Regulation of Hodgkin lymphoma cell differentiation by reactive oxygen species

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08728
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Kitasato University
• Principal Investigator: Horie Ryouichi 北里大学, 医療衛生学部, 教授 (80229228)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: ホジキンリンパ腫 / 分化 / 活性酸素 / HIF-1

Outline of Final Research Achievements

In this study we examined molecular mechanisms underlying in the differentiation of Hodgkin lymphoma (HL) cells. We found that hydrogen peroxide induces H and RS-like cells in HL cell lines, however this treatment induces cell death in unrelated lymphoid cell lines. Intracellular reactive oxygen species (ROS) of HL cell lines are low in immature cells compared to differentiated cells of HL cell lines. Microarray analyses revealed the enrichment of upregulated genes under hypoxic conditions in the immature cells of HL cell lines. Hypoxia inducible factor (HIF)-1α and its downstream molecule, heme oxygenase-1 (HO-1), a scavenger of ROS was preferentially expressed in the immature cells. HIF-1α and HO-1 inhibited differentiation of HL cell lines. These results indicate that induction of HO-1 via HIF-1α inhibits differentiation of immature HL cells by a reduction of ROS and its breakdown might trigger HL cell differentiation by accumulation of intracellular ROS.

Free Research Field

血液病理学

Academic Significance and Societal Importance of the Research Achievements

これまでHodgkinリンパ腫（HL）は大型のHodgkinおよびReed-Sternberg(H-RS)細胞を特徴とし、これらの細胞が腫瘍細胞として増殖すると考えられてきた。本研究はHL細胞にはがん幹細胞様の小型細胞集団が存在、中型細胞を経てH-RS細胞へ分化するという新しい視点に立ち、そのメカニズムが低酸素環境の模倣と活性酸素の制御にあることを明らかにした。本研究の成果は、がん細胞の分化機構を標的とした新しい治療法の開発につながると考えられる。