title: Epigenetic silencing of dual oxidase 1 by promoter hypermethylation in human hepatocellular carcinoma.
abstract: Dual oxidase 1 (DUOX1), which is the main sources for reactive oxygen species (ROS) production in the airway, are frequently silenced in human lung cancer. In poorly differentiated follicular thyroid carcinoma, a high expression of DUOX1 was associated with a reduced risk of death. However, the role of DUOX1 in human hepatocellular carcinoma (HCC) is still not clear. Here, we investigated DUOX1 expression and its promoter methylation status in primary HCC. To date, We found that expression of DUOX1 was decreased significantly in 76.9% (60/78) human hepatocellular carcinoma and 66.7% (6/9) liver cancer cell lines, compared with the paired adjacent non-tumor tissues and immortalized normal cell line. Moreover, which was well correlated with its promoter methylation status. Methylation was further detected in primary HCC, but none or occasionally in paired adjacent non-tumor tissues. Detailed methylation analysis of 35 CpG sites at a 324-bp promoter region by bisulfi te genomic sequencing (BGS) confi rmed its methylation. DUOX1 silencing could be reversed by chemical demethylation treatment with 5-aza-2'-deoxycytidine (5-Aza-dC), indicating direct epigenetic silencing. Restoring DUOX1 expression in lowly expressed cancer cells signifi cantly inhibited cancer cells growth and colony formation ability through the induction of G2/M phase cell cycle arrest and an increase in ROS generation, while knockdown of DUOX1 could markedly promote cancer cells proliferation. In conclusion, we demonstrate that epigenetic silencing of DUOX1 via promoter hypermethylation is common in human liver cancer cells and primary HCC and DUOX1 appears to be a functional tumor suppressor involved in liver carcinogenesis.
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University Shanghai 200040, China.
authors.forename: Qingxia
authors.initials: Q
authors.lastname: Ling
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University Shanghai 200040, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University Shanghai 200040, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University Shanghai 200040, China.
authors.forename: Jianming
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University Shanghai 200040, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University Shanghai 200040, China.
authors.forename: Kangkang
authors.initials: K
authors.lastname: Yu
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University Shanghai 200040, China.
authors.forename: Shengsen
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University Shanghai 200040, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University Shanghai 200040, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University Shanghai 200040, China.
authors.forename: Mingquan
authors.initials: M
authors.lastname: Chen
keywords: DUOX1; ROS; hepatocellular carcinoma; methylation