Involvement of Akt/mTOR in lung cancer and design of novel therapy targeting them

• Project/Area Number: 26460438
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Jichi Medical University
• Principal Investigator: DOBASHI Yoh 自治医科大学, 医学部, 准教授 (90231456)
• Co-Investigator(Kenkyū-buntansha): 北川 雅敏 浜松医科大学, 医学部, 教授 (50294971) ; 坪地 宏嘉 自治医科大学, 医学部, 教授 (50406055) ; 後藤 明輝 秋田大学, 医学(系)研究科(研究院), 教授 (90317090)
• Co-Investigator(Renkei-kenkyūsha): OOI Akishi 金沢大学, 医学部, 教授 (50160411) ; SUGIMURA Haruhiko 浜松医科大学, 医学部, 教授 (00196742) ; MATSUBARA Hirochika 山梨大学, 医学部, 講師 (00374166)
• Project Period (FY): 2014-04-01 – 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 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 肺癌 / Akt / 遺伝子増幅 / microRNA / p27 / MLPA / Ubiquitin ligase / 細胞周期制御因子 / ubiquitin ligase / Pirh2 / 遺伝子多型

Outline of Final Research Achievements

We analyzed the involvement of Akt in lung carcinomas. Results were, i) Microarray analysis revealed 28 miRNAs upregulated in AKT1 or AKT2-amplified carcinomas, including miR-200. Carcinomas with lymph vessel invasion had lower expression of miR-200a/b and in adenocarcinoma and in the early carcinomas, miR-200a was higher in AKT2-amplified group. MiR-200a was significantly correlated with the expression of its target, EphA. ii) Expressions of p27 and ubiquitin ligase Skp2, KPC and Pirh2 were analyzed. Cytoplasmic p27 was correlated with nodal metastasis and, inverse correlation between nuclear-p27 and Pirh2 was observed. Moreover, Pirh2 was correlated with Stage and overall survival. iii) We performed multiplex ligation-dependent probe amplification (MLPA) analysis with fluorescence in situ hybridization analysis and immunohistochemistry. By placing modified cutoff values, cases containing fewer cancer cells with gene increase could be picked up by MLPA using custom-made probes.

