AKT signaling in control of ATL tumorigenicity; unveiled mechanism for its heterogenous activation among ATL cell populations

• Project/Area Number: 15K06848
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Miyagi Prefectural Hospital Organization Miyagi Cancer Center
• Principal Investigator: Yamaguchi Kazunori 地方独立行政法人宮城県立病院機構宮城県立がんセンター(研究所), 発がん制御研究部, 上席主任研究員 (80373215)
• Research Collaborator: Sugamura Kazuo ; Nasu Kentaro ; Takanashi Tomoka
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 成人T細胞白血病 / AKTシグナル / AKT

Outline of Final Research Achievements

Human retrovirus HTLV-1 is an etiological agent for Adult T-cell leukemia/lymphoma (ATL), but additional cellular events such as aberrant modulation of signal transduction taking place for several decades after the initial HTLV-1 infection are totally unveiled. Previously we obtained highly tumorigenic populations of ATL-derived ST1 and TL-Om1 cells and found these cell populations exhibited an activated AKT signaling pathway, which may contribute to the malignancy observed in the ATL-derived cells. In this study we analyzed molecular mechanism underlying upregulation of AKT signaling in the highly tumorigenic ATL cells and found that PIK3IP1 and INPP5D, negative regulators for AKT signaling, are both inactivated in these cells. In addition, our observations suggest that activating phosphorylation of AKT might be accomplished by atypical kinase(s) in ATL cells.

Academic Significance and Societal Importance of the Research Achievements

HTLV-1ウイルス感染者は西日本を中心に数十万から百万人程度で、この内の５％程度がATLを発症すると推定されている。発症後の治療法として骨髄移植と抗ＣＣＲ４抗体治療が知られているが適用の年齢制限や抵抗性などの問題があり、新たな治療法の開発が望まれている。本研究はATL悪性化の一因としてAKTシグナル伝達系の活性化に着目し、その分子機構の解明を試みたもので、その成果は新たな治療戦略への寄与が期待される。

