Functional analyses and therapeutic application of novel tumor suppressor gene DUSP4 involved in invasion of pancreatic cancer

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K08651
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Oita University
• Principal Investigator: Hijiya Naoki 大分大学, 医学部, 准教授 (80305036)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 膵癌 / 浸潤 / MAPキナーゼ / 治療標的

Outline of Final Research Achievements

By comparing the genomic profiles of paired non-invasive and invasive carcinoma tissues collected from patients with intraductal papillary mucinous neoplasm, we demonstrate that the loss of 8p11.22-ter was more often associated with invasive tissues. Expression profiling in pancreatic cancer cell lines with and without 8p11.22-ter revealed that DUSP4, a MAPK phosphatase, was significantly downregulated in cells lacking 8p11.22-ter. Re-expression of DUSP4 in pancreatic cancer cells significantly suppressed invasiveness and anoikis resistance via ERK inactivation. Therefore, we found that blockade of ERK signaling by MEK inhibition was effective in an orthotopic xenograft model. Collectively, our findings reveal a genetic mechanism by which pancreatic intraepithelial lesions progress to invasive carcinomas, and highlight DUSP4 as a novel invasion suppressor that can be therapeutically exploited through manipulation of ERK signaling.

Free Research Field

医学

Academic Significance and Societal Importance of the Research Achievements

膵癌は最も予後不良な癌の一つで、5年生存率は10％に満たない。その理由として、①早期に浸潤癌に進展するため、根治切除術の適応になる症例が少ないこと、②既存の抗癌剤が奏功する症例が少ないことが挙げられる。したがって、浸潤に関わる分子メカニズムを解明して、それを治療標的とする新規治療法を開発すれば、膵癌の治療成績や予後は改善されることが期待できる。
本研究によって、膵癌の新規がん抑制遺伝子DUSP4が同定され、MAPキナーゼの治療標的としての重要性が確認された。