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1
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Komune N, Kuga R, Hongo T, Kuga D, Sato K, Nakagawa T. Impact of Positive-Margin Resection of External Auditory Canal Squamous Cell Carcinoma. Cancers (Basel) 2023; 15:4289. [PMID: 37686564 PMCID: PMC10486369 DOI: 10.3390/cancers15174289] [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: 07/13/2023] [Revised: 08/16/2023] [Accepted: 08/24/2023] [Indexed: 09/10/2023] Open
Abstract
BACKGROUND Positive-margin resection of external auditory canal squamous cell carcinoma (EAC-SCC) is still a major cause of recurrence. The aim of this study is to examine the clinical impact of positive-margin resection of EAC-SCCs. METHODS We retrospectively reviewed 40 surgical cases with en bloc temporal bone resection of EAC-SCC at a tertiary referral center from October 2016 to March 2022. RESULTS Two-year disease-specific, overall, and disease-free survival rates for all 40 cases reviewed were 85.2%, 88.85%, and 76.96%, respectively. En bloc resection with a negative margin significantly improved patient prognosis (p < 0.001). Positive-margin resection was observed in 9/40 cases (22.5%). Insufficient assessment of preoperative images was the cause in two of these cases. Postoperative lymph node metastasis and distant metastasis were observed in cases in which vascular, lymphatic duct or perineural invasion was found on postoperative pathological examination. In addition, three cases in which no vascular, lymphatic duct, or perineural invasion was found exhibited local recurrence during the follow-up period. Of the nine positive-margin resection cases, only two showed no postoperative recurrence. CONCLUSIONS Once positive-margin resections are confirmed, cases might have a high risk of tumor recurrence, even with the addition of postoperative adjuvant chemoradiotherapy.
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Affiliation(s)
- Noritaka Komune
- Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; (R.K.); (T.H.); (K.S.); (T.N.)
| | - Ryosuke Kuga
- Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; (R.K.); (T.H.); (K.S.); (T.N.)
- Department of Anatomic Pathology, Pathological, Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Takahiro Hongo
- Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; (R.K.); (T.H.); (K.S.); (T.N.)
| | - Daisuke Kuga
- Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
| | - Kuniaki Sato
- Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; (R.K.); (T.H.); (K.S.); (T.N.)
| | - Takashi Nakagawa
- Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; (R.K.); (T.H.); (K.S.); (T.N.)
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Cheng Z, Zhang X, Zhang Y, Li L, Chen P. Role of MMP-2 and CD147 in kidney fibrosis. Open Life Sci 2022; 17:1182-1190. [PMID: 36185410 PMCID: PMC9482425 DOI: 10.1515/biol-2022-0482] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 07/18/2022] [Accepted: 07/19/2022] [Indexed: 11/16/2022] Open
Abstract
Matrix metalloproteinase-2 (MMP-2) and cluster of differentiation 147 (CD147) both play important roles in the development of kidney fibrosis, and CD147 can induce the production and activation of MMP-2. In the early stage of kidney fibrosis, MMP-2 promotes extracellular matrix (ECM) production and accelerates the development of kidney fibrosis, while in the advanced stage, MMP-2 activity decreases, leading to reduced ECM degradation and making it difficult to alleviate kidney fibrosis. The reason for the decrease in MMP-2 activity in the advanced stage is still unclear. On the one hand, it may be related to hypoxia and endocytosis, which lead to changes in the expression of MMP-2-related active regulatory molecules; on the other hand, it may be related to insufficient CD147 function. At present, the specific process by which CD147 is involved in the regulation of MMP-2 activity is not completely clear, and further in-depth studies are needed to clarify the roles of both factors in the pathophysiology of kidney fibrosis.
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Affiliation(s)
- Zhengyuan Cheng
- Department of Internal Medicine, Ma'anshan People's Hospital Affiliated to Medical School of Southeast University, Hubei Road 45, Huashan District, Ma'anshan 243099, Anhui Province, China
| | - Xiaojuan Zhang
- Department of Nephrology, Jinling Hospital Affiliated to Nanjing University, Zhongshan East Road 305, Xuanwu District, Nanjing 210008, Jiangsu Province, China
| | - Yu Zhang
- Department of Pathology and Pathophysiology, Medical School, Southeast University, Dingjiaqiao 87, Gulou District, Nanjing 210009, Jiangsu Province, China
| | - Li Li
- Department of Pathology and Pathophysiology, Medical School, Southeast University, Dingjiaqiao 87, Gulou District, Nanjing 210009, Jiangsu Province, China
| | - Pingsheng Chen
- Department of Pathology and Pathophysiology, Medical School, Southeast University, Dingjiaqiao 87, Gulou District, Nanjing 210009, Jiangsu Province, China
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3
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Chuliá-Peris L, Carreres-Rey C, Gabasa M, Alcaraz J, Carretero J, Pereda J. Matrix Metalloproteinases and Their Inhibitors in Pulmonary Fibrosis: EMMPRIN/CD147 Comes into Play. Int J Mol Sci 2022; 23:ijms23136894. [PMID: 35805895 PMCID: PMC9267107 DOI: 10.3390/ijms23136894] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 06/15/2022] [Accepted: 06/15/2022] [Indexed: 02/06/2023] Open
Abstract
Pulmonary fibrosis (PF) is characterized by aberrant extracellular matrix (ECM) deposition, activation of fibroblasts to myofibroblasts and parenchymal disorganization, which have an impact on the biomechanical traits of the lung. In this context, the balance between matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs) is lost. Interestingly, several MMPs are overexpressed during PF and exhibit a clear profibrotic role (MMP-2, -3, -8, -11, -12 and -28), but a few are antifibrotic (MMP-19), have both profibrotic and antifibrotic capacity (MMP7), or execute an unclear (MMP-1, -9, -10, -13, -14) or unknown function. TIMPs are also overexpressed in PF; hence, the modulation and function of MMPs and TIMP are more complex than expected. EMMPRIN/CD147 (also known as basigin) is a transmembrane glycoprotein from the immunoglobulin superfamily (IgSF) that was first described to induce MMP activity in fibroblasts. It also interacts with other molecules to execute non-related MMP aactions well-described in cancer progression, migration, and invasion. Emerging evidence strongly suggests that CD147 plays a key role in PF not only by MMP induction but also by stimulating fibroblast myofibroblast transition. In this review, we study the structure and function of MMPs, TIMPs and CD147 in PF and their complex crosstalk between them.
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Affiliation(s)
- Lourdes Chuliá-Peris
- Department of Physiology, Faculty of Pharmacy, University of Valencia, 46100 Burjassot, Spain; (L.C.-P.); (C.C.-R.); (J.C.)
| | - Cristina Carreres-Rey
- Department of Physiology, Faculty of Pharmacy, University of Valencia, 46100 Burjassot, Spain; (L.C.-P.); (C.C.-R.); (J.C.)
| | - Marta Gabasa
- Unit of Biophysics and Bioengineering, Department of Biomedicine, School of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain; (M.G.); (J.A.)
| | - Jordi Alcaraz
- Unit of Biophysics and Bioengineering, Department of Biomedicine, School of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain; (M.G.); (J.A.)
- Thoracic Oncology Unit, Hospital Clinic Barcelona, 08036 Barcelona, Spain
- Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute for Science and Technology (BIST), 08028 Barcelona, Spain
| | - Julián Carretero
- Department of Physiology, Faculty of Pharmacy, University of Valencia, 46100 Burjassot, Spain; (L.C.-P.); (C.C.-R.); (J.C.)
| | - Javier Pereda
- Department of Physiology, Faculty of Pharmacy, University of Valencia, 46100 Burjassot, Spain; (L.C.-P.); (C.C.-R.); (J.C.)
- Correspondence:
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4
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Pan S, Su Y, Sun B, Hao R, Gao X, Han B. Knockout of CD147 inhibits the proliferation, invasion, and drug resistance of human oral cancer CAL27 cells in Vitro and in Vivo. Int J Biol Macromol 2021; 181:378-389. [PMID: 33766595 DOI: 10.1016/j.ijbiomac.2021.03.102] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 01/13/2021] [Accepted: 03/17/2021] [Indexed: 11/17/2022]
Abstract
With the development of modern biomedicine, research on the molecular mechanism of tumors has developed gradually. The CD147 gene has been applied to tumor molecular targeted therapy, and significant differences were found in the expression of the CD147 gene in different tumor tissues and normal tissues. Many previous studies have also shown that the expression of the CD147 gene plays a crucial role in the development of tumors. To understand whether CD147 can be used as a therapeutic target for oral cancer, CRISPR/Cas9 gene-editing technology was used to knock out the CD147 gene in cal27 cells to obtain knockout cell lines. Using CCK-8, Transwell, RT-PCR, and Western blotting, the proliferation and invasion abilities of the knockout cell lines were decreased significantly, and the expression of matrix metalloproteinase was also inhibited. Next, a subcutaneously transplanted tumor model in nude mice was constructed to detect the effect of the CD147 gene on tumors. Subcutaneous tumor growth and immunohistochemistry results showed that the proliferation and doxorubicin resistance of knockout cell line were significantly inhibited compared with those in the wild-type group. These results indicated that knocking out CD147 significantly reduced the proliferation and invasion of cal27 cells, and CD147 may be a potential therapeutic target for oral cancer.
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Affiliation(s)
- Siqi Pan
- Department of Biopharmacy, School of Pharmaceutical Sciences, Jilin University, Chang Chun, China
| | - Yu Su
- Department of Biopharmacy, School of Pharmaceutical Sciences, Jilin University, Chang Chun, China
| | - Bixi Sun
- Department of Biopharmacy, School of Pharmaceutical Sciences, Jilin University, Chang Chun, China
| | - Rubin Hao
- Department of Biopharmacy, School of Pharmaceutical Sciences, Jilin University, Chang Chun, China
| | - Xiaoshu Gao
- Department of Biopharmacy, School of Pharmaceutical Sciences, Jilin University, Chang Chun, China
| | - Bing Han
- Department of Biopharmacy, School of Pharmaceutical Sciences, Jilin University, Chang Chun, China.
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5
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Zhou Z, Long J, Wang Y, Li Y, Zhang X, Tang L, Chang Q, Chen Z, Hu G, Hu S, Li Q, Peng C, Chen X. Targeted degradation of CD147 proteins in melanoma. Bioorg Chem 2020; 105:104453. [PMID: 33197849 DOI: 10.1016/j.bioorg.2020.104453] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 09/28/2020] [Accepted: 10/31/2020] [Indexed: 02/07/2023]
Abstract
CD147 is a transmembrane glycoprotein and a member of immunoglobulin superfamily, is strongly expressed in melanoma cells. CD147 has a pivotal role in tumor development. Therefore, it is a potential drug target for melanoma. In this article, we report the discovery of the first CD147 protein proteolysis targeting chimeras (PROTACs) derived from the natural product pseudolaric acid B (PAB). The representative compound 6a effectively induced degradation of CD147 and inhibited melanoma cells in vitro and in vivo. 6a could be used as the novel type of anticancer agent or as a part of the molecular biology research toolkit used in the gain-of-function study of the dynamic roles of CD147 in cancer networks.