Research Products

• [Journal Article] Gene amplification of CCNE1, CCND1, and CDK6 in gastric cancers detected by multiplex ligation-dependent probe amplification and fluorescence in situ hybridization. (2017)
  • Author(s): Ooi A et al.
  • Journal Title: Hum Pathol. Volume: 61 Pages: 58-67
  • DOI: 10.1016/j.humpath.2016.10.025
  • NAID: 120006226784
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Regulation of p27 by ubiquitin ligases and its pathological significance in human lung carcinomas. (2017)
  • Author(s): Dobashi Y, Tsubochi H, Minegishi K, Kitagawa M, Otani S, Ooi A.
  • Journal Title: Hum Pathol. Volume: 66 Pages: 67-68
  • DOI: 10.1016/j.humpath.2017.05.022
  • Peer Reviewed / Open Access
• [Journal Article] Loss of YAP1 Defines Neuroendocrine Differentiation of Lung Tumors. (2017)
  • Author(s): Ito T, Matsubara D, Tanaka I, Makiya K, Tanei ZI, Kumagai Y, Shiu SJ, Nakaoka HJ, Ishikawa S, Isagawa T, Morikawa T, Shinozaki-Ushiku A, Goto Y, Nakano T, Tsuchiya T, Tsubochi H, Komura D, Aburatani H, Dobashi Y, Nakajima J, Endo S, Fukayama M, Sekido Y, Niki T, Murakami Y.
  • Journal Title: Can Sci. Volume: 107 Pages: 1527-1538
  • DOI: 10.1111/cas.13013
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] MicroRNAs associated with increased AKT gene number in human lung carcinoma (2017)
  • Author(s): Goto A, Dobashi Y, Tsubochi H, Maeda D, Ooi A
  • Journal Title: Hum Pathol. Volume: 印刷中 Pages: 1-10
  • DOI: 10.1016/j.humpath.2016.04.011
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Regulation of p27 by ubiquitin ligases and its pathological significance in human lung carcinomas. (2017)
  • Author(s): Dobashi. Y., Tsubochi, H. Minegishi, K., Kitagawa, M., Otani, S. and Ooi, A.
  • Journal Title: Hum Pathol. Volume: 印刷中
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A case of severe uterine bleeding postpartum following manual removal of placenta increta. (2016)
  • Author(s): Chikazawa, K., Akashi, K., Gomi, Y., Tachibana, K., Horiuchi, I., Dobashi, Y., Okochi, T., Hamamoto, K., Tanno, K. and Takagi K.
  • Journal Title: Taiwan J Obst. Gynecol. Volume: 55 Pages: 913-4
  • DOI: 10.1016/j.tjog.2015.09.008
  • Peer Reviewed
• [Journal Article] Fluorescent and chromogenic in situ hybridization of CEN17q as a potent useful diagnostic marker for Birt-Hogg-Dube syndrome-associated chromophobe renal cell carcinomas. (2016)
  • Author(s): Sasahira T, Ueda N, Kurihara M, Matsushima S, Ohmori H, Fujii K, Bhawal UK, Yamamoto K, Kirita T, Kuniyasu H
  • Journal Title: Hum Pathol. Volume: in press Pages: 127-136
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Semi-comprehensive analysis of gene amplification in gastric cancers using multiplex ligation-dependent probe amplification and fluorescence in situ hybridization. (2015)
  • Author(s): Ooi A, Oyama T, Nakamura R, Tajiri R, Ikeda H, Fushida Y, Nakamura H, Dobashi Y.
  • Journal Title: Mod Pathol Volume: in press Pages: 861-871
  • DOI: 10.1038/modpathol.2015.33
  • NAID: 120005593968
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Diverse involvement of isoforms and gene aberrations of Akt in human lung carcinomas. (2015)
  • Author(s): Dobashi Y, Tsubochi H, Matsubara H, Inoue J, Inazawa J, Endo S, Ooi A
  • Journal Title: Cancer Science Volume: - Pages: 772-781
  • DOI: 10.1111/cas.12669
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Association between AKT1 Gene Polymorphism rs2498794 and Smoking-Related Traits with reference to Cancer Susceptibility. (2015)
  • Author(s): Nishizawa, D., Kasai, S., Hasegawa, J., Sato，N., Tanioka, F., Sugimura, H., Ikeda, K. and Dobashi, Y.
  • Journal Title: Biomed Res Int. Volume: 2015.94. Pages: 316829-316829
  • DOI: 10.1155/2015/316829
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Epidemiological and pathobiological profiles of clostridium perfringens infections: review of consecutive series of 33 cases over a 13-year period. (2015)
  • Author(s): Shindo, Y., Dobashi, Y., Sakai, T., Monma, C., Miyatani, H., Yoshida, Y.
  • Journal Title: Int J Clin Exp Pathol. Volume: 8 Pages: 569-77
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Intratumoral heterogeneous amplification of ERBB2 and subclonal genetic diversity in gastric cancers revealed by multiple ligation-dependent probe amplification and fluorescence in situ hybridization (2014)
  • Author(s): Tajiri. R., Ooi. A., Fujimura, T., Dobashi, Y., Oyama, T., Nakamura, R. and Ikeda, H.
