Identification of responsible genes for advanced colorectal cancer: Development of in vitro system that mimics EMAST-related tumor-progression regulated by p53.

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K09229
• 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: Toho University
• Principal Investigator: Arita Michitsune 東邦大学, 医学部, 助教 (80307719)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: EMAST / DNAミスマッチ修復 / 低酸素 / p53 / 進行大腸癌

Outline of Final Research Achievements

Advanced colorectal cancers (CRCs) showing an elevated microsatellite alterations at selected tetra-nucleotide repeats (EMAST) correlates poor prognosis, suggesting that in vitro induction of EMAST in CRC cell lines should achieve to identify molecules relating to EMAST-associating malignancy. Based on the idea, we performed 1) improvement of culture condition inducing EMAST in CRC cells with higher rate and 2) establishment of high-throughput EMAST-detecting system using genome-edited cell lines. For culture condition, in addition to hypoxia and p53-deficiency which have been revealed to generate EMAST, we identified high-density of cells as additive factors to make higher rate of EMAST positive cells. Additionally, we found important clue of a molecular mechanism by which p53 contributes to EMAST generation. On the other hand, for an EMAST-detecting system, it remained to be continued due to unexpectedly modification of strategy.

Free Research Field

分子腫瘍学

Academic Significance and Societal Importance of the Research Achievements

本研究では、散発性大腸癌の悪性度とEMASTとの強い相関性に着目し、実験的EMAST誘導培養系を用いたEMAST関連悪性化機構の解明を試みた。研究期間中に、細胞密度を高く維持することでEMAST誘導高率を上げられること、ならびに、癌抑制分子p53にはゲノム上のEMASTマーカー領域に結合して安定性に寄与する可能性があることを明らかにした。反面、当初計画した簡便で迅速なEMAST検出法の開発が予定通りに進まず課題を残した。今後の進捗により検出法を確立すれば、本研究で見いだしたp53の新たな分子特性を生細胞で評価でき、p53を介したEMAST関連悪性化機構の解明が大きく進むと期待できる。