CAGE発現解析を用いた大腸がん肺転移予測マーカーの特定

• Project/Area Number: 18K08798
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55040:Respiratory surgery-related
• Research Institution: Juntendo University
• Principal Investigator: 柳沼 行宏 順天堂大学, 医学部, 非常勤講師 (60338415)
• Co-Investigator(Kenkyū-buntansha): 小見山 博光 順天堂大学, 医学部, 非常勤講師 (30348982) ; 茂櫛 薫 順天堂大学, 医学(系)研究科(研究院), 非常勤講師 (60569292)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Granted (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 大腸癌 / 肺転移 / CAGE / 腫瘍マーカー / 大腸がん / CAGE法 / マーカー

Outline of Annual Research Achievements

我々はこれまで大腸癌をはじめとする癌の鋭敏な新規マーカー開発、分子標的治療の可能性を探り研究を進めてきた。とくに大腸癌では転移はリンパ節のほか、肝、肺に多く見られるが、現在は転移巣に対しても積極的治療が選択される。転移においても早期発見、早期治療は大腸癌患者の平均余命を向上させると考えら れている。しかし現状では転移を検出するための「転移マーカー」は存在しない。そのため一様に抗癌剤投与を施すのが現状である。このような事情から、転移を予測可能な、あるいは早期に発見するために有効な「転移マーカー」の開発が今後の大腸癌治療の進歩をもたらすものと考えられる。
我々はCAGE（Cap Analysis of Gene Expression）法を適用し大腸癌の転移有り・無しの症例サンプル間での比較解析を行い、転移特異的な遺伝子を特定することによる新たな診断マーカーの開発を着想した。
本研究はCAGE法によって抽出した候補遺伝子群から、大腸がんの肺転移マーカーを特定することを主目的とする。癌部組織および採血検体を用いその遺伝子発現を解析、肺転移症例に特異的な発現昂進または抑制を示す遺伝子のうち血中マーカー候補を選別する。また術後の患者の追跡により、採血検体で特定したマーカーのレベル変動による術後肺転移の予測も目指していく。以上、本研究では大腸癌の肺転移を予測できうるマーカーを取得を目指す。 現状では評価できない肺転移リスク、また初期の肺転移を、診断可能にすることまでを目的とする。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

大腸がん肺転移を引き起こす原因遺伝子を突き止め、さらに大腸癌の肺転移マーカーを新たに開発することを目標とする。すでに患者から採取し保管してあるサンプルを用い、肺転移を起こした大腸がん原発巣の転移有り群と転移無し群の遺伝子の比較解析を行い、興味深い結果を得ている。

Strategy for Future Research Activity

複数のマーカー候補遺伝子群について、患者の臨床データを解析、さらに候補遺伝子の絞り込みを行う。腫瘍部よりRNAを抽出し転移巣の解析を行うことによって、肺転移マーカー候補を選別し肺転移マーカーを特定する計画である。

