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 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 ERK1/2-Hsp27; similarly, a higher level of p-IGF-1R and ERK1/2-Hsp27 signaling were 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 siRNA and with the chemical inhibitor Linsitinib (OSI-906). By either method, tumorigenesis was inhibited regardless of OVA66 expression; thus, mechanistically, IGF-1R likely lies downstream of OVA66 in cancer cells. We also found that OVA66 regulates expression of 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.