Format

Send to

Choose Destination
Int J Cancer. 2018 Jul 15;143(2):355-367. doi: 10.1002/ijc.31324. Epub 2018 Mar 8.

Distinct methylation profile of mucinous ovarian carcinoma reveals susceptibility to proteasome inhibitors.

Author information

1
Department of Pathology, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan.
2
Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
3
Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan.
4
Translational epigenetic center, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan.
5
Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
6
Department of Molecular Medicine/Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX.
7
Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
8
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, People's Republic of China.
9
Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, 410078, People's Republic of China.

Abstract

Mucinous type of epithelial ovarian cancer (MuOC) is a unique subtype with a poor survival outcome in recurrent and advanced stages. The role of type-specific epigenomics and its clinical significance remains uncertain. We analyzed the methylomic profiles of 6 benign mucinous adenomas, 24 MuOCs, 103 serous type of epithelial ovarian cancers (SeOCs) and 337 nonepithelial ovarian cancers. MuOC and SeOC exhibited distinct DNA methylation profiles comprising 101 genes, 81 of which exhibited low methylation in MuOC and were associated with the response to glucocorticoid, ATP hydrolysis-coupled proton transport, proteolysis involved in the cellular protein catabolic process and ion transmembrane transport. Hierarchical clustering analysis showed that the profiles of MuOC were similar to colorectal adenocarcinoma and stomach adenocarcinoma. Genetic interaction network analysis of differentially methylated genes in MuOC showed a dominant network module is the proteasome subunit beta (PSMB) family. Combined functional module and methylation analysis identified PSMB8 as a candidate marker for MuOC. Immunohistochemical staining of PSMB8 used to validate in 94 samples of ovarian tumors (mucinous adenoma, MuOC or SeOC) and 62 samples of gastrointestinal cancer. PSMB8 was commonly expressed in MuOC and gastrointestinal cancer samples, predominantly as strong cytoplasmic and occasionally weak nuclei staining, but was not expressed in SeOC samples. Carfilzomib, a second-generation proteasome inhibitor, suppressed MuOC cell growth in vitro. This study unveiled a mucinous-type-specific methylation profile and suggests the potential use of a proteasome inhibitor to treat MuOC.

KEYWORDS:

PSMB8; functional genetic interactions; methylation profiles; mucinous ovarian carcinoma; proteasome inhibitors

PMID:
29451304
PMCID:
PMC6001480
DOI:
10.1002/ijc.31324
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center