title: SEI1 induces genomic instability by inhibiting DNA damage response in ovarian cancer.
abstract: Previous studies have shown that the oncogene SEI1 is highly expressed in ovarian carcinomas, and promoting genomic instability. However, the molecular mechanism of SEI1 in promoting genomic instability remains unclear. We observed SEI1 overexpression in 30 of 46 cases of ovarian cancer compared to non-tumor tissues and the overexpression of SEI1 was positively associated with the tumor FIGO stage. Our functional studies revealed that overexpression of SEI1 could induce genomic instability and increased DNA strand breaks. In contrast, SEI1 co-localized with γH2AX and phosphorylated ATM and DNAPKcs in the nucleus. Furthermore, we found that overexpression of SEI1 induced translocation of the SEI1 protein from the cytoplasm to the nucleus; ATM and DNAPKcs were associated with the cytoplasm-to-nucleus translocation of SEI1. To further prove the correlation between the DNA damage response (DDR) and SEI1, we knocked down SEI1 expression in SEI1-transfected ovarian cancer cell lines. The expression of DDR proteins was significantly downregulated, and the number of micronuclei was significantly decreased. Together, these results define a new mechanism of SEI1 in the regulation of genomic stability and in the malignant progression of ovarian cancer.
authors.affiliation: Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China.
authors.forename: Jia
authors.initials: J
authors.lastname: You
authors.affiliation: Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China.
authors.forename: Yantao
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China.
authors.forename: Liqun
authors.initials: L
authors.lastname: Wang
authors.affiliation: Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China; Department of Genetics and Eugenics, Maternity and Child Care Center of Qinghuangdao, Qinghuangdao 066000, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China; Genetic Diagnosis Center, First People's Hospital of Yunnan Province, Yunnan 650032, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China.
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.affiliation: Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.affiliation: Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.affiliation: Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.affiliation: Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China.
authors.forename: Falin
authors.initials: F
authors.lastname: Wang
authors.affiliation: Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Xu
authors.affiliation: Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Tian
authors.affiliation: Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Liang
authors.affiliation: Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China.
authors.forename: Yating
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China.
authors.forename: Rongwei
authors.initials: R
authors.lastname: Guan
authors.affiliation: Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Bai
authors.affiliation: Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China.
authors.forename: Xiangning
authors.initials: X
authors.lastname: Meng
authors.affiliation: Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Clinical Oncology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China; State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Guan
authors.affiliation: Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China. Electronic address: zhangcy@ems.hrbmu.edu.cn.
authors.forename: Chunyu
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China; Key Laboratory of Medical Genetics, Harbin Medical University, Heilongjiang Higher Education Institutions, Harbin 150081, China. Electronic address: fusb@ems.hrbmu.edu.cn.
authors.forename: Songbin
authors.initials: S
authors.lastname: Fu
authors.affiliation: Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China. Electronic address: jinyan@ems.hrbmu.edu.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jin
mesh_terms: D021581:Active Transport, Cell Nucleus; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006657:Histones / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D034622:RNA Interference; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014162:Transfection; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; C109198:CIB1 protein, human; D002135:Calcium-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D009687:Nuclear Proteins; C402464:SERTAD1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: DDR; Genomic instability; Ovarian cancer; SEI1; SERTAD1