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Epigenetic silencing of SMOC1 in traditional serrated adenoma and colorectal cancer

2017; Impact Journals LLC; Volume: 9; Issue: 4 Linguagem: Inglês

10.18632/oncotarget.23523

1949-2553

Hironori Aoki, Eiichiro Yamamoto, Akira Takasawa, Takeshi Niinuma, Hiro‐o Yamano, Taku Harada, Hiro‐o Matsushita, Kenjiro Yoshikawa, Ryo Takagi, Eiji Harada, Yoshihito Tanaka, Yuko Yoshida, Tomoyuki Aoyama, Makoto Eizuka, Akira Yorozu, Hiroshi Kitajima, Masahiro Kai, Norimasa Sawada, Tamotsu Sugai, Hiroshi Nakase, Hiromu Suzuki,

Cholangiocarcinoma and Gallbladder Cancer Studies

// Hironori Aoki 1, * , Eiichiro Yamamoto 1, 2, * , Akira Takasawa 3 , Takeshi Niinuma 1 , Hiro-O Yamano 2 , Taku Harada 1 , Hiro-O Matsushita 4 , Kenjiro Yoshikawa 4 , Ryo Takagi 4 , Eiji Harada 4 , Yoshihito Tanaka 4 , Yuko Yoshida 4 , Tomoyuki Aoyama 3 , Makoto Eizuka 5 , Akira Yorozu 1 , Hiroshi Kitajima 1 , Masahiro Kai 1 , Norimasa Sawada 3 , Tamotsu Sugai 5 , Hiroshi Nakase 2 and Hiromu Suzuki 1 1 Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan 2 Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan 3 Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan 4 Department of Digestive Disease Center, Akita Red Cross Hospital, Akita, Japan 5 Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan * These authors contributed equally to this work Correspondence to: Hiromu Suzuki, email: hsuzuki@sapmed.ac.jp Keywords: SMOC1; colorectal cancer; traditional serrated adenoma; DNA methylation; CIMP Received: June 26, 2017 Accepted: November 30, 2017 Published: December 20, 2017 ABSTRACT 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.