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Sikora H, Gruba N, Wysocka M, Piwkowska A, Lesner A. Optimization of fluorescent substrates for ADAM17 and their utility in the detection of diabetes. Anal Biochem 2023; 681:115337. [PMID: 37783443 DOI: 10.1016/j.ab.2023.115337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 09/28/2023] [Accepted: 09/29/2023] [Indexed: 10/04/2023]
Abstract
ADAM17 (a disintegrin and metalloproteinase 17) is a sheddase that releases various types of membrane-associated proteins, including adhesive molecules, cytokines and their receptors, and inflammatory mediators. Evidence suggests that the enzyme is involved in the proteolytic cleavage of antiaging transmembrane protein Klotho (KL). What is more, reduced serum and urinary KL levels are observed in the early stages of chronic kidney disease. This study aimed to optimise the ADAM17 specific and selective fluorescent substrates. Then, the obtained substrate was used to detect the enzyme in urine samples of patients diagnosed with diabetes. It turned out that in all cases we were able to detect proteolytic activity, which was the opposite of the healthy samples.
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Affiliation(s)
- Honorata Sikora
- Department of Biomedical Chemistry, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308, Gdańsk, Poland
| | - Natalia Gruba
- Department of Environmental Technology, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63 Street, PL, 80-308, Gdańsk, Poland.
| | - Magdalena Wysocka
- Department of Biomedical Chemistry, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308, Gdańsk, Poland
| | - Agnieszka Piwkowska
- Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute Polish Academy of Sciences, Wita Stwosza 63, 80-308, Gdansk, Poland; Department of Molecular Biotechnology, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308, Gdansk, Poland
| | - Adam Lesner
- Department of Environmental Technology, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63 Street, PL, 80-308, Gdańsk, Poland
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Xu R, Kang HF, Liu HB, Qian JB. Role of a disintegrin and metalloproteinase 17 in malignant tumors of the digestive system. Shijie Huaren Xiaohua Zazhi 2020; 28:986-991. [DOI: 10.11569/wcjd.v28.i19.986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
A disintegrin and metalloproteinase 17 (ADAM17), also known as tumor necrosis factor-alpha converting enzyme, is widely distributed in mammalian cells and closely related to cell adhesion, migration, leukocyte recruitment, proteolysis, and other functions. ADAM17 plays an important role in the development of malignant tumors. On the one hand, it activates signaling pathways by mediating membrane protein shedding to participate in cell proliferation and angiogenesis. On the other hand, it plays an important role in tumor invasion and metastasis by degrading the cell basement membrane and extracellular matrix. Therefore, ADAM17 may be used as a potential target for tumor therapy. This article reviews the role of ADAM17 in malignant tumors of the digestive system.
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Affiliation(s)
- Rong Xu
- Department of Gastroenterology and Hepatology, the Second Affiliated Hospital of Nantong University, Nantong 226000, Jiangsu Province, China
| | - Hai-Feng Kang
- Department of Gastroenterology and Hepatology, the Second Affiliated Hospital of Nantong University, Nantong 226000, Jiangsu Province, China
| | - Hong-Bin Liu
- Department of Pathology, The Second Affiliated Hospital of Nantong University, Nantong 226000, Jiangsu Province, China
| | - Jun-Bo Qian
- Department of Gastroenterology and Hepatology, the Second Affiliated Hospital of Nantong University, Nantong 226000, Jiangsu Province, China
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Leiting JL, Murphy SJ, Bergquist JR, Hernandez MC, Ivanics T, Abdelrahman AM, Yang L, Lynch I, Smadbeck JB, Cleary SP, Nagorney DM, Torbenson MS, Graham RP, Roberts LR, Gores GJ, Smoot RL, Truty MJ. Biliary tract cancer patient-derived xenografts: Surgeon impact on individualized medicine. JHEP Rep 2020; 2:100068. [PMID: 32181445 PMCID: PMC7066236 DOI: 10.1016/j.jhepr.2020.100068] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Revised: 01/08/2020] [Accepted: 01/08/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND & AIMS Biliary tract tumors are uncommon but highly aggressive malignancies with poor survival outcomes. Due to their low incidence, research into effective therapeutics has been limited. Novel research platforms for pre-clinical studies are desperately needed. We sought to develop a patient-derived biliary tract cancer xenograft catalog. METHODS With appropriate consent and approval, surplus malignant tissues were obtained from surgical resection or radiographic biopsy and implanted into immunocompromised mice. Mice