Research Products

• [Journal Article] Long non-coding RNA HOTAIR up?regulates chemokine (C?C motif) ligand 2 and promotes proliferation of macrophages and myeloid?derived suppressor cells in hepatocellular carcinoma cell lines (2018)
  • Author(s): Fujisaka Yasuyuki、Iwata Tomoaki、Tamai Keiichi、Nakamura Mao、Mochizuki Mai、Shibuya Rie、Yamaguchi Kazunori、Shimosegawa Tooru、Satoh Kennichi
  • Journal Title: Oncology Letters Volume: 15 Pages: 509-514
  • DOI: 10.3892/ol.2017.7322
  • Peer Reviewed / Open Access
• [Journal Article] Periostin attenuates tumor growth by inducing apoptosis in colitis-related colorectal cancer (2018)
  • Author(s): Shimoyama Yusuke、Tamai Keiichi、Shibuya Rie、Nakamura Mao、Mochizuki Mai、Yamaguchi Kazunori、Kakuta Yoichi、Kinouchi Yoshitaka、Sato Ikuro、Kudo Akira、Shimosegawa Tooru、Satoh Kennichi
  • Journal Title: Oncotarget Volume: 9 Issue: 28 Pages: 20008-20017
  • DOI: 10.18632/oncotarget.25026
  • Peer Reviewed / Open Access
• [Journal Article] Periostin is a negative prognostic factor and promotes cancer cell proliferation in non-small cell lung cancer (2018)
  • Author(s): Okazaki Toshimasa、Tamai Keiichi、Shibuya Rie、Nakamura Mao、Mochizuki Mai、Yamaguchi Kazunori、Abe Jiro、Takahashi Satomi、Sato Ikuro、Kudo Akira、Okada Yoshinori、Satoh Kennichi
  • Journal Title: Oncotarget Volume: 9 Issue: 58 Pages: 31187-31199
  • DOI: 10.18632/oncotarget.25435
  • Peer Reviewed / Open Access
• [Journal Article] Biological and Pathological Roles of Ganglioside Sialidases (2018)
  • Author(s): Miyagi, T., Takahashi, K., Yamamoto, K., Shiozaki, K., Yamaguchi, K
  • Journal Title: Prog. Mol. Biol. Transl. Sci Volume: in press Pages: 121-150
  • DOI: 10.1016/bs.pmbts.2017.12.005
  • Peer Reviewed
• [Journal Article] Murine Sialidase Neu3 facilitates GM2 degradation and bypass in mouse model of Tay-Sachs disease (2018)
  • Author(s): Seyrantepe Volkan、Demir Secil Akyildiz、Timur Zehra Kevser、Von Gerichten Johanna、Marsching Christian、Erdemli Esra、Oztas Emin、Takahashi Kohta、Yamaguchi Kazunori、Ates Nurselin、D?nmez Demir Buket、Dalkara Turgay、Erich Katrin、Hopf Carsten、Sandhoff Roger、Miyagi Taeko
  • Journal Title: Experimental Neurology Volume: 299 Pages: 26-41
  • DOI: 10.1016/j.expneurol.2017.09.012
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Crucial role of carbonic anhydrase IX in tumorigenicity of xenotransplanted adult T-cell leukemia-derived cells. (2017)
  • Author(s): Nasu K, Yamaguchi K, Takanashi T, Tamai K, Sato I, Ine S, Sasaki O, Satoh K, Tanaka N, Tanaka Y, Fukushima T, Harigae H, Sugamura K.
  • Journal Title: Cancer Sci Volume: 108 Issue: 3 Pages: 435-443
  • DOI: 10.1111/cas.13163
  • NAID: 120006844097
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Neuraminidases 3 and 4 regulate neuronal function by catabolizing brain gangliosides (2017)
  • Author(s): Pan Xuefang、De Arag?o Camila De Britto Par?、Velasco-Martin Juan P.、Priestman David A.、Wu Harry Y.、Takahashi Kohta、Yamaguchi Kazunori、Sturiale Luisella、Garozzo Domenico、Platt Frances M.、Lamarche-Vane Nathalie、Morales Carlos R.、Miyagi Taeko、Pshezhetsky Alexey V.
  • Journal Title: The FASEB Journal Volume: 31 Issue: 8 Pages: 3467-3483
  • DOI: 10.1096/fj.201601299r
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Long non-coding RNA HOTAIR promotes cell migration by upregulating insulin growth factor?binding protein 2 in renal cell carcinoma (2017)
  • Author(s): Katayama Hiromichi、Tamai Keiichi、Shibuya Rie、Nakamura Mao、Mochizuki Mai、Yamaguchi Kazunori、Kawamura Sadafumi、Tochigi Tatsuo、Sato Ikuro、Okanishi Takamasa、Sakurai Kunie、Fujibuchi Wataru、Arai Yoichi、Satoh Kennichi
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 12016-12016
  • DOI: 10.1038/s41598-017-12191-z
  • NAID: 120006364089
  • Peer Reviewed / Open Access
• [Journal Article] Total synthesis of the proposed structure for aromin and its structural revision. (2016)
  • Author(s): Takahashi S, Satoh D, Hayashi M, Takahashi K, Yamaguchi K, Nakamura T, Koshino H.
  • Journal Title: J Org Chem Volume: 81 Issue: 22 Pages: 11222-11234
  • DOI: 10.1021/acs.joc.6b02187
  • Peer Reviewed
• [Journal Article] CD271 regulates the proliferation and motility of hypopharyngeal cancer cells (2016)
  • Author(s): Mochizuki M, Tamai K, Imai T, Sugawara S, Ogama N, Nakamura M, Matsuura K, Yamaguchi K, Satoh K, Sato I, Motohashi H, Sugamura K, Tanaka N
  • Journal Title: Sci Reｐ Volume: 6 Issue: 1 Pages: 30707-30707
  • DOI: 10.1038/srep30707
  • Peer Reviewed / Open Access
• [Journal Article] Xenotransplantation elicits salient tumorigenicity of adult T-cell leukemia-derived cells via aberrant AKT activation. (2016)
  • Author(s): Yamaguchi K, Takanashi T, Nasu K, Tamai K, Mochizuki M, Satoh I, Ine S, Sasaki O, Satoh K, Tanaka N, Harigae H, Sugamura K.
  • Journal Title: Cancer Sci. Volume: ePub Issue: 5 Pages: 638-643
  • DOI: 10.1111/cas.12921
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Identification of TL-Om1, an ATL Cell Line, as a Reference Material for Human T-Lymphotropic Virus 1 Quantitative PCR. (2015)
  • Author(s): Kuramitsu M, Okuma K, Yamagishi M, Yamochi T, Firouzi S, Momose H, Mizukami T, Takizawa K, Araki K, Sugamura K, Yamaguchi K, Watanabe T, Hamaguchi I.
  • Journal Title: Journal of Clinical Microbiology Volume: 53 Issue: 2 Pages: 587-596
  • DOI: 10.1128/jcm.02254-14
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] BEX2 は胆管癌における静止期癌幹細胞の維持に必要である (2018)
  • Author(s): 玉井 恵一、中村 真央、西條 聡、渋谷 莉恵、望月 麻衣、山 口 壹範、菅村 和夫、佐藤 賢一
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 肺扁平上皮癌の増殖は CD271 依存性である (2018)
  • Author(s): 望月 麻衣、中村 真央、渋谷 莉恵、山口 壹範、佐藤 賢一、菅 村 和夫、玉井 恵一
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Serial xenotransplantation elicits a highly tumorigenic potential in adult T-cell leukemia-derived cells (2017)
  • Author(s): Kazunori Yamaguchi, Yuka Takanashi, Mai Mochizuki, Osamu Sasaki, Kazuo Sugamura
  • Organizer: HTLV2017
  • Place of Presentation: 東京
  • Year and Date: 2017-03-07
  • Int'l Joint Research
• [Presentation] Serial xenotransplantation elicits a highly tumorigenic potential in adult T-cell leukemia-derived cells (2017)
  • Author(s): Kazunori Yamaguchi, Yuka Takanashi, Mai Mochizuki, Osamu Sasaki, Kazuo Sugamura
  • Organizer: The The 18th International Conference on Human Retrovirology: HTLV and Related Viruses
  • Int'l Joint Research
• [Presentation] 高造腫瘍能ATL 細胞における炭酸脱水酵素IX（CA9）発現亢進の意義. (2015)
  • Author(s): 那須健太郎, 山口壹範, 玉井恵一, 井根省二, 佐々木治, 佐藤賢一, 田中伸幸, 張替秀郎, 菅村和夫
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Remarks] 宮城県立がんセンター研究所発がん制御研究部 研究活動紹介
  • URL: https://www.miyagi-pho.jp/mcc/kenkyu/katsudou/hatugan-seigyo/index.html
• [Remarks]
  • URL: http://www.miyagi-pho.jp/mcc/kenkyu/hatugan-seigyo.html
• [Remarks] 宮城県立がんセンター研究所 発がん制御研究部
  • URL: http://www.miyagi-pho.jp/mcc/kenkyu/hatugan-seigyo.html