Research Products

• [Journal Article] Metastatic seeding of human colon cancer cell clusters expressing the hybrid epithelial/mesenchymal state. (2020)
  • Author(s): Mizukoshi K, Okazawa Y, Haeno H, Koyama Y, Sulidan K, Komiyama H, Saeki H, Ohtsuji N, Ito Y, Kojima Y, Goto M, Habu S, Hino O, Sakamoto K, Orimo A.
  • Journal Title: International Journal of Cancer, Volume: 146 Pages: 2547-2562
  • DOI: 10.1002/ijc.32672
  • Peer Reviewed / Open Access
• [Journal Article] Using the polymeric circulating tumor cell chip to capture circulating tumor cells in blood samples of patients with colorectal cancer (2020)
  • Author(s): Kure K, Hosoya M, Ueyama T, Fukaya M, Sugimoto K, Tomiki Y,Ohnaga T, Sakamoto K, Komiyama H.
  • Journal Title: ONCOLOGY LETTERS Volume: 19 Pages: 2286-2294
  • DOI: 10.3892/ol.2020.11335
  • Peer Reviewed / Open Access
• [Journal Article] Angiopoietin-2 as a Prognostic Factor in Patients with Incurable Stage IV Colorectal Cancer. (2020)
  • Author(s): Munakata S, Ueyama T, Ishihara H, Komiyama H, Tsukamoto R, Kawai M, Takahashi M, Kojima Y, Tomiki Y,
  • Journal Title: J Gastrointest Cancer Volume: 2020 Online ahead of print Pages: 000-000
  • DOI: 10.1007/s12029-020-00392-1
  • Peer Reviewed / Open Access
• [Journal Article] Stromal fibroblasts induce metastatic tumor cell clusters via epithelial-mesenchymal plasticity., (2019)
  • Author(s): Matsumura Y, Ito Y, Mezawa Y, Sulidan K, Daigo Y, Hiraga T, Mogushi K, Wali N, Suzuki H, Itoh T, Miyagi Y, Yokose T, Shimizu S, Takano A, Terao Y, Saeki H, Ozawa M, Abe M, Takeda S, Okumura K, Habu S, Hino O, Takeda K, Hamada M, Orimo A.
  • Journal Title: Life Sci. Alliance Volume: 2(4):e201900425. Pages: 1-24
  • DOI: 10.26508/lsa.201900425
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Estrogen Receptor-positive Ductal Carcinoma In Situ Frequently Overexpresses HER2 Protein Without Gene Amplification. (2019)
  • Author(s): Horimoto Y, Terao T, Tsutsumi Y, Tanabe M, Mogushi K, Hlaing MT, Sasaki R, Saeki H, Okazaki M, Sonoue H, Arakawa A, Saito M.
  • Journal Title: The American Journal of Surgical Pathology Volume: 43(9) Pages: 1221-1228
  • DOI: 10.1097/pas.0000000000001300
  • Peer Reviewed / Open Access
• [Journal Article] High-sensitivity detection of micrometastases in GFP-labelled colon tumor organoids extracted from patient-derived tumor xenografts. (2019)
  • Author(s): OkazawaY, Mizukoshi K, KoyamaY, Okubo S, Komiyama H, Kojima Y, Goto M, Habu S, Hino O, Sakamoto K, Orimo A.
  • Journal Title: J. Vis. Exp. Volume: 136(e57374) Pages: 136-136
  • DOI: 10.3791/57374
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondrial ribosomal protein PTCD3 mutations cause oxidative phosphorylation defects with Leigh syndrome (2019)
  • Author(s): Borna NN, Kishita Y, Kohda M, Lim SC, Shimura M, Wu Y, Mogushi K, Yatsuka Y, Harashima H, Hisatomi Y, Fushimi T, Ichimoto K, Murayama K, Ohtake A, Okazaki Y.
  • Journal Title: neurogenetics Volume: 20(1) Pages: 9-25
  • DOI: 10.1007/s10048-018-0561-9
  • Peer Reviewed
• [Journal Article] Comprehensive molecular and immunological characterization of hepatocellular carcinoma (2019)
  • Author(s): Shimada S, Mogushi K, Akiyama Y, Furuyama T, Watanabe S, Ogura T, Ogawa K, Ono H, Mitsunori Y, Ban D, Kudo A, Arii S, Tanabe M, Wands JR, Tanaka S.
  • Journal Title: EBioMedicine. Volume: 40 Pages: 457-470
  • DOI: 10.1016/j.ebiom.2018.12.058
