Approach to regulatory mechanism of copy number variation the gene amplified.
| Project/Area Number |
19K22566
|
|---|
| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
|
| Allocation Type | Multi-year Fund |
|---|
| Review Section |
Medium-sized Section 50:Oncology and related fields
|
|---|
| Research Institution | Kagoshima University |
|---|
Principal Investigator |
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
南 謙太朗 鹿児島大学, 医歯学総合研究科, 特任研究員 (20735956)
大槻 純男 熊本大学, 大学院生命科学研究部(薬), 教授 (60323036)
落合 博 広島大学, 統合生命科学研究科(理), 准教授 (60640753)
中岡 博史 公益財団法人佐々木研究所, 附属研究所, 部長(移行) (70611193)
|
|---|
| Project Period (FY) |
2019-06-28 – 2022-03-31
|
| Project Status |
Completed (Fiscal Year 2021)
|
| Budget Amount *help |
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2020: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2019: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
|
|---|
| Keywords | 遺伝子増幅 / BHLHE41 / 抗がん剤耐性 / ゲノム不安定性 / BAX / オートファジ― / コピー数変化 / ゲノム / オートファジー / がん抑制遺伝子 / 細胞死 / 肺がん / コピー数 / 薬剤耐性 |
|---|
| Outline of Research at the Start |
がん細胞では特定の遺伝子領域が増える遺伝子増幅という現象が知られている。正常なゲノムでも遺伝子のコピー数の変異(CNV)が12000程度が知られており、CNVは遺伝子多型の一種と考えられるが、悪性腫瘍での異常なコピー数の増加は正常細胞ではみられず監視機構の存在が想像される。
我々が単離した抗がん剤ゲムシタビン(GEM)耐性細胞では特定の遺伝子が増幅して耐性化している。BHLHE41をこの細胞に発現させるとRRM1のコピー数が減少して、GEM耐性が減弱した。
増幅ゲノムに結合する分子群とBHLHE41で誘導される分子群について調べて遺伝子のコピー数を制限する分子機構について解明する。
|
| Outline of Final Research Achievements |
Gene amplification is an abnormality in which the copy numbers of genomic genes highly increase in cancer cells. We found that expression of BHLHE41 suppresses gene amplification of the causative molecule of three drug-resistant cell lines. We analyzed genome changes in the copy number reduction of RRM1 gene by BHLHE41 using state-of-the-art NGS for whole genome sequence and genomic 3D structural changes. From the study on surgical resected lung cancer samples, BHLHE41 protein was expressed only in non-invasive lung cancer cells and was associated with a better prognosis of lung adenocarcinoma patients. BHLHE41 suppressed expression of the apoptosis-inducing molecule BAX, induced autophagic cell death, and also inhibited MYC oncogene-induced expression of several genes.
|
| Academic Significance and Societal Importance of the Research Achievements |
遺伝子増幅は発がんや薬剤耐性の原因であるが、その発生機構は不明である。BHLHE41の発現が遺伝子増幅の程度を減少させることから、BHLHE41の機能を知ることでゲノムの恒常性維持の機構への理解が深まり、増幅遺伝子を減少させる新たな癌治療の可能性が開かれる。肺がん細胞での検討からはBHLHE41の発現は肺がん細胞にオートファジー細胞死を誘導して抗腫瘍作用を持つと考えられる。現在がん遺伝子MYCを標的とするがん治療は確立していないが、BHLHE41はMYCが誘導する遺伝子を発現を抑制するので、BHLHE41の研究はMYCの抑制を介した治療の発展に端緒となることが期待される。
|
Report
(3 results)
Research Products
(12 results)
-
[Journal Article] Development of a highly sensitive method for the quantitative analysis of modified nucleosides using UHPLC-UniSpray-MS/MS2021
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
Related Report
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
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
-
[Journal Article] Involvement of ribosomal protein L11 expression in sensitivity of gastric cancer against 5?FU2020
Author(s)
Kawahata T, Kawahara K, Shimokawa M, Sakiyama A, Shiraishi T, Minami K, Yamamoto M, Shinsato Y, Arima K, Hamada T, Furukawa T.
-
Journal Title
Oncology Letters
Volume: 19
Pages: 2258-2264
DOI
Related Report
Peer Reviewed / Open Access
-
[Journal Article] FARP1 boosts CDC42 activity from integrin αvβ5 signaling and correlates with poor prognosis of advanced gastric cancer2020
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
Related Report
Peer Reviewed / Open Access
-
[Journal Article] Formin-like 1 (FMNL1) Is Associated with Glioblastoma Multiforme Mesenchymal Subtype and Independently Predicts Poor Prognosis2019
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
Related Report
Peer Reviewed / Open Access
-
[Journal Article] 5-Aza-2-deoxycytidine Enhances the Sensitivity of 5-Fluorouracil by Demethylation of the Thymidine Phosphorylase Promoter2019
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
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
-
[Journal Article] Oral aversion to dietary sugar, ethanol and glycerol correlates with alterations in specific hepatic metabolites in a mouse model of human citrin deficiency.2017
Author(s)
Saheki T, Inoue K, Ono H, Fujimoto Y, Furuie S, Yamamura KI, Kuroda E, Ushikai M, Asakawa A, Inui A, Eto K, Kadowaki T, Moriyama M, Sinasac DS, Yamamoto T, Furukawa T, Kobayashi K.
-
Journal Title
Molecular Genetics and Metabolism
Volume: 120
Issue: 4
Pages: 306-316
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
-
-
-
-
-
