Elucidation of mechanisms of metastatic ability and therapeutic resistance and development of novel therapeutic methods

• Project/Area Number: 18K08626
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Kagoshima University
• Principal Investigator: KURAHARA HIROSHI 鹿児島大学, 医歯学域医学系, 准教授 (70464469)
• Co-Investigator(Kenkyū-buntansha): 又木 雄弘 鹿児島大学, 鹿児島大学病院, 特任講師 (10444902) ; 前村 公成 鹿児島大学, 医歯学域医学系, 准教授 (30398292) ; 新地 洋之 鹿児島大学, 医歯学域医学系, 教授 (60284874) ; 夏越 祥次 鹿児島大学, 医歯学域医学系, 教授 (70237577)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: 網羅的スクリーニング / 癌遺伝子 / microRNA / EUS-FNA / 術前治療 / 化学放射線療法 / 再発 / shRNA

Outline of Final Research Achievements

We analyzed the RNA sequence-based microRNA (miRNA) signature of pancreatic ductal adenocarcinoma (PDAC) and identified multiple tumor-suppressive miRNA (miR-148a, miR-124-3p, miR-130-5p miR-204-5p, and miR-30c-5p) and their target genes (PHLA2, ITGA2, ITGB1, EPS8, RACGAP1, and TOP2A). Through network analysis of the RNA, we revealed a part of mechanism of tumor progression and acquisition of resistance to treatment which are intricately controlled.
We evaluated the levels of serum CA 19-9 and expression of several molecules (GLUT-1, p53 and PDGFR-β) in protein level, which are related to metastasis and resistance to treatment, using pretreatment specimens obtained by EUS-FNA. We demonstrated that these factors may be useful to select optimal therapeutic strategy for PDAC.

Academic Significance and Societal Importance of the Research Achievements

進行速度が速く，治療抵抗性が高い膵癌の治療成績を向上させるためには新規治療法および集学的な治療戦略の開発が急務である．我々は膵癌組織を用いた網羅的microRNAスクリーニングにより，複数の癌抑制性microRNAとそのターゲット遺伝子を同定した．それらを用いたネットワーク解析により，複雑にコントロールされた膵癌の進展や治療抵抗性獲得の一端を明らかにしたことで，膵癌に対する新規治療法の開発につながると思われる．
治療前の生検検体を用いて各種治療法（化学療法や放射線治療）に対する抵抗性や転移能を評価することにより最適な治療戦略の構築が可能になると思われる．

