Relationship Between NF-?B, MMP-9, And MICA Expression In Pituitary Adenomas Reveals A New Mechanism Of Pituitary Adenomas Immune Escape

Pituitary adenomas, derived from epithelial tumors, are clinically common tumor. Currently,The development of a tumor is a complex process with multiple stages that are closely related to the body's immune status, as well as the expression levels of multiple genes. As an important nuclear transcription factor, nuclear factor kappa B (NF-?B) plays a key role in signaling pathways for gene regulation concerning inflammation, immunity, cell proliferation, apoptosis, and other physiological or pathological activities, thus increasing the expression levels of multiple proteins, including MHC class I chain-related molecule A (MICA) and matrix metalloproteinase 9 (MMP-9) in human osteosarcoma. As a classic HLA class 1 molecule, MICA expressed on the surface of most epithelial tumor cells. There are two major isoforms of MICA:the membrane type, (mMICA) expressed on the cell surface; and the secretory type (sMICA), in the tumor microenvironment and blood. mMICA mediates immune cytotoxic effects on tumor cells in combination with NKG2D, while sMICA decreases the expression of NKG2D on NK cells, leading to tumor immune escape by reducing the cytotoxic activity of NK cells and the secretion of cytokines. The production of sMICA can occur via the hydrolysis of mMICA by MMPs. MMP-9 is an important gelatin enzyme of the MMP family and plays a key role in the degradation of the extracellular matrix. Tumor cells can release MICA,The proess can be blocked by inhibition of MMPs, concomitantly causing accumulation of MICA on the cell surface. The MMPs of tumor cells become sMICA via proteolytic shedding mMICA which may modulate NKG2D-mediated tumor immune surveillance. This study examined the relationships between the expression levels of NF-?B, MMP-9, and MICA in pituitary adenomas to provide a histological basis for the mechanistic research of the NKG2D-MICA pathway in pituitary adenomas immune escape.Immunohistochemistry case slice sources-Pathology randomly selected 40 paraffin-embedded Prolactinoma pituitary adenomas tissue sections(12 males and 28 females) and 30 paraffin-embedded Nonfunctional pituitary adenomas tissue sections(18 males and 12 females) in Binzhou Medical University Affiliated Hospital, including. Histological types:Prolactinoma pituitary adenomas specimens were obtained from 20 patients (12 males and 8 females) and Nonfunctional pituitary adenomas specimens were obtained from 17 patients (9 males and 8 females) diagnosed with pituitary adenoma by postoperative pathological confirmation that underwent complete resection in Neurosurgery at the Binzhou Medical University Affiliated Hospital between June 2011 and December 2013 for Quantitative real-time PCR and Western Blot. We also collected 15 cases of normal brain tissue from Binzhou Medical University Affiliated Hospital for Quantitative real-time PCR and Western Blot, similarly. Meanwhile, we collected 20 cases of pituitary adenomas patients and 20 cases of healthy human peripheral blood serum for ELISA test. All patients had no immune-related diseases and did not use immunosuppressive drugs. The patients obtain permission in this study and get Binzhou Medical College Hospital Medical Ethics Committee agree. Adenoma patients aged 28 to 78 years, and normal control group aged 25 to 68 years.Prolactinoma tissue was detected by immunohistochemical staining method to find expression of NF-?B, MMP-9, MICA and p-NF-KB protein, in the non-functioning pituitary adenoma tissues and normal brain tissue; Western Blot detected NF-?B, MMP-9, the expression of MICA and p-NF-?B in protein prolactinoma tissue, non-functioning pituitary adenoma tissues and normal brain tissue; ELISA method for detection of prolactin pituitary gland tumor patients, non-functioning pituitary adenoma patients and healthy human serum sMICA and expression of MMP-9; Qrt-PCR method was used to detect prolactinoma organizations, non-functioning pituitary adenoma tissues and normal brain tissue to find NF-Kb mRNA, MMP-9 mRNA, the expression of MICA mRNA.AND study NF-Kb,MMP-9, MICA correlation.by the Spearman correlation coefficient,NF-?B, MMP-9, the expression of MICA and p-NF-KB protein and NF-Kb mRNA, MMP-9 mRNA, MICA mRNA expression in prolactinoma organizations, non-functioning pituitary adenoma tissue were significantly higher than normal brain tissue,the difference was statistically significant. The serum of sMICA and MMP-9 in prolactinoma patients and non-functioning pituitary adenoma patients were significantly higher than in healthy human serum levels; Spearman correlation analysis show that MICA and NF-kB and MMP-9 have a significant positive correlation.This paper confirms the existence of NF-?B in patients of prolactin and nonfunctioning pituitary adenomas pituitary adenomas expression of MMP-9,MICA and p-NF-KB protein; peripheral blood sMICA, MMP-9 levels significantly increased. Spearman correlation analysis shows that NF-?B and MICA and MMP-9 has a significant positive correlation. Thus speculated: in pituitary adenomas, NF-?B activation the one hand promote MICA protein highly expression, on the other hand to induce high expression of MMP-9 protein MICA to hydrolyze MICA into sMICA, to promote tumor cell immune escape. How to improve the NKG2D receptor density surface of immune effector cells and enhance the expression of the tumor cell surface MICA protein and inhibit the formation of MICA protein shedding sMICA become a new part to immune escape of tumor cells.Avoid,in this study, NF-?B may provide histological basis for the regulation of pituitary adenomas MICA protein expression and shedding.