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Affiliation(s)
- Zhe Zhou
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jing Long
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yuan Wang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - YaYun Li
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xu Zhang
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ling Tang
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qi Chang
- Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China
| | - Zhuo Chen
- Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China
| | - GaoYun Hu
- Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China
| | - Shuo Hu
- Department of Nuclear Medicine, XiangYa Hospital, Central South University, Changsha, Hunan, China; Key Laboratory of Biological Nanotechnology of National Health Commission, Changsha, Hunan, China
| | - QianBin Li
- Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China.
| | - Cong Peng
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Xiang Chen
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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6
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Toyoma S, Suzuki S, Kawasaki Y, Yamada T. SDF-1/CXCR4 induces cell invasion through CD147 in squamous cell carcinoma of the hypopharynx. Oncol Lett 2020; 20:1817-1823. [PMID: 32724425 PMCID: PMC7377101 DOI: 10.3892/ol.2020.11744] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 04/08/2020] [Indexed: 12/01/2022] Open
Abstract
Hypopharyngeal squamous cell carcinoma (SCC) has a poor prognosis due to local invasion and metastasis. The chemokine receptor CXC chemokine receptor type 4 (CXCR4) and its ligand, stromal cell-derived factor 1 (SDF-1), play roles in tumor progression through unclear mechanisms. For the present study, we used a hypopharyngeal SCC cell line, FaDu, expressing CXCR4. We found that SDF-1 promotes migration and invasion of the FaDu cells. In addition, AMD3100, a specific antagonist of CXCR4, inhibited the binding of SDF-1 to CXCR4, resulting in a significant decrease in the FaDu cell migration induced by SDF-1. Stimulation of CXCR4 with SDF-1 induced an increase in the expression of CD147, a cell membrane protein; and this CD147 upregulation was abrogated by AMD3100. CD147 function-blocking antibodies also abolished the SDF-1-induced FaDu invasiveness. Our results suggested that SDF-1/CXCR4 mediate hypopharyngeal SCC cell migration and that CD147 is involved in the SDF-1/CXCR4-related tumor progression.
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Affiliation(s)
- Satoshi Toyoma
- Department of Otorhinolaryngology and Head and Neck Surgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Shinsuke Suzuki
- Department of Otorhinolaryngology and Head and Neck Surgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Yohei Kawasaki
- Department of Otorhinolaryngology and Head and Neck Surgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Takechiyo Yamada
- Department of Otorhinolaryngology and Head and Neck Surgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan
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7
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Miyazaki M, Aoki M, Okado Y, Koga K, Hamasaki M, Nakagawa T, Sakata T, Nabeshima K. Highly expressed tumoral emmprin and stromal CD73 predict a poor prognosis for external auditory canal carcinoma. Cancer Sci 2020; 111:3045-3056. [PMID: 32473077 PMCID: PMC7419056 DOI: 10.1111/cas.14508] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 05/15/2020] [Accepted: 05/19/2020] [Indexed: 12/20/2022] Open
Abstract
Squamous cell carcinoma of the external auditory canal (SCC-EAC) is rare and has a poor prognosis. The SCC-EAC cases with high-grade tumor budding (TB) or poorly differentiated clusters (PDCs) are associated with shorter survival than those with low-grade TB or PDCs. Extracellular matrix metalloproteinase inducer (emmprin) is a protein expressed in tumor cells that stimulates the production of MMP-2 by stromal fibroblasts to facilitate tumor invasion. Recently, we reported that emmprin forms a complex with CD73 to regulate MMP-2 production from fibroblasts in vitro. Here, we examined the association of emmprin and CD73 expression with TB or PDCs as well as with survival in 34 biopsy specimens of SCC-EAC patients. High tumoral emmprin expression was associated with high-grade TB, whereas high stromal CD73 expression was associated with high-grade PDCs. Furthermore, concurrent elevated expression of tumoral emmprin and stromal CD73 was determined to be an independent poor prognostic factor. In immunoprecipitation analyses, complex formation between emmprin and CD73 was demonstrated in vitro. Production of MMP-2 from fibroblasts was more abundant when cocultured with tumor cells than from fibroblasts cultured alone. Furthermore, MMP-2 production was reduced by the transfection of CD73 siRNA in fibroblasts cocultured with tumor cells. The colocalization of emmprin and CD73 was enhanced in not only the peripheral cells of the tumor cell clusters that interact with fibroblasts but also in the cells of intratumor clusters. Overall, this study provides novel insights into the roles of emmprin, CD73, and MMP-2 in tumor invasiveness.
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Affiliation(s)
- Masaru Miyazaki
- Department of Pathology, Fukuoka University Hospital and School of Medicine, Fukuoka, Japan.,Department of Otorhinolaryngology, Fukuoka University Hospital and School of Medicine, Fukuoka, Japan
| | - Mikiko Aoki
- Department of Pathology, Fukuoka University Hospital and School of Medicine, Fukuoka, Japan
| | - Yasuko Okado
- Department of Pathology, Fukuoka University Hospital and School of Medicine, Fukuoka, Japan.,Department of Otorhinolaryngology, Fukuoka University Hospital and School of Medicine, Fukuoka, Japan
| | - Kaori Koga
- Department of Pathology, Fukuoka University Hospital and School of Medicine, Fukuoka, Japan
| | - Makoto Hamasaki
- Department of Pathology, Fukuoka University Hospital and School of Medicine, Fukuoka, Japan
| | - Takashi Nakagawa
- Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Toshifumi Sakata
- Department of Otorhinolaryngology, Fukuoka University Hospital and School of Medicine, Fukuoka, Japan
| | - Kazuki Nabeshima
- Department of Pathology, Fukuoka University Hospital and School of Medicine, Fukuoka, Japan
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8
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Wang C, Xu C, Niu R, Hu G, Gu Z, Zhuang Z. MiR-890 inhibits proliferation and invasion and induces apoptosis in triple-negative breast cancer cells by targeting CD147. BMC Cancer 2019; 19:577. [PMID: 31196010 PMCID: PMC6567604 DOI: 10.1186/s12885-019-5796-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Accepted: 06/05/2019] [Indexed: 12/03/2022] Open
Abstract
Background Triple-negative breast cancer (TNBC) is a type of breast cancer with a high degree of malignancy. Because of the remarkable biological characteristics of high invasion, metastasis and recurrence, TNBC is often accompanied by a poor prognosis. As a molecular characteristic of TNBC, high expression of CD147 has been confirmed by a large number of studies. However, the mechanism of CD147 expression regulation in TNBC remains elusive. In this study, we investigated the roles of miR-890 in inhibiting CD147. Methods Quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) was used to detect CD147 mRNA and miR-890 level, and western blotting was used to detect CD147 protein. Bioinformatics screening and 3′-Untranslated Region (3′-UTR) luciferase assays were used to analyze the microRNAs (miRNA) binding site. Cell proliferation, apoptosis and invasion were assessed by using CCK-8, flow cytometry and transwell assays. Results The upregulation of miR-890 inhibited cell proliferation and invasion, induced apoptosis in MDA-MB-231 and HCC-70 TNBC cells by negatively regulating its target gene, CD147, and the upregulation of CD147 rescued the inhibitory effects of miR-890. miR-890 targeted CD147 by binding to its 3′-UTR. Further results showed that the upregulation of miR-890 also inhibited the expression of MMPs, the downstream genes of CD147, and promoted the cleavage of Caspase-3. The CD147 recovery experiment was further confirmed by the activity changes in the downstream MMPs of CD147. In addition, it was confirmed that the effect of CD147 in promoting TNBC cell proliferation and invasion, inhibiting apoptosis was related to the change in caspase-3 activity. Conclusion The downregulation of miR-890 is the potential cause of high CD147 expression in TNBC, which can promote the malignant transformation of TNBC.
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Affiliation(s)
- Cheng Wang
- Department of Breast surgery, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200040, China.,Department of Breast Surgery, Central Hospital of Huangpu District, Shanghai, 200020, China
| | - Cheng Xu
- Department of Breast Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, 200090, China
| | - Ruijie Niu
- Department of Breast Surgery, Central Hospital of Huangpu District, Shanghai, 200020, China
| | - Guangfu Hu
- Department of Breast Surgery, Central Hospital of Huangpu District, Shanghai, 200020, China
| | - Zhangyuan Gu
- Department of Breast surgery, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200040, China
| | - Zhigang Zhuang
- Department of Breast surgery, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200040, China.
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9
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Suzuki S, Toyoma S, Tsuji T, Kawasaki Y, Yamada T. CD147 mediates transforming growth factor-β1-induced epithelial-mesenchymal transition and cell invasion in squamous cell carcinoma of the tongue. Exp Ther Med 2019; 17:2855-2860. [PMID: 30906472 DOI: 10.3892/etm.2019.7230] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Accepted: 12/28/2018] [Indexed: 12/12/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT) is a physiological process in which epithelial cells attain the motile and invasive characteristics of mesenchymal cells, which results in the development of increased migratory and invasive cell behavior, serving as a vital mechanism of cancer progression. Hence, controlling the EMT for cancer treatment, including head and neck squamous cell carcinoma (HNSCC), is imperative. Among EMT-associated factors, transforming growth factor-β (TGF-β) is a well-established potent inducer. Recent research has revealed that CD147, a member of the immunoglobulin superfamily, promotes the EMT. However, the role of CD147 in the EMT and the following tumorigenicity in HNSCC has not been completely elucidated. This study aims to investigate the role of CD147 in the EMT and related tumorigenicity in HNSCC. The present study used two HNSCC cell lines, SAS and FaDu, for in vitro studies. In HNSCC cells, TGF-β1 induced spindle-shaped morphological changes, and western blot analysis revealed that TGF-β1 induced changes in EMT markers, downregulation of vimentin, and upregulation of E-cadherin, yet increased CD147. In addition, TGF-β1 increased cell migration in HNSCC cells. However, a TGF-β1-induced alteration in EMT makers was attenuated with CD147 silencing by small interfering RNA (siRNA) in SAS cells. In addition, the TGF-β1-induced cell invasion of SAS was attenuated with CD147 silencing. In conclusion, the present study suggests that CD147 mediates TGF-β1-induced EMT and tumorigenicity in HNSCC. Hence, CD147 may serve as a vital therapeutic target in HNSCC.
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Affiliation(s)
- Shinsuke Suzuki
- Department of Otorhinolaryngology, Head and Neck Surgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Satoshi Toyoma
- Department of Otorhinolaryngology, Head and Neck Surgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Tadahiro Tsuji
- Department of Otorhinolaryngology, Head and Neck Surgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Yohei Kawasaki
- Department of Otorhinolaryngology, Head and Neck Surgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Takechiyo Yamada
- Department of Otorhinolaryngology, Head and Neck Surgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan
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10
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Matsumoto T, Nagashio R, Ryuge S, Igawa S, Kobayashi M, Fukuda E, Goshima N, Ichinoe M, Jiang SX, Satoh Y, Masuda N, Murakumo Y, Saegusa M, Sato Y. Basigin expression as a prognostic indicator in stage I pulmonary adenocarcinoma. Pathol Int 2018; 68:232-240. [PMID: 29431238 DOI: 10.1111/pin.12646] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 01/09/2018] [Indexed: 02/06/2023]
Abstract
We established the KU-Lu-8 monoclonal antibody (MoAb) using a lung cancer cell line as an antigen and a random immunization method. The KU-Lu-8 MoAb recognizes basigin (BSG), which is a transmembrane-type glycoprotein that is strongly expressed on the cell membranes of lung cancer cells. This study aimed to clarify the relationships between BSG expression and clinicopathological parameters and determine the prognostic significance of BSG expression in pulmonary adenocarcinoma (AC) patients. To evaluate the significance of BSG expression in lung cancer, we immunohistochemically analyzed 113 surgically resected pulmonary adenocarcinomas, and the associations between BSG expression and various clinicopathological parameters were evaluated. Kaplan-Meier survival analysis and Cox proportional hazards models were used to investigate the effects of BSG expression on survival. Clinicopathologically, BSG expression was significantly associated with tumor differentiation, vascular invasion, lymphatic invasion, and a poor prognosis. In particular, BSG expression was significantly correlated with poorer survival in patients with stage I AC. The high BSG expression group (compared with the low BSG expression group) exhibited adjusted hazard ratios for mortality of 4.694. BSG expression is indicative of a poor prognosis in AC patients, particularly in those with stage I disease.
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Affiliation(s)
- Toshihide Matsumoto
- Department of Pathology, School of Medicine, Kitasato University, Kanagawa, Japan
| | - Ryo Nagashio
- Department of Applied Tumor Pathology, Graduate School of Medical Sciences, Kitasato University, Kanagawa, Japan
| | - Shinichiro Ryuge
- Department of Respiratory Medicine, School of Medicine, Kitasato University, Kanagawa, Japan
| | - Satoshi Igawa
- Department of Respiratory Medicine, School of Medicine, Kitasato University, Kanagawa, Japan
| | - Makoto Kobayashi
- Department of Applied Tumor Pathology, Graduate School of Medical Sciences, Kitasato University, Kanagawa, Japan
| | - Eriko Fukuda
- Division of Quantitative Proteomics Team, Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan
| | - Naoki Goshima
- Division of Quantitative Proteomics Team, Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan
| | - Masaaki Ichinoe
- Department of Pathology, School of Medicine, Kitasato University, Kanagawa, Japan
| | - Shi-Xu Jiang
- Department of Pathology, School of Medicine, Kitasato University, Kanagawa, Japan
| | - Yukitoshi Satoh
- Department of Thoracic and Cardiovascular Surgery, School of Medicine, Kitasato University, Kanagawa, Japan
| | - Noriyuki Masuda
- Department of Respiratory Medicine, School of Medicine, Kitasato University, Kanagawa, Japan
| | - Yoshiki Murakumo
- Department of Pathology, School of Medicine, Kitasato University, Kanagawa, Japan
| | - Makoto Saegusa
- Department of Pathology, School of Medicine, Kitasato University, Kanagawa, Japan
| | - Yuichi Sato
- Department of Applied Tumor Pathology, Graduate School of Medical Sciences, Kitasato University, Kanagawa, Japan
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Feng F, Wang B, Sun X, Zhu Y, Tang H, Nan G, Wang L, Wu B, Huhe M, Liu S, Diao T, Hou R, Zhang Y, Zhang Z. Metuzumab enhanced chemosensitivity and apoptosis in non-small cell lung carcinoma. Cancer Biol Ther 2017; 18:51-62. [PMID: 28055291 PMCID: PMC5323017 DOI: 10.1080/15384047.2016.1276126] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Targeted therapeutics is used as an alternative treatment of non-small cell lung cancer (NSCLC); however, treatment effect is far from being satisfactory, and therefore identification of new targets is needed. We have previously shown that metuzumab inhibit tumor growth in vivo. The present study was performed to investigate the anti-tumor efficacy of metuzumab combined with gemcitabine and cisplatin (GP), paclitaxel and cisplatin (TP) or navelbine and cisplatin (NP) regimens in multiple NSCLC cell lines. Our results demonstrate that, in comparison to single agent metuzumab or GP treated cells, metuzumab combined with GP display inhibitory effects on tumor growth. Furthermore, we found that metuzumab elevated the sensitivity of cell lines to gemcitabine, which was identified by MTT assay. Flow cytometric analysis showed that metuzumab combined with gemcitabine (GEM) treatment led to an obvious G1 arrest and an elevated apoptosis in A549, NCI-H460 and NCI-H520 cells. Western blot analysis also demonstrated a significantly reduced level of cyclin D1, Bcl-2, and an obviously increase level of Bax and full-length caspase-3 in A549, NCI-H460 and NCI-H520 cells treated with metuzumab/gemcitabine combination in comparison with single agent treated cells. In addition, metuzumab/gemcitabine treated A549, NCI-H460 and NCI-H520 cells also demonstrated a significantly increase in deoxycytidine kinase (dCK) protein level compared with single agent metuzumab or gemcitabine treated cells. Xenograft models also demonstrated that this metuzumab/gemcitabine combination led to upregulation of dCK. Taken together, the mechanisms of metuzumab combined with GP repress tumor growth were that the combined treatment significantly inhibited the tumor cell proliferation, apoptosis and cell cycle in vitro and in vivo and at least partially by induction of dCK expression. Our results suggested that metuzumab could significantly enhance chemosensitivity of human NSCLC cells to gemcitabine. Metuzumab/gemcitabine combination treatment may be a potentially useful therapeutic regimen for NSCLC patients.
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Affiliation(s)
- Fei Feng
- a National Translational Science Center for Molecular Medicine , Department of Cell Biology , Fourth Military Medical University , Xi'an , P.R. China
| | - Bin Wang
- a National Translational Science Center for Molecular Medicine , Department of Cell Biology , Fourth Military Medical University , Xi'an , P.R. China
| | - Xiuxuan Sun
- a National Translational Science Center for Molecular Medicine , Department of Cell Biology , Fourth Military Medical University , Xi'an , P.R. China
| | - Yumeng Zhu
- a National Translational Science Center for Molecular Medicine , Department of Cell Biology , Fourth Military Medical University , Xi'an , P.R. China
| | - Hao Tang
- b Pacific Meinuoke Biopharmaceutical Company , Changzhou , P.R. China
| | - Gang Nan
- a National Translational Science Center for Molecular Medicine , Department of Cell Biology , Fourth Military Medical University , Xi'an , P.R. China
| | - Lijuan Wang
- a National Translational Science Center for Molecular Medicine , Department of Cell Biology , Fourth Military Medical University , Xi'an , P.R. China
| | - Bo Wu
- a National Translational Science Center for Molecular Medicine , Department of Cell Biology , Fourth Military Medical University , Xi'an , P.R. China
| | - Muren Huhe
- a National Translational Science Center for Molecular Medicine , Department of Cell Biology , Fourth Military Medical University , Xi'an , P.R. China
| | - Shuangshuang Liu
- a National Translational Science Center for Molecular Medicine , Department of Cell Biology , Fourth Military Medical University , Xi'an , P.R. China
| | - Tengyue Diao
- a National Translational Science Center for Molecular Medicine , Department of Cell Biology , Fourth Military Medical University , Xi'an , P.R. China
| | - Rong Hou
- a National Translational Science Center for Molecular Medicine , Department of Cell Biology , Fourth Military Medical University , Xi'an , P.R. China
| | - Yang Zhang
- a National Translational Science Center for Molecular Medicine , Department of Cell Biology , Fourth Military Medical University , Xi'an , P.R. China
| | - Zheng Zhang
- a National Translational Science Center for Molecular Medicine , Department of Cell Biology , Fourth Military Medical University , Xi'an , P.R. China
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CD147 as a novel biomarker for predicting the prognosis and clinicopathological features of bladder cancer: a meta-analysis. Oncotarget 2017; 8:62573-62588. [PMID: 28977970 PMCID: PMC5617530 DOI: 10.18632/oncotarget.19257] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Accepted: 04/19/2017] [Indexed: 01/06/2023] Open
Abstract
Objective To assess the prognostic and clinicopathological characteristics of CD147 in human bladder cancer. Methods Studies on CD147 expression in bladder cancer were retrieved from PubMed, EMBASE, the Cochrane Library, Web of Science, China National Knowledge Infrastructure, and the WanFang databases. Outcomes were pooled with meta-analyzing softwares RevMan 5.3 and STATA 14.0. Results Twenty-four studies with 25 datasets demonstrated that CD147 expression was higher in bladder cancer than in non-cancer tissues (OR=43.64, P<0.00001). Moreover, this increase was associated with more advanced clinical stages (OR=73.89, P<0.0001), deeper invasion (OR=3.22, P<0.00001), lower histological differentiation (OR=4.54, P=0.0005), poorer overall survival (univariate analysis, HR=2.63, P<0.00001; multivariate analysis, HR=1.86, P=0.00036), disease specific survival (univariate analysis, HR=1.65, P=0.002), disease recurrence-free survival (univariate analysis, HR=2.78, P=0.001; multivariate analysis, HR=5.51, P=0.017), rate of recurrence (OR=1.91, P=0.0006), invasive depth (pT2∼T4 vs. pTa∼T1; OR=3.22, P<0.00001), and histological differentiation (low versus moderate-to-high; OR=4.54, P=0.0005). No difference was found among disease specific survival in multivariate analysis (P=0.067), lymph node metastasis (P=0.12), and sex (P=0.15). Conclusion CD147 could be a biomarker for early diagnosis, treatment, and prognosis of bladder cancer.
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Park GB, Ko HS, Kim D. Sorafenib controls the epithelial‑mesenchymal transition of ovarian cancer cells via EGF and the CD44‑HA signaling pathway in a cell type‑dependent manner. Mol Med Rep 2017. [PMID: 28627617 PMCID: PMC5561797 DOI: 10.3892/mmr.2017.6773] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Cluster of differentiation (CD) 44 and epidermal growth factor (EGF) are closely involved in cellular migration and have been used as stem cell markers. Although the hyaluronan (HA)‑binding CD44 is responsible for enhanced cellular motility, the mechanism underlying its actions in various cell types and clinical conditions have yet to be elucidated. In the present study, the multikinase inhibitor sorafenib was used to investigate the diverse effects of EGF stimulation on epithelial‑mesenchymal transition (EMT) in ovarian cancer cells using immunoblotting and reverse transcription‑polymerase chain reaction. In addition, the association between EGF and CD44/HA signaling pathways in the control of mesenchymal phenotype was determined by gene silencing with small interfering RNA transfection. EGF stimulation of ovarian cancer cells increased cellular migration, mesenchymal transition, CD44 expression and the activation of matrix metalloproteinase (MMP)‑2 and MMP‑9. Sorafenib effectively suppressed the loss of epithelial characteristics in EGF‑treated SK‑OV‑3 ovarian cancer cells, via targeting the mitogen‑activated protein kinase (MAPK)/extracellular signal‑regulated kinase (ERK) pathway. Although treatment of Caov‑3 ovarian cancer cells with sorafenib blocked the expression of mesenchymal phenotypes following EGF stimulation, EGF‑activated Caov‑3 cells exhibited reduced MAPK/ERK signaling. Furthermore, EGF‑activated Caov‑3 cells increased the expression of hyaluronan synthase 2 and HA‑CD44 ligation in EGF‑exposed Caov‑3 cells, which resulted in the activation of the Ras/Raf/MEK signaling pathway, amplification of migratory activity and the expression of mesenchymal markers, including N‑cadherin and vimentin. Furthermore, silencing EGFR in SK‑OV‑3 cells and CD44 in Caov‑3 cells suppressed their migratory activity, through inhibition of the MAPK/ERK pathway. The present results suggested that EGF‑mediated signaling may regulate metastasis and invasion of ovarian cancer cells, in a cancer cell type‑dependent manner.
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Affiliation(s)
- Ga Bin Park
- Department of Biochemistry, Kosin University College of Medicine, Busan 49267, Republic of Korea
| | - Hyun-Suk Ko
- Department of Anatomy, Inje University College of Medicine, Busan 47392, Republic of Korea
| | - Daejin Kim
- Department of Anatomy, Inje University College of Medicine, Busan 47392, Republic of Korea
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Hendrix AY, Kheradmand F. The Role of Matrix Metalloproteinases in Development, Repair, and Destruction of the Lungs. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2017; 148:1-29. [PMID: 28662821 DOI: 10.1016/bs.pmbts.2017.04.004] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Normal gas exchange after birth requires functional lung alveolar units that are lined with epithelial cells, parts of which are intricately fused with microvascular capillaries. A significant phase of alveolar lung development occurs in the perinatal period, continues throughout early stages in life, and requires activation of matrix-remodeling enzymes. Failure to achieve an optimum number of alveoli during lung maturation can cause several untoward medical consequences including disabling obstructive and/or restrictive lung diseases that limit physiological endurance and increase mortality. Several members of the matrix metalloproteinase (MMP) family are critical in lung remodeling before and after birth; however, their resurgence in response to environmental factors, infection, and injury can also compromise lung function. Therefore, temporal expression, regulation, and function of MMPs play key roles in developing and maintaining adequate oxygenation under steady state, as well as in diseased conditions. Broadly, with the exception of MMP2 and MMP14, most deletional mutations of MMPs fail to perturb lung development; however, their individual absence can alter the pathophysiology of respiratory diseases. Specifically, under stressed conditions such as acute respiratory infection and allergic inflammation, MMP2 and MMP9 can play a protective role through bacterial clearance and production of chemotactic gradient, while loss of MMP12 can protect mice from smoke-induced lung disease. Therefore, better understanding of the expression and function of MMPs under normal lung development and their resurgence in response respiratory diseases could provide new therapeutic options in the future.
