title: Overexpression of activin-A and -B in malignant mesothelioma - attenuated Smad3 signaling responses and ERK activation promote cell migration and invasive growth.
abstract: Activin-A and activin-B, members of the TGF-β superfamily, are regulators of reproductive functions, inflammation and wound healing. These dimeric molecules regulate various cellular activities such as proliferation, migration and suvival. Malignant mesothelioma is an asbestos exposure related tumor affecting mainly pleura and it usually has a dismal prognosis. Here, we demonstrate that both activin-A and -B are abundantly expressed in mesothelioma tumor tissue as well as in cultured primary and established mesothelioma cells. Migratory and invasive mesothelioma cells were also found to have attenuated activation of the Smad2/3 pathway in response to activins. Migration and invasive growth of the cells in three-dimentional matrix was prevented by inhibition of activin activity using a soluble activin receptor 2B (sActR2B-Fc). This was associated with decreased ERK activity. Furthermore, migration and invasive growth was significantly inhibited by blocking ERK phosphorylation. Mesothelioma tumors are locally invasive and our results clearly suggest that acivins have a tumor-promoting function in mesothelioma through increasing expression and switching from canonical Smad3 pathway to non-canonical ERK pathway signaling. Blocking activin activity offers a new therapeutic approach for inhibition of mesothelioma invasive growth.
authors.affiliation: Research Programs Unit, Translational Cancer Biology, University of Helsinki, Finland; Transplantation Laboratory, Haartman Institute, University of Helsinki, Finland.
authors.forename: Jenni A
authors.initials: JA
authors.lastname: Tamminen
authors.affiliation: Research Programs Unit, Translational Cancer Biology, University of Helsinki, Finland; Transplantation Laboratory, Haartman Institute, University of Helsinki, Finland.
authors.forename: Miao
authors.initials: M
authors.lastname: Yin
authors.affiliation: Helsinki University Central Hospital Laboratory, Helsinki, Finland; Department of Pathology, University of Helsinki, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Rönty
authors.affiliation: Helsinki University Central Hospital Laboratory, Helsinki, Finland; Department of Medicine, Division of Pulmonary Medicine, University of Helsinki, Finland.
authors.forename: Eva
authors.initials: E
authors.lastname: Sutinen
authors.affiliation: Helsinki University Central Hospital Laboratory, Helsinki, Finland; Department of Bacteriology and Immunology, University of Helsinki, Finland.
authors.forename: Arja
authors.initials: A
authors.lastname: Pasternack
authors.affiliation: Helsinki University Central Hospital Laboratory, Helsinki, Finland; Department of Bacteriology and Immunology, University of Helsinki, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Ritvos
authors.affiliation: Transplantation Laboratory, Haartman Institute, University of Helsinki, Finland; Helsinki University Central Hospital Laboratory, Helsinki, Finland; Department of Medicine, Division of Pulmonary Medicine, University of Helsinki, Finland.
authors.forename: Marjukka
authors.initials: M
authors.lastname: Myllärniemi
authors.affiliation: Research Programs Unit, Translational Cancer Biology, University of Helsinki, Finland; Transplantation Laboratory, Haartman Institute, University of Helsinki, Finland. Electronic address: katri.koli@helsinki.fi.
authors.forename: Katri
authors.initials: K
authors.lastname: Koli
mesh_terms: D030201:Activin Receptors, Type I / Q000378:metabolism; D030301:Activin Receptors, Type II / Q000378:metabolism; D028341:Activins / Q000235:genetics / Q000378:metabolism*; D000368:Aged; D002465:Cell Movement; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D008654:Mesothelioma / Q000378:metabolism* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D051900:Smad3 Protein / Q000378:metabolism*
chemical_list: C497790:SMAD3 protein, human; D051900:Smad3 Protein; C422405:activin A; C044147:activin B; D028341:Activins; D048049:Extracellular Signal-Regulated MAP Kinases; C424205:ACVR1C protein, human; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C425585:activin receptor type II-A
keywords: Activin; Invasive growth; Mesothelioma