Somatic alteration and depleted nuclear expression of BAP1 in human esophageal squamous cell carcinoma

Cancer Science

Takahiro Mori¹  Makiko Sumii¹  Fumiyoshi Fujishima³  Kazuko Ueno²  Mitsuru Emi⁴  Masao Nagasaki²  Chikashi Ishioka⁵ 

[1] Tohoku Community Cancer Services Program, Tohoku University Graduate School of Medicine, Sendai, Japan;Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan;Department of Pathology, Tohoku University Hospital, Sendai, Japan;Thoracic Oncology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA;Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan

关键词: BAP1;    deubiquitinase;    esophageal squamous cell carcinoma;    gene expression profiling;    somatic mutation;   

DOI  :  10.1111/cas.12722

来源: Wiley

【 摘 要 】

Abstract

BRCA1-associated protein 1 (BAP1) is a deubiquitinating enzyme that is involved in the regulation of cell growth. Recently, many somatic and germline mutations of BAP1 have been reported in a broad spectrum of tumors. In this study, we identified a novel somatic non-synonymous BAP1 mutation, a phenylalanine-to-isoleucine substitution at codon 170 (F170I), in 1 of 49 patients with esophageal squamous cell carcinoma (ESCC). Multiplex ligation-dependent probe amplification (MLPA) of BAP1 gene in this ESCC tumor disclosed monoallelic deletion (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 compared with wild-type BAP1. 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. Gene-ontology analyses indicated that the F170I mutation altered the expression of genes involved in oncogenic pathways. We found that one candidate, TCEAL7, previously reported as a putative tumor suppressor gene, was significantly induced by wild-type BAP1 as compared to F170I mutant BAP1. Furthermore, we found that the level of BAP1 expression in the nucleus was reduced in 44% of ESCC examined by immunohistochemistry (IHC). Because the nuclear localization of BAP1 is important for its tumor suppressor function, BAP1 may be functionally inactivated in a substantial portion of ESCC. Taken together, BAP1 is likely to function as a tumor suppressor in at least a part of ESCC.

【 授权许可】

CC BY-NC-ND   
© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

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