secreted protein and can be detected in a patient's sera. METHOD MK was studied in the sera of 215 children and adolescents without malignant disease using an enzyme-linked immunosorbent assay in order to determine the distribution of concentrations in a control population for pediatric oncology patients. Tested subjects either underwent surgical procedures or suffered from endocrinological diseases. RESULTS Elevated MK levels were found in patients with short stature, diabetes mellitus, obesity, and cleft lip and palate. These patients were subsequently excluded from the "non-cancer" group. MK serum levels did neither correlate with sex, age, weight or height nor showed a normal distribution (n= 152, range: 0.0-5.58 ng/ml, median: 0.0 ng/ml, mean: 0.26 ng/ml, SD: +/-0.61). CONCLUSION MK serum values in children and adolescents are widely spread and not normally distributed. The present results indicate that the MK expression is influenced by many factors apart from cancer, which have not yet been identified.
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Affiliation(s)
- Susanne Lucas
- Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany
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Muramatsu T. Midkine, a heparin-binding cytokine with multiple roles in development, repair and diseases. PROCEEDINGS OF THE JAPAN ACADEMY. SERIES B, PHYSICAL AND BIOLOGICAL SCIENCES 2010; 86:410-425. [PMID: 20431264 PMCID: PMC3417803 DOI: 10.2183/pjab.86.410] [Citation(s) in RCA: 129] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2009] [Accepted: 02/24/2010] [Indexed: 05/29/2023]
Abstract
Midkine is a heparin-binding cytokine or a growth factor with a molecular weight of 13 kDa. Midkine binds to oversulfated structures in heparan sulfate and chondroitin sulfate. The midkine receptor is a molecular complex containing proteoglycans. Midkine promotes migration, survival and other activities of target cells. Midkine has about 50% sequence identity with pleiotrophin. Mice deficient in both factors exhibit severe abnormalities including female infertility. In adults, midkine is expressed in damaged tissues and involved in the reparative process. It is also involved in inflammatory reactions by promoting the migration of leukocytes, induction of chemokines and suppression of regulatory T cells. Midkine is expressed in a variety of malignant tumors and promotes their growth and invasion. Midkine appears to be helpful for the treatment of injuries in the heart, brain, spinal cord and retina. Midkine inhibitors are expected to be effective in the treatment of malignancies, rheumatoid arthritis, multiple sclerosis, renal diseases, restenosis, hypertension and adhesion after surgery.
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Affiliation(s)
- Takashi Muramatsu
- Department of Health Science, Faculty of Psychological and Physical Science, Aichi Gakuin University. 12 Araike, Aichi, Japan.
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Abstract
Serum levels of midkine (MK), a heparin-binding growth factor, are elevated in adult cancer patients. We analyzed sera of pediatric tumor patients in comparison to a large number of children and adolescents without malignant disease. MK was studied in sera of 152 noncancer patients and 29 embryonal tumor patients (14 nephroblastoma, 10 neuroblastoma, and 5 rhabdomyosarcoma) using an enzyme-linked immunosorbent assay. Noncancer patients underwent elective surgical procedures or suffered from an endocrinologic disease. They had no evidence of inflammation or injury. MK serum levels were significantly higher in tumor patients (median 0.621 ng/mL) than in noncancer patients. About 86% of tumor patients were identified using a cut-off value of 0.176 ng/mL. MK values did neither correlate with tumor size nor with stage or histology, but decreased in half of the nephroblastoma patients after chemotherapy and surgery. MK values were found to be elevated in only 2 out of 5 rhabdomyosarcoma patients. MK may serve as an additional marker for the detection of pediatric embryonal tumors, but its clinical relevance for the evaluation of response to therapy needs further study.
