Abstract
BackgroundCervical cancer represents the third most commonly diagnosed cancer and the fourth leading cause of cancer-related deaths in women worldwide. Natural killer (NK) cells play an important role in the defense against viruses, intracellular bacteria and tumors. NKG2D, an activating receptor on NK cells, recognizes MHC class I chain-related molecules, such as MICA/B and members of the ULBP/RAET1 family. Tumor-derived soluble NKG2D-ligands have been shown to down-modulate the expression of NKG2D on NK cells. In addition to the down-modulation induced by soluble NKG2D-ligands, it has recently been described that persistent cell-cell contact can also down-modulate NKG2D expression. The goal of this study was to determine whether the NKG2D receptor is down-modulated by cell-cell contact with cervical cancer cells and whether this down-modulation might be associated with changes in NK cell activity.ResultsWe demonstrate that NKG2D expressed on NKL cells is down-modulated by direct cell contact with cervical cancer cell lines HeLa, SiHa, and C33A, but not with non-tumorigenic keratinocytes (HaCaT). Moreover, this down-modulation had functional implications. We found expression of NKG2D-ligands in all cervical cancer cell lines, but the patterns of ligand distribution were different in each cell line. Cervical cancer cell lines co-cultured with NKL cells or fresh NK cells induced a marked diminution of NKG2D expression on NKL cells. Additionally, the cytotoxic activity of NKL cells against K562 targets was compromised after co-culture with HeLa and SiHa cells, while co-culture with C33A increased the cytotoxic activity of the NKL cells.ConclusionsOur results suggest that differential expression of NKG2D-ligands in cervical cancer cell lines might be associated with the down-modulation of NKG2D, as well as with changes in the cytotoxic activity of NKL cells after cell-cell contact with the tumor cells.
Highlights
Cervical cancer represents the third most commonly diagnosed cancer and the fourth leading cause of cancer-related deaths in women worldwide
We investigated the expression of UL-16 Binding Protein (ULBP) family proteins (MIC family expression has been already described in a previous report) in cervical cancer cell lines and the possible modulation of the Natural-killer group 2 member D (NKG2D) receptor in a well-established Natural killer (NK) cell line (NKL), as well as in fresh NK cells
NKG2D-ligands are differentially expressed by cervical cancer cell lines and non-tumorigenic keratinocytes Depending on their origin, cancer cell lines may express different levels of NKG2D-ligands [33]
Summary
Cervical cancer represents the third most commonly diagnosed cancer and the fourth leading cause of cancer-related deaths in women worldwide. NKG2D, an activating receptor on NK cells, recognizes MHC class I chainrelated molecules, such as MICA/B and members of the ULBP/RAET1 family. One of the best-characterized activating receptors is NKG2D, which recognizes two structurally distinct families of ligands. One of these is composed of MHC class I chainrelated A and B (MICA/B) molecules. The other family of ligands is composed of the UL16-binding proteins (ULBPs) 1 to 6, originally identified through interactions with the human cytomegalovirus glycoprotein UL16 [13,14] Both families are expressed on a wide range of epithelial tumors, such as colon carcinoma, breast cancer, neuroblastoma, and others [13,15,16,17,18]
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