gene amplification

• Project/Area Number: 18K15248
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: University of Miyazaki (2020-2021); Kagoshima University (2018-2019)
• Principal Investigator: Minami Kentaro 宮崎大学, 医学部, 薬剤師 (20735956)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 遺伝子増幅 / 抗癌剤耐性 / 抗がん剤耐性 / 遺伝子増幅の減少 / タンパク質分解 / 増殖抑制 / 肺癌 / 腫瘍抑制因子

Outline of Final Research Achievements

Gene amplification is thought to be related to the breakage-fusion-bridge cycle, but the mechanism of development and maintenance are unclear.The purpose of this study was to analyze the mechanism of reduction of gene amplification by BHLHE41.When BHLHE41 is expressed, it takes 21 days for the amplified gene to decrease, and RNAseq analysis was performed to examine the genes changed during this period. In comparison between the day 0 and the day 2 of DOX treatment, where the gene for gene repair and replication had already changed on the day 2. Furthermore, the expression of these genes was higher on the day 28 than on the day 2. These results suggest that changes in these genes over a long period of time reduce gene amplification.

Academic Significance and Societal Importance of the Research Achievements

これまでに遺伝子増幅を持つ細胞にBHLHE41が発現すると遺伝子増幅が減少することを明らかにしている。
BHLHE41の発現初期から遺伝子増幅が減少する間に遺伝子修復や複製に関わる遺伝子が変化していたことから長期的にそれら遺伝子が変化し続けることで遺伝子増幅が減少することが示唆された。BHLHE41の発現制御メカニズムもメチル化やタンパク質分解が関わっていることを明らかした。遺伝子増幅の減少メカニズムやBHLHE41の制御分子がわかれば癌治療だけでなく他の疾患にも応用ができることが考えられる。

