Regulation of Hodgkin lymphoma cell differentiation by reactive oxygen species

• 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
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: ホジキンリンパ腫 / 分化 / 活性酸素 / HIF-1 / 細胞分化 / 低酸素誘導因子 / 幹細胞 / 活性酸素種

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.

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。

Research Products

• [Journal Article] Jietacins, azoxy natural products, as novel NF-kB inhibitors: discovery, synthesis, biological activity, and mode of action (2019)
  • Author(s): Mariko Watanabe, Akihiro Sugawara, Yoshihiko Noguchi, Tomoyasu Hirose, Satoshi Omura, Toshiaki Sunazuka, Ryouichi Horie
  • Journal Title: Eur. J. Med. Chem. Volume: 178 Pages: 636-647
  • DOI: 10.1016/j.ejmech.2019.05.079
  • Peer Reviewed
• [Journal Article] CD30 characterizes polylobated lymphocytes and disease progression in HTLV-1-infected individuals. (2018)
  • Author(s): Nakashima M, Yamochi T, Watanabe M, Uchimaru K, Utsunomiya A, Higashihara M, Watanabe T, Horie R.
  • Journal Title: Clin Cancer Res. Volume: 24 Issue: 21 Pages: 5445-5457
  • DOI: 10.1158/1078-0432.ccr-18-0268
  • Peer Reviewed / Open Access
• [Journal Article] Role of exosomes as a proinflammatory mediator in the development of EBV-associated lymphoma. (2018)
  • Author(s): Higuchi H, Yamakawa N, Imadome KI, Yahata T, Kotaki R, Ogata J, Kakizaki M, Fujita K, Lu J, Yokoyama K, Okuyama K, Sato A, Takamatsu M, Kurosaki N, Alba SM, Azhim A, Horie R, Watanabe T, Kitamura T, Ando K, Kashiwagi T, Matsui T, Okamoto A, Handa H, Kuroda M, Nakamura N, Kotani A.
  • Journal Title: Blood Volume: 131 Issue: 23 Pages: 2552-2567
  • DOI: 10.1182/blood-2017-07-794529
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Relationship between response to lusutrombopag and splenic volume. (2018)
  • Author(s): Uojima H, Arase Y, Itokawa N, Atsukawa M, Satoh T, Miyazaki K, Hidaka H, Sung JH, Kako M, Tsuruya K, Kagawa T, Iwakiri K, Horie R, Koizumi W.
  • Journal Title: World J Gastroenterol. Volume: 24 Issue: 46 Pages: 5271-5279
  • DOI: 10.3748/wjg.v24.i46.5271
  • Peer Reviewed
• [Journal Article] Trogocytosis of ligand-receptor complex and its intracellular transport in CD30 signalling. (2018)
  • Author(s): Nakashima M, Watanabe M, Uchimaru K, Horie R.
  • Journal Title: Biol Cell. Volume: 110 Pages: 1-16
  • Peer Reviewed / Open Access
• [Presentation] 活性酸素種によるホジキンリンパ腫細胞の分化とHIF-1αを介したHeme Oxygenase 1による分化制御機構 (2019)
  • Author(s): 中島誠、渡邉真理子、中野和民、内丸薫、堀江良一
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] CD30陽性HTLV-1感染細胞の特徴とブレンツキシマブベドチンの効果について (2018)
  • Author(s): 中島 誠、矢持 忠徳、渡邊 真理子、 宇都宮 與、東原 正明、渡邉 俊樹、内丸 薫、堀江 良一
  • Organizer: 第80回日本血液学会学術総会
• [Presentation] トロゴサイトーシスによるCD30 リガンド・レセプター複合体の細胞内移行機構の解析 (2018)
  • Author(s): Makoto Nakashima, Mariko Watanabe, Kaoru Uchimaru1, Ryouichi Horie
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] CD30リガンド刺激によるCD30+HTLV-1感染細胞の増殖とブレンツキシマブベドチンの効果の解析 (2018)
  • Author(s): 中島 誠、矢持 忠徳、渡邊 真理子、宇都宮 與、東原 正明、渡邉 俊樹、内丸 薫、堀江 良一
  • Organizer: 第5回日本HTLV-1学会学術集会
• [Presentation] 古典的Hodgkinリンパ腫におけるCD30を介したHSP90誘導とシグナル統合機構の解析 (2017)
  • Author(s): 堀江良一、渡邉真理子、内丸薫、中野和民、Marshall E. Kadin、渡邉俊樹、東原正明
  • Organizer: 第57回日本リンパ網内系学会総会
• [Presentation] CD30シグナルにおけるリガンド・レセプター複合体の内在化と細胞内輸送 (2017)
  • Author(s): 中島誠、渡邉真理子、内丸薫、堀江良一
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] 古典的Hodgkinリンパ腫におけるCD30を介したHSP90誘導とシグナル伝達制御機構の解析 (2017)
  • Author(s): 渡邉真理子、東原正明、堀江良一
  • Organizer: 第64回日本臨床検査医学会学術集会
• [Patent(Industrial Property Rights)] NF-κB阻害剤 (2017)
  • Inventor(s): 堀江良一他６名
  • Industrial Property Rights Holder: 学校法人北里研究所
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-181123
  • Filing Date: 2017