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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.
AuthorsWei Rao, Haowen Li, Feifei Song, Renfeng Zhang, Qinqin Yin, Ying Wang, Yebin Xi, Hailiang Ge
JournalCarcinogenesis (Carcinogenesis) Vol. 35 Issue 7 Pg. 1573-81 (Jul 2014) ISSN: 1460-2180 [Electronic] England
PMID24667688 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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
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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