The role of Fra-2 and SOX4 oncogene cascade in ATL and CTCLs

• Project/Area Number: 23591632
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Dermatology
• Research Institution: Kinki University
• Principal Investigator: HIGUCHI Tomonori 近畿大学, 医学部, 助教 (00448771)
• Co-Investigator(Kenkyū-buntansha): YOSHIE Osamu 近畿大学, 医学部, 教授 (10166910) ; NAKAYAMA Takashi 近畿大学, 薬学部, 教授 (60319663)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 皮膚腫瘍学 / SOX4 / Fra-2 / 成人T細胞白血病／リンパ腫（ATL） / 皮膚T細胞リンパ腫（CTCL） / HDAC8 / ATL / CTCL / ATLL

Research Abstract

Previously, we have shown that Fra-2 is consistently expressed and involved in CCR4 expression as well as cell growth in CCR4+ mature T-cell leukemias/lymphomas, including adult T-cell leukemia/lymphoma (ATL) and cutaneous T-cell lymphomas (CTCLs). Here, we we examine the expression and function of SOX4 in the oncogenesis of ATL and CTCLs. Fra-2 and SOX4 were consistently co-expressed in the clinical samples of ATL and CTCL. SOX4 promoter analysis demonstrated that Fra-2-JunD directly activates the SOX4 promoter via an AP-1 site. Furthermore, SOX4 siRNA significantly suppressed cell growth of ATL and CTCL cell lines. We found that SOX4 knockdown reduced the expression of genes such as GCKR, NAP1 and HDAC8. We also showed direct activation of the HDAC8 promoter by SOX4. Furthermore, HDAC8 knockdown significantly suppressed cell growth of ATL and CTCL cell lines. Taken together, these finding suggest that the Fra-2-SOX4 pathway has an important oncogenic role in ATL and CTCLs.

