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Highly Expressed Integrin-α8 Induces Epithelial to Mesenchymal Transition-Like Features in Multiple Myeloma with Early Relapse

  • Ryu, Jiyeon (Cancer Research Institute, Seoul National University College of Medicine) ;
  • Koh, Youngil (Department of Internal Medicine, Seoul National University Hospital) ;
  • Park, Hyejoo (Cancer Research Institute, Seoul National University College of Medicine) ;
  • Kim, Dae Yoon (Cancer Research Institute, Seoul National University College of Medicine) ;
  • Kim, Dong Chan (Cancer Research Institute, Seoul National University College of Medicine) ;
  • Byun, Ja Min (Department of Internal Medicine, Seoul National University Hospital) ;
  • Lee, Hyun Jung (Department of Internal Medicine, Dongguk University Ilsan Hospital) ;
  • Yoon, Sung-Soo (Cancer Research Institute, Seoul National University College of Medicine)
  • Received : 2016.08.31
  • Accepted : 2016.12.05
  • Published : 2016.12.31

Abstract

Despite recent groundbreaking advances in multiple myeloma (MM) treatment, most MM patients ultimately experience relapse, and the relapse biology is not entirely understood. To define altered gene expression in MM relapse, gene expression profiles were examined and compared among 16 MM patients grouped by 12 months progression-free survival (PFS) after autologous stem cell transplantation. To maximize the difference between prognostic groups, patients at each end of the PFS spectrum (the four with the shortest PFS and four with the longest PFS) were chosen for additional analyses. We discovered that integrin-${\alpha}8$ (ITGA8) is highly expressed in MM patients with early relapse. The integrin family is well known to be involved in MM progression; however, the role of integrin-${\alpha}8$ is largely unknown. We functionally overexpressed integrin-${\alpha}8$ in MM cell lines, and surprisingly, stemness features including $HIF1{\alpha}$, VEGF, OCT4, and Nanog, as well as epithelial mesenchymal transition (EMT)-related phenotypes, including N-cadherin, Slug, Snail and CXCR4, were induced. These, consequently, enhanced migration and invasion abilities, which are crucial to MM pathogenesis. Moreover, the gain of integrin-${\alpha}8$ expression mediated drug resistance against melphalan and bortezomib, which are the main therapeutic agents in MM. The cBioPortal genomic database revealed that ITGA8 have significant tendency to co-occur with PDGFRA and PDGFRB and their mRNA expression were up-regulated in ITGA8 overexpressed MM cells. In summary, integrin-${\alpha}8$, which was up-regulated in MM of early relapse, mediates EMT-like phenotype, enhancing migration and invasion; therefore, it could serve as a potential marker of MM relapse and be a new therapeutic target.

Keywords

epithelial-mesenchymal transition;gene expression profile;integrin-${\alpha}8$;multiple myeloma relapse

Acknowledgement

Supported by : Seoul National University, Korea Health Industry Development Institute (KHIDI)

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