Analyses of molecular bases of cancer stem cells and their differentiation in Hodgkin lymphoma

• Project/Area Number: 23590432
• 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: WATANABE MARIKO 北里大学, 大学病院, 研究技能員 (90270701)
• Co-Investigator(Kenkyū-buntansha): HORIE Ryouichi 北里大学, 医学部, 准教授 (80229228)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: ホジキンリンパ腫 / 癌幹細胞 / ニッチ / 細胞分化 / 分子標的療法

Research Abstract

We identified side population (SP fraction), which is thought to represent cancer stem cell like population and non-SP fraction, which is thought to represent differentiated cells in Hodgkin lymphoma cell lines, KMH2 and L428. SP consists of small cells, whereas non-SP contains relatively large mono nucleated cells and Hodgkin, Reed-Sternberg (H-RS) cells. CD30, a marker for HL is strongly expressed on both SP and non-SP. Both fractions also revealed strong activation of NF-kB. We sorted SP and non-SP and examined expression of mRNA using microarray analyses. The results indicated that molecules related to anti-oxidative stress are more frequently expressed in SP than non-SP. We also found that multi-nucleated cells are generated by abortive mitosis.

Research Products

• [Journal Article] ホジキンリンパ腫と未分化大細胞型リンパ腫におけるCD30過剰発現機構 (2014)
  • Author(s): 堀江良一
  • Journal Title: 血液内科 Volume: (印刷中)
• [Journal Article] Combined inhibition of NF-κB and Bcl-2 triggers synergistic reduction of viability and induces apoptosis in melanoma cells (2014)
  • Author(s): Watanabe M, Umezawa K, Higashihara M, Horie R
  • Journal Title: Oncol Res. Volume: 21(4) Issue: 4 Pages: 173-80
  • DOI: 10.3727/096504014x13887748696707
  • Peer Reviewed
• [Journal Article] Activation of Akt involves resistance to NF-κB inhibition and abrogation of both triggers synergistic apoptosis in lung adenocarcinoma cells (2014)
  • Author(s): Togano T, Watanabe M, Itoh K, Umezawa K, Masuda N, Higashihara M, Horie R
  • Journal Title: Lung Cancer Volume: 83 Issue: 2 Pages: 139-145
  • DOI: 10.1016/j.lungcan.2013.10.018
  • Peer Reviewed
• [Journal Article] Combined inhibition of NF-κB and Bcl-2 triggers synergistic reduction of viability and induces apoptosis in melanoma cells (2014)
  • Author(s): Watanabe M, Umezawa K, Higashihara M, Horie R.
  • Journal Title: Oncol Res Volume: 未定
  • Peer Reviewed
• [Journal Article] Hodgkinリンパ腫の発症・維持における炎症の役割 (2013)
  • Author(s): 堀江良一
  • Journal Title: 血液内科 Volume: 67 Pages: 460-466
  • URL: http://www.kahyo.com/item/KS201310-674
• [Journal Article] Molecularly-targeted strategy and NF-κB in lymphoid malignancies (2013)
  • Author(s): Horie R
  • Journal Title: J Clin ExpHematop Volume: 53(3) Pages: 185-95
  • NAID: 130003383993
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/24369220
  • Peer Reviewed
• [Journal Article] Current Molecular Targets of Lymphomas (2013)
  • Author(s): Horie R
  • Journal Title: Forum Immun Dis Ther Volume: 4(1) Issue: 1 Pages: 11-23
  • DOI: 10.1615/forumimmundisther.2013008322
• [Journal Article] Incidence and clinical significance of abberrant T-cell marker expression on diffuse large B-cell lymphoma cells. (2013)
  • Author(s): Suzuki Y, Yoshida T, Wang G, Aoki T, Katayama T, Miyamoto S, Miyazaki K, Iwabuchi K, Danbara M, Nakayama M, Horie R, Nakamine H, Sato Y, Nakamura N, Niitsu N.
  • Journal Title: Acta Hematologica Volume: 130 Issue: 4 Pages: 230-237
  • DOI: 10.1159/000348550
  • Peer Reviewed
• [Journal Article] Molecularly-targeted strategy and NF-κB in lymphoid malignancies (2013)
