title: Sohlh2 inhibits ovarian cancer cell proliferation by upregulation of p21 and downregulation of cyclin D1.
abstract: Spermatogenesis and oogenesis basic helix-loop-helix (bHLH) transcription factor 2 (Sohlh2) functions as a bhlh transcription factor to regulate mouse germ cell differentiation. Our previous data showed that Sohlh2 was highly expressed in human normal tissues, but low level of Sohlh2 was observed in many cancer cell lines, suggesting a possible role of Sohlh2 in tumorigenesis. In this study, we examined this possibility by using immunohistochemistry, MTT, 5-bromo-2-deoxyuridine, clonogenic assay and tumor xenograft techniques. Our results showed that the expression of Sohlh2 was decreased in epithelial ovarian carcinoma (EOC) tissues compared with benign ovarian tumors and ovarian tumors with low malignant potential. Forced expression of Sohlh2 led to a significant reduction in cancer cell proliferation in vitro and tumorigenesis in nude mice. Conversely, silencing of Sohlh2 enhanced ovarian cancer cell proliferation. Furthermore, Sohlh2 had opposite effects on its two direct targets p21 and cyclin D1: overexpression of Sohlh2 upregulated p21 but downregulated cyclin D1 expression. p21 knockdown could reverse the effects of Sohlh2 overexpression on inhibiting cell proliferation, and cyclin D1 knockdown could reverse the effects of Sohlh2 ablation on promoting cell proliferation. Thus, our data indicate that Sohlh2 likely functions as a tumor suppressor in EOCs, which is achieved by inducing p21 expression but repressing cyclin D1 expression.
authors.affiliation: Key Laboratory of the Ministry of Education for Experimental Teratology, Department of Histology and Embryology and Department of Pathology, School of Medicine, Shandong University, Jinan 250012, PR China, Department of Obstetrics and Gynecology, Provincial Hospital Affiliated to Shandong University, Jinan 250021, PR China and Department of Human Anatomy, School of Medicine, Shandong University, Jinan 250012, PR China.
authors.forename: Haiyu
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Key Laboratory of the Ministry of Education for Experimental Teratology, Department of Histology and Embryology and Department of Pathology, School of Medicine, Shandong University, Jinan 250012, PR China, Department of Obstetrics and Gynecology, Provincial Hospital Affiliated to Shandong University, Jinan 250021, PR China and Department of Human Anatomy, School of Medicine, Shandong University, Jinan 250012, PR China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Key Laboratory of the Ministry of Education for Experimental Teratology, Department of Histology and Embryology and Department of Pathology, School of Medicine, Shandong University, Jinan 250012, PR China, Department of Obstetrics and Gynecology, Provincial Hospital Affiliated to Shandong University, Jinan 250021, PR China and Department of Human Anatomy, School of Medicine, Shandong University, Jinan 250012, PR China.
authors.forename: Shufang
authors.initials: S
authors.lastname: Ji
authors.affiliation: Department of Pathology, School of Medicine, Shandong University, Jinan 250012, PR China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Hao
authors.affiliation: Department of Obstetrics and Gynecology, Provincial Hospital Affiliated to Shandong University, Jinan 250021, PR China and.
authors.forename: Yulan
authors.initials: Y
authors.lastname: Mu
authors.affiliation: Department of Human Anatomy, School of Medicine, Shandong University, Jinan 250012, PR China.
authors.forename: Jinhao
authors.initials: J
authors.lastname: Sun
authors.affiliation: Key Laboratory of the Ministry of Education for Experimental Teratology, Department of Histology and Embryology and Department of Pathology, School of Medicine, Shandong University, Jinan 250012, PR China, Department of Obstetrics and Gynecology, Provincial Hospital Affiliated to Shandong University, Jinan 250021, PR China and Department of Human Anatomy, School of Medicine, Shandong University, Jinan 250012, PR China haojing@sdu.edu.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: Hao
mesh_terms: D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D000077216:Carcinoma, Ovarian Epithelial; D002453:Cell Cycle; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D005187:Fallopian Tubes / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010053:Ovary / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019938:Cyclin D1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D012333:RNA, Messenger; C530104:CCND1 protein, human; C493956:CDKN1A protein, human; C000588675:SOHLH2 protein, human