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Ibusuki M, Fujimori H, Yamamoto Y, Ota K, Ueda M, Shinriki S, Taketomi M, Sakuma S, Shinohara M, Iwase H, Ando Y. Midkine in plasma as a novel breast cancer marker. Cancer Sci 2009; 100:1735-9. [PMID: 19538527 PMCID: PMC11159736 DOI: 10.1111/j.1349-7006.2009.01233.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2009] [Revised: 05/18/2009] [Accepted: 05/21/2009] [Indexed: 12/22/2022] Open
Abstract
Midkine, a heparin-binding growth factor, is up-regulated in many types of cancer. The aim of this study was to measure plasma midkine levels in patients with breast cancer and to assess its clinical significance. We examined plasma midkine levels in 95 healthy volunteers, 11 patients with ductal carcinoma in situ (DCIS), 111 patients with primary invasive breast cancer without distant metastasis (PIBC), and 25 patients with distant metastatic breast cancer (MBC), using an automatic immunoasssay analyzer (TOSOH AIA system). In PIBC, we studied the correlation between plasma midkine levels and clinicopathological factors. Immunoreactive midkine was detectable in the plasma of healthy volunteers, and a cut-off level of 750 pg/mL was established. In breast cancer patients, plasma midkine levels were increased above normal values. These elevated levels of midkine were seen in one (9.1%) of 11 patients with DCIS, 36 (32.4%) of 111 patients with PIBC, and 16 (64.0%) of 25 patients with MBC. Increased levels of midkine were correlated with menopausal status (P = 0.0497) and nuclear grade (P = 0.0343) in PIBC. Cancer detection rates based on midkine levels were higher than those based on three conventional markers including CA15-3 (P < 0.0001), CEA (P = 0.0077), and NCCST-439 (P < 0.0001). Detection rates of breast cancer using a combination of two conventional tumor markers (CA15-3/CEA, CA15-3/NCCST-439, or CEA/NCCST-439) with midkine is significantly higher than those using combination of three conventional tumor markers. Midkine may be a useful novel tumor marker for detection of breast cancer, superior to conventional tumor markers.
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Affiliation(s)
- Mutsuko Ibusuki
- Department of Breast and Endocrine Surgery, Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
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Hobo A, Yuzawa Y, Kosugi T, Kato N, Asai N, Sato W, Maruyama S, Ito Y, Kobori H, Ikematsu S, Nishiyama A, Matsuo S, Kadomatsu K. The growth factor midkine regulates the renin-angiotensin system in mice. J Clin Invest 2009; 119:1616-25. [PMID: 19451697 DOI: 10.1172/jci37249] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2008] [Accepted: 03/25/2009] [Indexed: 12/24/2022] Open
Abstract
The renin-angiotensin system plays a pivotal role in regulating blood pressure and is involved in the pathogenesis of kidney disorders and other diseases. Here, we report that the growth factor midkine is what we believe to be a novel regulator of the renin-angiotensin system. The hypertension induced in mice by 5/6 nephrectomy was accompanied by renal damage and elevated plasma angiotensin II levels and was ameliorated by an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin receptor blocker. Notably, ACE activity in the lung, midkine expression in the lung, and midkine levels in the plasma were all increased after 5/6 nephrectomy. Exposure to midkine protein enhanced ACE expression in primary cultured human lung microvascular endothelial cells. Furthermore, hypertension was not induced and renal damage was less severe in midkine-deficient mice. Supplemental administration of midkine protein to midkine-deficient mice restored ACE expression in the lung and hypertension after 5/6 nephrectomy. Oxidative stress might be involved in midkine expression, since expression of NADH/NADPH oxidase-1, -2, and -4 was induced in the lung after 5/6 nephrectomy. Indeed, the antioxidative reagent tempol reduced midkine expression and plasma angiotensin II levels and consequently ameliorated hypertension. These results suggest that midkine regulates the renin-angiotensin system and mediates the kidney-lung interaction after 5/6 nephrectomy.
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Affiliation(s)
- Akinori Hobo
- Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Kato N, Yuzawa Y, Kosugi T, Hobo A, Sato W, Miwa Y, Sakamoto K, Matsuo S, Kadomatsu K. The E-selectin ligand basigin/CD147 is responsible for neutrophil recruitment in renal ischemia/reperfusion. J Am Soc Nephrol 2009; 20:1565-76. [PMID: 19443639 DOI: 10.1681/asn.2008090957] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
E-selectin and its ligands are essential for extravasation of leukocytes in inflammation. Here, we report that basigin (Bsg)/CD147 is a ligand for E-selectin that promotes renal inflammation in ischemia/reperfusion. Compared with wild-type mice, Bsg-deficient (Bsg(-/-)) mice demonstrated striking suppression of neutrophil infiltration in the kidney after renal ischemia/reperfusion. Although E-selectin expression increased similarly between the two genotypes, Bsg(-/-) mice exhibited less renal damage, suggesting that Bsg on neutrophils contribute to renal injury in this model. Neutrophils expressed Bsg with N-linked polylactosamine chains and Bsg(-)(/)(-) neutrophils showed reduced binding to E-selectin. Bsg isolated from HL-60 cells bound to E-selectin, and tunicamycin treatment to abolish N-linked glycans from Bsg abrogated this binding. Furthermore, Bsg(-)(/)(-) neutrophils exhibited reduced E-selectin-dependent adherence to human umbilical vein endothelial cells in vitro. Injection of labeled neutrophils into mice showed that Bsg(-)(/)(-) neutrophils were less readily recruited to the kidney after renal ischemia/reperfusion than Bsg(+/+) neutrophils, regardless of the recipient's genotype. Taken together, these results indicate that Bsg is a physiologic ligand for E-selectin that plays a critical role in the renal damage induced by ischemia/reperfusion.