  • Author(s): Horie R
  • Journal Title: J Clin Exp Hematop Volume: 53 Pages: 185-95
  • NAID: 130003383993
  • Peer Reviewed
• [Journal Article] Synergistic effect of 5-azacytidine and NF-κB inhibitor DHMEQ on apoptosis induction in myeloid leukemia cells (2012)
  • Author(s): Togano T, Nakashima M, Watanabe M,Umezawa K, Watanabe T, Higashihara M, Horie R
  • Journal Title: Oncol Res. Volume: 20(12) Issue: 12 Pages: 571-7
  • DOI: 10.3727/096504013x13775486749371
  • Peer Reviewed
• [Journal Article] Surface CD3 expression proceeds through both myosin regulatory light chain 9 (MYL9)-dependent and MYL9-independent pathways in Jurkat cells (2012)
  • Author(s): Aoki T, Miyazaki K, Katayama T, Watanabe M, Horie R, Danbara M, Higashihara M
  • Journal Title: J Smooth Muscle Res. Volume: 48(5-6) Pages: 137-47
  • NAID: 10031151480
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/23538510
  • Peer Reviewed
• [Journal Article] Involvement of DNA binding domain in the cellular stability and importin affinity of NF-κB component RelB (2012)
  • Author(s): Takeiri, M., Horie, K., Takahashi, D., Watanabe, M., Horie, R., Simizu, S. & Umezawa, K
  • Journal Title: Organic & Biomolecular Chemistry Volume: 10 Issue: 15 Pages: 3053-3059
  • DOI: 10.1039/c2ob07104e
  • Peer Reviewed
• [Journal Article] Targeted Repression of Overexpressed CD30 Downregulates NF-κB and ERK1/2 Pathway in Hodgkin Lymphoma Cell Lines (2012)
  • Author(s): Watanabe M, Nakano K, Togano T, Nakashima M, Higashihara M, Kadin M.E., Watanabe, T, Horie R
  • Journal Title: Oncol Res. Volume: 19(10-11) Pages: 463-9
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/22715589
  • Peer Reviewed
• [Journal Article] Association of CD20 levels with clinicopathological parameters and its prognostic significance for patients with DLBCL (2012)
  • Author(s): Suzuki Y, Yoshida T, Wang G, Togano T, Miyamoto S, Miyazaki K, Iwabuchi K, Nakayama M, Horie R, Niitsu N, Sato Y, Nakamura N
  • Journal Title: Ann Hematol Volume: 91(7) Issue: 7 Pages: 997-1005
  • DOI: 10.1007/s00277-012-1407-4
  • Peer Reviewed
• [Journal Article] Ets-1 activates overexpression of JunB and CD30 in Hodgkin's lymphoma and anaplastic large-cell lymphoma (2012)
  • Author(s): Watanabe M, Itoh K, Togano T, Kadin ME, Watanabe T, Higashihara M, Horie R
  • Journal Title: Am J Pathol Volume: 180(2) Issue: 2 Pages: 831-8
  • DOI: 10.1016/j.ajpath.2011.10.007
  • Peer Reviewed
• [Journal Article] Surface CD3 expression proceeds through both myosin regulatory light chain 9 (MYL9)-dependent and MYL9-independent pathways in Jurkat cells. (2012)
  • Author(s): Aoki T, Miyazaki K, Katayama T, Watanabe M, Horie R, Danbara M, Higashihara M.
  • Journal Title: J Smooth Muscle Res. Volume: 48(5-6) Pages: 137-47
  • NAID: 10031151480
  • Peer Reviewed
• [Journal Article] A patient with acute lymphoblastic leukaemia presenting with an extremely high level (21.0%) of HbA1c (2011)
  • Author(s): Suzuki Y, Shichishima T, Yamashiro Y, Kimura H, Ishii R, Miyazaki K, Horie R, Moriya T, Hattori Y
  • Journal Title: Ann Clin Biochem Volume: 48(5) Issue: 5 Pages: 474-477
  • DOI: 10.1258/acb.2011.010121
  • Peer Reviewed
• [Journal Article] Re-appearance of hepatitis B virus following therapy with rituximab for lymphoma is not rare in Japanese patients with past hepatitis B virus infection (2011)
  • Author(s): Watanabe M, Shibuya A, Tsunoda Y, Danbara M, Ishii R, Ohsaka M, Takada J, Tanaka Y, Okuwaki Y, Minamino T, HidakaH, Nakazawa T, Horie R, Higashihara M, Koizumi W