were monitored for xenograft growth. Established xenografts were verified by a hepatobiliary pathologist. Xenograft characteristics were correlated with original patient/tumor characteristics and oncologic outcomes. A subset of xenografts were then genomically characterized using Mate Pair sequencing (MPseq). RESULTS Between October 2013 and January 2018, 87 patients with histologically confirmed biliary tract carcinomas were enrolled. Of the 87 patients, 47 validated PDX models were successfully generated. The majority of the PDX models were created from surgical resection specimens (n = 44, 94%), which were more likely to successfully engraft when compared to radiologic biopsies (p = 0.03). Histologic recapitulation of original patient tumor morphology was observed in all xenografts. Successful engraftment was an independent predictor for worse recurrence-free survival. MPseq showed genetically diverse tumors with frequent alterations of CDKN2A, SMAD4, NRG1, TP53. Sequencing also identified worse survival in patients with tumors containing tetraploid genomes. CONCLUSIONS This is the largest series of biliary tract cancer xenografts reported to date. Histologic and genomic analysis of patient-derived xenografts demonstrates accurate recapitulation of original tumor morphology with direct correlations to patient outcomes. Successful development of biliary cancer tumografts is feasible and may be used to direct subsequent therapy in high recurrence risk patients. LAY SUMMARY Patient biliary tract tumors grown in immunocompromised mice are an invaluable resource in the treatment of biliary tract cancers. They can be used to guide individualized cancer treatment in high-risk patients.
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Key Words
- CCA, cholangiocarcinoma
- ECM, extracellular matrix
- GBCA, gallbladder carcinoma
- HRs, hazard ratios
- LOH, loss of heterozygosity
- MatePair sequencing
- OPTR, overall patient take rate
- OS, overall survival
- PDX, patient-derived xenograft
- Patient-derived xenografts
- TTF, time to tumor formation
- TTH, time to tumor harvest
- biliary tract
- cholangiocarcinoma
- dCCA, distal cholangiocarcinoma
- gallbladder carcinoma
- iCCA, intrahepatic cholangiocarcinoma
- pCCA, perihilar cholangiocarcinoma
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Affiliation(s)
| | | | | | | | - Tommy Ivanics
- Department of Surgery, Henry Ford Medical Center, Detroit, MI
| | | | - Lin Yang
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN
| | - Isaac Lynch
- Department of Surgery, Mayo Clinic, Rochester, MN
| | | | | | | | | | | | - Lewis R. Roberts
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Gregory J. Gores
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
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Li W, Wang D, Sun X, Zhang Y, Wang L, Suo J. ADAM17 promotes lymph node metastasis in gastric cancer via activation of the Notch and Wnt signaling pathways. Int J Mol Med 2018; 43:914-926. [PMID: 30569104 PMCID: PMC6317666 DOI: 10.3892/ijmm.2018.4028] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 11/26/2018] [Indexed: 12/24/2022] Open
Abstract
Disintegrin and metalloproteinase domain-containing proteins (ADAMs) have been implicated in cell adhesion, signaling and migration. The aim of the present study was to identify key members of the ADAM protein family associated with the metastasis of gastric cancer and to evaluate their clinical significance. A total of 193 patients with gastric cancer and positive lymph node metastasis were enrolled. Key members of the ADAM family associated with lymph node metastasis were identified. The correlations between survival times and the clinicopathological features of patients were investigated. Furthermore, ADAM17 expression in gastric cancer cells with different metastatic potentials was determined. ADAM17 was overexpressed in BGC-823 cells and suppressed in SGC-7901 cells to further investigate its effects on cell viability and migration. The key pathways associated with ADAM17 were identified by gene set enrichment analysis (GSEA). It was found that ADAM9 and ADAM17 were significantly upregulated in gastric cancer and positive metastatic lymph node tissues. Further, there was a strong correlation between the survival times of patients and ADAM17 expression. ADAM17 was upregulated in gastric cancer cells with high metastatic potential. The viability of BGC-823 cells significantly increased following ADAM17 overexpression, whereas the viability and migration of SGC-7901 cells decreased following ADAM17 suppression. GSEA and western blot analysis revealed a positive correlation between the Notch and Wnt signaling pathways with ADAM17 expression. In conclusion, the increased expression of ADAM17 promoted the progression of gastric cancer, potentially via Notch and/or Wnt signaling pathway activation, and ADAM17 may serve as a useful prognostic marker.
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Affiliation(s)
- Wei Li
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Daguang Wang
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Xuan Sun
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yang Zhang
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Lei Wang
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Jian Suo
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
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Zhang Q, Wang C, Han X, Yang G, Ge Z, Zhang G. Knockdown of ADAM17 inhibits cell proliferation and increases oxaliplatin sensitivity in HCT-8 colorectal cancer through EGFR-PI3K-AKT activation. Biochem Biophys Res Commun 2018; 503:2333-2339. [DOI: 10.1016/j.bbrc.2018.06.158] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 06/27/2018] [Indexed: 11/25/2022]
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Sharma A, Sharma KL, Gupta A, Yadav A, Kumar A. Gallbladder cancer epidemiology, pathogenesis and molecular genetics: Recent update. World J Gastroenterol 2017; 23:3978-3998. [PMID: 28652652 PMCID: PMC5473118 DOI: 10.3748/wjg.v23.i22.3978] [Citation(s) in RCA: 259] [Impact Index Per Article: 32.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2016] [Revised: 02/01/2017] [Accepted: 06/01/2017] [Indexed: 02/06/2023] Open
Abstract
Gallbladder cancer is a malignancy of biliary tract which is infrequent in developed countries but common in some specific geographical regions of developing countries. Late diagnosis and deprived prognosis are major problems for treatment of gallbladder carcinoma. The dramatic associations of this orphan cancer with various genetic and environmental factors are responsible for its poorly defined pathogenesis. An understanding to the relationship between epidemiology, molecular genetics and pathogenesis of gallbladder cancer can add new insights to its undetermined pathophysiology. Present review article provides a recent update regarding epidemiology, pathogenesis, and molecular genetics of gallbladder cancer. We systematically reviewed published literature on gallbladder cancer from online search engine PubMed (http://www.ncbi.nlm.nih.gov/pubmed). Various keywords used for retrieval of articles were Gallbladder, cancer Epidemiology, molecular genetics and bullion operators like AND, OR, NOT. Cross references were manually searched from various online search engines (http://www.ncbi.nlm.nih.gov/pubmed,https://scholar.google.co.in/, http://www.medline.com/home.jsp). Most of the articles published from 1982 to 2015 in peer reviewed journals have been included in this review.
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You B, Gu M, Cao X, Li X, Shi S, Shan Y, You Y. Clinical significance of ADAM10 expression in laryngeal carcinoma. Oncol Lett 2016; 13:1353-1359. [PMID: 28454261 DOI: 10.3892/ol.2016.5546] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 10/24/2016] [Indexed: 12/21/2022] Open
Abstract
Recent findings suggest that upregulated a disintegrin and metalloproteinase (ADAM)10 expression participates in the progression of multiple types of cancer. However, the expression pattern and clinicopathological significance of ADAM10, and its potential prognostic role in laryngeal carcinoma remains to be explored. The present study firstly determined the significantly elevated expression status of ADAM10 protein and messenger RNA in laryngeal carcinoma tissues compared with that in adjacent non-tumor tissues by western blotting and reverse transcription-quantitative polymerase chain reaction analysis. Next, the expression of ADAM10 and the proliferation marker Ki-67 was examined in 78 laryngeal carcinoma and 35 adjacent non-tumor specimens using immunohistochemistry. Overexpressed ADAM10 in laryngeal carcinoma was detected, which correlated with T classification (P<0.01), clinical stage (P<0.01), pathology (P=0.034) and Ki-67 expression (P<0.01). Furthermore, the expression of ADAM10 was positively correlated with the expression of Ki-67 (R2=0.22; P<0.01). The Kaplan-Meier method revealed that the group with overexpressed ADAM10 exhibited shorter overall survival time compared with those with low ADAM10 expression. Our findings indicated that ADAM10 serves a notable role in the progression and prognosis of laryngeal carcinoma.
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Affiliation(s)
- Bo You
- Department of Otorhinolaryngology, Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Miao Gu
- Department of Otorhinolaryngology, Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Xiaolei Cao
- Department of Pathology, Medical School of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Xingyu Li
- Department of Pathology, Medical School of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Si Shi
- Department of Otorhinolaryngology, Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Ying Shan
- Department of Otorhinolaryngology, Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Yiwen You
- Department of Otorhinolaryngology, Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
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TLR4-mediated galectin-1 production triggers epithelial-mesenchymal transition in colon cancer cells through ADAM10- and ADAM17-associated lactate production. Mol Cell Biochem 2016; 425:191-202. [PMID: 27837433 DOI: 10.1007/s11010-016-2873-0] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 11/02/2016] [Indexed: 12/30/2022]
Abstract
Toll-like receptor 4 (TLR4) activation is a key contributor to the carcinogenesis of colon cancer. Overexpression of galectin-1 (Gal-1) also correlates with increased invasive activity of colorectal cancer. Lactate production is a critical predictive factor of risk of metastasis, but the functional relationship between intracellular lactate and Gal-1 expression in TLR4-activated colon cancer remains unknown. In this study, we investigated the underlying mechanism and role of Gal-1 in metastasis and invasion of colorectal cancer (CRC) cells after TLR4 stimulation. Exposure to the TLR4 ligand lipopolysaccharide (LPS) increased expression of Gal-1, induced EMT-related cytokines, triggered the activation of glycolysis-related enzymes, and promoted lactate production. Gene silencing of TLR4 and Gal-1 in CRC cells inhibited lactate-mediated epithelial-mesenchymal transition (EMT) after TLR4 stimulation. Gal-1-mediated activation of a disintegrin and metalloproteinase 10 (ADAM10) and ADAM 17 increased the invasion activity and expression of mesenchymal characteristics in LPS-activated CRC cells. Conversely, inhibition of ADAM10 or ADAM17 effectively blocked the generation of lactate and the migration capacity of LPS-treated CRC cells. Thus, the TLR4/Gal-1 signaling pathway regulates lactate-mediated EMT processes through the activation of ADAM10 and ADAM17 in CRC cells.
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You B, Shan Y, Shi S, Li X, You Y. Effects of ADAM10 upregulation on progression, migration, and prognosis of nasopharyngeal carcinoma. Cancer Sci 2015; 106:1506-14. [PMID: 26310711 PMCID: PMC4714676 DOI: 10.1111/cas.12800] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Revised: 08/04/2015] [Accepted: 08/22/2015] [Indexed: 01/11/2023] Open
Abstract
A disintegrin and metalloprotease 10 (ADAM10) is a typical member of the ADAMs family, which has been reported to be upregulated in various types of cancers and contribute to cancer progression and metastasis. However, little is known about the role of ADAM10 in nasopharyngeal carcinoma (NPC). The purpose of this study is to explore ADAM10 expression status and its biological functions in NPC. We first examined the expression of ADAM10 in NPC tissues and cell lines by immunohistochemistry, Western blotting, PCR, and immunofluorescence analysis. We observed that ADAM10 was significantly elevated in NPC and its expression level was correlated with T classification (P = 0.044), distant metastasis (P = 0.016), TNM clinical stage (P = 0.013), and proliferation marker Ki‐67 expression (P = 0.001). Patients with NPC with high expression of ADAM10 had shorter overall survival rates. In addition, knockdown of ADAM10 by RNAi was found to inhibit the CNE‐2 cell proliferation and migration. Our findings hinted that overexpression of ADAM10 promotes the progression and migration of NPC, which makes it a potential therapeutic target for the treatment of tumor metastases in NPC.
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Affiliation(s)
- Bo You
- Department of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Ying Shan
- Department of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Si Shi
- Department of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Xingyu Li
- Department of Pathology, Medical School of Nantong University, Nantong, China
| | - Yiwen You
- Department of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, China
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Gallbladder Cancer in the 21st Century. JOURNAL OF ONCOLOGY 2015; 2015:967472. [PMID: 26421012 PMCID: PMC4569807 DOI: 10.1155/2015/967472] [Citation(s) in RCA: 185] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2015] [Revised: 08/07/2015] [Accepted: 08/12/2015] [Indexed: 02/07/2023]
Abstract
Gallbladder cancer (GBC) is an uncommon disease in the majority of the world despite being the most common and aggressive malignancy of the biliary tree. Early diagnosis is essential for improved prognosis; however, indolent and nonspecific clinical presentations with a paucity of pathognomonic/predictive radiological features often preclude accurate identification of GBC at an early stage. As such, GBC remains a highly lethal disease, with only 10% of all patients presenting at a stage amenable to surgical resection. Among this select population, continued improvements in survival during the 21st century are attributable to aggressive radical surgery with improved surgical techniques. This paper reviews the current available literature of the 21st century on PubMed and Medline to provide a detailed summary of the epidemiology and risk factors, pathogenesis, clinical presentation, radiology, pathology, management, and prognosis of GBC.
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Liu S, Zhang W, Liu K, Ji B, Wang G. Silencing ADAM10 inhibits the in vitro and in vivo growth of hepatocellular carcinoma cancer cells. Mol Med Rep 2015; 11:597-602. [PMID: 25323956 DOI: 10.3892/mmr.2014.2652] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2013] [Accepted: 09/04/2014] [Indexed: 11/05/2022] Open
Abstract
A disintegrin and metalloprotease 10 (ADAM10) is a transmembrane protein associated with metastasis in a number of types of cancer. Little is known, however, regarding the role of ADAM10 in hepatocellular carcinoma (HCC). The aim of the present study was to evaluate whether downregulation of ADAM10 effects HCC cell proliferation, cell cycle, cell migration and cell invasion. A recombinant small hairpin RNA expression vector carrying ADAM10 was constructed and then transfected into the HepG2 human HCC cell line. In vitro cell proliferation, cell cycle, cell migration and cell invasion, and in vivo tumor growth were determined following the downregulation of ADAM10 by RNA interference. The results revealed that downregulation of ADAM10 expression in HepG2 tumor cells using the RNA silencing approach significantly suppressed cell proliferation, cell migration and cell invasion in vitro, and tumor growth in vivo. Furthermore, ADAM10 silencing was able to significantly reduce constitutive phosphorylation of phosphoinositide 3-kinase (PI3K) and Akt, which implies that ADAM10 is, at least partially, involved in the activation of the PI3K/Akt signaling pathway. These results suggest that ADAM10 is important in regulating the proliferation and metastasis of HCC. Thus, ADAM10 is a promising therapeutic target for the prevention of tumor metastases in HCC.
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Affiliation(s)
- Songyang Liu
- Department of Hepatopancreatobiliary Surgery, The First Hospital, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Wei Zhang
- Department of Hepatopancreatobiliary Surgery, The First Hospital, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Kai Liu
- Department of Hepatopancreatobiliary Surgery, The First Hospital, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Bai Ji
- Department of Hepatopancreatobiliary Surgery, The First Hospital, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Guangyi Wang
- Department of Hepatopancreatobiliary Surgery, The First Hospital, Jilin University, Changchun, Jilin 130021, P.R. China
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Zhang W, Liu S, Liu K, Wang Y, Ji B, Zhang X, Liu Y. A disintegrin and metalloprotease (ADAM)10 is highly expressed in hepatocellular carcinoma and is associated with tumour progression. J Int Med Res 2014; 42:611-618. [PMID: 24670536 DOI: 10.1177/0300060513505500] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Accepted: 08/26/2013] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE A disintegrin and metalloprotease (ADAM)10 has been implicated in the progression of various solid tumours. Little is known, however, about its role in hepatocellular carcinoma (HCC). The aim of the present study was to evaluate the protein and transcript level expression of ADAM10 in HCC patients. METHODS Samples of HCC and adjacent noncancerous liver tissue were taken during liver resection surgery. Immunostaining was used to measure ADAM10 protein expression levels and quantitative reverse- transcription polymerase chain reaction was used to measure ADAM10 mRNA expression levels. Levels of ADAM10 were compared, and a survival analysis undertaken. RESULTS In total, 98 HCC patient samples were studied. There were significant associations between protein levels of ADAM10 and tumour grade, amount of tumour differentiation, tumour size and the presence of metastasis. Furthermore, ADAM10 protein expression was significantly associated with shortened patient survival. CONCLUSIONS ADAM10 is strongly expressed in a large proportion of HCC cases, which is in agreement with findings in other tumour entities. Expression of ADAM10 may serve as a useful molecular marker for HCC.
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Affiliation(s)
- Wei Zhang
- Department of Hepatopancreatobiliary Surgery, The First Hospital, Jilin University, Changchun, Jilin Province, China
| | - Songyang Liu
- Department of Hepatopancreatobiliary Surgery, The First Hospital, Jilin University, Changchun, Jilin Province, China
| | - Kuai Liu
- Department of Hepatopancreatobiliary Surgery, The First Hospital, Jilin University, Changchun, Jilin Province, China
| | - Yingchao Wang
- Department of Hepatopancreatobiliary Surgery, The First Hospital, Jilin University, Changchun, Jilin Province, China
| | - Bai Ji
- Department of Hepatopancreatobiliary Surgery, The First Hospital, Jilin University, Changchun, Jilin Province, China
| | - Xuechun Zhang
- Department of Hepatopancreatobiliary Surgery, The First Hospital, Jilin University, Changchun, Jilin Province, China
| | - Yahui Liu
- Department of Hepatopancreatobiliary Surgery, The First Hospital, Jilin University, Changchun, Jilin Province, China
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Mario Uribe M, Clauio Heine T, Freddy Brito M, Diana Bravo L. Actualización en cáncer de vesícula biliar. REVISTA MÉDICA CLÍNICA LAS CONDES 2013. [DOI: 10.1016/s0716-8640(13)70202-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Trad A, Hansen HP, Shomali M, Peipp M, Klausz K, Hedemann N, Yamamoto K, Mauermann A, Desel C, Lorenzen I, Lemke H, Rose-John S, Grötzinger J. ADAM17-overexpressing breast cancer cells selectively targeted by antibody-toxin conjugates. Cancer Immunol Immunother 2013; 62:411-21. [PMID: 22940887 PMCID: PMC11028912 DOI: 10.1007/s00262-012-1346-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2012] [Accepted: 08/17/2012] [Indexed: 11/25/2022]
Abstract
A disintegrin and metalloproteinase 17 (ADAM17) is significantly upregulated not only in malignant cells but also in the pro-inflammatory microenvironment of breast cancer. There, ADAM17 is critically involved in the processing of tumor-promoting proteins. Therefore, ADAM17 appears to be an attractive therapeutic target to address not only tumor cells but also the tumor-promoting environment. In a previous study, we generated a monoclonal anti-ADAM17 antibody (A300E). Although showing no complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity, the antibody was rapidly internalized by ADAM17-expressing cells and was able to transport a conjugated toxin into target cells. As a result, doxorubicin-coupled A300E or Pseudomonas exotoxin A-loaded A300E was able to kill ADAM17-expressing cells. This effect was strictly dependent on the presence of ADAM17 on the surface of target cells. As a proof of principle, both immunotoxins killed MDA-MB-231 breast cancer cells in an ADAM17-dependent manner. These data suggest that the use of anti-ADAM17 monoclonal antibodies as a carrier might be a promising new strategy for selective anti-cancer drug delivery.
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Affiliation(s)
- Ahmad Trad
- Institute of Biochemistry, Christian-Albrechts-University of Kiel, Olshausenstr. 40, 24098 Kiel, Germany
| | - Hinrich P. Hansen
- Laboratory of Immunotherapy, Department I of Internal Medicine, University Clinic of Cologne, Cologne, Germany
| | - Mohammad Shomali
- Institute of Biochemistry, Christian-Albrechts-University of Kiel, Olshausenstr. 40, 24098 Kiel, Germany
| | - Matthias Peipp
- Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University, Kiel, Germany
| | - Katja Klausz
- Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University, Kiel, Germany
| | - Nina Hedemann
- Institute of Biochemistry, Christian-Albrechts-University of Kiel, Olshausenstr. 40, 24098 Kiel, Germany
| | - Kosuke Yamamoto
- Institute of Biochemistry, Christian-Albrechts-University of Kiel, Olshausenstr. 40, 24098 Kiel, Germany
| | - André Mauermann
- Institute of Biochemistry, Christian-Albrechts-University of Kiel, Olshausenstr. 40, 24098 Kiel, Germany
| | - Christine Desel
- Institute of Biochemistry, Christian-Albrechts-University of Kiel, Olshausenstr. 40, 24098 Kiel, Germany
| | - Inken Lorenzen
- Institute of Biochemistry, Christian-Albrechts-University of Kiel, Olshausenstr. 40, 24098 Kiel, Germany
| | - Hilmar Lemke
- Institute of Biochemistry, Christian-Albrechts-University of Kiel, Olshausenstr. 40, 24098 Kiel, Germany
| | - Stefan Rose-John
- Institute of Biochemistry, Christian-Albrechts-University of Kiel, Olshausenstr. 40, 24098 Kiel, Germany
| | - Joachim Grötzinger
- Institute of Biochemistry, Christian-Albrechts-University of Kiel, Olshausenstr. 40, 24098 Kiel, Germany
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Abstract
OBJECTIVE This study was designed to evaluate the expression and prognostic significance of A Disintegrin and Metalloproteinase17 (ADAM17) protein in patients with gastric cancer. BACKGROUND Tumor invasion and metastasis are primary causes for treatment failure or death among cancer patients. ADAM17 is a multidomain transmembrane glycoprotein involved in the release of several ligands that were shown to promote tumor formation and progression. Elevated expression of ADAM17 was detected in a number of human cancers and was associated with poor progression and prognosis of the diseases. In gastric cancer, however, the expression and prognostic significance of ADAM17 has not been fully elucidated. METHODS The expressions of ADAM17 and extracellular matrix metalloproteinase inducer (EMMPRIN), a protein implicated in tumor invasion and metastasis, were detected using the tissue microarray technique and immunohistochemical EnVision method and compared with clinicopathological parameters of patients with gastric cancer. RESULTS The expressions of ADAM17 and EMMPRIN were upregulated in gastric cancer lesions compared with their expressions in adjacent non-cancerous tissues (P < 0.01). High expression of ADAM17 was detected in 35.78% (156/436) of patients with gastric cancer and positively correlated with the expression of EMMPRIN (r = 0.738, P < 0.01). ADAM17 expression was associated with a number of clinicopathological parameters including depth of invasion and TNM stage of the tumor (P < 0.05). In each TNM stage, patients with high ADAM17 expression had a longer mean survival time than those with low expression (P < 0.05). Particularly, the mean survival time of stage II gastric cancer patients with low ADAM17 expression was longer than that of stage I patients with high ADAM17 expression (P < 0.01). Multivariate survival analysis suggested that, along with other parameters, ADAM17 and EMMPRIN expression were independent prognostic factors for patients with gastric cancer. CONCLUSIONS ADAM17 was implicated in the progression of gastric cancer. On the basis of the TNM stage, detection of ADAM17 expression will be helpful for predicting prognosis of gastric cancer.
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Andrén-Sandberg Å. Molecular biology of gallbladder cancer: potential clinical implications. NORTH AMERICAN JOURNAL OF MEDICAL SCIENCES 2012; 4:435-41. [PMID: 23112962 PMCID: PMC3482772 DOI: 10.4103/1947-2714.101979] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Gallbladder cancer (GBC) is a common malignancy of the biliary tract and involves the changes in multiple oncogenes and multiple genetic genes. Since over the past decade there has been an advance in the knowledge of the genetic basis of cancer, mainly as a result of the rapid progression of molecular technology; however, conventional therapeutic approaches have not had much impact on the course of this aggressive neoplasm. Knowledge of the molecular biology of GBC is rapidly growing. Genetic alterations in GBC include adenosine triphosphate-binding cassette transporter ABCG8, membrane-bound enzyme ADAM-17 of multi-functional gene family, and other genes including p53, COX2, XPC, and RASSF1A. The advances in molecular biology have potential implications for the detection of this disease, using Synuclein-gamma, Syndecan-1, glycoprotein 72 (TAG-72), tumor endothelial marker 8 protein (TEM8) and TNF-alpha. The use of these molecular diagnostic methods is of clinical importance for the gene replacement therapy, genetic prodrug activation therapy, and antisense immunology technology for the treatment of malignancy. The author reviewed recent publications on PubMed, and summarized molecular biology of GBC, with an emphasis on features of potential clinical implications for diagnosis and management.
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Affiliation(s)
- Åke Andrén-Sandberg
- Department of Surgery, Karolinska Institutet at Karolinska University Hospital, Huddinge, Stockholm, Sweden
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Trad A, Hedemann N, Shomali M, Pawlak V, Grötzinger J, Lorenzen I. Development of sandwich ELISA for detection and quantification of human and murine a disintegrin and metalloproteinase17. J Immunol Methods 2011; 371:91-6. [DOI: 10.1016/j.jim.2011.06.015] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2011] [Revised: 06/16/2011] [Accepted: 06/16/2011] [Indexed: 10/18/2022]
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18
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Xu Q, Liu X, Chen W, Zhang Z. Inhibiting adenoid cystic carcinoma cells growth and metastasis by blocking the expression of ADAM 10 using RNA interference. J Transl Med 2010; 8:136. [PMID: 21171968 PMCID: PMC3017514 DOI: 10.1186/1479-5876-8-136] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2010] [Accepted: 12/20/2010] [Indexed: 01/04/2023] Open
Abstract
Background Adenoid cystic carcinoma is one of the most common types of salivary gland cancers. The poor long-term prognosis for patients with adenoid cystic carcinoma is mainly due to local recurrence and distant metastasis. Disintegrin and metalloprotease 10 (ADAM 10) is a transmembrane protein associated with metastasis in a number of diverse of cancers. The aim of this study was to analyze the relationship between ADAM 10 and the invasive and metastatic potentials as well as the proliferation capability of adenoid cystic carcinoma cells in vitro and in vivo. Methods Immunohistochemistry and Western blot analysis were applied to detect ADAM 10 expression levels in metastatic cancer tissues, corresponding primary adenoid cystic carcinoma tissues, adenoid cystic carcinoma cell lines with high metastatic potential, and adenoid cystic carcinoma cell lines with low metastatic potential. RNA interference was used to knockdown ADAM 10 expression in adenoid cystic carcinoma cell lines with high metastatic potential. Furthermore, the invasive and metastatic potentials as well as the proliferation capability of the treated cells were observed in vitro and in vivo. Results It was observed that ADAM 10 was expressed at a significantly higher level in metastatic cancer tissues and in adenoid cystic carcinoma cell lines with high metastatic potential than in corresponding primary adenoid cystic carcinomas and adenoid cystic carcinoma cell lines with low metastatic potential. Additionally, silencing of ADAM 10 resulted in inhibition of cell growth and invasion in vitro as well as inhibition of cancer metastasis in an experimental murine model of lung metastases in vivo. Conclusions These studies suggested that ADAM 10 plays an important role in regulating proliferation and metastasis of adenoid cystic carcinoma cells. ADAM 10 is potentially an important therapeutic target for the prevention of tumor metastases in adenoid cystic carcinoma.
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Affiliation(s)
- Qin Xu
- Department of Oral and Maxillofacial Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China
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