title: Loss of miR-223 and JNK Signaling Contribute to Elevated Stathmin in Malignant Pleural Mesothelioma.
abstract: Malignant pleural mesothelioma (MPM) is often fatal, and studies have revealed that aberrant miRNAs contribute to MPM development and aggressiveness. Here, a screen of miRNAs identified reduced levels of miR-223 in MPM patient specimens. Interestingly, miR-223 targets Stathmin (STMN1), a microtubule regulator that has been associated with MPM. However, whether miR-223 regulates STMN1 in MPM and the functions of miR-223 and STMN1 in this disease are yet to be determined. STMN1 is also regulated by c-Jun N-terminal kinase (JNK) signaling, but whether this occurs in MPM and whether miR-223 plays a role are unknown. The relationship between STMN1, miR-223, and JNK was assessed using MPM cell lines, cells from pleural effusions, and MPM tissue. Evidence indicates that miR-223 is decreased in all MPM tissue compared with normal/healthy tissue. Conversely, STMN1 expression was higher in MPM cell lines when compared with primary mesothelial cell controls. Following overexpression of miR-223 in MPM cell lines, STMN1 levels were reduced, cell motility was inhibited, and tubulin acetylation induced. Knockdown of STMN1 using siRNAs led to inhibition of MPM cell proliferation and motility. Finally, miR-223 levels increased while STMN1 was reduced following the re-expression of the JNK isoforms in JNK-null murine embryonic fibroblasts, and STMN1 was reduced in MPM cell lines following the activation of JNK signaling.
  
  
  CONCLUSIONS
  miR-223 regulates STMN1 in MPM, and both are in turn regulated by the JNK signaling pathway. As such, miR-223 and STMN1 play an important role in regulating MPM cell motility and may be therapeutic targets.
authors.affiliation: Institute for Respiratory Health and Centre for Asthma, Allergy and Respiratory Research, School of Medicine and Pharmacology, University of Western Australia, Harry Perkins Institute of Medical Research, Nedlands, Western Australia, Australia. steve.mutsaers@resphealth.uwa.edu.au.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Birnie
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Yan Y
authors.initials: YY
authors.lastname: Yip
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, Melbourne, Victoria, Australia. School of Biomedical Science, Faculty of Medicine and Biomedical Science, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Dominic C H
authors.initials: DC
authors.lastname: Ng
authors.affiliation: Asbestos Diseases Research Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Michaela B
authors.initials: MB
authors.lastname: Kirschner
authors.affiliation: Asbestos Diseases Research Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Glen
authors.initials: G
authors.lastname: Reid
authors.affiliation: Institute for Respiratory Health and Centre for Asthma, Allergy and Respiratory Research, School of Medicine and Pharmacology, University of Western Australia, Harry Perkins Institute of Medical Research, Nedlands, Western Australia, Australia. Centre for Cell Therapy and Regenerative Medicine, School of Medicine and Pharmacology, University of Western Australia and Harry Perkins Institute of Medical Research, Perth, Western Australia, Australia.
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Prêle
authors.affiliation: Occupational Respiratory Epidemiology, School of Population Health, University of Western Australia, Crawley, Western Australia, Australia. Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
authors.forename: Arthur W Bill
authors.initials: AW
authors.lastname: Musk
authors.affiliation: Institute for Respiratory Health and Centre for Asthma, Allergy and Respiratory Research, School of Medicine and Pharmacology, University of Western Australia, Harry Perkins Institute of Medical Research, Nedlands, Western Australia, Australia.
authors.forename: Y C Gary
authors.initials: YC
authors.lastname: Lee
authors.affiliation: Institute for Respiratory Health and Centre for Asthma, Allergy and Respiratory Research, School of Medicine and Pharmacology, University of Western Australia, Harry Perkins Institute of Medical Research, Nedlands, Western Australia, Australia.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Thompson
authors.affiliation: Institute for Respiratory Health and Centre for Asthma, Allergy and Respiratory Research, School of Medicine and Pharmacology, University of Western Australia, Harry Perkins Institute of Medical Research, Nedlands, Western Australia, Australia. Centre for Cell Therapy and Regenerative Medicine, School of Medicine and Pharmacology, University of Western Australia and Harry Perkins Institute of Medical Research, Perth, Western Australia, Australia.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Mutsaers
authors.affiliation: Institute for Respiratory Health and Centre for Asthma, Allergy and Respiratory Research, School of Medicine and Pharmacology, University of Western Australia, Harry Perkins Institute of Medical Research, Nedlands, Western Australia, Australia.
authors.forename: Bahareh
authors.initials: B
authors.lastname: Badrian
mesh_terms: D000818:Animals; D001315:Australia; D045744:Cell Line, Tumor; D002465:Cell Movement; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D008654:Mesothelioma / Q000378:metabolism* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D016612:Paraffin Embedding; D061251:Primary Cell Culture; D050777:Stathmin / Q000235:genetics / Q000378:metabolism*
chemical_list: D048031:JNK Mitogen-Activated Protein Kinases; D035683:MicroRNAs; D050777:Stathmin; C525067:MIR223, human; C493995:STMN1 protein, human