The NKG D NKG DL
The NKG2D/NKG2DL system has an important role in tumor immune surveillance, and the NKG2D-activating receptor is expressed in various immune cells, including NK cells, NK T cells, and CD8+ T cells. MICA is one of the NKG2D ligands and is rarely expressed on healthy cells; however, its expression may increase because of a variety of cellular stresses, such as viral infection and malignancy transformation. MICA protein has 2 major isoforms in vivo, mMICA, which is located on the surfaces of cell membranes, and sMICA, which is secreted into tumor microenvironments and blood. MICA is highly expressed on a broad range of epithelial tumors, making them extremely susceptible to killing by NK cells. In contrast, tumors can escape the surveillance of the immune system through MICA shedding. sMICA binds to NKG2D and reduces its expression on the surface of NK cells by facilitating NKG2D internalization, which then inhibits the cytotoxicity of NK cells, thus promoting tumor immune escape. Chen et al. found that nuclear factor-kappa B, MMP-9, and MICA play roles in the immune escape of pituitary adenomas. Abnormal activation of the p38/MAPK pathway is closely related to tumor occurrence and development. The mechanism of p38/MAPK pathway activation is mediated by dual phosphorylation at the Thr-Gly-Tyr motif. In recent years, many studies have indicated that p38/MAPK-specific inhibitors could block MICA expression in endothelial cells, T cells, and thyroid cancer cells.18, 19, 20 These data indicate that the p38/MAPK pathway may regulate MICA expression through multiple mechanisms. In our study, the phospho-p38-positive rate was 100% in pituitary adenoma tissues, where it was expressed significantly greater than in normal make money tissues. Therefore, we conclude that the p38/MAPK pathway may have an important role in the occurrence and development of pituitary adenoma. Furthermore, we also found that MICA was overexpressed in pituitary adenoma tissues and was positively correlated to the expression of phospho-p38. This result indicated that the p38/MAPK pathway may regulate MICA expression in pituitary adenoma. MMP-9 is an important gelatin enzyme of the MMP family and is a downstream gene in the p38/MAPK pathway. Recent research demonstrated that the p38/MAPK pathway regulates the expression of many cytokines, transcription factors, and enzymes, for instance, tumor necrosis factor alpha, cyclooxygenase 2, matrix metalloproteinase 1, matrix metalloproteinase 2, and MMP-9. The p38/MAPK pathway regulates MMP-9 expression in breast cancer and bladder cancer cell lines,9, 22 and specific inhibition of the p38/MAPK pathway decreases MMP-9 secretion in tumor cells. We found that the expression of MMP-9 in pituitary adenomas was significantly greater than in normal brain tissues and that it was positively correlated with phospho-p38 expression, indicating that MMP-9 expression may be regulated by the p38/MAPK pathway in pituitary adenoma. Leifler et al. found that MMPs modify immune responses by cleaving a variety of receptors and adhesion molecules on cell surfaces, cytokines, and growth factors. Like the shedding of MICA, several studies showed that distinct MMPs are involved in different types of tumor cells. For instance, membrane-type matrix metalloproteinase 14 directly mediates MICA shedding, and MMP-9 may be involved in MICA shedding in osteosarcoma.7, 26 In this study, MMP-9, MICA, and phospho-p38 were overexpressed in pituitary adenoma tissues, and the expression levels of MMP-9 and MICA were positively correlated with the expression level of phospho-p38. In addition, we also found that the expression levels of sMICA and MMP-9 were significantly greater in the sera of patients with pituitary adenomas. Therefore, we speculated that the p38/MAPK pathway may increase MICA expression and induce the expression of MMP-9. MMP-9 mediates MICA shedding in pituitary adenoma cells, and sMICA then causes a decrease in the cytotoxicity of NK lymphocytes, which promotes immune escape in pituitary adenoma (Figure 6).