Expression levels of the metalloproteinase ADAM8 critically regulate proliferation, migration and malignant signalling events in hepatoma cells.

Published on Feb 1, 2021in Journal of Cellular and Molecular Medicine4.486
· DOI :10.1111/JCMM.16015
Tanzeela Awan1
Estimated H-index: 1
(RWTH Aachen University),
Aaron Babendreyer8
Estimated H-index: 8
(RWTH Aachen University)
+ 5 AuthorsAndreas Ludwig63
Estimated H-index: 63
(RWTH Aachen University)
Sources
Abstract
Hepatocellular carcinoma (HCC) is one of the most common metastatic tumours. Tumour growth and metastasis depend on the induction of cell proliferation and migration by various mediators. Here, we report that the A Disintegrin and Metalloproteinase (ADAM) 8 is highly expressed in murine HCC tissues as well as in murine and human hepatoma cell lines Hepa1-6 and HepG2, respectively. To establish a dose-dependent role of different ADAM8 expression levels for HCC progression, ADAM8 expression was either reduced via shRNA- or siRNA-mediated knockdown or increased by using a retroviral overexpression vector. These two complementary approaches revealed that ADAM8 expression levels correlated positively with proliferation, clonogenicity, migration and matrix invasion and negatively with apoptosis of hepatoma cells. Furthermore, the analysis of pro-migratory and proliferative signalling pathways revealed that ADAM8 expression level was positively associated with expression of β1 integrin as well as with the activation of focal adhesion kinase (FAK), mitogen-activated protein kinase (MAPK), Src kinase and Rho A GTPase. Finally, up-regulation of promigatory signalling and cell migration was also seen with a proteolytically inactive ADAM8 mutant. These findings reveal that ADAM8 is critically up-regulated in hepatoma cells contributes to cell proliferation and survival and furthermore induces pro-migratory signalling pathways independently of its proteolytic activity. By this, ADAM8 can promote cell functions most relevant for HCC growth and metastasis.
References62
Newest
#1Aaron Babendreyer (RWTH Aachen University)H-Index: 8
#2Lisa Molls (RWTH Aachen University)H-Index: 2
Last. Andreas Ludwig (RWTH Aachen University)H-Index: 63
view all 11 authors...
Abstract Reduced shear stress resulting from disturbed blood flow can impair endothelial integrity and drive the development of vascular inflammatory lesions. Metalloproteinases of the ADAM family have been implicated in the regulation of cell survival and inflammatory responses. Here we investigate the mechanism and function of ADAM15 upregulation in primary flow cultured endothelial cells. Transcriptomic analysis indicated that within the ADAM family ADAM15 mRNA is most prominently upregulated...
10 CitationsSource
#1Daniel Schick (RWTH Aachen University)H-Index: 2
#2Aaron Babendreyer (RWTH Aachen University)H-Index: 8
Last. Daniela Dreymueller (Saarland University)H-Index: 16
view all 13 authors...
Abstract Background and aims Members of the family of a disintegrin and metalloproteinases (ADAMs) and their substrates have been previously shown to modulate the inflammatory response in cardiac diseases, but studies investigating the relevance of ADAM8 are still rare. Our aim is to provide evidence for the inflammatory dysregulation of ADAM8 in vascular diseases and its association with disease severity. Methods Western-type diet fed Apoe−/− and Ldlr−/− mice and artery ligation served as murin...
6 CitationsSource
#1Jonathan D. Humphries (Wellcome Trust Centre for Cell-Matrix Research)H-Index: 30
#2Megan R. Chastney (Wellcome Trust Centre for Cell-Matrix Research)H-Index: 2
Last. Martin J. Humphries (Wellcome Trust Centre for Cell-Matrix Research)H-Index: 101
view all 4 authors...
Integrin adhesion complexes (IACs) have evolved over millions of years to integrate metazoan cells physically with their microenvironment. It is presumed that the simultaneous interaction of thousands of integrin receptors to binding sites in anisotropic extracellular matrix (ECM) networks enables cells to assemble a topological description of the chemical and mechanical properties of their surroundings. This information is then converted into intracellular signals that influence cell positionin...
135 CitationsSource
#1R Sonntag (RWTH Aachen University)H-Index: 7
#2Nives Giebeler (RWTH Aachen University)H-Index: 1
Last. Christian Liedtke (RWTH Aachen University)H-Index: 34
view all 18 authors...
E-type cyclins E1 (CcnE1) and E2 (CcnE2) are regulatory subunits of cyclin-dependent kinase 2 (Cdk2) and thought to control the transition of quiescent cells into the cell cycle. Initial findings indicated that CcnE1 and CcnE2 have largely overlapping functions for cancer development in several tumor entities including hepatocellular carcinoma (HCC). In the present study, we dissected the differential contributions of CcnE1, CcnE2, and Cdk2 for initiation and progression of HCC in mice and patie...