  • Journal Title: Hum. Pathol Volume: 45(4) Pages: 725-34
  • DOI: 10.1016/j.humpath.2013.11.004
  • NAID: 120005440337
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Genetic aberrations as the targets of oncology research: Involvement of paraffin-embedded tissues. (2014)
  • Author(s): Dobashi. Y., Goto. A., Endo, T., and Ooi, A.
  • Journal Title: Histol. Histopathol. Volume: 29 Pages: 191-205
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Clonal profiling of mixed lobular and ductal carcinoma revealed by multiplex ligation-dependent probe amplification and fluorescence in situ hybridization. (2014)
  • Author(s): Tajiri, R., Inokuchi, M., Sawada-Kitamura, S., Kawashima, H., Nakamura, R., Oyama, T., Dobashi, Y., Ooi, A.
  • Journal Title: Pathol. Int. Volume: 64 Pages: 231-6
  • NAID: 120005463366
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Solitary fibrous tumor of the thymus with variegated epithelial components. (2014)
  • Author(s): Tsubochi, H., Endo, T., Sogabe, M., Endo, S., Morinaga, S. and Dobashi, Y.
  • Journal Title: Int J Clin Exp Pathol. Volume: 7 Pages: 7477-84
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] MLPA とFISH を用いた乳癌における遺伝子増幅の準網羅的検索 (2017)
  • Author(s): 大井 章史、中村 律子、尾山 武、池田 博子、土橋 洋
  • Organizer: 第106回日本病理学会総会
  • Place of Presentation: 東京
  • Year and Date: 2017-04-28
• [Presentation] 肺癌でAKT 遺伝子増幅に伴い変動するmicroRNA とそのターゲット (2017)
  • Author(s): 土橋 洋、後藤 明輝、松原 大祐、椙村 春彦、大井 章史
  • Organizer: 第106回日本病理学会総会
  • Place of Presentation: 東京
  • Year and Date: 2017-04-27
• [Presentation] 肺癌でAKT 遺伝子増幅に伴い変動するmicroRNA とそのターゲット (2017)
  • Author(s): 土橋 洋、後藤 明輝、椙村 春彦、大井 章史
  • Organizer: 第106回日本病理学会総会
• [Presentation] 癌におけるMLPとFISH法によるCCNDE1, CCND1, CDK6 遺伝子増幅の解析 (2017)
  • Author(s): 大井 章史、尾山 武、中村 律子、土橋 洋
  • Organizer: 第106回日本病理学会総会
• [Presentation] Gene amplification of CCNDE1, CCND1 and CDK6 in gastric cancers detected by MLPA and FISH. (2016)
  • Author(s): 大井 章史、尾山 武、中村 律子、土橋 洋
  • Organizer: 第75回日本癌学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] 胃癌におけるサイクリンE, D1, CDK6増幅のMLPAおよびFISHによる検索. (2016)
  • Author(s): 大井 章史、田尻 亮輔、中村 律子、尾山 武、池田 博子、土橋 洋.
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台
  • Year and Date: 2016-05-14
• [Presentation] 胃癌におけるサイクリンE, D1, CDK6増幅のMLPAおよびFISHによる検索 (2016)
  • Author(s): 大井 章史、田尻 亮輔、中村 律子、尾山 武、池田 博子、土橋 洋
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台
  • Year and Date: 2016-05-14
• [Presentation] ヒト肺癌における細胞周期抑制因子p27の3種ubiquitin ligaseによる制御. (2016)
  • Author(s): 土橋 洋、後藤 明輝、山田 茂樹、大井 章史.
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台
  • Year and Date: 2016-05-12
• [Presentation] ヒト肺癌における細胞周期抑制因子p27の3種ubiquitin ligaseによる制御 (2016)
  • Author(s): 土橋 洋、後藤 明輝、山田 茂樹、大井 章史.
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台
  • Year and Date: 2016-05-12
• [Presentation] 肺癌におけるYAP1欠如と神経内分泌分化について (2015)
  • Author(s): 松原 大祐、伊東 剛、田中 一大、石川 俊平、後藤 悌、中野 智 之、土橋 洋、中島 淳、遠藤 俊輔、深山 正久、関戸 好孝、仁 木 利郎、村上 善則.
  • Organizer: 第74回日本癌学会総会
  • Place of Presentation: 名古屋名古屋
  • Year and Date: 2015-10-09
• [Presentation] AKT increase and associated change in microRNA expression in human lung carcinomas (2015)
  • Author(s): 土橋 洋、後藤 明輝、井上 純、稲澤 譲治、大井 章史
  • Organizer: 第74回日本癌学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] 肺癌でAKT遺伝子増幅に伴い変動するmicroRNAとその意義. (2015)
  • Author(s): 土橋 洋、椙村 春彦、山田 茂樹、大井 章史.
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-05-02
• [Presentation] ＭLPAとFISHを用いた進行胃癌における遺伝子増幅の準網羅的検索 (2015)
  • Author(s): 大井 章史、尾山 武、中村 律子、田尻 亮輔、池田 博子、土橋 洋
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-05-01
• [Presentation] Significance of Akt activation and AKT gene increases in bone and soft tissue tumors. (2014)
  • Author(s): 土橋 洋、坪地 宏嘉、井上 純、大井 章史.
  • Organizer: 第 73回日本癌学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25
• [Presentation] ＭLPAとFISHを用いた胃癌における増幅遺伝子の準網羅的検索. (2014)
  • Author(s): 大井 章史、田尻 亮輔、尾山 武、中村 律子、土橋 洋.
  • Organizer: 第 73回日本癌学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25
• [Presentation] ヒト肺癌におけるAKT 遺伝子、蛋白質の異常とその意義. (2014)
  • Author(s): 土橋 洋、椙村 春彦、山田 茂樹、大井 章史.
  • Organizer: 第 103回日本病理学会総会
  • Place of Presentation: 広島
  • Year and Date: 2014-04-24
• [Presentation] MLPAとFISHを用いた胃癌における遺伝子増幅の準網羅的検索. (2014)
  • Author(s): 大井 章史、田尻 亮輔、中村 律子、尾山 武、池田 博子、土橋 洋.
  • Organizer: 第 103回日本病理学会総会
  • Place of Presentation: 広島
  • Year and Date: 2014-04-24
• [Book] 細胞傷害と細胞増殖. シンプル病理学(第7版) (2015)
  • Author(s): 土橋 洋 (笹野 公伸, 岡田 保, 安井 弥編)
  • Total Pages: 15
  • Publisher: 南江堂