Research Products

• [Journal Article] Generation of colonic IgA-secreting cells in the cecal patch (2014)
  • Author(s): Masahata, K., Umemoto, E., Kayama, H., Kotani, M., Nakamura, S., Kurakawa, T., Kikuta, J., Gotoh, K., Motooka, D., Sato, S., Higuchi, T., Baba, Y., Kurosaki, T., Kinoshita, M., Shimada, Y., Kimura, T., Okumura, R., Takeda, A., Tajima, M., Yoshie, O., Fukuzawa, M., Kiyono, H., Fagarasan, S., Iida, T., Ishii, M., Takeda, K
  • Journal Title: Nature Comm Volume: 5 Issue: 1 Pages: 3704-3704
  • DOI: 10.1038/ncomms4704
  • Peer Reviewed / Open Access
• [Journal Article] Generation of colonic IgA-secreting cells in the caecal patch. (2014)
  • Author(s): Kazunori Masahata, Eiji Umemoto, Hisako Kayama, Manato Kotani, Shota Nakamura, Takashi Kurakawa, Junichi Kikuta, Kazuyoshi Gotoh, Daisuke Motooka, Shintaro Sato, Tomonori Higuchi, Yoshihiro Baba, Tomohiro Kurosaki, Makoto Kinoshita, Yosuke Shimada, Taishi Kimura, Ryu Okumura, Akira Takeda, Masaru Tajima et al.
  • Journal Title: Nature Communications Volume: in press
  • Peer Reviewed
• [Journal Article] International Union of Pharmacology. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors. (2013)
  • Author(s): Francoise Bachelerie, Adit Ben-Baruch, Amanda M. Burkhardt, Christophe Combadiere, Joshua M. Farber, Gerard J. Graham, Richard Horuk, Alexander Hovard Sparre-Ulrich, Massimo Locati, Andrew D. Luster, Alberto Mantovani, Kouji Matsushima, Philip M. Murphy, Robert Nibbs, Hisayuki Nomiyama, Christine A. Power et al.
  • Journal Title: Pharmacological Reviews Volume: 66(1) Issue: 1 Pages: 1-79
  • DOI: 10.1124/pr.113.007724
  • Peer Reviewed
• [Journal Article] Paracrine activation of MET promotes peritoneal carcinomatosis in scirrhous gastric cancer. (2013)
  • Author(s): Zhao L, Yano S, et al.
  • Journal Title: Cancer Sci Volume: 104 Issue: 12 Pages: 1640-6
  • DOI: 10.1111/cas.12301
  • NAID: 120005830610
  • Peer Reviewed
• [Journal Article] Genome diversification mechanism of rodent and Lagomorpha chemokine genes. (2013)
  • Author(s): Kanako Shibata, Hisayuki Nomiyama, Osamu Yoshie, Sumio Tanase.
  • Journal Title: BioMed Research International Volume: 2013 Pages: 856265-856265
  • DOI: 10.1155/2013/856265
  • Peer Reviewed
• [Journal Article] SOX4 is a direct target gene of FRA-2 and induces expression of HDAC8 in adult T-cell leukemia/lymphoma. (2013)
  • Author(s): Tomonori Higuchi, Takashi Nakayama, Tokuzo Arao, Kazuto Nishio, Osamu Yoshie.
  • Journal Title: Blood Volume: 121(18) Issue: 18 Pages: 3640-3649
  • DOI: 10.1182/blood-2012-07-441022
  • Peer Reviewed
• [Journal Article] The importance of CCR4 and CCR6 in experimental autoimmune encephalomyelitis. (2013)
  • Author(s): Kota Moriguchia, Katsuichi Miyamoto, Noriko Tanaka, Osamu Yoshie, Susumu Kusunoki.
  • Journal Title: Journal of Neuroimmunology Volume: 257(1-2) Issue: 1-2 Pages: 53-58
  • DOI: 10.1016/j.jneuroim.2013.02.002
  • Peer Reviewed
• [Journal Article] Chemokine CXCL16 suppresses liver metastasis of colorectal cancer via augmentation of tumor-infiltrating natural killer T cells in a murine model. (2013)
  • Author(s): Ji-Ye Kee et al.
  • Journal Title: Oncology Reports Volume: 29(3) Issue: 3 Pages: 975-982
  • DOI: 10.3892/or.2012.2185
  • Peer Reviewed
• [Journal Article] Systematic classification of vertebrate chemokines based on conserved synteny and evolutionary history. (2013)
  • Author(s): Hisayuki Nomiyama et al.
  • Journal Title: Gene to Cells Volume: 18(1) Issue: 1 Pages: 1-16
  • DOI: 10.1111/gtc.12013
  • Peer Reviewed
• [Journal Article] SOX4 is a direct target gene of FRA-2 and induces expression of HDAC8 in adult T-cell leukemia/lymphoma. (2013)
  • Author(s): Tomonori Higuchi et al.
  • Journal Title: Blood Volume: in press
  • Peer Reviewed
• [Journal Article] The chemokine superfamily revisited. (2012)
  • Author(s): Albert Zlotnik et al.
  • Journal Title: Immunity Volume: 36(5) Issue: 5 Pages: 705-716
  • DOI: 10.1016/j.immuni.2012.05.008
  • Peer Reviewed
• [Journal Article] Expression and function of FRA2/JUND in cutaneous T-cell lymphomas (2012)
  • Author(s): Nakayama T, Higuchi T, Oiso N, Kawada A, Yoshie O
