Novel approach to overcome malignant cancer by targeting Y-box binding protein-1(YB-1)

• Project/Area Number: 24650646
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Clinical oncology
• Research Institution: Kyushu University
• Principal Investigator: KUWANO Michihiko 九州大学, 薬学研究科(研究院), 特任教授 (80037431)
• Co-Investigator(Kenkyū-buntansha): ODA Yoshinao 九州大学, 医学(系)研究科(研究院), 教授 (70291515)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: YB-1核内局在 / 予後不良因子 / HER2発現 / ERα発現 / 乳癌 / 胃癌 / YB-1標的治療 / 分子標的薬感受性 / ERalpha発現 / YB-1タンパク質 / 分子生物学 / 増殖因子受容体 / HER2/ErbB2 / 分子標的治療薬 / ラパチニブ / がん治療適正化 / 免疫組織解析

Research Abstract

HER2 overexpression is a predictive factor of poor prognosis in patients with gastric cancer. Currently, the HER2-targeted antibody, trastuzumab, has improved the efficacy of therapy for HER2-positive advanced stomach cancer. This study demonstrated that Y-box binding protein-1 (YB-1) knockdown suppressed the expression of HER2, affecting drug resistance to lapatinib, a dual kinase inhibitor of EGFR and HER2, in gastric cancer cells. Moreover, nuclear YB-1 expression was also specifically correlated with expression of HER2 in human gastric cancer. YB-1-HER2 axis could thus contribute to further development of personalized therapeutics by HER2-targeted drugs against gastric cancer.

Research Products

• [Journal Article] Nuclear Y-box-binding protein-1 is a poor prognostic marker and related to epidermal growth factor receptor in uterine cervical cancer (2014)
  • Author(s): Nishio, S., Ushijima, K., Yamaguchi, T., Sasajima, Y., Tsuda, H., Kasamatsu, T., Kage, M., Ono, M., Kuwano, M., and Kamura, T.
  • Journal Title: Gynecologic Oncology Volume: 132 Issue: 3 Pages: 703
  • DOI: 10.1016/j.ygyno.2014.01.045
• [Journal Article] FGFR1 activation is an escape mechanism in human lung cancer cells resistant to afatinib, a pen-EGFR family kinase inhibitor (2014)
  • Author(s): Azuma,K., Kawahara, A., Sonoda, K., Nakashima, K., Tashiro, K., Watari, K., Izumi, H., Kage, M., Kuwano, M., Ono, M., and Hoshino, T.
  • Journal Title: Oncotarget Volume: (in press)
• [Journal Article] Circadian regulation of mTOR by the ubiquitin pathway in renal cell carcinoma (2014)
  • Author(s): Okazaki, H., Matsunaga, N., Fujioka, T., Okazaki, F., Akagawa, Y., Tsurudome, Y., Ono, M,. Kuwano, M., Koyanagi, S., and Ohdo, S.
  • Journal Title: Cancer Res. Volume: 74 Issue: 2 Pages: 543-551
  • DOI: 10.1158/0008-5472.can-12-3241
  • Peer Reviewed
• [Journal Article] Circadian regulation of mTOR by the ubiquitin pathway in renal cell carcinoma. (2014)
  • Author(s): Okazaki H, Matsunaga N, Fujioka T, Okazaki F, Akagawa Y, Tsurudome Y, Ono M, Kuwano M, Koyanagi S, and Ohdo S.
  • Journal Title: Cancer Res. Volume: 74 Pages: 543-551
  • Peer Reviewed
• [Journal Article] Nuclear Y-box-binding protein is a poor prognostic marker and related to epidermal growth factor receptor in uterine cervical cancer. (2014)
  • Author(s): Nishio S., Ushijima K., Yamaguchi T., Sasajima Y., Tsuda H., Kasamatsu T., Kage M., Ono M., Kuwano M., and Kamura T.
  • Journal Title: Gynecologic Oncology Volume: 132 Pages: 703-708
  • Peer Reviewed
• [Journal Article] Mutual regulation between Raf/MEK/ERK signaling and Y-box-binding protein-1 promotes prostate cancer progression (2013)
  • Author(s): Imada, K, Shiota, M., Kohashi, K., Kuroiwa, K., Song, Y., Sugimoto, M., Naito, S., Oda, Y.