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of genes and pathways, including the CXCL2 axis, altered by DNA methylation in hepatocellular carcinoma. (2019)
  • Author(s): Subat S, Mogushi K, Yasen M, Kohda T, Ishikawa Y, Tanaka H.
  • Journal Title: Journal of cancer research and clinical oncology Volume: 145(3) Pages: 675-684
  • DOI: 10.1007/s00432-018-2824-0
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pharmacological targeting of neutrophil serine proteases prevents lethality in dextran sulfate sodium (DSS)-induced colitis in mice. (2018)
  • Author(s): Ro H, Munakata S, Ueyama T, Komiyama H, Takahashi M, Kojima Y, Tomiki Y, Sakamoto K
  • Journal Title: J Gastrointest Dig Syst Volume: 8 Pages: 551-551
  • DOI: 10.4172/2161-069x.1000551
  • Peer Reviewed / Open Access
• [Journal Article] COQ2 variants in Parkinson's disease and multiple system atrophy. (2018)
  • Author(s): Mikasa M, Kanai K, Li Y, Yoshino H, Mogushi K, Hayashida A, Ikeda A, Kawajiri S, Okuma Y, Kashihara K, Sato T, Kondo H, Funayama M, Nishioka K, Hattori N.
  • Journal Title: Journal of Neural Transmission Volume: - Pages: 937-944
  • DOI: 10.1007/s00702-018-1885-1
  • Peer Reviewed
• [Journal Article] Elucidation of inhibitory effects on metastatic sentinel lymph nodes of breast cancer during One-Step Nucleic Acid Amplification (2018)
  • Author(s): Horimoto Y, Tanabe M, Kazuno S, Miura Y, Mogushi K, Sonoue H, Arakawa A, Kajino K, Kobayashi T, Saito M.
  • Journal Title: Scientific Reports Volume: 8(1):7563 Pages: 1-7
  • DOI: 10.1038/s41598-018-25911-w
  • Peer Reviewed / Open Access
• [Journal Article] FABP4 overexpressed in intratumoral hepatic stellate cells within hepatocellular carcinoma with metabolic risk factors. (2018)
  • Author(s): Chiyonobu N、Shimada S、Akiyama Y、Mogushi K、Itoh M、Akahoshi K、Matsumura S、Ogawa K、Ono H、Mitsunori Y、Ban D、Kudo A、Arii S、Suganami T、Yamaoka S、Ogawa Y、Tanabe M、Tanaka S
  • Journal Title: Am. J. Pathol. Volume: 188 Pages: 1213-1224
  • DOI: 10.1016/j.ajpath.2018.01.012
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Non-small cell lung carcinoma with diffuse co-expression of thyroid transcription factor-1 and ΔNp63/p40. (2018)
  • Author(s): Hayashi Takuo、Takamochi Kazuya、Yanai Yuka、Mitani Keiko、Tomita Hisashi、Mogushi Kaoru、Suehara Yoshiyuki、Takahashi Fumiyuki、Suzuki Kenji、Saito Tsuyoshi、Yao Takashi
  • Journal Title: Hum Pathol Volume: S0046-8177 Pages: 177-181
  • DOI: 10.1016/j.humpath.2018.01.023
  • Peer Reviewed / Open Access
• [Journal Article] Tumor sidedness and enriched gene groups for efficacy of first-line cetuximab treatment in metastatic colorectal cancer. (2018)
  • Author(s): Sunakawa Y, Mogushi K, Lenz HJ, Zhang W, Tsuji A, Takahashi T, Denda T, Shimada K, Kochi M, Nakamura M, Kotaka M, Ichikawa W. et al
  • Journal Title: Molecular Cancer Therapeutics Volume: 17(12) Pages: 2788-2795
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Tumor suppressor functions of DAXX through histone H3.3/H3K9me3 pathway in pancreatic neuroendocrine tumors. (2018)
  • Author(s): Ueda H, Akiyama Y, Shimada S, Mogushi K, Serizawa M, Matsumura S, Mitsunori Y, Aihara A, Ban D, Ochiai T, Kudo A, Tanabe M, Tanaka S.
  • Journal Title: Endocrine-Related Cancer Volume: 25(6) Pages: 619-631
  • DOI: 10.1530/erc-17-0328
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] <i>KCTD12</i> is negatively regulated by Kit in gastrointestinal stromal tumors (2018)
