title: The Transient Receptor Potential Melastatin 7 Channel Regulates Pancreatic Cancer Cell Invasion through the Hsp90α/uPA/MMP2 pathway.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a very poor prognosis. There is an urgent need to better understand the molecular mechanisms that regulate PDAC cell aggressiveness. The transient receptor potential melastatin 7 (TRPM7) is a nonselective cationic channel that mainly conducts Ca2+and Mg2+. TRPM7 is overexpressed in numerous malignancies including PDAC. In the present study, we used the PANC-1 and MIA PaCa-2 cell lines to specifically assess the role of TRPM7 in cell invasion and matrix metalloproteinase secretion. We show that TRPM7 regulates Mg2+homeostasis and constitutive cation entry in both PDAC cell lines. Moreover, cell invasion is strongly reduced by TRPM7 silencing without affecting the cell viability. Conditioned media were further studied, by gel zymography, to detect matrix metalloproteinase (MMP) secretion in PDAC cells. Our results show that MMP-2, urokinase plasminogen activator (uPA), and heat-shock protein 90α (Hsp90α) secretions are significantly decreased in TRPM7-deficient PDAC cells. Moreover, TRPM7 expression in human PDAC lymph node metastasis is correlated to the channel expression in primary tumor. Taken together, our results show that TRPM7 is involved in PDAC cell invasion through regulation of Hsp90α/uPA/MMP-2 proteolytic axis, confirming that this channel could be a promising biomarker and possibly a target for PDAC metastasis therapy.
authors.affiliation: Laboratoire de Physiologie Cellulaire et Moléculaire-EA4667, UFR Sciences, Université de Picardie Jules Verne, F-80039 Amiens, France; SFR CAP-Santé (FED 4231).
authors.forename: Pierre
authors.initials: P
authors.lastname: Rybarczyk
authors.affiliation: Laboratoire de Physiologie Cellulaire et Moléculaire-EA4667, UFR Sciences, Université de Picardie Jules Verne, F-80039 Amiens, France; SFR CAP-Santé (FED 4231).
authors.forename: Alison
authors.initials: A
authors.lastname: Vanlaeys
authors.affiliation: SFR CAP-Santé (FED 4231); UMR CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Université de Reims Champagne Ardenne (URCA), F-51095 Reims, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Brassart
authors.affiliation: Laboratoire de Physiologie Cellulaire et Moléculaire-EA4667, UFR Sciences, Université de Picardie Jules Verne, F-80039 Amiens, France; SFR CAP-Santé (FED 4231).
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dhennin-Duthille
authors.affiliation: Service d'anatomie pathologique, CHU d'Amiens, Université de Picardie Jules Verne, F-80000 Amiens, France, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Chatelain
authors.affiliation: Laboratoire de Physiologie Cellulaire et Moléculaire-EA4667, UFR Sciences, Université de Picardie Jules Verne, F-80039 Amiens, France; SFR CAP-Santé (FED 4231); Service d'anatomie pathologique, CHU d'Amiens, Université de Picardie Jules Verne, F-80000 Amiens, France, France.
authors.forename: Henri
authors.initials: H
authors.lastname: Sevestre
authors.affiliation: Laboratoire de Physiologie Cellulaire et Moléculaire-EA4667, UFR Sciences, Université de Picardie Jules Verne, F-80039 Amiens, France; SFR CAP-Santé (FED 4231).
authors.forename: Halima
authors.initials: H
authors.lastname: Ouadid-Ahidouch
authors.affiliation: Laboratoire de Physiologie Cellulaire et Moléculaire-EA4667, UFR Sciences, Université de Picardie Jules Verne, F-80039 Amiens, France; SFR CAP-Santé (FED 4231). Electronic address: mathieu.gautier@u-picardie.fr.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Gautier
mesh_terms: D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D015870:Gene Expression; D020868:Gene Silencing; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008207:Lymphatic Metastasis; D008274:Magnesium / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D008954:Models, Biological; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D015398:Signal Transduction; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
chemical_list: D018841:HSP90 Heat-Shock Proteins; C533585:HSP90AA2P protein, human; D050053:TRPM Cation Channels; D017346:Protein Serine-Threonine Kinases; C486583:TRPM7 protein, human; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2; D008274:Magnesium; D002118:Calcium