Elucidation of molecular mechanisms underlying development and progression of rare cancers caused by alteration of transcriptional regulation

• Project/Area Number: 15K06836
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Kumamoto University
• Principal Investigator: Kadomatsu Tsuyoshi 熊本大学, 大学院生命科学研究部(医), 助教 (90555757)
• Co-Investigator(Renkei-kenkyūsha): ENDO Motoyoshi 熊本大学, 大学院生命科学研究部, 助教 (40398243) ; BABA Masaya 熊本大学, 国際先端医学研究機構, 准教授 (10347304)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); 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: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 稀少がん / 転写制御 / がん微小環境 / 腎細胞がん / 骨肉腫 / 希少がん / 転座 / がん制御遺伝子

Outline of Final Research Achievements

In this study, we investigated the molecular mechanisms underlying development and progression of rare cancers from the point of view of alteration of transcriptional regulatory mechanisms. We found that TFE3 fusion gene, which is a causative gene for Xp11.2 translocation renal cell carcinoma, increases the ANGPTL2 expression and that TFE3 fusion gene-mediated ANGPTL2 induction could be implicated in development and progression of Xp11.2 translocation renal cell carcinoma. In addition, we showed that changes in tumor microenvironments in the primary tumor tissue increase the IL-6 expression in osteosarcoma cells through TET2-mediated DNA demethylation and that IL-6 signaling accelerates lung metastasis by enhancing the expression of an adhesion molecule and metabolic reprograming in osteosarcoma cells. Moreover, our current results suggested that inhibition of IL-6 signaling in osteosarcoma cells could be a novel therapeutic approach for lung metastasis in osteosarcoma.

