Abstract
Insulin-like growth factor binding protein-3 (IGFBP-3) plays an essential role in radiosensitivity of esophageal squamous cell carcinoma (ESCC). However, the underlying mechanism is not completely understood. Here, we observed that IGFBP-3 had favorable impact on the tumorigenicity of ESCC cells in nude mice by using an in vivo imaging system (IVIS) to monitor tumor growth treated with ionizing radiation (IR). Downregulation of IGFBP-3 expression enhanced tumor growth, inhibited anti-proliferative and apoptotic activity and result in IR resistance in vivo. Cell cycle antibody array suggested that silencing IGFBP-3 promoted transition from G0/G1 to S phase, perhaps though influencing Smad3 dephosphorylation and retinoblastoma protein (Rb) phosphorylation. Downregulation of P21 and P27, and upregulation of p-P27 (phospho-Thr187), cyclin-dependent kinase 2 (CDK2), and cyclin E1 might contribute to the G0/G1 to S phase transition promoted by IGFBP-3. Our results suggest that Smad3-P27/P21-cyclin E1/CDK2-phosphorylated retinoblastoma protein pathways might be involved in this IGFBP-3 mediated radiosensitivity transition in ESCC.
Highlights
A recent study showed that nimotuzumab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody that binds to the extracellular domain of the EGFR and inhibits epidermal growth factors binding, increases esophageal squamous cell carcinoma (ESCC) radiosensitivity dependent on the upregulation of IGFBP-317
A previous study reported that a novel molecule downstream of the EGFR in primary and immortalized human esophageal epithelial cells IGFBP-3 was suppressed by the activation of EGF-induced EGFRs in ESCC cell lines[17,21,22]
There is evidence that levels of IGFBP-3 in EGFR-overexpressing ESCC cells are responsible, for the increased radiosensitivity conferred by nimotuzumab, which improved the radiosensitivity of ESCC cells with high EGFR expression[17]
Summary
A recent study showed that nimotuzumab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody that binds to the extracellular domain of the EGFR and inhibits epidermal growth factors binding, increases ESCC radiosensitivity dependent on the upregulation of IGFBP-317. Reduced IGFBP-3 expression may be a risk factor for advanced clinicopathologic classification and poor patient survival and could serve as a prognostic marker for the evaluation of ESCC patients[18]. Given these findings and the biological importance of IGFBP-3, we sought to determine the role of IGFBP-3 in ESCC radiosensitivity and its potential mechanisms
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