title: Exon 4 deletion variant of epidermal growth factor receptor enhances invasiveness and cisplatin resistance in epithelial ovarian cancer.
abstract: Recently, de4 EGFR, a variant of epidermal growth factor receptor (EGFR) with exon 4 deletion, was identified in glioblastoma and ovarian cancer. However, its biological function on ovarian cancer is still not clear. In this study, the expression profile of de4 EGFR and its contribution to epithelial ovarian cancer cells proliferation, invasiveness and drug resistance were studied. Our results showed that 48.6% (35/72) of epithelial ovarian cancer tissues had de4 EGFR expression and the expression ratio positively correlated with clinical stages. Compared with EGFR transfectants, de4 EGFR transfectants exhibited significantly higher level of invasiveness in vitro. Mechanistically, de4 EGFR significantly upregulated the extracellular regulated protein kinase, AKT, focal adhesion kinase (FAK) and Src phosphorylation and matrix metalloproteinase-9 expression while downregulated the expression of E-cadherin. Additionally, knockdown of FAK obviously suppressed de4 EGFR-induced invasiveness. Interestingly, de4 EGFR transfectants displayed significantly lower sensitivity to cisplatin than EGFR transfectants, which could be ascribed to the upregulation of Bcl-2 and downregulation of BAD in the de4 EGFR transfectants. Collectively, these results demonstrate that de4 EGFR plays an important role in the invasiveness and cisplatin resistance in epithelial ovarian cancer cells and may provide a new potential therapeutic target for epithelial ovarian cancer.
authors.affiliation: Obstetrics & Gynecology Hospital of Fudan University, Shanghai 200011, China and.
authors.forename: Pengnan
authors.initials: P
authors.lastname: Zhang
authors.forename: Pengfei
authors.initials: P
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Zhou
authors.forename: Hua
authors.initials: H
authors.lastname: Jiang
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhang
authors.forename: Bizhi
authors.initials: B
authors.lastname: Shi
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Pan
authors.forename: Huiping
authors.initials: H
authors.lastname: Gao
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.forename: Zonghai
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D000077216:Carcinoma, Ovarian Epithelial; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics*; D005091:Exons / Q000235:genetics*; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; D066246:ErbB Receptors; D051416:Focal Adhesion Protein-Tyrosine Kinases; D002945:Cisplatin