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Affiliation(s)
- Amanda Y Hendrix
- Section of Pulmonary and Critical Care, and Immunology, Baylor College of Medicine, Houston, TX, United States
| | - Farrah Kheradmand
- Section of Pulmonary and Critical Care, and Immunology, Baylor College of Medicine, Houston, TX, United States.
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Geng JJ, Tang J, Yang XM, Chen R, Zhang Y, Zhang K, Miao JL, Chen ZN, Zhu P. Targeting CD147 for T to NK Lineage Reprogramming and Tumor Therapy. EBioMedicine 2017; 20:98-108. [PMID: 28571672 PMCID: PMC5478251 DOI: 10.1016/j.ebiom.2017.05.022] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Revised: 05/16/2017] [Accepted: 05/16/2017] [Indexed: 11/18/2022] Open
Abstract
CD147 is highly expressed on the surface of numerous tumor cells to promote invasion and metastasis. Targeting these cells with CD147-specific antibodies has been validated as an effective approach for lung and liver cancer therapy. In the immune system, CD147 is recognized as a co-stimulatory receptor and impacts the outcome of thymic selection. Using T cell-specific deletion, we showed here that in thymus CD147 is indispensable for the stable αβ T cell lineage commitment: loss of CD147 biases both multipotent DN (double negative) and fully committed DP (double positive) cells into innate NK-like lineages. Mechanistically, CD147 deficiency results in impaired Wnt signaling and expression of BCL11b, a master transcription factor in determining T cell identity. In addition, functional blocking of CD147 by antibody phenocopies genetic deletion to enrich NK-like cells in the periphery. Furthermore, using a melanoma model and orthotopic liver cancer transplants, we showed that the augmentation of NK-like cells strongly associates with resistance against tumor growth upon CD147 suppression. Therefore, besides its original function in tumorigenesis, CD147 is also an effective surface target for immune modulation in tumor therapy.
DN, DP cells were reprogrammed into innate NK-like cells after thymic CD147 deleted Loss of CD147 results in impaired Bcl11b expression and T-lineages development, which can be rescued by Wnt3a stimulation. CD147 is an vital target for immune modulation via NK-like cells in tumor therapy. Tumor therapy is a difficult task and many methods have been used. Among them, tumor immunotherapy is a focus in the field and has made great progress. In this study, we found CD147 is an vital target for immune modulation via NK-like cells in tumor therapy, which means CD147 antibody may be through regulating immune cells to achieve tumor therapy. Although CD147 antibody has been used for liver cancer, making clear the mechanism of CD147 antibody mediated tumor therapy may be benefit for guiding clinical treatment.
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Affiliation(s)
- Jie-Jie Geng
- Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shan'xi 710032, PR China; Department of Cell Biology, Fourth Military Medical University, Xi'an, Shan'xi 710032, PR China
| | - Juan Tang
- Department of Cell Biology, Fourth Military Medical University, Xi'an, Shan'xi 710032, PR China
| | - Xiang-Min Yang
- Department of Cell Biology, Fourth Military Medical University, Xi'an, Shan'xi 710032, PR China
| | - Ruo Chen
- Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shan'xi 710032, PR China; Department of Cell Biology, Fourth Military Medical University, Xi'an, Shan'xi 710032, PR China
| | - Yang Zhang
- Department of Cell Biology, Fourth Military Medical University, Xi'an, Shan'xi 710032, PR China
| | - Kui Zhang
- Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shan'xi 710032, PR China
| | - Jin-Lin Miao
- Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shan'xi 710032, PR China
| | - Zhi-Nan Chen
- Department of Cell Biology, Fourth Military Medical University, Xi'an, Shan'xi 710032, PR China.
| | - Ping Zhu
- Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shan'xi 710032, PR China.
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Li H, Wu D, Shi S, Xu Y, Wei L, Liu J, Liu Y. Expression and clinical significance of CD147 in renal cell carcinoma: a meta-analysis. Oncotarget 2017; 8:51331-51344. [PMID: 28881651 PMCID: PMC5584252 DOI: 10.18632/oncotarget.17376] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Accepted: 02/21/2017] [Indexed: 01/02/2023] Open
Abstract
Objective To assess clinical significance of CD147 in renal cell carcinoma. Methods Collect case-control studies which focus on CD147's expression in renal cell carcinoma. Trails were retrieved from CBM, CNKI, Wan-fang database, PubMed, Cochrane Library and Embase. According to the inclusion and exclusion criteria, data extraction and quality assessment were done by two researchers independently, and outcomes were pooled with Revman5.3 and STATA14.0. Results A total of 11 studies were confirmed, among which renal cell carcinoma 887 cases, non-cancer 505cases. As for the positive rate of CD147, there are statistical differences among survival, renal cell carcinoma tissue vs. non-cancer tissues [OR= 8.19, P= 0.0002], with vs. without lymph node metastases [OR= 6.52, P= 0.001], clinical stage III~IV vs. II~I [OR= 4.07, P< 0.00001], histopathological stage III~IV vs. II [OR= 3.01, P= 0.002], histopathological stage III~IV vs. I [OR= 7.50, P< 0.00001], tumor size [OR= 5.01, P= 0.0007]. No significant difference was tested among different age, gender, histological types and Position of cancer. Conclusion As shown in our results, CD 147 may participate the whole course of carcinogenesis of renal cell carcinoma, which might be valuable for the diagnosis, treatment and prognosis.
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Affiliation(s)
- Hui Li
- Reproductive Department, Xiangya Hospital, Central South University, Changsha, China
| | - Dongwen Wu
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Shupeng Shi
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Yadong Xu
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Ling Wei
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Jing Liu
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Yanting Liu
- Xiangya School of Medicine, Central South University, Changsha, China
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Ju HL, Ro SW. Making cancer fat: reprogramming of lipid metabolism by CD147 in hepatocellular carcinoma. Chin J Cancer Res 2016; 28:380-2. [PMID: 27478325 PMCID: PMC4949285 DOI: 10.21147/j.issn.1000-9604.2016.03.14] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Affiliation(s)
- Hye-Lim Ju
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 120-752, South Korea
| | - Simon Weonsang Ro
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 120-752, South Korea
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Upregulation of EMMPRIN (OX47) in Rat Dorsal Root Ganglion Contributes to the Development of Mechanical Allodynia after Nerve Injury. Neural Plast 2015; 2015:249756. [PMID: 26697232 PMCID: PMC4677233 DOI: 10.1155/2015/249756] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 06/24/2015] [Accepted: 06/28/2015] [Indexed: 12/14/2022] Open
Abstract
Matrix metalloproteinases (MMPs) are widely implicated in inflammation and tissue remodeling associated with various neurodegenerative diseases and play an important role in nociception and allodynia. Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) plays a key regulatory role for MMP activities. However, the role of EMMPRIN in the development of neuropathic pain is not clear. Western blotting, real-time quantitative RT-PCR (qRT-PCR), and immunofluorescence were performed to determine the changes of messenger RNA and protein of EMMPRIN/OX47 and their cellular localization in the rat dorsal root ganglion (DRG) after nerve injury. Paw withdrawal threshold test was examined to evaluate the pain behavior in spinal nerve ligation (SNL) model. The lentivirus containing OX47 shRNA was injected into the DRG one day before SNL. The expression level of both mRNA and protein of OX47 was markedly upregulated in ipsilateral DRG after SNL. OX47 was mainly expressed in the extracellular matrix of DRG. Administration of shRNA targeted against OX47 in vivo remarkably attenuated mechanical allodynia induced by SNL. In conclusion, peripheral nerve injury induced upregulation of OX47 in the extracellular matrix of DRG. RNA interference against OX47 significantly suppressed the expression of OX47 mRNA and the development of mechanical allodynia. The altered expression of OX47 may contribute to the development of neuropathic pain after nerve injury.
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Functional role of EMMPRIN in the formation and mineralisation of dental matrix in mouse molars. J Mol Histol 2014; 46:21-32. [PMID: 25501684 DOI: 10.1007/s10735-014-9603-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Accepted: 12/08/2014] [Indexed: 12/11/2022]
Abstract
Our previous research has shown that the extracellular matrix metalloproteinase inducer (EMMPRIN) is expressed during and may function in the early development of tooth germs. In the present study, we observed the specific expression of EMMPRIN in ameloblasts and odontoblasts during the middle and late stages of tooth germ development using immunohistochemistry. Furthermore, to extend our understanding of the function of EMMPRIN in odontogenesis, we used an anti-EMMPRIN function-blocking antibody to remove EMMPRIN activity in tooth germ culture in vitro. Both the formation and mineralisation of dental hard tissues were suppressed in the tooth germ culture after the abrogation of EMMPRIN. Meanwhile, significant reductions in VEGF, MMP-9, ALPL, ameloblastin, amelogenin and enamelin expression were observed in antibody-treated tooth germ explants compared to control and normal serum-treated explants. The current results illustrate that EMMPRIN may play a critical role in the processing and maturation of the dental matrix.
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Suzuki S, Ishikawa K. Combined inhibition of EMMPRIN and epidermal growth factor receptor prevents the growth and migration of head and neck squamous cell carcinoma cells. Int J Oncol 2013; 44:912-7. [PMID: 24379084 DOI: 10.3892/ijo.2013.2238] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2013] [Accepted: 12/09/2013] [Indexed: 11/06/2022] Open
Abstract
It has been reported that the epidermal growth factor receptor (EGFR) expression is associated with the extracellular matrix metalloproteinase inducer (EMMPRIN) in some solid tumors; however, the relationship of EMMPRIN with EGFR in head and neck cancers is not fully understood. To determine the relationship between EMMPRIN and EGFR in head and neck squamous cell carcinoma (HNSCC), HNSCC cells were stimulated with epidermal growth factor (EGF), a ligand of EGFR. EMMPRIN expression in HNSCC cells was upregulated by EGF. In addition, EGF stimulation induced HNSCC cell invasion and MMP-9 expression. This increase in invasion and MMP-9 expression was abrogated by downmodulation of EMMPRIN. Furthermore, to determine the effects of combined EMMPRIN and EGFR targeting in HNSCC, HNSCC cells were treated with an EMMPRIN function-blocking antibody and the EGFR inhibitor AG1478. This combined treatment resulted in greater inhibition of HNSCC cell proliferation and migration compared with the individual agents alone. These results suggest that EMMPRIN mediates EGFR-induced tumorigenicity and that combined targeting of EMMPRIN and EGFR may be an efficacious treatment approach.
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Affiliation(s)
- Shinsuke Suzuki
- Department of Otorhinolaryngology and Head and Neck Surgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Kazuo Ishikawa
- Department of Otorhinolaryngology and Head and Neck Surgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan
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Li R, Pan Y, He B, Xu Y, Gao T, Song G, Sun H, Deng Q, Wang S. Downregulation of CD147 expression by RNA interference inhibits HT29 cell proliferation, invasion and tumorigenicity in vitro and in vivo. Int J Oncol 2013; 43:1885-94. [PMID: 24064772 DOI: 10.3892/ijo.2013.2108] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Accepted: 09/02/2013] [Indexed: 11/06/2022] Open
Abstract
We investigated the effect of CD147 silencing on HT29 cell proliferation and invasion. We constructed a novel short hairpin RNA (shRNA) expression vector pYr-mir30-shRNA. The plasmid was transferred to HT29 cells. The expression of CD147, MCT1 (lactate transporters monocarboxylate transporter 1) and MCT4 (lactate transporters monocarboxylate transporter 4) were monitored by quantitative PCR and western blotting, respectively. The MMP-2 (matrix metalloproteinase-2) and MMP-9 (matrix metalloproteinase-9) activities were determined by gelatin zymography assay, while the intracellular lactate concentration was determined by the lactic acid assay kit. WST-8 assay was used to determine the HT29 cell proliferation and the chemosensitivity. Invasion assay was used to determine the invasion of HT29 cells. In addition, we established a colorectal cancer model, and detected CD147 expression in vivo. The results showed that the expression of CD147 and MCT1 was significantly reduced at both mRNA and protein levels, and also the activity of MMP-2 and MMP-9 was reduced. The proliferation and invasion were decreased, but chemosensitivity to cisplatin was increased. In vivo, the CD147 expression was also significantly decreased, and reduced the tumor growth after CD147 gene silencing. The results demonstrated that silencing of CD147 expression inhibited the proliferation and invasion, suggesting CD147 silencing might be an adjuvant gene therapy strategy to chemotherapy.