Research Products

• [Journal Article] Development of a highly sensitive method for the quantitative analysis of modified nucleosides using UHPLC-UniSpray-MS/MS (2021)
  • Author(s): Kogaki T, Ohshio I, Ura H, Iyama S, Kitae K, Morie T, Fujii S, Sato S, Nagata T, Takeda AH, Aoki M, Ueda K, Minami K, Yamamoto M, Kawahara K, Furukawa T, Sato M, Ueda Y, Jingushi K, Tozuka Z, Saigusa D, Hase H, Tsujikawa K.
  • Journal Title: J Pharm Biomed Anal. Volume: 197 Pages: 113943-113954
  • DOI: 10.1016/j.jpba.2021.113943
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ALKBH4 promotes tumourigenesis with a poor prognosis in non-small-cell lung cancer. (2021)
  • Author(s): Kentaro Jingushi,Masaya Aoki,Kazuhiro Ueda,Takahiro Kogaki,Masaya Tanimoto,Yuya Monoe,Masayuki Ando,Takuya Matsumoto,Kentaro Minami,Yuko Ueda,Kaori Kitae,Hiroaki Hase,Toshiyuki Nagata,Aya Harada-Takeda,Masatatsu Yamamoto,Kohichi Kawahara,Kazuhiro Tabata,Tatsuhiko Furukawa,Masami Sato,Kazutake Tsujikawa
  • Journal Title: Scientific reports Volume: 11 Issue: 1 Pages: 8677-8677
  • DOI: 10.1038/s41598-021-87763-1
  • Peer Reviewed / Open Access
• [Journal Article] BHLHE41/DEC2 Expression Induces Autophagic Cell Death in Lung Cancer Cells and Is Associated with Favorable Prognosis for Patients with Lung Adenocarcinoma. (2021)
  • Author(s): Toshiyuki Nagata, Kentaro Minami, Masatatsu Yamamoto, Tsubasa Hiraki, Masashi Idogawa, Katsumi Fujimoto, Shun Kageyama, Kazuhiro Tabata, Kohichi Kawahara, Kazuhiro Ueda, Ryuji Ikeda, Yukio Kato, Masaaki Komatsu, Akihide Tanimoto, Tatsuhiko Furukawa, Masami Sato
  • Journal Title: International journal of molecular sciences Volume: 22 Issue: 21 Pages: 11509-11509
  • DOI: 10.3390/ijms222111509
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cancer type SLCO1B3 promotes epithelial mesenchymal transition resulting in the tumour progression of non small cell lung cancer. (2021)
  • Author(s): Hase H, Aoki M, Matsumoto K, Nakai S, Nagata T, Takeda A, Ueda K, Minami K, Kitae K, Jingushi K, Ueda Y, Yamamoto M, Furukawa T, Sato M, Tsujikawa K.
  • Journal Title: Oncol Report Volume: 45 Issue: 1 Pages: 309-316
  • DOI: 10.3892/or.2020.7839
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Combination of hydroxyurea and tranilast suppresses gemcitabine resistance induced by ribonucleotide reductase M1 in gemcitabine-resistant cells (2020)
  • Author(s): Shinagawa N, Minami K, Ishida T, Hijioka H, Yamamoto M, Kawahara K, Furukawa T, Nakamura N
  • Journal Title: Oral Sci Int Volume: - Issue: 3 Pages: 1-9
  • DOI: 10.1002/osi2.1096
  • Peer Reviewed / Open Access
• [Journal Article] FARP1 boosts CDC42 activity from integrin αvβ5 signaling and correlates with poor prognosis of advanced gastric cancer (2020)
  • Author(s): Hirano T, Shinsato Y, Tanabe K, Higa N, Kamil M, Kawahara K, Yamamoto M, Minami K, Shimokawa M, Arigami T, Yanagita S, Matushita D, Uenosono Y, Ishigami S, Kijima Y, Maemura K, Kitazono I, Tanimoto A, Furukawa T, Natsugoe S
  • Journal Title: Oncogenesis Volume: 9 Issue: 2 Pages: 13-13
  • DOI: 10.1038/s41389-020-0190-7
  • Peer Reviewed / Open Access
• [Journal Article] Formin-like 1 (FMNL1) Is Associated with Glioblastoma Multiforme Mesenchymal Subtype and Independently Predicts Poor Prognosis (2019)
  • Author(s): Higa N, Shinsato Y, Kamil M, Hirano T, Takajo T, Shimokawa M, Minami K, Yamamoto M, Kawahara K, Yonezawa H, Hirano H, Furukawa T, Yoshimoto K, Arita K
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 24 Pages: 6355-6355
  • DOI: 10.3390/ijms20246355
  • Peer Reviewed / Open Access
• [Journal Article] 5-Aza-2-deoxycytidine Enhances the Sensitivity of 5-Fluorouracil by Demethylation of the Thymidine Phosphorylase Promoter (2019)
  • Author(s): Nishizawa Y, Ikeda R, Yamamoto M, Kawahara K, Shinsato Y, Minami K, Nitta M, Terazono H, Akiyama SI, Furukawa T, Takeda Y
  • Journal Title: Anticancer Research Volume: 39 Issue: 8 Pages: 4129-4136
