Id-1 promotes tumorigenicity and metastasis of human esophageal cancer cells through activation of PI3K/AKT signaling pathway.

Abstract

Id-1 (inhibitor of differentiation or DNA binding) is a helix-loop-helix protein that is overexpressed in many types of cancer including esophageal squamous cell carcinoma (ESCC). We previously reported that ectopic Id-1 expression activates the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling pathway in human esophageal cancer cells. In this study, we confirmed a positive correlation between Id-1 and phospho-AKT (Ser473) expressions in ESCC cell lines, as well as in ESCC on a tissue microarray. To investigate the significance of Id-1 in esophageal cancer progression, ESCC cells with stable ectopic Id-1 expression were inoculated subcutaneously into the flank of nude mice and were found to form larger tumors that showed elevated Ki-67 proliferation index and increased angiogenesis, as well as reduced apoptosis, compared with control cells expressing the empty vector.The Id-1-overexpressing cells also exhibited enhanced metastatic potential in the experimental metastasis assay. Treatment with the PI3K inhibitor LY294002 attenuated the tumor promotion effects of Id-1, indicating that the effects were mediated by the PI3K/AKT signaling pathway. In addition, our in vitro experiments showed that ectopic Id-1 expression altered the expression levels of markers associated with epithelial-mesenchymal transition and enhanced the migration ability of esophageal cancer cells. The Id-1-overexpressing ESCC cells also exhibited increased invasive potential, which was in part due to PI3K/AKT-dependent modulation of matrix metalloproteinase-9 expression. In conclusion, our results provide the first evidence that Id-1 promotes tumorigenicity and metastasis of human esophageal cancer in vivo and that the PI3K inhibitor LY294002 can attenuate these effects.

• Authors: Bin Li, Sai Wah Tsao, Yuk Yin Li, Xianghong Wang, Ming Tat Ling, Yong Chuan Wong, Qing Yu He, Annie L M Cheung
• Journal: International journal of cancer (Int J Cancer) Vol. 125 Issue 11 Pg. 2576-85 (Dec 01 2009) ISSN: 1097-0215 [Electronic] United States
• PMID: 19551863 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ID1 protein, human
• Inhibitor of Differentiation Protein 1
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Apoptosis
• Blotting, Western
• Carcinoma, Squamous Cell (metabolism, pathology)
• Cell Movement
• Cell Proliferation
• Esophageal Neoplasms (metabolism, pathology)
• Female
• Fluorescent Antibody Technique
• Humans
• Immunoenzyme Techniques
• Inhibitor of Differentiation Protein 1 (physiology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Invasiveness
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction
• Tumor Cells, Cultured
• Wound Healing
• Xenograft Model Antitumor Assays