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.
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Authors | Wei Rao, Haowen Li, Feifei Song, Renfeng Zhang, Qinqin Yin, Ying Wang, Yebin Xi, Hailiang Ge |
Journal | Carcinogenesis
(Carcinogenesis)
Vol. 35
Issue 7
Pg. 1573-81
(Jul 2014)
ISSN: 1460-2180 [Electronic] England |
PMID | 24667688
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]. |
Chemical References |
- Antigens, Neoplasm
- RNA, Small Interfering
- Receptor, IGF Type 1
- Mitogen-Activated Protein Kinases
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Topics |
- Animals
- Antigens, Neoplasm
(chemistry, genetics, metabolism)
- Apoptosis
- Blotting, Western
- Cell Cycle
- Cell Movement
- Cell Proliferation
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Immunoenzyme Techniques
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Mitogen-Activated Protein Kinases
(metabolism)
- Neoplasm Invasiveness
- Neoplasms
(metabolism, pathology)
- Ovarian Neoplasms
(metabolism, pathology)
- Protein Array Analysis
- RNA, Small Interfering
(genetics)
- Receptor, IGF Type 1
(antagonists & inhibitors, genetics, metabolism)
- Tumor Cells, Cultured
- Xenograft Model Antitumor Assays
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