Document Detail


Functional heterogeneity of osteopontin isoforms in non-small cell lung cancer.
MedLine Citation:
PMID:  20689445     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
INTRODUCTION: Osteopontin (OPN) is a multifunctional protein with an important but poorly understood role in non-small cell lung cancer (NSCLC) pathogenesis. Moreover, the role of the three known mRNA isoforms (OPNa, OPNb, and OPNc) has not been reported. We hypothesize that OPN isoforms play different roles in determining the metastatic potential of NSCLC.
METHODS: We amplified mRNA for each OPN isoform in NSCLC tumors and matched normal lung. The functional impact of each isoform was evaluated by transfecting cDNA plasmids specific to each isoform into NSCLC cell lines and comparing behavior to empty vector controls in scratch closure, cell proliferation, soft-agar colony formation, and Matrigel invasion assays. Gene array was used to evaluate differences in downstream targets and was compared with a panel of markers for epithelial-mesenchymal transition (EMT).
RESULTS: OPNa expression was increased in 91% of NSCLC tumors compared with matched lung. OPNa overexpression significantly increased activity in scratch closure, proliferation, soft-agar colony formation, and Matrigel invasion assays compared with controls in all cell lines. OPNb overexpression produced a less significant modulation of function. OPNc overexpression significantly decreased activity in proliferation, colony formation, and invasion assays compared with controls. Expression arrays revealed an increase in EMT with OPNa overexpression but not OPNc. Differences were validated by quantitative reverse transcriptase-polymerase chain reaction.
CONCLUSIONS: Overexpression of the individual OPN isoforms in NSCLC results in divergent functional phenotypes. OPNa produced an aggressive phenotype, whereas OPNc produced a more indolent phenotype. Exon 4, which is transcribed in OPNa but absent in OPNc, may be central to this phenomenon and could serve as a target for isoform-specific inhibition of OPN in NSCLC.
Authors:
Chandra M V Goparaju; Harvey I Pass; Justin D Blasberg; Nathalie Hirsch; Jessica S Donington
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer     Volume:  5     ISSN:  1556-1380     ISO Abbreviation:  J Thorac Oncol     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-09-27     Completed Date:  2011-02-03     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  101274235     Medline TA:  J Thorac Oncol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1516-23     Citation Subset:  IM    
Affiliation:
Department of Cardiothoracic Surgery, New York University School of Medicine, New York City, New York 10016, USA.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis
Blotting, Western
Carcinoma, Non-Small-Cell Lung / genetics*,  metabolism,  pathology
Cell Adhesion
Cell Line, Tumor
Cell Movement
Cell Proliferation
Colony-Forming Units Assay
Epithelial-Mesenchymal Transition
Gene Expression Profiling
Humans
Lung Neoplasms / genetics*,  metabolism,  pathology
Oligonucleotide Array Sequence Analysis
Osteopontin / genetics*,  metabolism
Protein Isoforms
RNA, Messenger / genetics
Reverse Transcriptase Polymerase Chain Reaction
Tumor Markers, Biological / genetics*,  metabolism
Wound Healing
Grant Support
ID/Acronym/Agency:
1UL1RR029893/RR/NCRR NIH HHS; 5 U01 CA111295-02/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Protein Isoforms; 0/RNA, Messenger; 0/Tumor Markers, Biological; 106441-73-0/Osteopontin
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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