543회 정기세미나_박종국 박사님(원자력의학원)

다음 주 목요일 (4월 15일) 이번 학기 두 번째 정기세미나를 개최합니다. 

연자는 원자력의학원의 박종국 박사님이십니다. 

시간: 2021년 4월 15일(목) 오후5시

장소: 강원대학교 의생명과학대학 B-128

zoom link:  https://kangwon-ac-kr.zoom.us/j/82162646818

Novel Immunological Component of γ-ionizing Radiation-Induced Invasion of Cancer Cells

박종국 박사(원자력의학원)

1. We demonstrated that γ-ionizing radiation (IR) triggers the invasion/migration of A549 cells via activation of an EGFR–p38/ERK–STAT3/CREB-1–EMT pathway. Additionally, we have reported the involvement of a novel intracellular signaling mechanism in γ-ionizing radiation (IR)-induced migration/invasion. Expression of receptor-interacting protein (RIP) 1 was initially increased upon exposure of A549, a non-small cell lung cancer (NSCLC) cell line, to IR. IR-induced RIP1 is located downstream of EGFR and involved in the expression/activity of matrix metalloproteases (MMP-2 and MMP-9) and vimentin, suggesting a role in epithelial-mesenchymal transition (EMT). Our experiments showed that IR-induced RIP1 sequentially induces Src-STAT3-EMT to promote invasion/migration. Inhibition of RIP1 kinase activity and expression blocked induction of EMT by IR and suppressed the levels and activities of MMP-2, MMP-9 and vimentin. IR-induced RIP1 activation was additionally associated with stimulation of the transcriptional factor NF-κB. Specifically, exposure to IR triggered NF-κB activation and inhibition of NF-κB suppressed IR-induced RIP1 expression, followed by a decrease in invasion/migration as well as EMT. Based on the collective results, we propose that IR concomitantly activates EGFR and NF-κB and subsequently triggers the RIP1–Src/STAT3–EMT pathway, ultimately promoting metastasis.

2. Next, we also studied that interleukin-1β (IL-1β) contributes to the γ-ionizing radiation (IR)-induced increase of migration/invasion in A549 lung cancer cells, and that this occurs via RIP1 upregulation. We initially observed that the protein expression and secreted concentration of IL-1β were increased upon exposure of A549 cells to IR. We then demonstrated that IR-induced IL-1β is located downstream of the NF-κB–RIP1 signaling pathway. Treatments with siRNA and specific pharmaceutical inhibitors of RIP1 and NF-κB suppressed the IR-induced increases in the protein expression and secreted concentration of IL-1β. IL-1Ra, an antagonist of IL-1β, treatment suppressed the IR-induced epithelial-mesenchymal transition (EMT) and IR-induced invasion/migration in vitro. These results suggest that IL-1β could regulate IR-induced EMT. We also found that IR could induce the expression of IL-1β expression in vivo and that of IL-1 receptor (R) I/II in vitro and in vivo. The IR-induced increases in the protein levels of IL-1 RI/II and IL-1β suggest that an autocrine loop between IL-1β and IL-1 RI/II might play important roles in IR-induced EMT and migration/invasion. Based on these collective results, we propose that IR concomitantly activates NF-κB and RIP1 to trigger the NF-κB–RIP1–IL-1β–IL-1RI/II–EMT pathway, ultimately promoting metastasis

학력 및 약력

1989-1993   건국대학교 생명과학과(B.S.)

1993-1997   건국대학교 생명과학과(M.S.)

1998-2002   서강대학교 생명과학과(Ph.D.)

2002-2003   Researcher, Pharmgenia Co. Seoul, Korea

2003-2004   PostDoc, Cancer Institute, Korea University, Seoul, Korea

2004-2005   PostDoc, Cell and Cancer Biology Branch, NIH/NCI, Bethesda, MD, USA

2006-현재   Senior Researcher, Lab of Radiation Tumor Physiology, KIRAMS

주요발표논문 (최근)

1.        Kang AR, Cho JH, Lee NG, Kwon JH, Song JY, Hwang SG, Jung IS, Kim JS, Um HD, Oh SC, Park JK. Radiation-induced IL-1β expression and secretion promote cancer cell migration/invasion via activation of the NF-κB-RIP1 pathway. Biochem Biophys Res Commun 2021 534:973-979

2.        Kang AR, Cho JH, Lee NG, Song JY, Hwang SG, Lee DH, Um HD, Park JK. RIP1 Is a Novel Component of γ–ionizing Radiation-Induced Invasion of Non-Small Cell Lung Cancer Cells.  Int J Mol Sci. 2020 Jun 28;21(13):E4584.