34 CitationsSource
#1Catharina Conrad (WWU: University of Münster)H-Index: 6
#2Malena GötteH-Index: 1
Last. Jörg W. BartschH-Index: 26
view all 15 authors...
Metastatic breast cancer affects long-term survival and is a major cause of cancer death for women worldwide. The Metalloprotease-Disintegrin ADAM8 promotes breast cancer development and brain metastasis in a mouse breast cancer model. Here, abundant ADAM8 expression was detected in primary human breast tumors and associated brain metastases. To investigate the function of ADAM8 in metastasis, MB-231 breast cancer cells with ADAM8 knockdown (MB-231_shA8) and scramble control cells (MB-231_shCtrl...
25 CitationsSource
#1Daniela Dreymueller (RWTH Aachen University)H-Index: 16
#2Jessica Pruessmeyer (RWTH Aachen University)H-Index: 14
Last. Andreas Ludwig (RWTH Aachen University)H-Index: 63
view all 9 authors...
Alveolar leukocyte recruitment is a hallmark of acute lung inflammation and involves transmigration of leukocytes through endothelial and epithelial layers. The disintegrin and metalloproteinase (ADAM) 8 is expressed on human isolated leukocytic cells and can be further upregulated on cultured endothelial and epithelial cells by proinflammatory cytokines. By shRNA mediated knockdown we show that leukocytic ADAM8 is required on monocytic THP-1 cells for chemokine-induced chemotaxis as well as tra...
15 CitationsSource
#1Song-Cheng YinH-Index: 8
#2Zhan Li (PRC: China Medical University (PRC))H-Index: 6
Last. Huimian XuH-Index: 38
view all 8 authors...
BACKGROUND: The prognostic significance of proliferating cell nuclear antigen (PCNA) expression in gastric cancer has long been assessed, yet results remain controversial. Therefore, we performed a meta-analysis to assess the prognostic value and clinicopathological significance of PCNA in gastric cancer. METHODS: A systematic literature search of PubMed, EMBASE, and the Cochrane Library databases was conducted. Summary odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs...
11 CitationsSource
#1Sonia G. Das (Tufts University)H-Index: 7
#2Mathilde Romagnoli (Curie Institute)H-Index: 10
Last. Gail E. Sonenshein (Tufts University)H-Index: 79
view all 7 authors...
ADAM8 (a disintegrin and metalloproteinase 8) protein promotes the invasive and metastatic phenotype of triple-negative breast cancer (TNBC) cells. High ADAM8 expression in breast cancer patients is an independent predictor of poor prognosis. Here, we investigated whether ADAM8 regulates specific miRNAs, their roles in aggressive phenotype, and potential use as biomarkers of disease. Microarray analysis was performed on RNA from MDA-MB-231 cells after transient ADAM8 knockdown using TaqMan miRNA...
23 CitationsSource
#1Fangyong DongH-Index: 1
#2Michael EibachH-Index: 1
Last. Christopher NimskyH-Index: 67
view all 14 authors...
Background Despite multimodal treatment, glioblastoma (GBM) therapy with temozolomide (TMZ) remains inefficient due to chemoresistance. Matrix metalloproteinase (MMP) and a disintegrin and metalloprotease (ADAM), increased in GBM, could contribute to chemoresistance and TMZ-induced recurrence of glioblastoma.
24 CitationsSource
#1Tobias Pasqualon (RWTH Aachen University)H-Index: 7
#2Jessica Pruessmeyer (RWTH Aachen University)H-Index: 14
Last. Andreas LudwigH-Index: 63
view all 14 authors...
// Tobias Pasqualon 1 , Jessica Pruessmeyer 1 , Vera Jankowski 2 , Aaron Babendreyer 1 , Esther Groth 1 , Julian Schumacher 1 , Andrea Koenen 1 , Sarah Weidenfeld 1 , Nicole Schwarz 3 , Bernd Denecke 4 , Holger Jahr 5 , Daniela Dreymueller 1 , Joachim Jankowski 2 , Andreas Ludwig 1 1 Institute of Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany 2 Institute of Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany 3 Institute of Molecular and Cellular Anato...
23 CitationsSource
Cited By1
Newest
#1Tanzeela Awan (RWTH Aachen University)H-Index: 1
#2Aaron Babendreyer (RWTH Aachen University)H-Index: 8
Last. Andreas Ludwig (RWTH Aachen University)H-Index: 63
view all 10 authors...
Acute and chronic liver inflammation is driven by cytokine and chemokine release from various cell types in the liver. Here, we report that the induction of inflammatory mediators is associated with a yet undescribed upregulation of the metalloproteinase ADAM8 in different murine hepatitis models. We further show the importance of ADAM8 expression for the production of inflammatory mediators in cultured liver cells. As a model of acute inflammation, we investigated liver tissue from lipopolysacc...
Source