  • Journal Title: Clin. Cancer Res. Volume: 19(17) Issue: 17 Pages: 4638-4650
  • DOI: 10.1158/1078-0432.ccr-12-3705
  • Peer Reviewed
• [Journal Article] Peroxiredoxins, thioredoxin, and Y-box-binding protein-1 are involved in the pathogenesis and progression of dialysis-associated renal cell carcinoma (2013)
  • Author(s): Fushimi F., Taguchi K., Izumi H., Kohno K., Kuwano M., Ono M., Nakashima Y., Takesue T., Naito S., Oda Y.
  • Journal Title: Virchows Archiv Volume: 463 Issue: 4 Pages: 553-562
  • DOI: 10.1007/s00428-013-1460-y
  • Peer Reviewed
• [Journal Article] Erlotinib resistance in lung cancer cells mediated by integrinβ1/Src/Akt-driven bypass signaling (2013)
  • Author(s): Kanda, R., Kage, M., Ono M, et al. 計12名
  • Journal Title: Cancer Res Volume: 73 Issue: 20 Pages: 6243-6253
  • DOI: 10.1158/0008-5472.can-12-4502
  • Peer Reviewed
• [Journal Article] N-myc downstream-regulated gene 1 promotes tumor inflammatory angiogenesis through JNK activation and autocrine loop of interleukin-1α by human gastric cancer cells (2013)
  • Author(s): Murakami, Y., Watari, K., Ono, M, et al. 計11名
  • Journal Title: J Biol Chem Volume: 288 Issue: 35 Pages: 25025-25037
  • DOI: 10.1074/jbc.m113.472068
  • Peer Reviewed
• [Journal Article] Y-box binding protein-1 (YB-1) contributes to both HER2/ErbB2 expression and lapatinib sensitivity in human gastric cancer cells. (2013)
  • Author(s): Shibata T, Kan H, Murakami Y, Ureshino H, Watari K, Kawahara A, Kage M, Hattori S, Ono M, Kuwano M.
  • Journal Title: Molecular cancer therapeutics Volume: 12 Issue: 5 Pages: 737-746
  • DOI: 10.1158/1535-7163.mct-12-1125
  • Peer Reviewed
• [Journal Article] Sorting nexin 2-mediated membrane trafficking of c-Met contributes to sensitivity of molecular targeted drugs (2013)
  • Author(s): Ogi, S., Fujita, H., Kashihara, M., Yamamoto, C., Sonoda, K., Okamoto, I., Nakagawa, K., Ohdo, S., Tanaka, Y., Kuwano, M., Ono, M.
  • Journal Title: Cancer Sci. Volume: 104 Issue: 5 Pages: 573-583
  • DOI: 10.1111/cas.12117
  • Peer Reviewed
• [Journal Article] Y-box binding protein-1 (YB-1) contributes to both HER2/ErbB2 expression and lapatinib sensitivity in human gastric cancer cells. (2013)
  • Author(s): Shibata, T., Kan, H., Murakami, Y., Ureshino, H., Watari, K., Kawahara, A., Kage, M., Hattori, S., Ono, M., and Kuwano, M.
  • Journal Title: Molec. Cancer Therapeut. Volume: 12 Pages: 737-746
  • Peer Reviewed
• [Journal Article] Erlotinib resistance in lung cancer cells mediated by integrinβ1/Src/Akt-driven bypass signaling. (2013)
  • Author(s): Kanda, R., Kawahara, A., Watari, K., Murakami, Y., Sonoda, K., Maeda, M., Fujita, H., Kage, M., Uramoto, H., Costa, C., Kuwano, M., and Ono, M.
  • Journal Title: Cancer Res. Volume: 73 Pages: 6243-6253
  • Peer Reviewed
• [Journal Article] N-myc downstream regulated gene 1 (NDRG1) promotes metastasis of human scirrhous gastric cancer cells through epithelial mesenchymal transition (2012)
  • Author(s): Ureshino, H., Kage, M., Ono, M, et al. 計12名
  • Journal Title: PLoS ONE Volume: 7 Issue: 7 Pages: e41312-e41312
  • DOI: 10.1371/journal.pone.0041312
  • Peer Reviewed
• [Journal Article] Loss of Activating EGFR Mutant Gene Contributes to Acquired Resistance to EGFR Tyrosine Kinase Inhibitors in Lung Cancer Cells (2012)
  • Author(s): Tabara K, Kanda R, Sonoda K, Kubo T, Murakami Y, Kawahara A, Azuma K, Abe H, Kage M, Yoshinaga A, Tahira T, Hayashi K, Arao T, Nishio K, Rosell R, Kuwano M, Ono M
  • Journal Title: PLoS One Volume: 7巻 Issue: 7 Pages: e41017-e41017
  • DOI: 10.1371/journal.pone.0041017
  • Peer Reviewed
• [Journal Article] NDRG1/Cap43/Drg-1 may predict tumor angiogenesis and poor outcome in patients with lung cancer (2012)
  • Author(s): Azuma, K., Kawahara, A., Hattori, S., Taira, T., Tsurutani, J., Watari, K., Shibata, T., Murakami, Y., Takamori, S., Ono, M., Izumi, H., Kage, M., Yanagawa, T., Nakagawa, K., Hoshino, T., Kuwano, M.
  • Journal Title: Journal of Thoracic Oncology Volume: (In press) Issue: 5 Pages: 779-789
  • DOI: 10.1097/jto.0b013e31824c92b4
  • Peer Reviewed
• [Journal Article] The antitumor effect of a novel angiogenesis inhibitor (an octahydronaphthalene derivative) targeting both VEGF receptor and NF-kB pathway (2012)
  • Author(s): Watari, K., Nakamura, M., Fukunaga, Y., Furuno, A., Shibata, T., Kawahara, A., Hosoi, F., Kuwano T., Kuwano, M., Ono, M.
  • Journal Title: International Journal of Cancer Volume: (In press) Issue: 2 Pages: 310-321
  • DOI: 10.1002/ijc.26356
  • Peer Reviewed
• [Journal Article] Association of the expression of mutant epidermal growth factor receptor protein as determined with mutation-specific antibodies in non-small cell lung cancer with progression-free survival after gefitinib treatment (2011)
  • Author(s): Azuma, K., Okamoto, I., Kawahara, A., Taira, T., Nakashima, K., Hattori. S., Kinoshita, T., Takeda, M., Nakagawa, K., Takamori, S., Kuwano, M., Ono, M., Kage, M.
  • Journal Title: Journal of Thoracic Oncology Volume: 6 Issue: 1 Pages: 122-127
  • DOI: 10.1097/jto.0b013e31822eeba2
  • Peer Reviewed
• [Presentation] Y-box binding protein-1(YB-1) activation may modify the responses to endocrine and HER2-targeted therapeutics in breast cancer (2014)
  • Author(s): Kuwano,M.,Shibata, T., Kawahara,A., Hattori,S., Watari, K.,Murakami,Y., Izumi,H., Kohno,K., Kage,M., Ono,M.
  • Organizer: 第12回日本臨床腫瘍学会学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2014-07-18
• [Presentation] Y-box binding protein-1 YB-1 negatively regulates ER<expression accompanying by enhanced HER2/ErbB2 expression in breast cancer (2014)
  • Author(s): Shibata,T., Izumi, H., Kawahara,A., Hattori, S., Fukumitsu, C., Takahashi, R., Watari, K., Murakami,Y., Kohno,K., Ito, K., Kage,M., Kuwano, M., Ono.M.
  • Organizer: AACR Annual Meeting 2014
  • Place of Presentation: San Diego, CA
• [Presentation] Overcoming drug resistance to gemcitabine in pancreas cancer cells by targeting activated PI3K/mTOR pathway (2014)
  • Author(s): Murakami, Y., Shinoda,A., Watari, K., Nabeshima, H., Kawahara, A., Nagayama, D., Naito, Y., Higaki, K., Inoue,M., Kuwano, M., Ono, M.
