Control of Head and neck cancer by inhibitory peptides for DKK3 functional domain.

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K09908
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 57020:Oral pathobiological science-related
• Research Institution: Nagasaki University
• Principal Investigator: KATASE Naoki 長崎大学, 医歯薬学総合研究科(歯学系), 助教 (30566071)
• Co-Investigator(Kenkyū-buntansha): 藤田 修一 長崎大学, 医歯薬学総合研究科(歯学系), 准教授 (00181355) ; 西松 伸一郎 川崎医科大学, 医学部, 教授 (20222185) ; 山内 明 川崎医科大学, 医学部, 教授 (80372431)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 頭頚部扁平上皮癌 / 口腔癌 / DKK3 / 遺伝子機能解析

Outline of Final Research Achievements

We previously reported that DKK3 functions as tumor-promoting factor in head and neck squamous cell carcinoma (HNSCC) through activation of Akt. To establish a new therapeutic agent targeting DKK3 protein for HNSCC, we developped complimentary peptides for the functional domain of DKK3 protein. Firstly, we focused on two cysteine rich domains (CRDs), and showed that both of CRD1 and CRD2 are necessary for exertion of the oncogenic function of DKK3. Secondry, we designed complimentary peptides against the certain amino acid sequences within the CRDs. The peptides successfully suppressed Akt activation by DKK3 and consequent celelular proliferation, migration and invasion in HNSCC-derived cells. We also investigated the expression and function of CKAP4, which was newly reported as a receptor for DKK3 in HNSCC. The data showed that DKK3 and CKAP4 expression was associated with poorer prognosis of HNSCC, and antibodies against DKK3 or CKAP4 showed anticancer effects in HNSCC cells.

Free Research Field

病理学・口腔病理学

Academic Significance and Societal Importance of the Research Achievements

本研究成果からは、DKK3の機能ドメインが２つのcysteine rich domain(CRD)にあることが明らかになり、さらにCRD内の特定のアミノ酸配列を標的とした相補性ペプチドが実際にDKK3タンパクの機能を阻害でき、既存の抗がん剤よりも低用量で腫瘍の増殖等を抑制できることが示された。この成果はDKK3が頭頚部扁平上皮癌の治療標的となることを示すだけでなく、DKK3タンパクの本質的機能の一端を明らかにした点で学術的意義が大きく、さらに実現可能性の高いペプチドベースの中分子創薬を開拓した点で社会的意義が非常に大きい。