Personalized cancer management based on microRNA biomarkers

• Project/Area Number: 16K07146
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor diagnostics
• Research Institution: Fukushima Medical University
• Principal Investigator: Ishigame Teruhide 福島県立医科大学, 医学部, 助教 (50583358)
• Co-Investigator(Kenkyū-buntansha): 岡山 洋和 福島県立医科大学, 医学部, 講師 (20583397) ; 竹之下 誠一 福島県立医科大学, 医学部, 教授 (10167489) ; 千田 峻 福島県立医科大学, 医学部, 博士研究員 (40769642)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: マイクロRNA / 消化器癌 / 胃癌 / リンパ節転移

Outline of Final Research Achievements

Although this study originally aimed to investigate microRNAs that are specific to the lymph node involvement in gastric cancer, our microRNA screening strategies were not able to identify potential candidates. We then attempted to focus on the identification of microRNAs that regulate an immune checkpoint molecule, programmed cell death ligand 1 (PD-L1), since immunotherapy against the interaction between PD-1/PD-L1 has recently emerged as a promising strategy for gastrointestinal tract cancers. A comprehensive microRNA screening was conducted using The Cancer Genome Atlas (TCGA) dataset combined with microRNA target prediction programs, followed by the analysis of microarray-based mRNA/miRNA expression datasets and formalin-fixed paraffin-embedded (FFPE) samples by immunohistochemistry and qRT-PCR. Here we identified a tumor suppressive microRNA, miR-148a that can negatively regulate PD-L1, via direct binding to 3'UTR of PD-L1 mRNA.

Academic Significance and Societal Importance of the Research Achievements

マイクロRNAは標的遺伝子機能を制御することで発癌や癌の進展に重要な役割を担うことが知られている。癌診療においては、癌の診断、予後バイオマーカーや治療反応予測因子、さらに薬剤としての有用性が報告されているものもある。本研究で得られたマイクロRNAの機能や臨床的意義の知見が癌におけるマイクロRNAのさらなる理解や個別化医療の糸口へつながることが期待される。

Research Products

• [Journal Article] microRNA-148a-3p regulates immunosuppression in DNA mismatch repair-deficient colorectal cancer by targeting PD-L1 (2019)
  • Author(s): Ashizawa Mai、Okayama Hirokazu、Ishigame Teruhide、Thar Min Aung Kyi、Saito Katsuharu、Ujiie Daisuke、Murakami Yuko、Kikuchi Tomohiro、Nakayama Yuko、Noda Masaru、Tada Takeshi、Endo Hisahito、Fujita Shotaro、Sakamoto Wataru、Saito Motonobu、Saze Zenichiro、Momma Tomoyuki、Ohki Shinji、Mimura Kosaku、Kono Koji
  • Journal Title: Molecular Cancer Research Volume: Epub ahead of print Issue: 6 Pages: 1403-1413
  • DOI: 10.1158/1541-7786.mcr-18-0831
  • Peer Reviewed / Open Access
• [Journal Article] Clinical significance of soluble intercellular adhesion molecule-1 and interleukin-6 in patients with extrahepatic cholangiocarcinoma (2017)
  • Author(s): Shimura T, Shibata M, Gonda K, Kofunato Y, Okada R, Ishigame T, Kimura T, Kenjo A, Marubashi S, Kono K, Takenoshita S
  • Journal Title: Journal of Investigative Surgery Volume: 印刷中 Issue: 6 Pages: 475-482
  • DOI: 10.1080/08941939.2017.1358310
  • Peer Reviewed
• [Journal Article] PD-L1 expression is mainly regulated by interferon gamma associated with JAK-STAT pathway in gastric cancer (2017)
  • Author(s): Mimura Kousaku、Teh Jun Liang、Okayama Hirokazu、Shiraishi Kensuke、Kua Ley-Fang、Koh Vivien、Smoot Duane T.、Ashktorab Hassan、Oike Takahiro、Suzuki Yoshiyuki、Fazreen Zul、Asuncion Bernadette R.、Shabbir Asim、Yong Wei-Peng、So Jimmy、Soong Richie、Kono Koji
  • Journal Title: Cancer Science Volume: 109 Issue: 1 Pages: 43-53
  • DOI: 10.1111/cas.13424
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CDX2 is involved in microRNA?associated inflammatory carcinogenesis in gastric cancer (2017)
  • Author(s): Saito Motonobu、Okayama Hirokazu、Saito Katsuharu、Ando Jin、Kumamoto Kensuke、Nakamura Izumi、Ohki Shinji、Ishi Yoshimasa、Takenoshita Seiichi
  • Journal Title: Oncology Letters Volume: 14 Pages: 6184-6190
  • DOI: 10.3892/ol.2017.6956
  • Peer Reviewed
• [Journal Article] ミスマッチ修復機構欠損を有する大腸癌におけるMicroRNAによるPD-L1制御機構 (2017)
  • Author(s): 芦澤舞、岡山洋和、Aung Kyi Thar Min、野田勝、青砥慶太、中島隆宏、石亀輝英、三村耕作、河野浩二
  • Journal Title: 癌と化学療法 Volume: 44 Pages: 889-891
• [Presentation] Identification of microRNAs that target PD-L1 in mismatch repair-deficient colorectal cancer (2018)
  • Author(s): Ashizawa M, Okayama H, Ishigame T, Mimura K, Kono K
  • Organizer: ASCO-SITC CLINICAL IMMUNO-ONCOLOGY SYMPOSIUM
  • Int'l Joint Research
• [Presentation] Targeting the tumor microenvironment in dMMR/MSI-H colorectal cancer (2018)
  • Author(s): Okayama H, Ashizawa M, Kikuchi T, Sakamoto W, Fujita S, Endo H, Saito M, Momma T, Ohki S, Kono K
  • Organizer: 第73回日本消化器外科学会総会
• [Presentation] Identification of microRNAs that target PD-L1 in mismatch repair-deficient colorectal cancer (2018)
  • Author(s): 芦澤舞,岡山洋和,石亀輝英,Thar Min Aung Kyi,氏家大輔,村上祐子,菊池智宏,野田勝,青砥慶太,中島隆宏,早瀬傑,坂本渉,藤田正太郎,遠藤久仁,齋藤元伸,門馬智之,佐瀬善一郎,三村耕作,大木進司,丸橋繁,河野浩二
  • Organizer: 第118回日本外科学会定期学術集会
• [Presentation] 胃癌患者における腫瘍内CD15/CD8陽性細胞比の臨床的意義 (2018)
  • Author(s): 渡邊 淳一郎, 木村 隆, 武藤 亮, 佐藤 直哉, 小船戸 康英, 石亀 輝英, 岡田 良, 見城 明, 志村 龍男, 河野 浩二, 丸橋 繁
  • Organizer: 日本外科学会定期学術集会 118回
• [Presentation] 脱フコシル化抗体を用いたADCCの検討 (2017)
  • Author(s): 中島 隆宏,河野 浩二,芦澤 舞,千田 峻,野田 勝,青砥 慶太,立花 和之進,岡山 洋和,早瀬 傑,坂本 渉,石亀 輝英,齋藤 元伸,志村 龍男,大竹 徹,竹之下 誠一
  • Organizer: 第117回日本外科学会定期学術集会
• [Presentation] ミスマッチ修復機構欠損を有する大腸癌におけるmicroRNAによるPD-L1調整機構 (2017)
  • Author(s): 芦澤 舞,岡山 洋和,Min Aung Kyi Thar,野田 勝,青砥 慶太,中島 隆宏,石亀 輝英,円谷 彰,丸橋 繁,河野 浩二
  • Organizer: 第72回日本消化器外科学会総会