  • Organizer: AACR Annual Meeting 2014
  • Place of Presentation: San Diego, CA
• [Presentation] がん薬物治療の新しい創出とがん生物学-基礎研究者の立場から- (2013)
  • Author(s): 桑野信彦
  • Organizer: 第30回日本薬学会九州支部大会
  • Place of Presentation: 佐世保市(シンポジウム)
• [Presentation] Integrinβ1依存性バイパスシグナルによる肺癌のEGFR-TKI耐性獲得機序-Integrin beta1/Src/Akt-driven Bypass Signaling Pathway confers EGFR-TKI Resistance in Lung Cancer Cells (2013)
  • Author(s): 小野眞弓、神田利奈、渡公佑、園田佳保里、前田雅史、村上雄一、河原明彦、鹿毛政義、浦本秀隆、桑野信彦
  • Organizer: 第72回日本癌学会学術振興会
  • Place of Presentation: 横浜市(イングリッシュオーラルセッション)
• [Presentation] Y-box結合タンパク-1(YB-1)はヒト胃癌においてHER2/ErbB2発現とラパチニブの感受性を制御する (2013)
  • Author(s): 柴田智博、菅仁史、村上雄一、渡公佑、河原明彦、鹿毛政義、和泉弘人、桑野信彦、小野眞弓
  • Organizer: 第17回日本がん分子標的治療学会学術集会
  • Place of Presentation: 京都
• [Presentation] The Integrinβ1/Src/Akt-driven Bypass Signaling Pathway Contributes to Erlotinib Resistance in Lung Cancer. (2013)
  • Author(s): Mayumi Ono, Rina Kanda, Kosuke Watari, Akihiko Kawahara, Masayoshi Kage, Hidetaka Uramoto, Michihiko Kuwano.
  • Organizer: AACR Annual Meeting 2013
  • Place of Presentation: アメリカ、ワシントン
• [Presentation] Y-box結合タンパク-1(YB-1)はヒト胃癌においてHER2/ErbB2発現とラパチニブの感受性を制御する. (2013)
  • Author(s): 柴田智博、菅仁史、村上雄一、渡公佑、河原明彦、鹿毛政義、和泉弘人、桑野信彦、小野眞弓
  • Organizer: 第17回日本がん分子標的治療学会学術集会
  • Place of Presentation: 京都府
• [Presentation] がん血管新生はN-myc downstream regulated gene-1(NDRG1)によって特異的に制御される. (2013)
  • Author(s): 渡 公佑、柴田智博、村上雄一、桑野信彦、小野眞弓
  • Organizer: 第22回日本がん転移学会学術集会・総会
  • Place of Presentation: 長野県
• [Presentation] Integrinβ1依存性バイパスシグナルによる肺癌のEGFR-TKI耐性獲得機序－Integrinbeta1/Src/Akt-driven Bypass Signaling Pathway confers EGFR-TKI Resistance in Lung Cancer Cells. (2013)
  • Author(s): 小野眞弓、神田利奈、渡 公佑、園田佳保里、前田雅史、村上雄一、河原明彦、鹿毛政義、浦本秀隆、桑野信彦
  • Organizer: 第72回日本癌学会学術振興会
  • Place of Presentation: 神奈川県
• [Presentation] がん薬物治療の新しい創出とがん生物学－基礎研究者の立場から (2013)
  • Author(s): 桑野信彦
  • Organizer: 第30回 日本薬学会九州支部大会
  • Place of Presentation: 長崎県
  • Invited
• [Presentation] Y-box結合タンパク-1(YB-1)はヒト胃癌においてHER2/ErbB2発現とラパチニブの感受性を制御する. (2013)
  • Author(s): 柴田智博、菅仁史、村上雄一、渡公佑、河原明彦、鹿毛政義、和泉弘人、桑野信彦、小野眞弓．
  • Organizer: 第17回日本がん分子標的治療学会学術集会
  • Place of Presentation: 京都
• [Presentation] NDRG1は胃癌の血管新生をIL-1/AP-1を介して促進する―NDRG1 promotes tumor angiogenesis through interleukin-1 (IL-1)/AP-1 activation pathway in human gastric cancer cells (2012)
  • Author(s): 村上雄一、渡公佑、嬉野浩樹、河原明彦、鹿毛政義、桑野信彦、小野眞弓
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 北海道
  • Year and Date: 2012-09-20
• [Presentation] JSMO10周年記念企画わが国における臨床腫瘍学の歩みと今後の展望～JSMOの歴史と展望～ : 2)JSMO設立後10年の歩み:学術集会 (2012)
  • Author(s): 桑野信彦
  • Organizer: 第10回日本臨床腫瘍学会
  • Place of Presentation: 大阪(パネリスト)
  • Year and Date: 2012-07-26
• [Presentation] N-myc downstream regulated gene-1(NDRG1)はがん血管新生に重要な役割をはたす―NDRG1-deficient mice exhibit suppression of tumor angiogenesis and macrophage infiltration (2012)
  • Author(s): 渡公佑、柴田智博、村上雄一、桑野信彦、小野眞弓
  • Organizer: 第21回日本がん転移学会学術集会・総会
  • Place of Presentation: 広島(ワークショップ)
  • Year and Date: 2012-07-12
• [Presentation] Sorting nexin 2 (SNX2) controls drug sensitivity to molecular targeted anticancer agents through membrane trafficking of c-Met protein in cancer cell (2012)
  • Author(s): Ono, M., Ogi, S., Yamamoto,C., Fujita, H., Kuwano.M.
