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A disintegrin and metalloprotease 8 (ADAM8), also known as CD156. Its basic structure is composed of highly conserved sequences, which are divided into 8 domains. From the N-terminus to the C-terminus, the signal peptide, the leader domain, the metalloprotease domain, the de-integrin domain, the cysteine-rich Domain, epidermal growth factor domain, transmembrane domain, and cytoplasmic domain. At the same time, due to the presence of the metalloproteinase domain and the de-integrase domain in the ADAM8 outer domain, it is also known as disintegrin-metalloproteinase.
Studies have shown that the physiological functions of ADAM8 mainly include the following two aspects: (1) ADAM8 has the function of proteolytic enzyme, which can release the extracellular functional region of cell surface proteins, thereby affecting the function of various cytokines and participating in the degradation of ECM. (2) ADAM8 can compete with matrix proteins for binding to integrin and participate in the regulation of cell signaling, cell cycle, cell morphology, and cell movement.
Figure 1. Structure of ADAM8 and its catalytic activity. (Yim, et al. 2016)
ADAM8 and Lung Cancer
Studies have shown that the expression of ADAM8 in non-small cell lung cancer (NSCLC) tissues is significantly higher than that of normal control tissues. Tissue microarray results show that There is a certain correlation between ADAM8 expression and tumor cell lymph node metastasis and TNM (tumor node metastasis) staging. The higher the staging, the more obvious the lymph node metastasis of tumor cells, and the higher the expression of corresponding ADAM8.
Moreover, glia analysis showed that the lung cancer cell lines NIH3T3 and COS-7 transfected with ADAM8 cDNA showed significantly enhanced invasive activity on Matrigel compared with cell lines transfected with mock phage, indicating high ADAM8 Expression is beneficial to the invasion and metastasis of tumor cells. In addition, the results also showed that there was no significant difference in the expression level of ADAM8 between squamous cell carcinoma and adenocarcinoma. This result is consistent with the results of Zhang et al. The above results indicate that overexpression of ADAM8 is closely related to the metastasis of NSCLC. Therefore, ADAM8 can be used as an auxiliary diagnostic method for NSCLC in clinical practice and has important clinical value.
ADAM8 and Liver Cancer
Studies have shown that ADAM8 protein is abnormally expressed during the development of pancreatic cancer and is closely related to the metastasis of pancreatic cancer cells. The study found that the expression of ADAM8 was significantly increased in pancreatic ductal adenocarcinoma, and the increase of ADAM8 protein and mRNA levels was negatively correlated with the survival time of patients. However, after silencing ADAM8 gene, the invasiveness of pancreatic cancer cells was significantly inhibited. The tumor cell proteolytic enzyme activity in the culture supernatant was significantly decreased.
Through observing the migration ratio of fluorescently labeled pancreatic cancer cells on the basement membrane, Puolakkainen et al. found that anti-inflammatory macrophages can promote the migration of tumor cells in the pancreatic cancer basement membrane by inducing the expression of ADAM8. After analyzing the pancreatic ductal adenocarcinoma cells with different ADAM8 expression, Schlomann et al. found that the migration and permeation of pancreatic ductal adenocarcinoma cells are closely related to the expression level of ADAM8, and mechanism studies have shown that ADAM8 can regulate a variety of matrix metalloproteinases (MMPs) activity to control the metastasis of pancreatic ductal adenocarcinoma.
ADAM8 and Liver Cancer
Clinical studies have shown that the expression of ADAM8 is closely related to the clinicopathological features of liver cancer and the survival of patients. Zhang et al. found that the expression of ADAM8 was closely related to tumor size, differentiation, recurrence and metastasis of liver cancer patients by immunohistochemical analysis of tissue samples from 105 patients with liver cancer. Survival analysis showed that high expression of ADAM8 can lead to poor prognosis in patients with liver cancer. In addition, multivariate analysis showed that the expression level of ADAM8 is an independent prognostic parameter for overall survival in patients with liver cancer.
Zhang et al. found that the expression of ADAM8 in liver tumor tissues was significantly higher than that in normal liver tissues by transplanting HepG2 cells into nude mice. The results also found that the high expression of ADAM8 is positively correlated with the level of serum alpha fetoprotein (AFP), tumor size, histological differentiation, stage of tumor development, and the probability of tumor recurrence and metastasis. Knockout of ADAM8 by lentiviral vector can significantly reduce cell growth, migration and invasion in vitro. The in vivo results are consistent with in vitro.
ADAM8 and Breast Cancer
ADAM8 is overexpressed in a variety of breast cancer tissues, and experiments have shown that ADAM8 is closely associated with breast cancer metastasis. Studies have shown that the use of microarray data analysis can determine that ADAM8 is one of the downstream targets of the NF-κB RelB multistage pathway, which can promote breast cancer invasion. After using breast cancer subtype microarray stratification studies, researchers found that the expression of ADAM8 gene in heterogeneous grades and subtypes was heterogeneous in all stages of in situ breast cancer to invasive breast cancer. A publicly available microarray analysis database by Romagnoli et al. showed that ADAM8 is often overexpressed in highly aggressive breast cancer, such as triple-negative breast cancer, and is closely associated with poor prognosis.