MICA Regulates the Expression of DAP10 and Signals through an Independent PI3K Pathway in NKG2D Positive Cervical Cancer Cells

Abstract

NKG2D receptor engages ligands such as MICA and MICB, which activates cytotoxicity in NK cells leading to the destruction of tumour cells expressing these ligands. In normal human lymphoid cells the association of DAP10 with NKG2D is essential for signalling and important for its cell surface expression. However, the mechanism of the NKG2D/DAP10 complex upregulation is not completely understood in cancer. Also, the role of DAP10 in the activation of the PI3/AKT signaling pathway in cervical cancer has not been fully elucidated. In the present study, we investigated the role of MICA in the regulation of DAP10 in cervical cancer cells. First, we demonstrate the presence of the NKG2D/DAP10 complex in different tumour cell lines by flow cytometry. Also, we demonstrate that MICA upregulates the expression of DAP10 in cervical cancer cells in a time dependent manner by immunoblotting. We found that the AKT kinase is constitutively phosphorylated and MICA induced an increase in tyrosine phosphorylation. Furthermore, this activation is independent of the PI3K in cervical cancer cell lines as determined by immunoblotting and flow cytometry. Our results provide evidence supporting the notion that MICA functions as a stimulatory molecule to regulate the expression of the receptor adapter DAP10 in cervical cancer cells and thus may contribute to their proliferation and survival. The possibility that the NKG2D-DAP10 complex is widely expressed in different types of cancer may confer an advantage to transformed cells to survive in the tumour microenvironment and escape from the immune surveillance.