Research Products

• [Journal Article] Effectiveness of Adjuvant Therapy in Patients with Pancreatic Cancer Who Underwent Neoadjuvant Therapy (2021)
  • Author(s): Kurahara H, Mataki Y, Idichi T, Iino S, Kawasaki Y, Arigami T, Mori S, Sasaki K, Shinchi H, Ohtsuka T.
  • Journal Title: Annals of Surgical Oncology Volume: Feb 19 Issue: 11 Pages: 6238-6245
  • DOI: 10.1245/s10434-021-09712-6
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Molecular Pathogenesis of Pancreatic Ductal Adenocarcinoma: Impact of miR-30c-5p and miR-30c-2-3p Regulation on Oncogenic Genes. (2020)
  • Author(s): Tanaka T, Okada R, Hozaka Y, Wada M, Moriya S, Satake S, Idichi T, Kurahara H, Ohtsuka T, Seki N.
  • Journal Title: Cancers Volume: 12 Issue: 10 Pages: 2731-2731
  • DOI: 10.3390/cancers12102731
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lung recurrence and its therapeutic strategy in patients with pancreatic cancer (2020)
  • Author(s): Kurahara Hiroshi、Maemura Kosei、Mataki Yuko、Tanoue Kiyonori、Iino Satoshi、Kawasaki Yota、Idichi Tetsuya、Arigami Takaaki、Mori Shinichiro、Shinden Yoshiaki、Higashi Michiyo、Ueno Shinichi、Shinchi Hiroyuki、Natsugoe Shoji
  • Journal Title: Pancreatology Volume: 20 Issue: 1 Pages: 89-94
  • DOI: 10.1016/j.pan.2019.11.015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Significance of 18F-Fluorodeoxyglucose (FDG) Uptake in Response to Chemoradiotherapy for Pancreatic Cancer (2019)
  • Author(s): Kurahara H, Maemura K, Mataki Y, Sakoda M, Iino S, Kawasaki Y, Arigami T, Mori S, Kijima Y, Ueno S, Shinchi H, Natsugoe S
  • Journal Title: Ann Surg Oncol Volume: 26 Issue: 2 Pages: 644-651
  • DOI: 10.1245/s10434-018-07098-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gene regulation by antitumor miR-130b-5p in pancreatic ductal adenocarcinoma: the clinical significance of oncogenic EPS8. (2019)
  • Author(s): Fukuhisa H, Seki N, Idichi T, Kurahara H, Yamada Y, Toda H, Kita Y, Kawasaki Y, Tanoue K, Mataki Y, Maemura K, Natsugoe S.
  • Journal Title: J Hum Genet. Volume: - Issue: 6 Pages: 521-534
  • DOI: 10.1038/s10038-019-0584-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gene Regulation by Antitumor miR-204-5p in Pancreatic Ductal Adenocarcinoma: The Clinical Significance of Direct RACGAP1 Regulation. (2019)
  • Author(s): Khalid M, Idichi T, Seki N, Wada M, Yamada Y, Fukuhisa H, Toda H, Kita Y, Kawasaki Y, Tanoue K, Kurahara H, Mataki Y, Maemura K, Natsugoe S.
  • Journal Title: Cancers (Basel) Volume: 11 Issue: 3 Pages: 327-327
  • DOI: 10.3390/cancers11030327
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Significance of glucose transporter 1 (GLUT-1) expression in the therapeutic strategy for pancreatic ductal adenocarcinoma (2018)
  • Author(s): Kurahara H, Maemura K, Mataki Y, Sakoda M, Iino S, Kawasaki Y, Arigami T, Mori S, Kijima Y, Ueno S, Shinchi H, Natsugoe S.
  • Journal Title: Ann Surg Oncol Volume: 25 Issue: 5 Pages: 1432-1439
  • DOI: 10.1245/s10434-018-6357-1
  • Peer Reviewed / Open Access
• [Journal Article] Molecular pathogenesis of pancreatic ductal adenocarcinoma: Impact of passenger strand of pre-miR-148a on gene regulation. (2018)
  • Author(s): Idichi T, Seki N, Kurahara H, Fukuhisa H, Toda H, Shimonosono M, Okato A, Arai T, Kita Y, Mataki Y, Kijima Y, Maemura K, Natsugoe S.
  • Journal Title: Cancer Sci. Volume: 109 Issue: 6 Pages: 2013-2026
  • DOI: 10.1111/cas.13610
  • Peer Reviewed / Open Access
• [Journal Article] A therapeutic strategy for resectable pancreatic cancer based on risk factors of early recurrence. (2018)
  • Author(s): Kurahara H, Maemura K, Mataki Y, Sakoda M, Iino S, Kawasaki Y, Arigami T, Mori S, Kijima Y, Ueno S, Shinchi H, Natsugoe S.
  • Journal Title: Pancreas Volume: 47 Issue: 6 Pages: 753-758
  • DOI: 10.1097/mpa.0000000000001066
  • Peer Reviewed
• [Presentation] 切除不能膵癌および切除境界膵癌に対する化学放射線療法 (2018)
  • Author(s): 蔵原 弘，前村公成，又木雄弘，迫田雅彦，飯野 聡，川崎洋太，橋口真征，上野真一，新地洋之，夏越祥次
  • Organizer: 第118回日本外科学会
• [Presentation] Efficacy of neoadjuvant chemoradiotherapy for pancreatic ductal adenocarcinoma (2018)
  • Author(s): Hiroshi Kurahara, Kosei Maemura, Yuko Mataki, Masahiko Sakoda, Satoshi Iino, Yota Kawasaki, Motoyuki Hashiguchi, Shinichi Ueno, Hiroyuki Shinchi, Shoji Natsugoe
  • Organizer: 第30回日本肝胆膵外科学会
• [Presentation] 膵癌に対する術前化学放射線療法における予後を反映する効果判定 (2018)
  • Author(s): 蔵原 弘，前村公成，又木雄弘，迫田雅彦，飯野 聡，川崎洋太，橋口真征，新地洋之，夏越祥次
  • Organizer: 第49回日本膵臓学会
• [Presentation] Significance of neoadjuvant chemoradiotherapy for locally advanced pancreatic cancer (2018)
  • Author(s): Hiroshi Kurahara, Kosei Maemura, Yuko Mataki, Masahiko Sakoda, Satoshi Iino, Yota Kawasaki, Motoyuki Hashiguchi, Shinichi Ueno, Hiroyuki Shinchi, Shoji Natsugoe
  • Organizer: IHPBA 2018
  • Int'l Joint Research
• [Presentation] 早期再発の危険因子に基づく切除可能膵癌に対する治療戦略 (2018)
  • Author(s): 蔵原 弘，前村公成，又木雄弘，迫田雅彦，飯野 聡，川崎洋太，橋口真征，上野真一，新地洋之，夏越祥次
  • Organizer: 第27回日本がん転移学会