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Affiliation(s)
- Rui Li
- Department of Life Sciences, Nanjing Normal University, Nanjing, Jiangsu 210006, P.R. China
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Grass GD, Tolliver LB, Bratoeva M, Toole BP. CD147, CD44, and the epidermal growth factor receptor (EGFR) signaling pathway cooperate to regulate breast epithelial cell invasiveness. J Biol Chem 2013; 288:26089-26104. [PMID: 23888049 DOI: 10.1074/jbc.m113.497685] [Citation(s) in RCA: 88] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The immunoglobulin superfamily glycoprotein CD147 (emmprin; basigin) is associated with an invasive phenotype in various types of cancers, including malignant breast cancer. We showed recently that up-regulation of CD147 in non-transformed, non-invasive breast epithelial cells is sufficient to induce an invasive phenotype characterized by membrane type-1 matrix metalloproteinase (MT1-MMP)-dependent invadopodia activity (Grass, G. D., Bratoeva, M., and Toole, B. P. (2012) Regulation of invadopodia formation and activity by CD147. J. Cell Sci. 125, 777-788). Here we found that CD147 induces breast epithelial cell invasiveness by promoting epidermal growth factor receptor (EGFR)-Ras-ERK signaling in a manner dependent on hyaluronan-CD44 interaction. Furthermore, CD147 promotes assembly of signaling complexes containing CD147, CD44, and EGFR in lipid raftlike domains. We also found that oncogenic Ras regulates CD147 expression, hyaluronan synthesis, and formation of CD147-CD44-EGFR complexes, thus forming a positive feedback loop that may amplify invasiveness. Last, we showed that malignant breast cancer cells are heterogeneous in their expression of surface-associated CD147 and that high levels of membrane CD147 correlate with cell surface EGFR and CD44 levels, activated EGFR and ERK1, and activated invadopodia. Future studies should evaluate CD147 as a potential therapeutic target and disease stratification marker in breast cancer.
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Affiliation(s)
- G Daniel Grass
- From the Department of Regenerative Medicine and Cell Biology and
| | | | - Momka Bratoeva
- From the Department of Regenerative Medicine and Cell Biology and
| | - Bryan P Toole
- From the Department of Regenerative Medicine and Cell Biology and; the Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425.
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Expression of HAb18G/CD147 and its localization correlate with the progression and poor prognosis of non-small cell lung cancer. Pathol Res Pract 2013; 209:345-52. [PMID: 23602236 DOI: 10.1016/j.prp.2013.02.015] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2012] [Revised: 01/11/2013] [Accepted: 02/21/2013] [Indexed: 01/27/2023]
Abstract
This study was designed to investigate the association of HAb18G/CD147 expression and localization with clinicopathological parameters and prognosis in NSCLC. Two hundred and eight (208) specimens of surgically resected NSCLC were stained by immunohistochemistry utilizing mouse anti-human HAb18G/CD147 monoclonal antibody. High levels of HAb18G/CD147 expression were associated with male gender, smoking history, tumor position, distant metastasis status, and clinical stage (p<0.05) in squamous cell carcinoma. In adenocarcinomas, HAb18G/CD147 expression was associated with male gender, tumor diameter, differentiation, lymph node status, distant metastasis status, and clinical stage (p<0.05). HAb18G/CD147 expression with higher PU was predominantly localized in the tumor cell membranes rather than in cytoplasms. In squamous cell carcinomas, membranous localization of HAb18G/CD147 was linked to distant metastasis status and TNM stage (p<0.05). Cytoplasmic localization of HAb18G/CD147 was associated with male gender and smoking history. In adenocarcinomas, membranous localization of HAb18G/CD147 correlated with tumor diameter, differentiation and distant metastasis (p<0.05). Univariate analysis indicated that patients with high HAb18G/CD147 expression and membranous localization predicted poor prognosis in both squamous cell carcinomas and adenocarcinomas. Multivariate analysis showed that lymph node status (HR=1.762, 95%CI 1.105-2.811, p=0.017), distant metastasis status (HR=3.789, 95%CI 2.196-6.539, p=0.000), expression (HR=6.632, 95%CI 2.457-17.904, p=0.000), and localization (HR=0.520, 95%CI 0.341-0.794, p=0.002) were good or excellent independent predictors of patient survival. HAb18G/CD147 is a biomarker characterizing progression and survival of NSCLC. More importantly, its cellular localizations should be considered in the analysis of clinicopathological characteristics and prognostic factors in NSCLC.
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Huang T, Chen MH, Wu MY, Wu XY. Correlation between expression of extracellular matrix metalloproteinase inducer and matrix metalloproteinase-2 and cervical lymph node metastasis of nasopharyngeal carcinoma. Ann Otol Rhinol Laryngol 2013; 122:210-5. [PMID: 23577575 DOI: 10.1177/000348941312200311] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVES We evaluated the expression of extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase-2 (MMP-2) in nasopharyngeal carcinoma (NPC) and studied their relationship with cervical lymph node metastasis. METHODS Immunohistochemical staining was used to detect the expression of EMMPRIN and MMP-2 in specimens from patients with chronic nasopharyngitis (CN), nonmetastastic NPC (NM-NPC), and lymph node-metastatic NPC (LNM-NPC). RESULTS The rates of positive EMMPRIN expression in CN, NM-NPC, and LNM-NPC were 13.3%, 30.0%, and 66.7%, respectively. Significant differences were found between the rates in CN and LNM-NPC (p <0.01) and between the rates in NM-NPC and LNM-NPC (p = 0.01). In the LNM-NPC group, NPC cells had a higher rate of expression of EMMPRIN in tumor metastases than in the primary tumor (81.8% versus 66.7%; p = 0.01). The rates of positive MMP-2 expression in CN, NM-NPC, and LNM-NPC were 13.3%, 35.0%, and 60.6%, respectively. A significant difference was found between the rates in CN and LNM-NPC (p < 0.01). In the LNM-NPC group, NPC cells had a higher rate of MMP-2 expression in tumor metastases than in the primary tumor (72.7% versus 60.6%; p <0.01). The expressions of MMP-2 and EMMPRIN were highly correlated (rs = 0.466; p <0.01). CONCLUSIONS Nasopharyngeal carcinoma cells may attain enhanced metastastic capability through the expression of MMP-2 induced by EMMPRIN.
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Affiliation(s)
- Tian Huang
- Institute of Inflammation and Immune Diseases, Shantou University Medical College, Shantou, People's Republic of China
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Gabison E, Khayati F, Mourah S, Menashi S. Cell membrane vesicles as a tool for the study of direct epithelial-stromal interaction: lessons from CD147. Methods Mol Biol 2013; 1066:103-111. [PMID: 23955737 DOI: 10.1007/978-1-62703-604-7_9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
Communication between the epithelial and stromal tissue layers, separated by basement membrane, is known to provide the information necessary for development, differentiation, and homeostasis. These interactions are altered in benign or malignant diseases, in particular when the basement membrane barrier is disrupted allowing a greater proximity between the two cell layers that triggers tissue remodeling. Epithelial-stromal interactions (ESI) have been examined in vitro by various approaches that can be broadly divided into interactions arising from secreted diffusible factors and interactions through direct cell-cell contact. Here we describe a method for the study of direct ESI through CD147, an adhesion molecule present on the epithelial cell surface and which is known to interact with stromal cells, such as fibroblasts and endothelial cells, and signal them to increase production of matrix metalloproteinases. This method can be extended to other adhesion molecules involved in ESI.
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Affiliation(s)
- Eric Gabison
- Univ Paris Diderot and Fondation A. de Rothschild, Paris, France
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Omi Y, Shibata N, Okamoto T, Obara T, Kobayashi M. The role of CD147 in the invasiveness of follicular thyroid carcinoma cells. Thyroid 2012; 22:383-94. [PMID: 22280229 DOI: 10.1089/thy.2010.0426] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND In patients without metastases, capsular and vascular invasion must be noted to make the diagnosis of follicular thyroid carcinoma (FTC). Some patients are initially diagnosed as follicular adenoma (FA) but develop metastases, indicating the original lesion was FTC. A diagnostic marker for FTCs that appear to be FAs by conventional histopathology is urgently needed. CD147 is a transmembrane glycoprotein that induces matrix metalloproteinases (MMPs) and participates in carcinoma invasion. The objective of this study was to determine whether CD147 is upregulated in FTC and if measures directed against it could reduce the invasive activity of FTC cells. METHODS The expression levels of CD147, MMP-1, MMP-2, MMP-3, MMP-7, and MMP-9 in surgical specimens of normal thyroid (n=8), FA (n=20), and FTC (n=9) was determined using immunoblot and immunohistochemical techniques. CD147 protein expression levels of epithelial growth factor stimulated FTC-133 cell lines was measured by immunoblotting with and without cell signaling inhibitors such as wortmannin, PD98059, SP600125, and SB203580. This was also done after exposure to short-hairpin interference RNA directed against CD147. RESULTS Immunoblot analysis of thyroid tissues revealed significant increases in signals for CD147, MMP-3, MMP-7, and MMP-9 in FTC compared with FA or normal tissue, or both. Immunohistochemical analysis revealed colocalization of determinants of CD147 with those of all of MMPs studied, mainly in follicular cells in normal and neoplastic cells in FA and FTC; their immunoreactivities were to some extent more intense in the FTC than FA or normals. In FTC-133 cells, immunoreactive signals for CD147 were upregulated by epidermal growth factor (EGF), and the EGF-driven increases in CD147 were prevented by inhibitors against phosphoinositol-3 kinase (PI3K), extracellular signal-regulated protein kinase (ERK), or c-Jun N-terminal kinase (JNK) but not p38. RNA interference targeted against CD147 reduced the invasive activity of FTC-133 cells and was associated with downregulation of MMP-2, MMP-3, MMP-7, and MMP-9. CONCLUSIONS These results provide in vivo evidence for CD147 upregulation in FTC and in vitro evidence for EGF-stimulated CD147 induction via the PI3K, ERK, and JNK pathways. They suggest the involvement of CD147 in the invasiveness of FTC cells via regulation of MMPs.
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Affiliation(s)
- Yoko Omi
- Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan.
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Arendt BK, Walters DK, Wu X, Tschumper RC, Huddleston PM, Henderson KJ, Dispenzieri A, Jelinek DF. Increased expression of extracellular matrix metalloproteinase inducer (CD147) in multiple myeloma: role in regulation of myeloma cell proliferation. Leukemia 2012; 26:2286-96. [PMID: 22460757 DOI: 10.1038/leu.2012.91] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Multiple myeloma (MM) is preceded by the asymptomatic pre-malignant state, monoclonal gammopathy of undetermined significance (MGUS). Although MGUS patients may remain stable for years, they are at increased risk of progressing to MM. A better understanding of the relevant molecular changes underlying the transition from an asymptomatic to symptomatic disease state is urgently needed. Our studies show for the first time that the CD147 molecule (extracellular matrix metalloproteinase inducer) may be having an important biological role in MM. We first demonstrate that CD147 is overexpressed in MM plasma cells (PCs) vs normal and pre-malignant PCs. Next, functional studies revealed that the natural CD147 ligand, cyclophilin B, stimulates MM cell growth. Moreover, when MM patient PCs displaying bimodal CD147 expression were separated into CD147(bright) and CD147(dim) populations and analyzed for proliferation potential, we discovered that CD147(bright) PCs displayed significantly higher levels of cell proliferation than did CD147(dim) PCs. Lastly, CD147-silencing significantly attenuated MM cell proliferation. Taken together, these data suggest that the CD147 molecule has a key role in MM cell proliferation and may serve as an attractive target for reducing the proliferative compartment of this disease.