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Affiliation(s)
- Noritoshi Kato
- Department of Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan
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Wang Y, Xing H, Tian Z, Tang K, Wang J, Xu Z, Rao Q, Wang M, Wang J. Overexpression of Midkine promotes the viability of BA/F3 cells. Biochem Biophys Res Commun 2009; 384:341-6. [PMID: 19409372 DOI: 10.1016/j.bbrc.2009.04.119] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2009] [Accepted: 04/22/2009] [Indexed: 10/20/2022]
Abstract
Midkine (MK), a heparin-binding growth factor, has been reported to be overexpressed in a variety of human solid tumors. In the previous study, we found that MK was overexpressed in bone marrow samples derived from acute leukemia (AL) patients. To elucidate the role of MK, we stably transfected MK in IL-3-dependent BA/F3 cells. The results indicated that the capacity of proliferation and colony formation was significantly increased in the MK-transfected subclones than in the empty vector-transfected subclones. MK potentiated proliferation of BA/F3 cells by promoting cell cycle progression. Apoptosis assays showed a remarkable reduction of apoptosis in MK expressing subclones. Exogenous MK could induce the phosphorylation of Raf-1, and inhibit the expression of Bax in BA/F3 cells. These results indicate that MK might be involved in the pathogenesis of leukemia and could be taken as an ideal diagnostic marker and molecular target for the treatment of acute leukemia.
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Affiliation(s)
- Yang Wang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, PR China
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Xu Y, Qu X, Zhang X, Luo Y, Zhang Y, Luo Y, Hou K, Liu Y. Midkine positively regulates the proliferation of human gastric cancer cells. Cancer Lett 2009; 279:137-44. [PMID: 19250738 DOI: 10.1016/j.canlet.2009.01.024] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2008] [Revised: 01/07/2009] [Accepted: 01/20/2009] [Indexed: 11/16/2022]
Abstract
Midkine (MDK), a heparin-binding growth factor, modulates the proliferation and migration of various cells, is often highly expressed in many malignant tumors, and may act as an oncoprotein. We found that MDK is overexpressed in clinical human gastric cancer tissues relative to its expression in adjacent noncancerous tissues. To further investigate the biological activities of MDK in gastric cancer, we introduced the MDK gene into human SGC7901 gastric cancer cells, where it contributed to the proliferation of SGC7901 cells in vitro and in vivo. Conversely, the knockdown of MDK expression by siRNA resulted in significantly reduced proliferation of BGC823 cells. Our study also shows that MDK activates both the Akt and ERK1/2 pathways and upregulates the expression of several cell-cycle-related proteins, including cyclin A, cyclin D1, Cdk2, Cdk4, and Cdk6, which in part explains the contribution of MDK to gastric cancer cell survival and growth. These results demonstrate that MDK contributes to gastric cancer cell proliferation and suggest that it plays an important role in the development of human gastric cancer.
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Affiliation(s)
- Yingying Xu
- Department of Medical Oncology, The First Hospital, China Medical University, 155 North Nanjing Street, Heping District, Shenyang City 110001, China
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Zhang ZH, Du LJ, Xiang D, Zhu SY, Wu MY, Lu HL, Yu Y, Han W. Expression and purification of bioactive high-purity human midkine in Escherichia coli. J Zhejiang Univ Sci B 2009; 10:79-86. [PMID: 19235265 PMCID: PMC2644747 DOI: 10.1631/jzus.b0820385] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2008] [Accepted: 01/16/2009] [Indexed: 02/04/2023]
Abstract
Midkine is a heparin-binding growth factor, which plays important roles in the regulation of cell growth and differentiation. The non-tagged recombinant human midkine (rhMK) is therefore required to facilitate its functional studies of this important growth factor. In the present work, rhMK was expressed in Escherichia coli (E. coli) BL21 (DE3). The expression of midkine was efficiently induced by isopropyl-beta-D-thiogalactopyranoside (IPTG). After sonication, midkine was recovered in an insoluble form, and was dissolved in guanidine hydrochloride buffer. Renaturation of the denatured protein was carried out in the defined protein refolding buffer, and the refolded protein was purified using S-Sepharose ion-exchange chromatography. The final preparation of the rhMK was greater than 98% pure as measured by sodium dodecylsulfate-polyacrylamid gel electrophoresis (SDS-PAGE) and reverse phase high performance liquid chromatography (RP-HPLC). The purified rhMK enhanced the proliferation of NIH3T3 cells.
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Affiliation(s)
- Zhong-hui Zhang
- Laboratory of Regenoromics, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Li-juan Du
- College of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Di Xiang
- Laboratory of Regenoromics, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Shun-ying Zhu
- Shanghai Municipality Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Ming-yuan Wu
- Laboratory of Regenoromics, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Hui-li Lu
- Laboratory of Regenoromics, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Yan Yu
- Shanghai Municipality Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Wei Han
- Laboratory of Regenoromics, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
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Abstract
Midkine (MK) is a heparin-binding growth factor with its gene first identified in embryonal carcinoma cells at early stages of retinoic acid-induced differentiation. MK is frequently and highly expressed in a variety of human carcinomas. Furthermore, the blood MK level is frequently elevated with advance of human carcinomas, decreased after surgical removal of the tumors. Thus, it is expected to become a promising marker for evaluating the progress of carcinomas. There is mounting evidence that MK plays a significant role in carcinogenesis-related activities, such as proliferation, migration, anti-apoptosis, mitogenesis, transforming, and angiogenesis. In addition, siRNA and anti-sense oligonucleotides for MK have yielded great effects in anti-tumor activities. Therefore, MK appears to be a potential candidate molecular target of therapy for human carcinomas. In this paper, we review MK targeting at nucleoli in different tumor cells and its role in carcinogenesis to deepen our understanding of the mechanism of MK involved in carcinogenesis.
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Promotion of glioma cell survival by acyl-CoA synthetase 5 under extracellular acidosis conditions. Oncogene 2008; 28:9-19. [DOI: 10.1038/onc.2008.355] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Toyoda E, Doi R, Kami K, Mori T, Ito D, Koizumi M, Kida A, Nagai K, Ito T, Masui T, Wada M, Tagawa M, Uemoto S. Midkine promoter-based conditionally replicative adenovirus therapy for midkine-expressing human pancreatic cancer. J Exp Clin Cancer Res 2008; 27:30. [PMID: 18717994 PMCID: PMC2529268 DOI: 10.1186/1756-9966-27-30] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2008] [Accepted: 08/21/2008] [Indexed: 11/10/2022] Open
Abstract
Background To develop a novel therapeutic strategy for human pancreatic cancer using a midkine promoter-based conditionally replicating adenovirus. Methods We examined midkine mRNA expression and midkine protein expression by seven human pancreatic cancer cell lines (AsPC-1, BxPC-3, CFPAC-1, HPAC, MIAPaCa-2, PANC-1, and Suit-2), as well as by non-cancerous pancreatic tissue and pancreatic cancers. Midkine promoter activity was measured in cancer cell lines by the dual luciferase reporter assay. Adenoviral transduction efficiency was assessed by fluorescent staining of cancer cell lines using adenovirus type 5 containing the green fluorescent protein gene (Ad5GFP). Replication of adenovirus type 5 containing the 0.6 kb midkne promoter (Ad5MK) was assessed by the detection of E1 protein in cancer cell lines. The cytotoxicity of Ad5MK for cancer cells was evaluated from the extent of growth inhibition after viral infection. Infection and replication were also assessed in nude mice with subcutaneous Suit-2 tumors by intratumoral injection of Ad5MK, Ad5GFP, or vehicle. E1a mRNA expression in the treated tumors and expression of the replication-specific adenoviral hexon protein were evaluated. Finally, the anti-tumor activity of Ad5MK against intraperitoneal xenografts of Suit-2 pancreatic cancer cells was examined after intraperitoneal injection of the virus. Results Both midkine mRNA expression and midkine protein expression were strong in AsPC-1 and CFPAC-1 cell liens, moderate in BxPC-3, HPAC, and Suit-2 cell lines, and weak in PANC-1 and MIAPaCa-2 cell lines. Expression of midkine mRNA was significantly stronger in pancreatic cancers than in non-cancerous pancreatic tissues. The relative luciferase activity mediated by the 0.6 kb midkne fragment in AsPC-1, PANC-1, and Suit-2 cell lines was approximately 6 to 20 times greater than that in midkne-negative MIAPaCa-2 cell lines. Pancreatic cancer cell lines exhibited a heterogeneous adenoviral transduction profile. E1A expression was higher in cell lines with strong midkine expression than in cell lines with weak midkine expression. Ad5MK showed much greater cytotoxicity for midkine-expressing Suit-2 and PANC-1 cell lines than for midkine-negative MIAPaCa-2 cell lines. In the Suit-2 subcutaneous xenograft model, expression of E1A was detected in Ad5MK-treated tumors, but not in untreated and Ad5GFP-treated tumors. In the Suit-2 intraperitoneal xenograft model, the Ad5MK group survived for significantly longer than the Ad5GFP, PBS, and untreated groups. Conclusion Ad5MK has an anti-tumor effect against human pancreatic cancer cell lines that express midkine mRNA. Midkine promoter-based conditionally replicative adenovirus might be a promising new gene therapy for pancreatic cancer.
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Affiliation(s)
- Eiji Toyoda
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kyoto University, Japan.
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Jin Z, Lahat G, Korchin B, Nguyen T, Zhu QS, Wang X, Lazar AJ, Trent J, Pollock RE, Lev D. Midkine Enhances Soft-Tissue Sarcoma Growth: A Possible Novel Therapeutic Target. Clin Cancer Res 2008; 14:5033-42. [DOI: 10.1158/1078-0432.ccr-08-0092] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Fujita H, Banno H, Yamanouchi D, Kobayashi M, Yamamoto K, Komori K. Pitavastatin Inhibits Intimal Hyperplasia in Rabbit Vein Graft. J Surg Res 2008; 148:238-43. [DOI: 10.1016/j.jss.2007.08.017] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2007] [Revised: 08/14/2007] [Accepted: 08/21/2007] [Indexed: 11/27/2022]
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Tanabe K, Matsumoto M, Ikematsu S, Nagase S, Hatakeyama A, Takano T, Niikura H, Ito K, Kadomatsu K, Hayashi SI, Yaegashi N. Midkine and its clinical significance in endometrial carcinoma. Cancer Sci 2008; 99:1125-30. [PMID: 18422745 PMCID: PMC11159489 DOI: 10.1111/j.1349-7006.2008.00796.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Midkine (MK) is a secreted heparin-binding growth factor. Several types of human cancer have increased MK expression with elevated serum levels. The purpose of this study was to determine whether MK was expressed in endometrial carcinoma and to evaluate the clinicopathological significance of serum MK in patients with endometrial carcinoma. Immunohistochemical expression of MK was evaluated in 85 endometrial carcinoma samples and 33 controls. MK expression was significantly higher in the carcinomas than in normal endometrium (P < 0.001). Interestingly, MK expression was highest at the margins of invasion and low in the superficial areas of the tumor samples. Using ELISA, we compared serum MK concentration in 120 endometrial carcinoma patients with the concentration in 46 patients with benign gynecologic tumors. Serum MK value in patients with cancer was significantly higher than that in the patients with benign diseases (P = 0.01). Patients with positive lymph node metastasis or recurrence, or cancer death, had a higher serum MK level (P = 0.008, P = 0.009, respectively). In conclusion, MK immunoreactivity in endometrial carcinoma is significantly higher than in normal endometrium. Additionally, preoperative serum MK levels are significantly correlated with prognosis and the presence of lymph node metastasis. Thus, MK may be a useful serum biomarker for identifying high risk patients of endometrial carcinoma.
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Affiliation(s)
- Kojiro Tanabe
- Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
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