Newly identified REIC receptor regulates the immune responses against tumors

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K15320
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Okayama University
• Principal Investigator: Kinoshita Rie 岡山大学, 医歯薬学総合研究科, 助教 (40518297)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: REIC / 受容体

Outline of Final Research Achievements

REIC is a tumor suppressor gene and has been studied as a promising therapeutic gene for cancer gene therapy. Intratumoral injection of adenovirus vector carrying the human REIC (Ad-REIC) elicits cancer cell-specific apoptosis and anti-cancer immune responses. but the role of secretory REIC protein is still poorly understood.
In the present study, we identified some new receptors of the REIC protein by LC-Ms and immunoprecipitation methods. Further analyses showed that the secretory REIC protein induced the phosphorylation of ERK and AKT through the new identified receptors in NK cells and neuronal-like SH-SY5Y cells and suppressed the stress-induced cytotoxicity and the expression of some inflammatory cytokines.
Taken together, our results indicate that the secretory REIC protein is responsible for cellular homeostasis. Because REIC/Dkk-3 is a naturally circulating serum protein, the upregulation REIC/Dkk-3 protein expression could be a promising option for cancer therapy.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

がん抑制遺伝子REICは、多岐にわたるがん種において発現が低下しており、がん遺伝子治療薬として開発が進められている。しかし正常細胞や免疫細胞においての分泌REICタンパク質の詳細な分子機構は未解明であった。本研究は、REICタンパク質の新規受容体を同定し、全身の重要臓器における恒常性維持機構へのREICの関与を分子レベルで解明することに寄与した。現在、REICはタンパク質製剤としても開発を進めており、本研究の成果である抗がん免疫活性化に重要なタンパク質ドメインの特定は、治療薬早期実用化を大きく推進する。