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Affiliation(s)
- B K Arendt
- Department of Immunology, Mayo Clinic, College of Medicine, Rochester, MN 55905, USA
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Ke X, Li L, Dong HL, Chen ZN. Acquisition of anoikis resistance through CD147 upregulation: A new mechanism underlying metastasis of hepatocellular carcinoma cells. Oncol Lett 2012; 3:1249-1254. [PMID: 22783427 DOI: 10.3892/ol.2012.658] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2012] [Accepted: 02/17/2012] [Indexed: 11/05/2022] Open
Abstract
Acquisition of anoikis resistance is a prerequisite for the metastasis of hepatocellular carcinoma (HCC) cells. Activation of growth factor signaling pathways and rearrangement of the cytoskeleton have been reported as vital steps in this process. However, key molecules involved in anoikis resistance remain to be determined. The aim of this study was to investigate the effect of CD147 on HCC cells resistant to anoikis. The human SMMC-7221 human HCC cell line was used. Immunofluorescence was used to investigate the expression levels of CD147. Anoikis-induced cell death was assessed using trypan blue exclusion. In the present study, the results showed that SMMC-7721 HCC cells exhibited significant morphological changes when suspended in culture medium supplemented with 1% methocel and a subpopulation of cells resistant to anoikis was acquired with higher viability and invasion ability. CD147 was identified to be significantly increased in cells resistant to anoikis, when compared to the parental cells. CD147 knockdown by siRNA notably induced cell anoikis, partially through the inactivation of PI3K/Akt pathway. All of these evidence provide a novel CD147-related mechanism underlying the metastasis of HCC cells.
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Affiliation(s)
- Xia Ke
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237
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Preliminary study on the effects of carbon dioxide and nitrogen pneumoperitoneums on endometriotic lesions. Arch Gynecol Obstet 2012; 286:389-93. [PMID: 22441658 PMCID: PMC3397125 DOI: 10.1007/s00404-011-2206-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2011] [Accepted: 12/29/2011] [Indexed: 11/06/2022]
Abstract
Objective To determine the effects of carbon dioxide (CO2) and nitrogen (N2) pneumoperitoneums on endometriosis (EMs) lesions. Methods Female Wistar rats were randomized into the following 3 groups: CO2 (N = 20), N2 (N = 22) and air pneumoperitoneums (N = 9). After 5 weeks of establishment models, do the pneumoperitoneums. Then measure the size of EMs lesions and the related factors of serum and tissue after 1, 2, and 4 weeks of pneumoperitoneums. Results (1) One week after the pneumoperitoneum was established, the EMs lesions in the CO2 group were largest in volume, whereas at 4 weeks the EMs lesions in the CO2 group were smaller than the N2 group. (2) The level of ICAM-1 and TIMP-2 of serum in CO2 and N2 group after 2 weeks of pneumoperitoneum were higher than air group. (3) The expression of CD44v6, ICAM-1, MMP-2 and VEGF of tissue in CO2 and N2 group after 1, 2 and 4 weeks of pneumoperitoneum were lower than air group, TIMP-2 and ENS were higher than air group. Conclusion After a CO2 pneumoperitoneum, EMs lesions were reduced in volume, suggesting an inhibitory effect on EMs lesions.
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Zhu H, Zhao J, Zhu B, Collazo J, Gal J, Shi P, Liu L, Ström AL, Lu X, McCann RO, Toborek M, Kyprianou N. EMMPRIN regulates cytoskeleton reorganization and cell adhesion in prostate cancer. Prostate 2012; 72:72-81. [PMID: 21563192 PMCID: PMC3158271 DOI: 10.1002/pros.21408] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2011] [Accepted: 03/30/2011] [Indexed: 01/01/2023]
Abstract
BACKGROUND Proteins on cell surface play important roles during cancer progression and metastasis via their ability to mediate cell-to-cell interactions and navigate the communication between cells and the microenvironment. METHODS In this study a targeted proteomic analysis was conducted to identify the differential expression of cell surface proteins in human benign (BPH-1) versus malignant (LNCaP and PC-3) prostate epithelial cells. We identified EMMPRIN (extracellular matrix metalloproteinase inducer) as a key candidate and shRNA functional approaches were subsequently applied to determine the role of EMMPRIN in prostate cancer cell adhesion, migration, invasion as well as cytoskeleton organization. RESULTS EMMPRIN was found to be highly expressed on the surface of prostate cancer cells compared to BPH-1 cells, consistent with a correlation between elevated EMMPRIN and metastasis found in other tumors. No significant changes in cell proliferation, cell cycle progression, or apoptosis were detected in EMMPRIN knockdown cells compared to the scramble controls. Furthermore, EMMPRIN silencing markedly decreased the ability of PC-3 cells to form filopodia, a critical feature of invasive behavior, while it increased expression of cell-cell adhesion and gap junction proteins. CONCLUSIONS Our results suggest that EMMPRIN regulates cell adhesion, invasion, and cytoskeleton reorganization in prostate cancer cells. This study identifies a new function for EMMPRIN as a contributor to prostate cancer cell-cell communication and cytoskeleton changes towards metastatic spread, and suggests its potential value as a marker of prostate cancer progression to metastasis.
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Affiliation(s)
- Haining Zhu
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536
- Department of Toxicology, University of Kentucky, Lexington, KY 40536
| | - Jun Zhao
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536
| | - Beibei Zhu
- Division of Urology, Department of Surgery, University of Kentucky, Lexington, KY 40536
| | - Joanne Collazo
- Department of Toxicology, University of Kentucky, Lexington, KY 40536
- Division of Urology, Department of Surgery, University of Kentucky, Lexington, KY 40536
| | - Jozsef Gal
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536
| | - Ping Shi
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536
| | - Li Liu
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536
| | - Anna-Lena Ström
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536
| | - Xiaoning Lu
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536
| | - Richard O. McCann
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536
| | - Michal Toborek
- Department Neurosurgery, College of Medicine, University of Kentucky, Lexington, KY 40536
| | - Natasha Kyprianou
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536
- Department of Toxicology, University of Kentucky, Lexington, KY 40536
- Division of Urology, Department of Surgery, University of Kentucky, Lexington, KY 40536
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Zhu S, Li Y, Mi L, Zhang Y, Zhang L, Gong L, Han X, Yao L, Lan M, Chen Z, Zhang W. Clinical impact of HAb18G/CD147 expression in esophageal squamous cell carcinoma. Dig Dis Sci 2011; 56:3569-76. [PMID: 21789540 DOI: 10.1007/s10620-011-1812-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2010] [Accepted: 06/25/2011] [Indexed: 12/09/2022]
Abstract
BACKGROUND HAb18G/CD147 expression has been associated with many tumor invasion molecules, which play important roles in recurrence and poor differentiation of esophageal squamous cell carcinoma (ESCC). However, the clinical implications of HAb18G/CD147 in ESCC are still unclear. AIMS In this study, we clarified the clinical significance of HAb18G/CD147 and characterized the association between HAb18G/CD147 and tumor invasion in ESCC cases. METHODS Tumor tissues were obtained from 86 ESCC patients who underwent surgical resection between 2002 and 2005. All patients that had received previous therapy were excluded. ESCC tissues were analyzed by IHC using anti HAb18G/CD147 antibody. The expression of HAb18G/CD147 mRNA in esophageal cancer cell lines was analyzed by RT-PCR. RESULTS HAb18G/CD147 was uniformly expressed in EC109 and EC871214 cell lines, but negatively expressed in EPC2, esophageal normal squamous cell line. HAb18G/CD147 mainly localized to the membrane of tumor cells in 84.9% of ESCC patients (64 out of 86 cases). Furthermore, we also found that higher HAb18G/CD147 expression levels significantly correlated with lymph node metastasis, depth of tumor invasion and differentiation (P < 0.05). But the expression levels of HAb18G/CD147 in lymph node metastatic tissues were almost equal to that in the primary tumor tissues. Furthermore, lymph node metastasis and expression of HAB18G/CD147 were independent prognostic indicators in ESCC. CONCLUSIONS The expression of HAb18G/CD147 might be involved in the progression and survival of ESCC. Therefore, HAb18G/CD147 could be a clinical marker for the poor prognosis in ESCC patients and may also be a potentially therapeutic target to improve the progression of ESCC.
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Affiliation(s)
- Shaojun Zhu
- The Helmholtz Sino-German Research Laboratory for Cancer, Department of Pathology, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, Shaanxi, People's Republic of China
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Pons M, Cousins SW, Alcazar O, Striker GE, Marin-Castaño ME. Angiotensin II-induced MMP-2 activity and MMP-14 and basigin protein expression are mediated via the angiotensin II receptor type 1-mitogen-activated protein kinase 1 pathway in retinal pigment epithelium: implications for age-related macular degeneration. THE AMERICAN JOURNAL OF PATHOLOGY 2011; 178:2665-81. [PMID: 21641389 DOI: 10.1016/j.ajpath.2011.02.006] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2010] [Revised: 01/25/2011] [Accepted: 02/22/2011] [Indexed: 01/08/2023]
Abstract
Accumulation of various lipid-rich extracellular matrix (ECM) deposits under the retinal pigment epithelium (RPE) has been observed in eyes with age-related macular degeneration (AMD). RPE-derived matrix metalloproteinase (MMP)-2, MMP-14, and basigin (BSG) are major enzymes involved in the maintenance of ECM turnover. Hypertension (HTN) is a systemic risk factor for AMD. It has previously been reported that angiotensin II (Ang II), one of the most important hormones associated with HTN, increases MMP-2 activity and its key regulator, MMP-14, in RPE, inducing breakdown of the RPE basement membrane, which may lead to progression of sub-RPE deposits. Ang II exerts most of its actions by activating the mitogen-activated protein kinase (MAPK) signaling pathway. Herein is explored the MAPK signaling pathway as a potential key intracellular modulator of Ang II-induced increase in MMP-2 activity and MMP-14 and BSG protein expression. It was observed that Ang II stimulates phosphorylation of extracellular signal-regulated kinase (ERK) and p38 MAPK in RPE cells and ERK/p38 and Jun N-terminal kinase (JNK) in mice. These effects were mediated by Ang II type 1 receptors. Blockade of ERK or p38 MAPK abrogated the increase in MMP-2 activity and MMP-14 and BSG proteins in ARPE-19 cells. A better understanding of the molecular events by which Ang II induces ECM dysregulation is of critical importance to further define its contribution to the progression of sub-RPE deposits in AMD patients with HTN.
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Affiliation(s)
- Marianne Pons
- Bascom Palmer Eye Institute, University of Miami, Miami, Florida, USA
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Ranogajec I, Jakić-Razumović J, Puzović V, Gabrilovac J. Prognostic value of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) and aminopeptidase N/CD13 in breast cancer patients. Med Oncol 2011; 29:561-9. [PMID: 21611838 DOI: 10.1007/s12032-011-9984-y] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2010] [Accepted: 05/11/2011] [Indexed: 01/18/2023]
Abstract
The aim of this study was to analyse the expression of matrix metalloproteinase-2(MMP-2), matrix metalloproteinase-9 (MMP-9) and aminopeptidase APN/CD13 in breast carcinoma samples, and their possible prognostic value in breast cancer patients. The expression of MMP-2, MMP-9 and APN/CD13 in tumor cells was analysed in 138 breast carcinomas by immunohistochemical staining of tumor cells using the semiquantitative method for the detection of cytoplasmic and membrane reaction in tumor cells as well as stromal cells positivity. MMP-2 was positive in tumor cells of 52.9% patients and in stromal cells of 74.6% patients, while MMP-9 positive tumor and stromal cells were found in 84.8 and 63.8% patients, respectively. Tumor cell APN/CD13 expression was found in 36.2% patients. Stromal cell MMP-2 expression correlated significantly with tumor size and neoangiogenesis. A positive correlation was also observed between tumor cell MMP-9 expression and hormone receptor status. Stromal cell coexpression of MMP-2/MMP-9 correlated significantly with tumor size. APN/CD13 expression in tumor cells significantly correlated with tumor type and neoangiogenesis. Overall survival was significantly shorter in patients with MMP-2, MMP-2/MMP-9 positive tumor cells, and tended to be shorter in patients with APN/CD13 positive tumor cells. Coexpression of MMP-2/MMP-9 in tumor cells was an independent risk factor for patient survival (OD = 13.9). Our results suggest that MMP-2, MMP-9, APN/CD13 expression and MMP-2/MMP-9 coexpression in combination with other standard prognostic factors can serve as a poor prognostic factor in the evaluation of breast cancer prognosis.
