title: Transformation of human ovarian surface epithelial cells by Krüppel-like factor 8.
abstract: We have previously demonstrated that Krüppel-like factor 8 (KLF8) participates in oncogenic transformation of mouse fibroblasts and is highly overexpressed in human ovarian cancer. In this work, we first correlated KLF8 overexpression with the aggressiveness of ovarian patient tumors and then tested if KLF8 could transform human ovarian epithelial cells. Using the immortalized non-tumorigenic human ovarian surface epithelial cell line T80 and retroviral infection, we generated cell lines that constitutively overexpress KLF8 alone or its combination with the known ovarian oncogenes c-Myc, Stat3c and/or Akt and examined the cell lines for anchorage-independent growth and tumorigenesis. The soft agar clonogenic assay showed that T80/KLF8 cells formed significantly more colonies than the mock cells. Interestingly, the cells expressing both KLF8 and c-Myc formed the largest amounts of colonies, greater than the sum of colonies formed by the cells expressing KLF8 and c-Myc alone. These results suggested that KLF8 might be a weak oncogene that works cooperatively with c-Myc to transform ovarian cells. Surprisingly, overexpression of KLF8 alone was sufficient to induce tumorigenesis in nude mice resulting in short lifespan irrespective of whether the T80/KLF8 cells were injected subcutaneously, intraperitoneally or orthotopically into the ovarian bursa. Histopathological studies confirmed that the T80/KLF8 tumors were characteristic of human serous ovarian carcinomas. Comparative expression profiling and functional studies identified the cell cycle regulators cyclin D1 and USP44 as primary KLF8 targets and effectors for the T80 transformation. Overall, we identified KLF8 overexpression as an important factor in human ovarian carcinoma pathogenesis.
authors.affiliation: Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL, USA.
authors.forename: H
authors.initials: H
authors.lastname: Lu
authors.affiliation: Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL, USA.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Urvalek
authors.affiliation: Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL, USA.
authors.forename: T
authors.initials: T
authors.lastname: Li
authors.affiliation: Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, FL, USA.
authors.forename: H
authors.initials: H
authors.lastname: Xie
authors.affiliation: Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL, USA.
authors.forename: L
authors.initials: L
authors.lastname: Yu
authors.affiliation: Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D010053:Ovary / Q000473:pathology; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases / Q000235:genetics / Q000378:metabolism
chemical_list: C530104:CCND1 protein, human; C507402:KLF8 protein, human; D051741:Kruppel-Like Transcription Factors; D012097:Repressor Proteins; D019938:Cyclin D1; C579216:USP44 protein, human; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases