S-Space College of Medicine/School of Medicine (의과대학/대학원) Program in Cancer Biology (협동과정-종양생물학전공) Theses (Ph.D. / Sc.D._협동과정-종양생물학전공)
Roles of integrin-α8 and PIM1 as key molecules related to multiple myeloma cell migration and invasion
다발골수종 세포의 이동 및 침입 경로 조절에 관여하는 integrin-α8과 PIM1의 역할
- 의과대학 협동과정 종양생물학전공
- Issue Date
- 서울대학교 대학원
- 다발골수종의 재발 기전
- 학위논문 (박사)-- 서울대학교 대학원 : 종양생물학전공, 2017. 2. 윤성수.
- Multiple myeloma (MM) is characterized by clonal proliferation of malignant plasma cells in the bone marrow (BM). Despite the recent remarkable advances in 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 profile was examined and compared among 16 MM patients grouped by 12 months progression-free survival (PFS) after autologous stem cell transplantation. 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 to maximize the difference between different prognostic groups. We discovered that integrin-α8 (ITGA8) is highly expressed in MM patients with early relapse. The integrin family is well documented 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 phenotype, including N-cadherin, Slug, Snail and CXCR4 were induced. These, consequently, enhanced migration and invasion abilities, which are crucial mechanism of 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 platelet derived growth factor receptor (PDGFRA and PDGFRB), and ITGA8 have a significant tendency to co-occur that their mRNA expression was up-regulated in ITGA8 overexpressed MM cells.
Since CXCL12 (SDF-1α), which is secreted from the BM microenvironment, is a crucial chemokine for MM cell migration and invasion, we also investigated serine/threonine kinase PIM1 as a regulator of CXCL12 expression in MM bone marrow stroma cells (BMSCs). PIM1 expression was induced in MM BMSCs when co-cultured with MM cell lines, and the positive correlation between CXCL12 and PIM1 expression was identified in BM aspirates from 15 MM patients. The PIM1 blockade in MM BMSCs either by PIM1 silencing or pan-PIM inhibitor, AZD1208, CXCL12 expression was significantly repressed. Consequently, MM cell migration was abolished through PIM1 blocked MM BMSCs culture supernatant. Furthermore, CXCR4 signaling, pCXCR4 and pERK, in MM cells was altered when co-cultured with PIM inhibited MM-BMSCs. In summary, our results suggest integrin-α8 and PIM1 as a mediator of MM cell migration and invasion. Integrin-α8 could serve as a potential marker of MM relapse and could be a new therapeutic target. In addition, PIM1 may be a promising target in regulating CXCL12 and modulate BM niche that is less receptive for MM cells.