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Affiliation(s)
- Irena Ranogajec
- Department of Clinical Cytology, SUNCE Polyclinic, Trnjanska Cesta 108, 10000 Zagreb, Croatia.
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Lee JH, Chung SW, Park IH, Lee SH, Lee SH, Lee HM. Expression of Extracellular Matrix Metalloproteinase Inducer in Nasal Polyps. Am J Rhinol Allergy 2010; 24:127-31. [DOI: 10.2500/ajra.2010.24.3503] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Background Extracellular matrix metalloproteinase inducer (EMMPRIN) is a transmembrane glycoprotein that belongs to the immunoglobulin superfamily. The presence of EMMPRIN in nontumoral tissues suggests a role in other physiological and pathological situations, which may be associated with increased matrix metalloproteinase expression. The purpose of this study was to investigate the expression of EMMPRIN mRNA (OMIM *606080) and to localize the EMMPRIN protein in nasal polyps and healthy nasal mucosa. Methods The expression of EMMPRIN was investigated in the nasal polyps of 10 patients undergoing endonasal sinus surgery and compared with nasal mucosal samples obtained from 10 healthy controls. EMMPRIN mRNA was extracted from the tissues, and then a reverse transcription–polymerase chain reaction was performed. Western blot analysis was used to analyze differences in the levels of expression of EMMPRIN protein between patients with nasal polyps and healthy controls, and the EMMPRIN protein was localized in immunohistochemical staining and quantitative analysis of immunopositivity. Results The levels of expression of EMMPRIN mRNA and protein were significantly increased in patients with nasal polyps compared with healthy controls. EMMPRIN protein was expressed in the epithelium and infiltrating inflammatory cells of nasal polyps and the healthy nasal mucosa. The percentages of the immune-stained area and the number of EMMPRIN-immunopositive inflammatory cells per millimeter were significantly elevated in nasal polyps compared with controls. Conclusion EMMPRIN is expressed in nasal mucosa and in nasal polyps, and the level of EMMPRIN expression is increased in nasal polyps. These results suggest that the increased expression of EMMPRIN may play a role in the pathogenesis of nasal polyps.
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Affiliation(s)
- Jang-Hyeog Lee
- Department of Otorhinolaryngology–Head and Neck Surgery, Guro Hospital, Korea University College of Medicine, Seoul, South Korea
| | - Seung Won Chung
- Department of Otorhinolaryngology–Head and Neck Surgery, Guro Hospital, Korea University College of Medicine, Seoul, South Korea
| | - Il-Ho Park
- Department of Otorhinolaryngology–Head and Neck Surgery, Guro Hospital, Korea University College of Medicine, Seoul, South Korea
| | - Sang Hag Lee
- Department of Otorhinolaryngology–Head and Neck Surgery, Guro Hospital, Korea University College of Medicine, Seoul, South Korea
| | - Seung Hoon Lee
- Department of Otorhinolaryngology–Head and Neck Surgery, Guro Hospital, Korea University College of Medicine, Seoul, South Korea
| | - Heung-Man Lee
- Department of Otorhinolaryngology–Head and Neck Surgery, Guro Hospital, Korea University College of Medicine, Seoul, South Korea
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Rucci N, Millimaggi D, Mari M, Del Fattore A, Bologna M, Teti A, Angelucci A, Dolo V. Receptor Activator of NF-κB Ligand Enhances Breast Cancer–Induced Osteolytic Lesions through Upregulation of Extracellular Matrix Metalloproteinase Inducer/CD147. Cancer Res 2010; 70:6150-60. [DOI: 10.1158/0008-5472.can-09-2758] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Moonsom S, Tayapiwatana C, Wongkham S, Kongtawelert P, Kasinrerk W. A Competitive ELISA for quantifying serum CD147: reduction of soluble CD147 levels in cancer patient sera. Hybridoma (Larchmt) 2010; 29:45-52. [PMID: 20199151 DOI: 10.1089/hyb.2009.0096] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
CD147/EMMPRIN (extracellular matrix metalloproteinase inducer) is a cell surface glycoprotein that displays increased expression in many cancers. It has been previously demonstrated to participate in cancer metastasis and progression. In this study we used an anti-CD147 monoclonal antibody and a recombinant CD147 protein generated in our laboratory to establish a competitive ELISA for quantifying serum CD147 levels. Unexpectedly, the CD147 level was highest in sera of normal subjects and significantly reduced in sera of cancer patients. There was no significant difference in serum CD147 level between benign, non-metastatic, and metastatic stages of cancers. In regard to liver diseases, the maximal CD147 level was observed in sera of patients with hepatitis and hepatocellular carcinoma, and significantly decreased in patients with liver cirrhosis and cholangiocarcinoma. Our results imply that there may be homeostasis of CD147 levels in sera under normal physiological conditions, while such a level is altered in cancer patients.
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Affiliation(s)
- Seangdeun Moonsom
- Biomedical Technology Research Center, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency at the Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
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Sidhu SS, Nawroth R, Retz M, Lemjabbar-Alaoui H, Dasari V, Basbaum C. EMMPRIN regulates the canonical Wnt/β-catenin signaling pathway, a potential role in accelerating lung tumorigenesis. Oncogene 2010; 29:4145-56. [PMID: 20514014 DOI: 10.1038/onc.2010.166] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Buergy D, Fuchs T, Kambakamba P, Mudduluru G, Maurer G, Post S, Tang Y, Nakada MT, Yan L, Allgayer H. Prognostic impact of extracellular matrix metalloprotease inducer: immunohistochemical analyses of colorectal tumors and immunocytochemical screening of disseminated tumor cells in bone marrow from patients with gastrointestinal cancer. Cancer 2009; 115:4667-78. [PMID: 19569245 DOI: 10.1002/cncr.24516] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Extracellular matrix metalloprotease inducer (EMMPRIN) induces matrix metalloproteinase (MMP) expression, tumor-stroma cell interaction, and invasion/angiogenesis. The objectives of the current study were to find the first evidence of a prognostic impact of total and relative EMMPRIN expression in colorectal cancer cells and to analyze EMMPRIN in bone marrow-disseminated tumor cells and normal cells from 2 different gastrointestinal cancer entities. METHODS Tumors and normal tissues from 40 patients with colorectal cancer who were followed prospectively (median follow-up, 31 months) were analyzed for EMMPRIN by immunohistochemistry. Bone marrow from 51 patients (13 patients with gastric cancer and 38 patients with colorectal cancer) with evidence of disseminated tumor cells was screened for EMMPRIN in tumor cells and normal cells (cytokeratin 18/EMMPRIN double immunocytochemistry). RESULTS A significant correlation between poor disease-specific survival (P=.037; Kaplan-Meier method; Mantel-Cox log-rank tests) and an increased ratio of EMMPRIN in tumor cells versus corresponding normal epithelial cells were observed. Furthermore, the relative increase of EMMPRIN was associated with a trend toward poor overall and recurrence-free survival. High relative EMMPRIN expression was associated significantly with positive metastasis status (M1) (P=.001) and with a trend towards advanced pathologic tumor classification. Sixteen percent of disseminated tumor cells in bone marrow samples from patients with colorectal cancer and 48.5% of disseminated tumor cells in bone marrow samples from patients with gastric cancer stained positive for EMMPRIN, and EMMPRIN on micrometastatic cells was associated significantly with parameters of tumor progression (M status, noncurative resectability). A minority of normal bone marrow cells were stained for EMMPRIN, suggesting their suitability for molecular targeting. CONCLUSIONS To the authors' knowledge, this study was the first to indicate that increased relative EMMPRIN protein in tumor-specific cells compared with normal cells predicts poor disease-specific survival in patients with colorectal cancer and that EMMPRIN in primary and bone marrow-disseminated tumor cells is associated with clinical markers of tumor progression in patients with colorectal/gastric cancer.
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Affiliation(s)
- Daniel Buergy
- Department of Experimental Surgery, Medical Faculty Mannheim, University Heidelberg, Heidelberg, Germany
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Lizarbe TR, Tarín C, Gómez M, Lavin B, Aracil E, Orte LM, Zaragoza C. Nitric oxide induces the progression of abdominal aortic aneurysms through the matrix metalloproteinase inducer EMMPRIN. THE AMERICAN JOURNAL OF PATHOLOGY 2009; 175:1421-30. [PMID: 19779140 DOI: 10.2353/ajpath.2009.080845] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Nitric Oxide (NO) is involved in the development and progression of abdominal aortic aneurysms (AAA). We found that inhibition of inducible NO synthase (iNOS) protects mice in an elastase-induced AAA model, significantly inhibiting the production of matrix metalloproteinase-13 (MMP-13). The extracellular MMP inducer (EMMPRIN; CD147) was increased in human AAA biopsies and in wild-type murine AAA but not in AAA from iNOS null mice. In cells overexpressing ectopic EMMPRIN, MMP-13 secretion was stimulated, whereas silencing of EMMPRIN by RNA interference led to significant inhibition of MMP-13 expression. In addition, elastase infusion of MMP-13 null mouse aortas induced a significant increase of EMMPRIN but reduced aortic dilatation when compared with wild-type mice, suggesting that NO-mediated AAA may be mediated through EMMPRIN induction of MMP-13. These findings were further verified in elastase-infused iNOS null mice, in which daily administration of NO caused a significant aortic dilatation and the expression of EMMPRIN and MMP-13. By contrast, in iNOS wild-type mice, pharmacological inhibition of iNOS by administration of 1400 W induced a reduction of aortic diameter and inhibition of MMP-13 and EMMPRIN expression when compared with control mice. Our results suggest that NO may regulate the development of AAA in part by inducing the expression of EMMPRIN and modulating the activity of MMP-13 in murine and human aneurysms.
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Affiliation(s)
- Tania R Lizarbe
- Institutional Fundación Centro Nacional de Investigaciones Cardiovasculares, Madrid 28029, Spain
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41
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Bonoiu A, Mahajan SD, Ye L, Kumar R, Ding H, Yong KT, Roy I, Aalinkeel R, Nair B, Reynolds JL, Sykes DE, Imperiale MA, Bergey EJ, Schwartz SA, Prasad PN. MMP-9 gene silencing by a quantum dot-siRNA nanoplex delivery to maintain the integrity of the blood brain barrier. Brain Res 2009; 1282:142-55. [PMID: 19477169 PMCID: PMC2762384 DOI: 10.1016/j.brainres.2009.05.047] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2009] [Revised: 05/11/2009] [Accepted: 05/12/2009] [Indexed: 12/01/2022]
Abstract
The matrix-degrading metalloproteinases (MMPs), particularly MMP-9, are involved in the neuroinflammation processes leading to disrupting of the blood brain barrier (BBB), thereby exacerbating neurological diseases such as HIV-1 AIDS dementia and cerebral ischemia. Nanoparticles have been proposed to act as non-viral gene delivery vectors and have great potential for therapeutic applications in several disease states. In this study, we evaluated the specificity and efficiency of quantum dot (QD) complexed with MMP-9-siRNA (nanoplex) in downregulating the expression of MMP-9 gene in brain microvascular endothelial cells (BMVEC) that constitute the BBB. We hypothesize that silencing MMP-9 gene expression in BMVECs and other cells such as leukocytes may help prevent breakdown of the BBB and inhibit subsequent invasion of the central nervous system (CNS) by infected and inflammatory cells. Our results show that silencing of MMP-9 gene expression resulted in the up-regulation of extracellular matrix (ECM) proteins like collagen I, IV, V and a decrease in endothelial permeability, as reflected by reduction of transendothelial resistance across the BBB in a well validated in-vitro BBB model. MMP-9 gene silencing also resulted in an increase in expression of the gene tissue inhibitor of metalloproteinase-1 (TIMP-1). This indicates the importance of a balance between the levels of MMP-9 and its natural inhibitor TIMP-1 in maintaining the basement membrane integrity. These studies promise the application of a novel nanoparticle based siRNA delivery system in modulating the MMP-9 activity in BMVECs and other MMP-9 producing cells. This will prevent neuroinflammation and maintain the integrity of the BBB.
