title: Sohlh2 inhibits human ovarian cancer cell invasion and metastasis by transcriptional inactivation of MMP9.
abstract: Identifying key mediators of cancer invasion and metastasis is crucial to the development of new and more effective therapies. We previously identified Sohlh2 as an important inhibitor of ovarian cancer cell proliferation. However, the function of Sohlh2 in cell migration and invasion remains unknown. In this paper, we report a novel Sohlh2 to MMP9 signaling pathway in the invasive ovarian cancer. Using immunohistochemistry staining, we revealed Sohlh2 expression was inversely correlated with the invasive human ovarian cancers. In vitro experiments, forced expression of Sohlh2 led to a significant reduction in cancer cell migration and invasion. Conversely, silencing of Sohlh2 enhanced ovarian cancer cell migration and invasion. Experiments using nude mice demonstrated that the ectopic Sohlh2 expression inhibited the HO8910 cell capability of the metastasis to the lungs and livers. Ectopic overexpression of Sohlh2 in the invasive HO8910 cells reduced the MMP9 expression, whereas Sohlh2 knockdown from the non-invasive, SKOV3 cells increased the MMP9 expression. Promoter activation and binding analyses indicated that Sohlh2 repressed the MMP9 expression by directly acting on the MMP9 gene promoter. Inhibition of MMP9 dramatically blocked the Sohlh2 knockdown-enhanced SKOV3 cell invasion, and ectopic expression of MMP9 compensated for the anti-invasive activity of Sohlh2 in HO8910 cells. Overall, these results demonstrate for the first time that Sohlh2 functions as a tumor metastasis suppressor. Modulation of Sohlh2 expression has the potential to be a target for cancer therapy. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Department of Histology and Embryology, School of Medicine, Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan, PR China.
authors.forename: Haiyu
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pathology, School of Medicine, Shandong University, Jinan, PR China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Hao
authors.affiliation: Department of Galactophore Surgery, Weifang People's Hospital, Weifang, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Histology and Embryology, School of Medicine, Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan, PR China.
authors.forename: Shufang
authors.initials: S
authors.lastname: Ji
authors.affiliation: Department of Histology and Embryology, School of Medicine, Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan, PR China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Histology and Embryology, School of Medicine, Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan, PR China.
authors.forename: Wenfang
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Histology and Embryology, School of Medicine, Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan, PR China.
authors.forename: Qinghao
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Department of Human Anatomy, School of Medicine, Shandong University, Jinan, PR China.
authors.forename: Jinhao
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Histology and Embryology, School of Medicine, Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Hao
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D020780:Matrix Metalloproteinase 9; C000588675:SOHLH2 protein, human; C579270:MMP9 protein, human
keywords: MMP9; Sohlh2; epithelial ovarian carcinoma; invasion; metastasis