  • Author(s): Suehara Y, Akaike K, Mukaihara K, Kurisaki-Arakawa A, Kubota D, Okubo T, Mitomi H, Mitani K, Takahashi M, Toda-Ishii M1, Kim Y, Tanabe Y, Takagi T, Hayashi T, Mogushi K, Kaneko K, Yao T, Saito T.
  • Journal Title: Oncotarget Volume: 9(43) Pages: 27016-27026
  • DOI: 10.18632/oncotarget.25469
  • Peer Reviewed / Open Access
• [Journal Article] GCH1 mutations in dopa-responsive dystonia and Parkinson’s disease. (2018)
  • Author(s): Yoshino H, Nishioka K, Li Y, Oji Y, Oyama G, Hatano T, Machida Y, Shimo Y, Hayashida A, Ikeda A, Mogushi K, Shibagaki Y, Hosaka A, Iwanaga H, Fujitake J, Ohi T, Miyazaki D, Sekijima Y, Oki M, Kusaka H, Fujimoto KI Ugawa Y, Funayama M, Hattori N.
  • Journal Title: J Neurol. Volume: 265(8) Pages: 1860-1870
  • DOI: 10.1007/s00415-018-8930-8
  • Peer Reviewed / Open Access
• [Journal Article] Clinical features of squamous cell lung cancer with anaplastic lymphoma kinase (ALK)-rearrangement: a retrospective analysis and review (2018)
  • Author(s): Watanabe J, Togo S, Sumiyoshi I, Namba Y, Suina K, Mizuno T, Kadoya K, Motomura H, Iwai M, Nagaoka T, Sasaki S, Hayashi T, Uekusa T, Abe K, Urata Y, Sakurai F, Mizuguchi H, Kato S, Takahashi K.
  • Journal Title: Oncotarget Volume: 9(35) Pages: 24000-24013
  • DOI: 10.18632/oncotarget.25257
  • Peer Reviewed / Open Access
• [Journal Article] Correction: Radiotherapy increases plasma levels of tumoral cell-free DNA in non-small cell lung cancer patients. (2018)
  • Author(s): Kageyama SI, Nihei K, Karasawa K, Sawada T, Koizumi F, Yamaguchi S, Kato S, Hojo H, Motegi A, Tsuchihara K, Akimoto T.
  • Journal Title: Oncotarget Volume: 9(34) Pages: 23844-23844
  • DOI: 10.18632/oncotarget.25378
  • Peer Reviewed / Open Access
• [Journal Article] Intermittent Withdrawal of Oxaliplatin for Alleviating Neurotoxicity during Oxaliplatin-Based Chemotherapy for Japanese Patients with Inoperable or Metastatic Colorectal Cancer: A Phase 2 Multicenter Study (2018)
  • Author(s): Kato S, Imai H, Gamoh M, Takahata T, Ohori H, Yasuda K, Niitani T, Murakawa Y, Amagai K, Isobe H, Shindo Y, Kuroki M, Sakamoto Y, Shimodaira H, Yoshioka T, Ishioka C.
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 245(1) Issue: 1 Pages: 21-28
  • DOI: 10.1620/tjem.245.21
  • NAID: 130006733224
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed / Open Access
• [Journal Article] Radiotherapy increases plasma levels of tumoral cell-free DNA in non-small cell lung cancer patients (2018)
  • Author(s): Kageyama S, Nihei K, Karasawa K,, Sawada T, Koizumi F, Yamaguchi S, Kato S, Hojo H, Motegi A, Tsuchihara K, Akimoto T.
  • Journal Title: Oncotarget. Volume: 10;9(27) Pages: 19368-19378
  • DOI: 10.18632/oncotarget.25053
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 四次治療のトラベクテジン投与にて長期の無増悪生存期間が得られている平滑筋肉腫再発の1症例 (2018)
  • Author(s): 野崎 由美, 山口 茂夫, 高木 辰哉, 加藤 俊介
  • Journal Title: 癌と化学療法 Volume: 46巻2号 Pages: 275-277
  • Peer Reviewed
• [Presentation] 網羅的解析を用いた新規結腸癌診断マーカーの探索. (2019)
  • Author(s): 塚本亮一, 小見山博光, 河野眞吾, 河合雅也, 高橋玄, 小島豊, 冨木裕一, 坂本一博
  • Organizer: 第57回日本癌治療学会学術集会, 福岡.
• [Presentation] 患者大腸癌細胞集団の中間型上皮間葉移行を介した浸潤・転移機構. (2019)
  • Author(s): 水越幸輔，岡澤 裕，波江野 洋，小山 侑，大久保捷奇，Kaidiliavi Sulidan，伊藤恭彦，小見山博光，杉本起一，小島 豊，五藤倫敏，垣生園子，樋野興夫，折茂 彰，坂本一博
  • Organizer: 第30回日本消化器癌発生学会総会，横浜.
• [Remarks] 順天堂大学大学院 下部消化管外科学
  • URL: https://www.juntendo.ac.jp/graduate/laboratory/labo/kabusyoukakan/
• [Remarks] 順天堂大学大学院 下部消化管外科学
  • URL: https://www.juntendo.ac.jp/graduate/laboratory/labo/kabusyoukakan/