  • DOI: 10.21873/anticanres.13571
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MicroRNA-130b functions as an oncomiRNA in non-small cell lung cancer by targeting tissue inhibitor of metalloproteinase-2 (2019)
  • Author(s): Hirono T, Jingushi K, Nagata T, Sato M, Minami K, Aoki M, Takeda AH, Umehara T, Egawa H, Nakatsuji Y, Kitae K, Ueda Y, Hase H, Yamamoto M, Shinsato Y, Kawahara K, Furukawa T, Tsujikawa K.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 6956-6956
  • DOI: 10.1038/s41598-019-43355-8
  • Peer Reviewed / Open Access
• [Journal Article] High filamin-C expression predicts enhanced invasiveness and poor outcome in glioblastoma multiforme (2019)
  • Author(s): Kamil M, Shinsato Y, Higa N, Hirano T, Idogawa M, Takajo T, Minami K, Shimokawa M, Yamamoto M, Kawahara K, Yonezawa H, Hirano H, Furukawa T, Yoshimoto K, Arita K.
  • Journal Title: Br J Cancer Volume: 120 Issue: 8 Pages: 819-826
  • DOI: 10.1038/s41416-019-0413-x
  • Peer Reviewed / Open Access
• [Journal Article] Thymidine catabolism promotes NADPH oxidase-derived reactive oxygen species (ROS) signalling in KB and yumoto cells (2018)
  • Author(s): Tabata S, Yamamoto M, Goto H, Hirayama A, Ohishi M, Kuramoto T, Mitsuhashi A, Ikeda R, Haraguchi M, Kawahara K, Shinsato Y, Minami K, Saijo A, Toyoda Y, Hanibuchi M, Nishioka Y, Sone S, Esumi H, Tomita M, Soga T, Furukawa T, Akiyama SI.
  • Journal Title: Sci Rep. Volume: 8 Issue: 1 Pages: 6760-6760
  • DOI: 10.1038/s41598-018-25189-y
  • NAID: 120006875668
  • Peer Reviewed / Open Access
• [Journal Article] Thymidine phosphorylase in cancer aggressiveness and chemoresistance (2018)
  • Author(s): Furukawa T, Tabata S, Yamamoto M, Kawahara K, Shinsato Y, Minami K, Shimokawa M, Akiyama SI.
  • Journal Title: Pharmacological Research Volume: 28 Pages: 15-20
  • DOI: 10.1016/j.phrs.2018.03.019
  • Peer Reviewed / Open Access
• [Presentation] Integrin β5 inhibitor can suppress gastric cancer cell invasiveness through Integrinβ5-FARP1-CDC42 cascade (2022)
  • Author(s): 古川龍彦、南謙太朗、河原康一、山本雅達
  • Organizer: 第95回 日本薬理学会年会
• [Presentation] FARP1はインテグリンαvβ5によるCDC42の活性化に関わり、進行胃がんの予後に関わる (2021)
  • Author(s): 古川龍彦、河原康一、南謙太朗
  • Organizer: 第25回 日本がん分子標的治療学会学術集会
• [Presentation] オートファジー誘導分子DEC2 によるアポトーシス誘導因子BAXの発現抑制 (2021)
  • Author(s): 坂本洸大、山本雅達、南謙太朗、古川龍彦、河原康一、武井孝行、吉田昌弘
  • Organizer: 第58回 化学関連支部合同九州大会
• [Presentation] FARP1 binds with integrinavb5 and FARP1 expression is correlate to poor prognoses of advanced gastric cancer patients (2021)
  • Author(s): 古川龍彦、南 謙太朗、山本雅達、河原康一
  • Organizer: 第80回 日本癌学会学術総会
• [Presentation] BHLHE41 a prognositic factor of lung adenocarcinoma, can (2020)
  • Author(s): 古川 龍彦、南 謙太朗、山本 雅達、河原 康一、新里 能成
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] BHLHE41/DEC2によって遺伝子増幅は減少する (2019)
  • Author(s): 南謙太朗、山本雅達、中岡博史、落合博、下川倫子、河原康一、井ノ上逸朗、古川龍彦
  • Organizer: 第42回日本分子生物学会
• [Presentation] 遺伝子増幅を制御する分子による抗癌剤耐性の克服 (2019)
  • Author(s): 南謙太朗、中岡博史、山本雅達、新里能成、河原康一、井ノ上逸朗、古川龍彦
  • Organizer: 第11回トランスポーター研究会九州部会
• [Presentation] DEC2は肺腺癌においてオートファジー細胞死を誘導する (2019)
  • Author(s): 南 謙太朗, 山本 雅達, 新里 能成, 河原 康一, 佐藤 雅美, 古川 龍彦
  • Organizer: 第78回日本癌学会
• [Presentation] Degradation of tumor suppressor BHLHE41 by ubiquitin-proteasome pathway (2018)
  • Author(s): Kentaro Minami, Ikuko Watanabe, Toshiyuki Nagata, Masatatsu Yamamoto, Yoshinari Shinsato, Kouichi Kawahara, Kazumasa Sekihara,Masumi Sato Tatsuhiko Furukawa
  • Organizer: The 41st Annual meeting of the molecular biology society of japan
• [Presentation] 腫瘍抑制因子DEC2のユビキチン・プロテアソーム系による発現制御 (2018)
  • Author(s): 渡邊いく子、南謙太朗、永田俊行、山本雅達、新里能成、河原康一、下川倫子、佐藤雅美、古川龍彦
  • Organizer: 第71回 日本薬理学会 西南部会
• [Presentation] Degradation of tumor suppressor BHLHE41 by ubiquitin-proteasome pathway (2018)
  • Author(s): Kentaro Minami, Masatatsu Yamamoto, Yoshinari Shinsato, Kouichi Kawahara, Kazumasa Sekihara,Masumi Sato Tatsuhiko Furukawa
  • Organizer: The 77th Annual meeting of the Japanese cancer association