title: OVA66 increases cell growth, invasion and survival via regulation of IGF-1R-MAPK signaling in human cancer cells.
abstract: Ovarian cancer-associated antigen 66 (OVA66), also known as CML66 (GenBank Accession No. AF283301), was first identified in an ovarian carcinoma complementary DNA (cDNA) expression library and was shown to play a role in tumorigenesis. Here, we find that OVA66 influences tumorigenesis by regulating the type I insulin-like growth factor receptor (IGF-1R) signaling pathway. Stable knockdown of OVA66 in cancer cells attenuated phosphorylation of IGF-1R and extracellular signal-regulated kinase 1/2 (ERK1/2)-Hsp27; similarly, a higher level of p-IGF-1R and ERK1/2-Hsp27 signaling was also detected after OVA66 overexpression in HO8910 cells. In vivo knockdown of OVA66 both reduced tumor burden in nude mice and decreased phosphorylation of IGF-1R, ERK1/2 and hsp27. We blocked IGF-1R function both by small interfering RNA (siRNA) and with the chemical inhibitor Linsitinib (OSI-906). By either method, tumorigenesis was inhibited regardless of OVA66 expression; thus, mechanistically, IGF-1R, probably, lies downstream of OVA66 in cancer cells. We also found that OVA66 regulates expression of murine double minute 2 (MDM2); this attenuates ubiquitination of IGF-1R in response to IGF-1 stimulation and promotes active ERK1/2 signaling. Thus, we propose that combined overexpression of OVA66 and MDM2 promotes oncogenesis by enhancing activation of the IGF-1R-ERK1/2 signaling pathway.
authors.affiliation: School of Medicine, Shanghai Institute of Immunology, Shanghai Jiaotong University, 280 South Chongqing Road, Shanghai 200025, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Rao
authors.affiliation: School of Medicine, Shanghai Institute of Immunology, Shanghai Jiaotong University, 280 South Chongqing Road, Shanghai 200025, PR China.
authors.forename: Haowen
authors.initials: H
authors.lastname: Li
authors.affiliation: School of Medicine, Shanghai Institute of Immunology, Shanghai Jiaotong University, 280 South Chongqing Road, Shanghai 200025, PR China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Song
authors.affiliation: School of Medicine, Shanghai Institute of Immunology, Shanghai Jiaotong University, 280 South Chongqing Road, Shanghai 200025, PR China.
authors.forename: Renfeng
authors.initials: R
authors.lastname: Zhang
authors.affiliation: School of Medicine, Shanghai Institute of Immunology, Shanghai Jiaotong University, 280 South Chongqing Road, Shanghai 200025, PR China.
authors.forename: Qinqin
authors.initials: Q
authors.lastname: Yin
authors.affiliation: School of Medicine, Shanghai Institute of Immunology, Shanghai Jiaotong University, 280 South Chongqing Road, Shanghai 200025, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Medicine, Shanghai Institute of Immunology, Shanghai Jiaotong University, 280 South Chongqing Road, Shanghai 200025, PR China.
authors.forename: Yebin
authors.initials: Y
authors.lastname: Xi
authors.affiliation: School of Medicine, Shanghai Institute of Immunology, Shanghai Jiaotong University, 280 South Chongqing Road, Shanghai 200025, PR China gehl@shsmu.edu.cn.
authors.forename: Hailiang
authors.initials: H
authors.lastname: Ge
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D015153:Blotting, Western; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D040081:Protein Array Analysis; D034741:RNA, Small Interfering / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D034741:RNA, Small Interfering; D017526:Receptor, IGF Type 1; D020928:Mitogen-Activated Protein Kinases