Investigation of potential therapeutic strategies for esophageal squamous cell carcinoma focused on the functional modification of cancer stimulating RNA editing.

• Project/Area Number: 18K07910
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Kawasaki Medical School
• Principal Investigator: MASUDA Kiyoshi 川崎医科大学, 医学部, 教授 (00457318)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: RNA編集 / RNA結合蛋白質 / 食道癌 / 食道扁平上皮癌 / 食道がん

Outline of Final Research Achievements

We found that ADAR1 was highly expressed in esophageal squamous cell carcinoma (ESCC). Knockdown of ADAR1 suppressed cell proliferation. Comprehensive analysis using microarrays suggested that ADAR1 may suppress the immune response and apoptosis and contribute to the survival of cancer cells. In ADAR1 knockdown cells, the binding between the target genes and cancer stimulating RBPs (csRBPs) were increased/decreased and then the amounts of mRNAs were altered. These results suggested that ADAR1 may cause A-to-I RNA editing in the 3’UTR of mRNAs that control cell growth, infiltration, and cancer immunity, and regulate association between csRBP and target mRNAs. In conclusion, ADAR1 may be a hub factor that induces disruption of the post-transcriptional regulatory mechanism in ESCC cells.

Academic Significance and Societal Importance of the Research Achievements

これまで、RNA編集異常の病態への関与は、神経変性疾患や精神疾患、一部の希少疾患で報告されているが、これらの分子機構は不明である。癌組織は正常組織に比べRNA編集活性が亢進しており、癌特異的なRNA編集パターンが見られることから、RNA編集不全と発癌との関連性が示唆されているが、癌特異的なRNA編集のほとんどが非翻訳領域に集中しており、機能予測が困難なことから、これらを直接結びつける分子機構の解明には至っていない。本研究結果は、食道癌におけるRBPが作る大きな機能モジュール内でのRNA編集の生物学的意義解明の端緒となる。

Research Products

• [Journal Article] Functionally confirmed compound heterozygous ADAM17 missense loss-of-function variants cause neonatal inflammatory skin and bowel disease 1 (2021)
  • Author(s): Imoto I, Saito M, Suga K, Kohmoto T, Otsu M, Horiuchi K, Nakayama H, Higashiyama S, Sugimoto M, Sasaki A, Homma Y, Shono M, Nakagawa R, Hayabuchi Y, Tange S, Kagami S, Masuda K
  • Journal Title: Scientific reports Volume: 11 Issue: 1 Pages: 9552-9552
  • DOI: 10.1038/s41598-021-89063-0
  • NAID: 120007188413
  • Peer Reviewed / Open Access
• [Journal Article] Claudin-6 is a single prognostic marker and functions as a tumor-promoting gene in a subgroup of intestinal type gastric cancer (2020)
  • Author(s): Kohmoto T, Masuda K, Shoda K, Takahashi R, Ujiro S, Tange S, Ichikawa D, Otsuji E, Imoto I
  • Journal Title: Gastric Cancer Volume: 23 Issue: 3 Pages: 403-417
  • DOI: 10.1007/s10120-019-01014-x
  • NAID: 40022220036
  • Peer Reviewed / Open Access
• [Journal Article] Toll‐Like Receptor 9 Plays a Pivotal Role in Angiotensin II Induced Atherosclerosis (2019)
  • Author(s): Fukuda Daiju、Nishimoto Sachiko、Aini Kunduziayi、Tanaka Atsushi、Nishiguchi Tsuyoshi et al.
  • Journal Title: Journal of the American Heart Association Volume: 8 Issue: 7
  • DOI: 10.1161/jaha.118.010860
  • NAID: 120006602927
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic significance of GAD1 overexpression in patients with resected lung adenocarcinoma (2019)
  • Author(s): Tsuboi M, Kondo K, Masuda K, Tange S, Kajiura K, Kohmoto T, Takizawa H, Imoto I, Tangoku A
  • Journal Title: Cancer Medicine Volume: 8 Issue: 9 Pages: 4189-4199
  • DOI: 10.1002/cam4.2345
  • Peer Reviewed / Open Access
• [Journal Article] Novel compound heterozygous CDH23 variants in a patient with Usher syndrome type I. (2019)
  • Author(s): Okano S, Makita Y, Katada A, Harabuchi Y, Kohmoto T, Naruto T, Masuda K, Imoto I.
  • Journal Title: Hum Genome Var. Volume: 6 Issue: 1 Pages: 8-8
  • DOI: 10.1038/s41439-019-0037-y
  • Peer Reviewed / Open Access
• [Journal Article] Primary microcephaly caused by novel compound heterozygous mutations in ASPM. (2018)
  • Author(s): Okamoto N, Kohmoto T, Naruto T, Masuda K, Imoto I.
  • Journal Title: Hum Genome Var. Volume: 5 Issue: 1 Pages: 18015-18015
  • DOI: 10.1038/hgv.2018.15
  • Peer Reviewed / Open Access
• [Journal Article] Diverse roles of RNA-binding proteins in cancer traits and their implications in gastrointestinal cancers. (2018)
  • Author(s): Masuda K, Kuwano Y.
  • Journal Title: Wiley Interdiscip Rev RNA. Volume: 10 Issue: 3
  • DOI: 10.1002/wrna.1520
  • Peer Reviewed / Open Access
• [Presentation] KHSRP involved in esophageal squamous cell carcinoma progression by inducing the expression of a set of oncogenic miRNAs (2019)
  • Author(s): Masuda K, Kohmoto T, Imoto I
  • Organizer: Cell Symposium: Regulatory RNAs
  • Int'l Joint Research