  • Journal Title: Liver Int. Volume: 31(3) Issue: 3 Pages: 340-7
  • DOI: 10.1111/j.1478-3231.2010.02417.x
  • Peer Reviewed
• [Journal Article] The side population, as a precursor of Hodgkin and Reed-Sternberg cells and a target for nuclear factor-κB inhibitors in Hodgkin's lymphoma (2011)
  • Author(s): Nakashima M, Ishii Y, Watanabe M, Togano T, Umezawa K, Higashihara M, Watanabe T, Horie R
  • Journal Title: Cancer Sci Volume: 101(11) Issue: 11 Pages: 2490-6
  • DOI: 10.1111/j.1349-7006.2010.01693.x
  • NAID: 10027834044
  • Peer Reviewed
• [Presentation] CD30 repression triggers global gene responses and anti-proliferative effects in Hodgkin lymphoma (2013)
  • Author(s): 堀江良一, 渡邉真理子, 中野和民, 栂野富輝, Marshall E. Kadin, 渡邉俊樹, 東原正明
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2013-10-12
• [Presentation] he regulation of ''inflammatory niche'' with tumor derived small RNAs (2013)
  • Author(s): 山川奈津子, 横山和明, Jun Lu, 今留謙一, 渡辺俊樹, 堀江良一, 穂積勝人, 八幡崇, 安藤潔, 中村直哉, 幸谷愛
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2013-10-11
• [Presentation] Hodgkinリンパ腫と未分化大細胞型リンパ腫におけるCD30過剰発現機構の解析 (2013)
  • Author(s): 堀江良一, 渡邉真理子, 伊藤金次, 栂野富輝, KADIN Marshall E, 渡邉俊樹, 東原正明
  • Organizer: 第53回日本リンパ網内系学会総会
  • Place of Presentation: 京都
• [Presentation] Hodgkinリンパ腫と未分化大細胞性リンパ腫におけるCD30過剰発現機構の解析 (2012)
  • Author(s): 堀江良一, 渡邉真理子, 伊藤金次, 栂野富輝, Kdin E Marshall, 渡邉俊樹, 東原正明
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2012-10-21
• [Presentation] The function of small RNAs conjugated in exosome in inflammatory niche of EBV positive lymphoma (2012)
  • Author(s): Ai Kotani, Jen Lu, Toshiki Watanabe, Ryoichi Horie, Kiyoshi Ando, Naoya Nakamura
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2012-10-20
• [Presentation] Molecular mechanisms of CD30 overexpression in Hodgkin’s lymphoma and anaplastic large-cell lymphoma (2012)
  • Author(s): Ryouichi Horie, Mariko Watanabe, Kinji Itoh, Tomiteru Togano, Marshall E. Kadin, Toshiki Watanabe, Masaaki Higashihara
  • Organizer: 日本血液学会 第74回日本血液学会学術集会
  • Place of Presentation: 京都
• [Presentation] Hodgkinリンパ腫の前駆細胞における分子基盤の解析と分子標的療法の基礎的検討 (2011)
  • Author(s): 堀江良一, 中島誠, 渡邉真理子, 栂野冨輝, 梅澤一夫, 渡邉俊樹, 東原正明
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-15
• [Presentation] EBV陽性リンパ腫微小環境における分泌性EBVコードmiRNA (2011)
  • Author(s): 井上優希, 中村直哉, 阿部幸一郎, 豊嶋孝恵, 堀江良一, 渡邉俊樹, 安藤潔, 幸谷愛
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-15
• [Presentation] Side populationはHodgkin,Reed‐Sternberg細胞の前駆細胞集団でNF‐κB阻害薬DHMEQの標的となる。 (2011)
  • Author(s): 堀江良一, 中島誠, 石井有実子, 渡邉真理子, 栂野富輝, 渡邉俊樹, 梅澤一夫, 東原正明
  • Organizer: 第51回日本リンパ網内系学会総会
  • Place of Presentation: 福岡
• [Presentation] Hodgkinリンパ腫の前駆細胞における分子基盤の解析と分子標的療法の基礎的検討 (2011)
  • Author(s): 堀江良一、中島誠、渡邉真理子、栂野冨輝、梅澤一夫、渡邉俊樹、東原正明
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋国際会議場
• [Presentation] Hodgkinリンパ腫と未分化大細胞型リンパ腫におけるCD30過剰発現機構の解析
  • Author(s): 堀江良一、渡邉真理子、伊藤金次、栂野富輝、KADIN Marshall E、渡邉俊樹、東原正明
  • Organizer: 第53回日本リンパ網内系学会総会
  • Place of Presentation: 京都
• [Presentation] CD30 repression triggers global gene responses and anti-proliferative effects in Hodgkin lymphoma
  • Author(s): 堀江良一、渡邉真理子、中野和民、栂野富輝、Marshall E. Kadin、渡邉俊樹、東原正明
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌
• [Book] 実験医学増刊Vol.30 (2012)
  • Author(s): 堀江良一, 他
  • Total Pages: 224
  • Publisher: 羊土社
• [Book] 病理と臨床Vol.29 2011年臨時増刊号 (2011)
  • Author(s): 堀江良一, 他
  • Total Pages: 545
  • Publisher: 文光社