Osteopontin (OPN/SPP1) isoforms collectively enhance tumor cell invasion and dissemination in esophageal adenocarcinoma
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Jules Lin1, Amy L. Myers1, Zhuwen Wang1, Derek J. Nancarrow1, Daysha Ferrer-Torres1, Amy Handlogten1, Kimmy Leverenz1, Julia Bao1, Dafydd G. Thomas2, Thomas D. Wang3, Mark B. Orringer1, Rishindra M. Reddy1, Andrew C. Chang1, David G. Beer1, Lin Lin1
1Section of Thoracic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, USA
2Department of Pathology, University of Michigan, Ann Arbor, MI, USA
3Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
Lin Lin, e-mail: [email protected]
David G. Beer, e-mail: [email protected]
Keywords: OPN/SPP1 isoforms, co-overexpression, collective function, esophageal adenocarcinoma
Received: March 11, 2015 Accepted: May 14, 2015 Published: June 01, 2015
Esophageal adenocarcinoma (EAC) is often diagnosed at an advanced stage, thus understanding the molecular basis for EAC invasion and metastasis is critical. Here we report that SPP1/OPN was highly overexpressed in primary EACs and intracellularly localized to tumor cells. We further demonstrate that all known OPN isoforms (OPNa, b, c, 4 and 5) were frequently co-overexpressed in primary EACs. Distinct pro-invasion and dissemination phenotypes of isoform-specific OPNb and OPNc stable transfectants were observed. Expression of OPNb significantly enhanced cell migration and adhesion to laminin. In contrast, OPNc cells showed significantly decreased cell migration yet increased cell detachment. Enhanced invasion, both in vitro and in vivo, was observed for OPNb- but not OPNc-expressing cells. Inhibition of RGD integrins, one family of OPN receptors, attenuated OPNb cell migration, abrogated OPNb cell adhesion and significantly reduced OPNb cell clonogenic survival but did not affect OPNc phenotypes, indicating that OPNb but not OPNc acts through integrin-dependent signaling. Differential expression of vimentin, E-cadherin and β-catenin in OPN stable cells may account for the variation in cell adhesion and detachment between these isoforms. We conclude that while all OPN isoforms are frequently co-overexpressed in primary EACs, isoforms OPNb and OPNc enhance invasion and dissemination through collective yet distinct mechanisms.
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