  • Journal Title: Anticancer Res Volume: 32(4) Pages: 1367-73
  • Peer Reviewed
• [Journal Article] Selective down-regulation of Th2 cell-mediated airway inflammation in mice by pharmacological intervention of CCR4 (2012)
  • Author(s): Kaminuma, O, et al
  • Journal Title: Clin.Exp.Allergy Volume: 42 Issue: 2 Pages: 315-25
  • DOI: 10.1111/j.1365-2222.2011.03847.x
  • Peer Reviewed
• [Journal Article] Expression and Function of FRA2/JUND in Cutaneous T-Cell Lymphomas. (2012)
  • Author(s): Takashi Nakayama et al.
  • Journal Title: Anticancer Research Volume: 32(4) Pages: 1367-1373
  • Peer Reviewed
• [Journal Article] In situ expression of the CCL20-CCR6 axis in lymphocyte-rich gastric cancer and its potential role in the formation of lymphoid stroma (2011)
  • Author(s): Ohtani H, Nakayama T, Yoshie O
  • Journal Title: Pathol Int Volume: 61(11) Issue: 11 Pages: 645-651
  • DOI: 10.1111/j.1440-1827.2011.02717.x
  • NAID: 10031185135
  • Peer Reviewed
• [Journal Article] A family tree of vertebrate chemokine receptors for a unified nomenclature (2011)
  • Author(s): Nomiyama H, Osada N, Yoshie O
  • Journal Title: Dev Comp Immunol Volume: 35(7) Issue: 7 Pages: 705-715
  • DOI: 10.1016/j.dci.2011.01.019
  • NAID: 120003039872
  • Peer Reviewed
• [Journal Article] c-Maf suppresses human T-cell leukemia virus type 1 Tax by competing for CREB-binding protein (2011)
  • Author(s): Hieshima K, Nagakubo D, Shigeta A, Tanaka Y, Hoshino H, Tsukasaki K, Yamada Y, Yoshie O
  • Journal Title: Cancer Sci Volume: 102(4) Issue: 4 Pages: 890-894
  • DOI: 10.1111/j.1349-7006.2011.01873.x
  • NAID: 10029292861
  • Peer Reviewed
• [Presentation] Attenuation of bleomycin-induced mice pulmonary fibrosis by in vivo treatment of HSP27 siRNA (2014)
  • Author(s): Park AM, Yoshie O, Watanabe A, Higuchi T, Honda E, Munakata H
  • Organizer: SFRRI2014
  • Place of Presentation: 京都国際会議場(京都府京都市)
• [Presentation] Attenuation of bleomycin-induced mice pulmonary fibrosis by in vivo treatment of HSP27 siRNA. (2014)
  • Author(s): Ah-Mee Park, Osamu Yoshie, Akiko Watanabe, Tomonori Higuchi, Eiko Honda, Hiroshi Munakata
  • Organizer: SFRRI2014
  • Place of Presentation: 京都国際会議場（京都府京都市）
• [Presentation] Fra-2-SOX4 oncogenic cascade plays a critical role in cell growth of adult T-cell leukemia/lymphoma (2013)
  • Author(s): Higuchi T, Nakayama T, Yoshie O
  • Organizer: 第72回日本癌学会学術集会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市)
• [Presentation] Fra-2-SOX4 oncogenic cascade plays a critical role in cell growth of adult T-cell leukemia/lymphoma. (2013)
  • Author(s): Tomonori Higuchi, Takashi Nakayama, Osamu Yoshie.
  • Organizer: 第72回日本癌学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
• [Presentation] Induction of FosB by Tax induces CCL22 in HTLV-1-infected T cells, leading to HTLV-1 (2012)
  • Author(s): Higuchi T, Hieshima K, Nakayama T, Yoshie O
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌(北海道札幌市)
• [Presentation] Induction of FosB by Tax induces CCL22 in HTLV-1-infected T cells, leading to HTLV-1 (2012)
  • Author(s): Tomonori Higuchi et al.
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌（北海道札幌市）
• [Presentation] Fra-2-SOX4 oncogenic cascade plays a critical role in cell growth of CCR4+ mature T-cell malignancies (2011)
  • Author(s): Higuchi T, Nakayama T, Shigeta A, Yoshie O
  • Organizer: JSICR-MMCB2011
  • Place of Presentation: ANAゲートタワーホテル大阪(大阪府泉佐野市)
  • Year and Date: 2011-05-25
• [Presentation] CCL26/eotaxin-3 attracts killer lymphocytes by intracting with CX3CR1 (2011)
  • Author(s): Nakayama T, Higuchi T, Shigeta A, Yoshie O
  • Organizer: JSICR-MMCB2011
  • Place of Presentation: ANAゲートタワーホテル大阪(大阪府泉佐野市)
  • Year and Date: 2011-05-25
• [Presentation] Fra-2-SOX4 oncogenic cascade plays a critical role in cell growth of CCR4+ mature T-cell malignancies (2011)
  • Author(s): Tomonori Higuchi et al.
  • Organizer: JSICR-MMCB2011
  • Place of Presentation: ANAゲートタワーホテル大阪（大阪府泉佐野市）
• [Presentation] CCL26/eotaxin-3 attracts killer lymphocytes by interacting with CX3CR1 (2011)
  • Author(s): Takashi Nakayama et al.
  • Organizer: JSICR-MMCB2011
  • Place of Presentation: ANAゲートタワーホテル大阪（大阪府泉佐野市）