title: Highly Expressed Integrin-α8 Induces Epithelial to Mesenchymal Transition-Like Features in Multiple Myeloma with Early Relapse.
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-α8 (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-α8 is largely unknown. We functionally overexpressed integrin-α8 in MM cell lines, and surprisingly, stemness features including HIF1α, 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-α8 expression mediated drug resistance against melphalan and bortezomib, which are the main therapeutic agents in MM. The cBioPortal genomic database revealed thatITGA8have significant tendency to co-occur withPDGFRAandPDGFRBand their mRNA expression were up-regulated inITGA8overexpressed MM cells. In summary, integrin-α8, 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.
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Ryu
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Korea.
authors.forename: Youngil
authors.initials: Y
authors.lastname: Koh
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea.
authors.forename: Hyejoo
authors.initials: H
authors.lastname: Park
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea.
authors.forename: Dae Yoon
authors.initials: DY
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea.
authors.forename: Dong Chan
authors.initials: DC
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Korea.
authors.forename: Ja Min
authors.initials: JM
authors.lastname: Byun
authors.affiliation: Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang 10326, Korea.
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea.|Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Korea.
authors.forename: Sung-Soo
authors.initials: SS
authors.lastname: Yoon
mesh_terms: D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D039001:Integrin alpha Chains / Q000096:biosynthesis* / Q000378:metabolism; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D014162:Transfection
chemical_list: D039001:Integrin alpha Chains; C093856:integrin alpha8
keywords: epithelial-mesenchymal transition; gene expression profile; integrin-α8; multiple myeloma relapse