Epigenetic silencing of SMOC1 in traditional serrated adenoma and colorectal cancer
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Hironori Aoki1,*, Eiichiro Yamamoto1,2,*, Akira Takasawa3, Takeshi Niinuma1, Hiro-O Yamano2, Taku Harada1, Hiro-O Matsushita4, Kenjiro Yoshikawa4, Ryo Takagi4, Eiji Harada4, Yoshihito Tanaka4, Yuko Yoshida4, Tomoyuki Aoyama3, Makoto Eizuka5, Akira Yorozu1, Hiroshi Kitajima1, Masahiro Kai1, Norimasa Sawada3, Tamotsu Sugai5, Hiroshi Nakase2 and Hiromu Suzuki1
1Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
2Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
3Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
4Department of Digestive Disease Center, Akita Red Cross Hospital, Akita, Japan
5Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
*These authors contributed equally to this work
Hiromu Suzuki, email: [email protected]
Keywords: SMOC1; colorectal cancer; traditional serrated adenoma; DNA methylation; CIMP
Received: June 26, 2017 Accepted: November 30, 2017 Published: December 20, 2017
Colorectal sessile serrated adenoma/polyps (SSA/Ps) are well-known precursors of colorectal cancer (CRC) characterized by BRAF mutation and microsatellite instability. By contrast, the molecular characteristics of traditional serrated adenoma (TSAs) are not fully understood. We analyzed genome-wide DNA methylation in TSAs having both protruding and flat components. We identified 11 genes, including SMOC1, methylation of which progressively increased during the development of TSAs. SMOC1 was prevalently methylated in TSAs, but was rarely methylated in SSA/Ps (p < 0.001). RT-PCR and immunohistochemistry revealed that SMOC1 was expressed in normal colon and SSA/Ps, but its expression was decreased in TSAs. Ectopic expression of SMOC1 suppressed proliferation, colony formation and in vivo tumor formation by CRC cells. Analysis of colorectal lesions (n = 847) revealed that SMOC1 is frequently methylated in TSAs, high-grade adenomas and CRCs. Among these, SMOC1 methylation was strongly associated with KRAS mutation and CpG island methylator phenotype (CIMP)-low. These results demonstrate that epigenetic silencing of SMOC1 is associated with TSA development but is rarely observed in SSA/Ps. SMOC1 expression could thus be a diagnostic marker of serrated lesions, and SMOC1 methylation could play a role in neoplastic pathways in TSAs and conventional adenomas.
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