Research Products

• [Journal Article] TET2-dependent IL-6 induction mediated by the tumor microenvironment promotes tumor metastasis in osteosarcoma. (2018)
  • Author(s): Itoh H, Kadomatsu T, Tanoue H, Yugami M, Miyata K, Endo M, Morinaga J, Kobayashi E, Miyamoto T, Kurahashi R, Terada K, Mizuta H, Oike Y.
  • Journal Title: Oncogene Volume: 印刷中 Issue: 22 Pages: 2903-2920
  • DOI: 10.1038/s41388-018-0160-0
  • Peer Reviewed / Open Access
• [Journal Article] Age-dependent increase in angiopoietin-like protein 2 accelerates skeletal muscle loss in mice. (2018)
  • Author(s): Zhao J, Tian Z, Kadomatsu T, Xie P, Miyata K, Sugizaki T, Endo M, Zhu S, Fan H, Horiguchi H, Morinaga J, Terada K, Yoshizawa T, Yamagata K, Oike Y.
  • Journal Title: J Biol Chem Volume: 293 Issue: 5 Pages: 1596-1609
  • DOI: 10.1074/jbc.m117.814996
  • Peer Reviewed / Open Access
• [Journal Article] Association of circulating ANGPTL 3, 4, and 8 levels with medical status in a population undergoing routine medical checkups: A cross-sectional study. (2018)
  • Author(s): Morinaga J, Zhao J, Endo M, Kadomatsu T, Miyata K, Sugizaki T, Okadome Y, Tian Z, Horiguchi H, Miyashita K, Maruyama N, Mukoyama M, Oike Y.
  • Journal Title: PLoS One Volume: 13 Issue: 3 Pages: e0193731-e0193731
  • DOI: 10.1371/journal.pone.0193731
  • Peer Reviewed / Open Access
• [Journal Article] Angiopoietin-like protein 2 promotes chondrogenic differentiation during bone growth as a cartilage matrix factor. (2018)
  • Author(s): Tanoue H, Morinaga J, Yoshizawa T, Yugami M, Itoh H, Nakamura T, Uehara Y, Masuda T, Odagiri H, Sugizaki T, Kadomatsu T, Miyata K, Endo M, Terada K, Ochi H, Takeda S, Yamagata K, Fukuda T, Mizuta H, Oike Y.
  • Journal Title: Osteoarthritis Cartilage Volume: 26 Issue: 1 Pages: 108-117
  • DOI: 10.1016/j.joca.2017.10.011
  • Peer Reviewed / Open Access
• [Journal Article] Circulating ANGPTL2 Levels Increase in Humans and Mice Exhibiting Cardiac Dysfunction (2018)
  • Author(s): Tian Z, Miyata K, Morinaga J, Horiguchi H, Kadomatsu T, Endo M, Zhao J, Zhu S, Sugizaki T, Sato M, Terada K, Okumura T, Murohara T, Oike Y.
  • Journal Title: Circulation Journal Volume: 82 Issue: 2 Pages: 437-447
  • DOI: 10.1253/circj.CJ-17-0327
  • NAID: 130006320284
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Journal Article] Treatment of diabetic mice with the SGLT2 inhibitor TA-1887 antagonizes diabetic cachexia and decreases mortality. (2017)
  • Author(s): Sugizaki T, Zhu S, Guo G, Matsumoto A, Zhao J, Endo M, Horiguchi H, Morinaga J, Tian Z, Kadomatsu T, Miyata K, Itoh H, Oike Y
  • Journal Title: NPJ Aging Mech Dis Volume: 3 Issue: 1 Pages: 12-12
  • DOI: 10.1038/s41514-017-0012-0
  • Peer Reviewed / Open Access
• [Journal Article] ANGPTL2 ― A New Causal Player in Accelerating Heart Disease Development in the Aging ― (2017)
  • Author(s): Oike Y, Tian Z, Miyata K, Morinaga J, Endo M, Kadomatsu T.
  • Journal Title: Circulation Journal Volume: 81 Issue: 10 Pages: 1379-1385
  • DOI: 10.1253/circj.CJ-17-0854
  • NAID: 130006099927
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Journal Article] ANGPTL2 expression in intestinal stem cell niche controls epithelial regeneration and homeostasis. (2017)
  • Author(s): Horiguchi H, Endo M, Kawane K, Kadomatsu T, Terada K, Morinaga J, Araki K, Miyata K, Oike Y,
  • Journal Title: EMBO Journal Volume: 36 Issue: 4 Pages: 409-424
  • DOI: 10.15252/embj.201695690
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Macrophage-derived angiopoietin-like protein 2 exacerbates brain damage by accelerating acute inflammation after ischemia-reperfusion. (2016)
  • Author(s): Amadatsu T, Morinaga J, Kawano T, Terada K, Kadomatsu T, Miyata K, Endo M, Kasamo D, Kuratsu JI & Oike Y
  • Journal Title: PLOS ONE Volume: 11 Issue: 11 Pages: e0166285-e0166285
  • DOI: 10.1371/journal.pone.0166285
  • Peer Reviewed / Open Access
• [Journal Article] ANGPTL2 activity in cardiac pathologies accelerates heart failure by perturbing cardiac function and energy metabolism. (2016)
  • Author(s): Tian Z, Miyata K, Kadomatsu T, Horiguchi H, Fukushima H, Tohyama S, Ujihara Y, Okumura T, Yamaguchi S, Zhao J, Endo M, Morinaga J, Sato M, Sugizaki T, Zhu S, Terada K, Sakaguchi H, Komohara Y, Takeya M, Takeda N, Araki K, Manabe I, Fukuda K, Otsu K, Wada J, Murohara T, Mohri S, Yamashita JK, Sano M, Oike Y.
  • Journal Title: Nature Communications Volume: 7 Issue: 1 Pages: 13016-13016
  • DOI: 10.1038/ncomms13016
  • NAID: 120006345014
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Angiopoietin-like protein 2 increases renal fibrosis by accelerating transforming growth factor-β signaling in chronic kidney disease. (2016)
  • Author(s): Jun Morinaga, Tsuyoshi Kadomatsu, Keishi Miyata, Motoyoshi Endo, Kazutoyo Terada, Zhe Tian, Taichi Sugizaki, Hiroki Tanigawa, Jiabin Zhao, Shunshun Zhu, Michio Sato, Kimi Araki, Ken-ichi Iyama, Kengo Tomita, Masashi Mukoyama, Kimio Tomita, Kenichiro Kitamura, Yuichi Oike
  • Journal Title: Kidney International Volume: 89 Issue: 2 Pages: 327-341
  • DOI: 10.1016/j.kint.2015.12.021
  • Peer Reviewed
• [Journal Article] The role of ANGPTL2-induced chronic inflammation in lifestyle diseases and cancer (2015)
  • Author(s): Yuichi Oike, Tsuyoshi Kadomatsu, Motoyoshi Endo
  • Journal Title: Inflammation and Regeneration Volume: 35 Issue: 4 Pages: 193-202
  • DOI: 10.2492/inflammregen.35.193
  • NAID: 130005103502
  • ISSN: 1880-8190, 1880-9693
  • Peer Reviewed
• [Presentation] Role of angiopoietin-like protein 2 in tumor development and metastasis (2017)
  • Author(s): Tsuyoshi Kadomatsu
  • Organizer: 「新規バイオ医薬ピロール・イミダゾール（PI）ポリアミドの創薬開発国際シンポジウム」平成28年度 日本大学学部連携研究推進シンポジウム
  • Place of Presentation: 日本大学（東京都）
  • Year and Date: 2017-02-24
  • Int'l Joint Research / Invited
• [Presentation] がん微小環境変化による組織恒常性維持機構の活性化とがん病態進展の分子機構 (2016)
  • Author(s): 門松 毅
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2016-12-02
• [Presentation] 生活習慣病・がんの共通分子機構とSASPとしてのアンジオポエチン様因子2シグナル (2015)
  • Author(s): 門松 毅、尾池雄一
  • Organizer: BMB 2015 （第38回日本分子生物学会年会 第88回日本生化学会大会 合同大会）
  • Place of Presentation: 神戸ポートピアホテル（神戸市）
  • Year and Date: 2015-12-03
• [Book] サイトカイン・増殖因子キーワード事典 (2015)
  • Author(s): 門松 毅、尾池雄一
  • Total Pages: 420
  • Publisher: 羊土社
• [Book] 血管医学 特集：臓器の記憶と血管代謝ニッシェ (2015)
  • Author(s): 門松 毅、尾池雄一
  • Total Pages: 112
  • Publisher: メディカルレビュー社
• [Remarks] 熊本大学大学院生命科学研究部 分子遺伝学分野
  • URL: http://www.kumamoto-u-molgene.jp
• [Remarks] 熊本大学大学院生命科学研究部 分子遺伝学分野
  • URL: http://molegene.kumamoto-u.ac.jp