  • Organizer: AACR Annual Meeting 2012
  • Place of Presentation: Chicago, Illinois. USA
• [Presentation] Sorting nexin 2 (SNX2) controls drug sensitivity to molecular targeted anticancer agents through membrane trafficking of c-Met protein in cancer cell. (2012)
  • Author(s): Mayumi Ono, Sayaka Ogi, Chizuko Yamamoto, Hideaki Fujita, Michihiko Kuwano.
  • Organizer: AACR Annual Meeting 2012
  • Place of Presentation: アメリカ シカゴ
• [Presentation] ヒト肝細胞癌の悪性進展への上皮間葉系転換（EMT）の関与と新しい治療標的分子の探索 (2012)
  • Author(s): 野田正樹、渡 公佑、村上雄一、和泉弘人、荒尾徳三、西尾和人、桑野信彦、小野眞弓．
  • Organizer: 第16回（平成24年度）日本がん分子標的治療学会学術集会
  • Place of Presentation: 福岡
• [Presentation] N-myc downstream regulated gene-1（NDRG1）はがん血管新生に重要な役割をはたす (2012)
  • Author(s): 渡 公佑、柴田智博、河原明彦、村上雄一、鹿毛政義、桑野信彦、小野眞弓．
  • Organizer: 第16回（平成24年度）日本がん分子標的治療学会学術集会
  • Place of Presentation: 福岡
• [Presentation] N-myc downstream regulated gene-1 （NDRG1）はがん血管新生に重要な役割をはたす―NDRG1-deficient mice exhibit suppression of tumor angiogenesis and macrophage infiltration (2012)
  • Author(s): 渡 公佑、柴田智博、村上雄一、桑野信彦、小野眞弓．
  • Organizer: 第21回日本がん転移学会学術集会・総会
  • Place of Presentation: 広島
• [Presentation] JSMO10周年記念企画 わが国における臨床腫瘍学の歩みと今後の展望 ～JSMOの歴史と展望～：２）JSMO設立後10年の歩み：学術集会 (2012)
  • Author(s): 桑野信彦．
  • Organizer: 第10回日本臨床腫瘍学会
  • Place of Presentation: 大阪
  • Invited
• [Presentation] Interleukin-1 （IL-1）と下流シグナル活性化による肺癌のリンパ節転移亢進の機序と制御―Interleukin 1 promotes lymph node metastasis by lung cancer cells through modification of tumor stromal cells (2012)
  • Author(s): 柴田智博、渡 公佑、河原明彦、村上雄一、鍋島弘嗣、東 公一、鹿毛政義、向田直史、桑野信彦、高橋 隆、小野眞弓．
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 北海道
• [Presentation] 肺癌の活性化EGFR標的薬剤に対する新規耐性獲得メカニズム―A novel mechanism for acquired resistance to EGFR-TKI in human lung cancer: loss of activating mutant EGFR gene allele (2012)
  • Author(s): 神田利奈、村上雄一、河原明彦、東 公一、鹿毛政義、田平知子、桑野信彦、小野眞弓．
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 北海道