Somatic alteration and depleted nuclear expression of BAP1 in human esophageal squamous cell carcinoma; survey for molecular targeted medicine

2015 Fiscal Year Final Research Report

• Project/Area Number: 25462010
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Tohoku University
• Principal Investigator: Mori Takahiro 東北大学, 医学(系)研究科(研究院), 教授 (00323030)
• Co-Investigator(Kenkyū-buntansha): CHIBA Natsuko 東北大学, 加齢医学研究所, 教授 (50361192)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 食道扁平上皮癌 / BAP1遺伝子 / 脱ユビキチン化 / 癌化

Outline of Final Research Achievements

In this study, we identified a novel somatic non-synonymous BAP1 mutation, F170I, in one of 49 patients with ESC. MLPA of BAP1 gene in this ESC tumor disclosed LOH, suggesting BAP1 alterations on both alleles in this tumor. The deubiquitinase activity and the auto-deubiquitinase activity of F170I-mutant BAP1 were markedly suppressed. In addition, wild-type BAP1 mostly localizes to the nucleus, whereas the F170I mutant preferentially localized in the cytoplasm. Microarray analysis revealed that expression of the F170I mutant drastically altered gene expression profiles compared with expressed wild-type BAP1, genes involved in oncogenic pathways. Furthermore, we found that the level of BAP1 expression in the nucleus was reduced in 44% of ESCs examined by immunohistochemistry (IHC). Because the nuclear localization of BAP1 is important for its tumor suppressor function, BAP1 may be functionally inactivated in substantial portion of ESCs.

Free Research Field

臨床腫瘍学