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Affiliation(s)
- Adela Bonoiu
- Institute for Lasers, Photonics and Biophotonics, University at Buffalo, The State University of New York, Buffalo, New York, 14260-3000
| | - Supriya D. Mahajan
- Department of Medicine, Division of Allergy, Immunology, and Rheumatology, University at Buffalo, The State University of New York, and Kaleida Health, Buffalo, New York, 14203
| | - Ling Ye
- Institute for Lasers, Photonics and Biophotonics, University at Buffalo, The State University of New York, Buffalo, New York, 14260-3000
| | - Rajiv Kumar
- Institute for Lasers, Photonics and Biophotonics, University at Buffalo, The State University of New York, Buffalo, New York, 14260-3000
| | - Hong Ding
- Institute for Lasers, Photonics and Biophotonics, University at Buffalo, The State University of New York, Buffalo, New York, 14260-3000
| | - Ken-Tye Yong
- Institute for Lasers, Photonics and Biophotonics, University at Buffalo, The State University of New York, Buffalo, New York, 14260-3000
| | - Indrajit Roy
- Institute for Lasers, Photonics and Biophotonics, University at Buffalo, The State University of New York, Buffalo, New York, 14260-3000
| | - Ravikumar Aalinkeel
- Department of Medicine, Division of Allergy, Immunology, and Rheumatology, University at Buffalo, The State University of New York, and Kaleida Health, Buffalo, New York, 14203
| | - Bindukumar Nair
- Department of Medicine, Division of Allergy, Immunology, and Rheumatology, University at Buffalo, The State University of New York, and Kaleida Health, Buffalo, New York, 14203
| | - Jessica L Reynolds
- Department of Medicine, Division of Allergy, Immunology, and Rheumatology, University at Buffalo, The State University of New York, and Kaleida Health, Buffalo, New York, 14203
| | - Donald E Sykes
- Department of Medicine, Division of Allergy, Immunology, and Rheumatology, University at Buffalo, The State University of New York, and Kaleida Health, Buffalo, New York, 14203
| | - Marco A Imperiale
- Department of Medicine, Division of Allergy, Immunology, and Rheumatology, University at Buffalo, The State University of New York, and Kaleida Health, Buffalo, New York, 14203
| | - Earl J. Bergey
- Institute for Lasers, Photonics and Biophotonics, University at Buffalo, The State University of New York, Buffalo, New York, 14260-3000
| | - Stanley A. Schwartz
- Department of Medicine, Division of Allergy, Immunology, and Rheumatology, University at Buffalo, The State University of New York, and Kaleida Health, Buffalo, New York, 14203
| | - Paras N. Prasad
- Institute for Lasers, Photonics and Biophotonics, University at Buffalo, The State University of New York, Buffalo, New York, 14260-3000
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Määttä M, Tervahartiala T, Kaarniranta K, Tang Y, Yan L, Tuukkanen J, Sorsa T. Immunolocalization of EMMPRIN (Cd147) in the Human Eye and Detection of Soluble Form of EMMPRIN in Ocular Fluids. Curr Eye Res 2009; 31:917-24. [PMID: 17114117 DOI: 10.1080/02713680600932290] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
PURPOSE To study the cellular distribution of extracellular matrix metalloproteinase inducer (EMMPRIN; CD147) in the human eye and the corneal and retinal pigment epithelium cell lines and its possible existence as a soluble protein in ocular fluids. METHODS Immunohistochemistry was performed on human eyes and for cell cultures. Different EMMPRIN isoforms were analyzed by Western blotting in ocular fluids. RESULTS EMMPRIN immunostaining could be detected in the corneal and conjunctival epithelium, the endothelium, and in the stromal keratocytes, the retinal pigment epithelium, several retinal layers and nerve fibers in the optic nerve head. Both cell lines deposit EMMPRIN on the cell membranes. Soluble EMMPRIN could also be detected in the tear fluid, aqueous humor, and vitreous samples in the form of multiple immunoreactive species. CONCLUSIONS EMMPRIN is specifically expressed in the human eye only by certain tissue structures, thus suggesting specialized functions. The protein also exists naturally in soluble forms in ocular fluids representing presumably monomeric and multimeric forms, a notion that confirm and further extends its previously known role mainly as a transmembrane protein. These findings suggest that EMMPRIN can regulate not only cell surface functions in the human eye but also certain peri- and extracellular functions.
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Affiliation(s)
- Marko Määttä
- Department of Ophthalmology, Oulu University Hospital, Oulu, Finland.
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Yuasa J, Toyama Y, Miyauchi T, Maekawa M, Yuasa S, Ito H. Specific localization of the basigin protein in human testes from normal adults, normal juveniles, and patients with azoospermia. Andrologia 2009. [DOI: 10.1111/j.1439-0272.2001.tb01499.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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Voigt H, Vetter-Kauczok CS, Schrama D, Hofmann UB, Becker JC, Houben R. CD147 impacts angiogenesis and metastasis formation. Cancer Invest 2009; 27:329-33. [PMID: 19160100 DOI: 10.1080/07357900802392675] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
CD147 is highly expressed on many tumor cells; its role for tumor invasiveness and metastasis has been deduced from its capacity to induce MMPs, i.e., MMP-1, -2, -3, and -9. However, in the murine B16 melanoma model, MMP-2/-9 expression occurs independent of CD147. To scrutinize the impact of CD147 on metastasis formation and angiogenesis in this model, CD147 was stably knocked down in B16 cells. This silencing of CD147 expression resulted in a reduced capability of the tumor cells to metastasize to the draining lymph nodes. Notably, the CD147 knock down caused a decreased VEGF expression in vivo accompanied by reduced blood vessel formation. Thus, in the B16 melanoma model, CD147 promotes metastasis formation by induction of angiogenesis in an MMP independent manner.
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Affiliation(s)
- Heike Voigt
- Department of Dermatology, Julius-Maximilians-University, Würzburg, Germany
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Aggelis V, Craven RA, Peng J, Harnden P, Cairns DA, Maher ER, Tonge R, Selby PJ, Banks RE. Proteomic identification of differentially expressed plasma membrane proteins in renal cell carcinoma by stable isotope labelling of a von Hippel-Lindau transfectant cell line model. Proteomics 2009; 9:2118-30. [DOI: 10.1002/pmic.200800756] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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A soluble factor (EMMPRIN) in exudate influences knee motion after total arthroplasty. Knee Surg Sports Traumatol Arthrosc 2009; 17:298-304. [PMID: 19089410 DOI: 10.1007/s00167-008-0688-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2008] [Accepted: 11/11/2008] [Indexed: 01/21/2023]
Abstract
Few studies have been conducted to investigate biological factors that affect postoperative knee motion after total knee arthroplasty (TKA). The purpose of this study is to test the hypothesis that range of knee motion (ROM) at 4 weeks after TKA is correlated with the concentration of extracellular matrix metalloproteinase inducer (EMMPRIN) and transforming growth factor (TGF)-beta1 in the exudative fluid harvested from the joint after surgery. A prospective measurement study was conducted with 20 osteoarthritis patients who underwent TKA. At 48 h after surgery, the exudate was harvested from a closed drainage system. Enzyme-linked immunosorbent assay was performed to measure the concentration of TGF-beta1, EMMPRIN, MMP-1, 2, 9, tissue inhibitor of metalloproteinase-1, and Hyalunonan. Knee flexion angle was measured before and at 4 weeks after surgery. There was a significant correlation between the EMMPRIN levels and knee flexion angle (r = 0.557, p = 0.0148). Western blot analysis of the exudate showed a prominent band for EMMPRIN at 27 kDa. On the other hand, there was no correlation between the TGF-beta1 levels and the knee flexion angle. This study showed that EMMPRIN levels after TKA affect the postoperative ROM. As to clinical relevance, EMMPRIN in the exudate after TKA is a promising biological indicator to predict difficulty in restoring postoperative ROM.
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Chen Y, Zhang H, Gou X, Horikawa Y, Xing J, Chen Z. Upregulation of HAb18G/CD147 in activated human umbilical vein endothelial cells enhances the angiogenesis. Cancer Lett 2009; 278:113-21. [PMID: 19223118 DOI: 10.1016/j.canlet.2009.01.004] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2008] [Revised: 12/24/2008] [Accepted: 01/05/2009] [Indexed: 01/13/2023]
Abstract
Previous studies demonstrated that CD147 molecule, highly expressed on the surface of various malignant tumor cells, significantly correlated with the malignancy of these cancers; however, the role of HAb18G/CD147 in endothelial cells has yet to be established. In this study, we found that the expression of HAb18G/CD147 was significantly upregulated in activated HUVECs. The inhibition of HAb18G/CD147 expression by specific siRNA led to significantly decreased angiogenesis in vitro. Our data indicate that HAb18G/CD147 may regulate angiogenesis via several mechanisms including proliferation, survival, migration, MMPs secretion, and PI3K/Akt activation. Our findings for the first time suggest that upregulation of HAb18G/CD147 in activated HUVECs might play an important role in angiogenesis.
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Affiliation(s)
- Yanke Chen
- Department of Cell Biology and Cell Engineering Research Center and State Key Laboratory of Cancer Biology, Fourth Military Medical University, 17 West Changle Street, Xi'an 710032, China
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Szymanowska M, Hendry KA, Robinson C, Kolb AF. EMMPRIN (basigin/CD147) expression is not correlated with MMP activity during adult mouse mammary gland development. J Cell Biochem 2009; 106:52-62. [DOI: 10.1002/jcb.21975] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Gabison EE, Huet E, Baudouin C, Menashi S. Direct epithelial–stromal interaction in corneal wound healing: Role of EMMPRIN/CD147 in MMPs induction and beyond. Prog Retin Eye Res 2009; 28:19-33. [DOI: 10.1016/j.preteyeres.2008.11.001] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Hanata K, Yamaguchi N, Yoshikawa K, Mezaki Y, Miura M, Suzuki S, Senoo H, Ishikawa K. Soluble EMMPRIN (extra-cellular matrix metalloproteinase inducer) stimulates the migration of HEp-2 human laryngeal carcinoma cells, accompanied by increased MMP-2 production in fibroblasts. ACTA ACUST UNITED AC 2008; 70:267-77. [PMID: 18431027 DOI: 10.1679/aohc.70.267] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The basement membrane functions as a barrier against the invasion of cancer cells. It is therefore important to investigate the mechanism of basement membrane degradation by matrix metalloproteinases (MMPs). Previously, cancer cells were long considered to be the major source of MMPs; however, current evidence indicates that most MMPs in cancer tissue are produced by stromal rather than cancer cells. A glycoprotein highly expressed on the cancer-cell membrane, EMMPRIN (extra-cellular matrix metalloproteinase inducer), exhibits the potential role of the MMP inductor in stromal cells. Depending on the cell type, EMMPRIN can stimulate the production of MMP-1, MMP-2, and MMP-3. We here report that soluble full-length EMMPRIN is liberated from HEp-2 human laryngeal epidermoid carcinoma cells, probably via microvesicle shedding. Soluble EMMPRIN stimulates human fibroblasts to produce MMP-2, after which the augmented migration of HEp-2 cells occurs, as observed in an invasion chamber assay with separately cultured fibroblasts. An anti-EMMPRIN function-blocking antibody reduced MMP-2 activity in the conditioned medium and inhibited the migration of HEp-2; obviously, EMMPRIN activity contributes to cancer-cell migration. We postulate that soluble EMMPRIN probably triggers the promotion of cancer invasion in vivo.
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Affiliation(s)
- Kyoshi Hanata
- Department of Otolaryngology, Akita University School of Medicine, Akita, Japan.
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