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A disintegrin and metalloproteinase with thrombospondin motifs 8 are abbreviated as ADAMTS8. ADAMTS8, also known as METH-2, is an 890 amino acid multidomain protein comprising a TSR similar to the ADAMTS5 2 layer. Mouse Adamts8 is located on chromosome 9 and human ADAMTS8 is located on chromosome 11q25. The metalloproteinase can be classified into a subset of proteoglycans.
ADAMTS8 is secreted to the ECM via its N-terminal signal peptide. It also has a precursor that is most likely to help it maintain the incubation period of the enzyme. A furin cleavage site "RTKR" exists between the prodomain and the metalloproteinase domain. The metalloproteinase domain is characterized by a zinc-binding motif "HTLAHELG". The helper domain includes a disintegrin domain, two TSRs, a cysteine-rich domain, and a spacer domain. Even though the mature protein form has a theoretical molecular weight of 75 kDa, a 95 kDa size was observed in SDS-PAGE indicating possible glycosylation of the metalloprotease. Autocatalytic or other protease-mediated cleavage was also observed, resulting in a shorter isoform of the metalloproteinase.
ADAMTS8 has a narrow tissue distribution, showing moderate to high levels of normal human tissue including adult and fetal lungs, aorta, brain, fetal heart, fetal kidney, appendix, and bladder. Like ADAMTS-1, ADAMTS8 is expressed in the normal brain of adults. It was found by Northern blot that ADAMTS8 is mainly expressed in adult tissues such as lung, brain, heart, and placenta. Compared to ADAMTS1, the expression of ADAMTS8 is limited and less abundant. In fetal tissues, ADAMTS8 is abundantly expressed in the lung and moderately expressed in the brain and kidney. There is no expression in many primary cell lines of endothelial origin, dermal fibroblasts and vascular smooth muscle cells.
ADAMTS8 and Angiogenesis
Like ADAMTS1, ADAMTS8 is also an effective endogenous angiogenesis inhibitor. ADAMTS8 inhibits endothelial cell proliferation in a reversible manner. This inhibition is also specific for endothelial cell-derived cells because the proliferation rate of smooth muscle after fibroblast and ADAMTS8 treatment is not affected. Using CAM assays and Matrigel plug assays, studies have shown that ADAMTS8 inhibits angiogenesis in vivo. It is worth noting that the inhibitory effect of ADAMTS8 is in the nanomolar range and is more effective than the endogenous angiogenesis inhibitor TSP1.
ADAMTS8 and Rheumatoid Arthritis
Rheumatoid arthritis (RA) is autoimmune arthritis with early manifestations of increased levels of inflammation, synovial cell proliferation, and vasospasm formation, followed by articular cartilage and bone destruction, which ultimately leads to joint deformity and loss of function.
Therefore, how to effectively control the activity of the disease and the progress of joint deformity will be beneficial to the prognosis of the disease.ADAMTS8 is a cellular glycoprotein that is mainly expressed on the surface of immune cells and is involved in the inflammatory response. The expression of ADAMTS8 in synovial neutrophils of patients with RA was higher than that of blood-derived neutrophil ADAMTS8, and the expression of ADAMTS8 in synovial neutrophils was correlated with the degree of joint inflammation. And ADAMTS8 enhances osteoclast activity and aggravates bone destruction. These findings suggest that ADAMTS8 is involved in the pathogenesis of RA through the inflammatory response pathway.
ADAMTS8 and Intervertebral Disc Degeneration
Intervertebral disc degeneration (IDD) is the pathological basis of many spinal degenerative diseases. Although its mechanism is still not fully understood, it is generally believed that the significant increase in the extracellular matrix (ECM) degradation metabolism of the intervertebral disc is one of the important reasons. Related studies have shown that ADAMTS8 can cleave fibronectin (FN) into FN-f containing N-terminal to VRAA271 site at specific sites in articular cartilage, thereby increasing the accumulation of FN-f. FN loses its original biological function and function and aggravates the cartilage degeneration process.
ADAMTS8 and Cancer
Choi et al. found that the ectopic expression of ADAMTS8 significantly reduced the phosphorylation of MEK and ERK by studying the effects of ADAMTS8 expression on some downstream effectors of EGFR. ADAMTS8 inhibits cell migration by disrupting stress fiber formation. These findings indicate that ADAMTS8 acts as a pro-apoptotic TSG by inhibiting EGFR-MEK-ERK signaling, which is normally silenced by promoter CpG methylation in common cancers.
Figure 1. Proposed mechanism of the tumor suppressive function of ADAMTS8 through suppressing the EGFR–MEK–ERK signaling pathway. (Choi, et al. 2014)
Chen et al. found that ADAMTS8 is down-regulated in gastric cancer cell lines compared to normal gastric cells. The expression of ADAMTS8 in gastric cancer cell lines SGC7901, MCG803, BGC823 and MKN45 was lower compared to the normal gastric mucosal cell line GES1. We also found that ADAMTS8 is less expressed in gastric cancer tissues but is widely expressed in non-tumor tissues. This study provides evidence that ADAMTS8 may play a role as a tumor suppressor in gastric cancer. Furthermore, gastric cancer with lymph node metastasis was found to exhibit significantly lower ADAMTS8 expression. The results may indicate a possible association between ADAMTS8 and gastric cancer invasiveness.
ADAMTS8 expresses epigenetic silencing in brain cancer, non-small cell lung cancer, and thyroid cancer. Reports indicate that 67% of lung adenocarcinomas and 50% of lung squamous cell carcinomas have abnormal hypermethylation of ADAMTS8, but the methylation status of the ADAMTS8 promoter is independent of age, differentiation, or TNM status. The study found that the methylation of the ADAMTS8 gene was significantly higher in primary gastric tumors than in non-tumor tissues. These data suggest that DNA methylation may play an important role in the expression of ADAMTS8 in gastric cancer cells and tissues. In addition, lower levels of ADAMTS8 mRNA in gastric cancer are closely associated with higher levels of gene methylation.
Studies by Dunn et al have shown that the expression of ADAMTS8 is down-regulated in normal brain and brain tumors. The study analyzed 22 gliomas, 4 meningiomas, 6 metastases, 1 hemangioblastoma and 1 medulloblastoma, all of which showed a decrease in ADAMTS8 expression.
Kilic et al. have shown that ADAMTS8 is highly expressed in gastric cancer and lymph node metastasis, indicating that ADAMTS8 plays an important role in carcinogenesis and lymphatic metastasis. Results From current research, it is suggested that ADAMTS8 may be a promising target for novel and alternative treatment of gastric cancer.