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A disintegrin and metalloproteinase with thrombospondin motifs 9 is also known as ADAMTS9. ADAMTS9 is located on chromosome 3p14.2-14.3. ADAMTS9 contains 15 layers of TSR and Ç-ends in a GON-1 domain. The GON-1 domain is highly homologous to the C. elegans gon-1 gene involved in gonadal development. Therefore, ADAMTS9 is an ortholog of the gon-1 gene of Caenorhabditis elegans. This metalloprotease also belongs to a subgroup of proteoglycans because it has the same catalytically active site as ADAMTS1 and can cleave versican and aggrecan.
Since Northern blot was unable to detect any ADAMTS9 in fetal and adult tissues, RT-PCR was used to study the expression of this protease. The highest expression of ADAMTS9 was observed in human adult tissues such as the heart, placenta and skeletal muscle. Low expression was observed in the spleen, thymus, prostate and small intestine. ADAMTS9 is also expressed in the testis and ovary, revealing its possible role in gonadal development, which can be attributed to its GON-1 domain.
Available data indicate that ADAMTS9 is an independent angiogenesis inhibitor. Scholars have suggested that ADAMTS9+ /- mice have an increase in corneal blood vessels and an increase in vascular density at the site of tumor metastasis. Gene knockout of ADAMTS9 in human EC increases the increase in tube-like substances in the matrix, as well as the increase in tube-like substances in ex vivo tissues. Unlike ADAMTS1 cleavage to produce TSP, ADAMTS9 exerts its anti-angiogenic effect by lysing different substrates by acting as a hydrolase. It is unclear whether ADAMTS9 exerts its anti-tumor function as its own hydrolase function or whether it interacts with other substances to perform its function.
The umbilical cord is the only fetal-maternal connection in the placental mammal that conducts blood from the fetus for exchange in the placenta. ADAMTS reshapes temporary ECM during different morphogenesis. Nandadasa et al. showed that loss of ADAMTS9 function altered the dynamics of extracellular matrix (ECM) and reduced the proliferation of vascular smooth muscle cells (VSMC). The Adams9Gt/Gt ADAMTS9-GT (brown) is reduced in cell surface-restricted versican conversion. Altering ECM kinetics may affect the release and transport of Shh and PDGF-B, or through ECM induction of cilia. ADAMTS9 has been identified as a key component of the pathways involved in ECM kinetics and cell regulation.
The multifunctional protease activity of ADAMTS9 is shown to be important in cardiac development and homeostasis. Due to the accumulation of versican, the haploid of Adamts9 in mice causes defects in the myocardium and aortic wall. Upregulation of the ADAMTS9 transcript was observed in the immortalized chondrocyte line C-28/I2 following cytokine stimulation involving a mixture of IL-1β, TNF-α, and interferon-γ. Knockout of Adamts9 expression using lentiviral shRNA in 3D chondrocyte culture resulted in increased matrix deposition and reduced aggrecan degradation. It is shown that the importance of Adams9 is in cartilage destruction during pathological conditions such as arthritis.
Figure 1. ADAMTS9-mediated ECM dynamics regulates VSMC development in the umbilical cord. (Nandadasa. et al. 2015).
The results of Lin et al. suggested for the first time that four key SNPs (rs73832338, rs9985304, rs4317088 and rs9831846) in the ADAMTS9 gene may lead to increased susceptibility to cognitive aging. Demircan et al found that the expression level of ADAMTS-9 was up-regulated in the spinal cord of mice after injury. In the genome-wide association study by Fritsche et al., the ADAMTS9 rs6795735 SNP is also associated with age-related macular degeneration, which usually occurs in the elderly.
ADAMTS9 is involved in the process of heparin-binding epidermal growth factor shedding regulation. Overexpression of ADAMTS9 stimulates the heparin-binding epidermal growth factor shedding process under the action of TPA, while metalloproteinase-expressed mutations inhibit TPA-stimulated heparin-binding epidermal growth factor shedding.
ADAMTS9 and Cancer
The ADAMTS9 gene has a 1.61 Mb tumor suppressor region in the 3p12-14 region, and the genes in this segment are often hypermethylated due to abnormalities in the promoter. This resulted in down-regulation or even loss of ADAMTS9 expression in esophageal cancer cells and orthotopic esophageal cancer tissues. Therefore, in 2007, ADAMTS9 was first identified as an esophageal cancer suppressor gene. Subsequently, several studies have observed that ADAMTS9 plays a role in promoting apoptosis, inhibiting cancer cell growth, and inhibiting angiogenesis in nasopharyngeal carcinoma, gastric cancer, colon cancer, and pancreatic cancer. ADAMTS9 is now considered a clear tumor suppressor gene.
ADAMTS9 and its similar ADAMTS20 play an important role in the development of melanocytes. These ADAMTS members have a special structure in their auxiliary area, similar to C. A module in elegans Gon1 that plays an important role in the morphology and development of the gonads. In the 15/16 esophageal cancer cell line, ADAMTS9 appears to be down-regulated or deleted, accompanied by methylation of the promoter region.
In the experiment on nasopharyngeal carcinoma, ADAMTS9 was also identified as a tumor suppressor.
It was also identified as a tumor suppressor in the experiment of nasopharyngeal carcinoma. Deletion of patient ADAMTS9 gene expression is accompanied by lymph node metastasis. Studies on gastric cancer have found that ADAMTS9 inhibits the AKT/mTOR pathway and that methylation levels are inversely proportional to survival in patients with gastric cancer.
ADAMTS9 is silenced or downregulated in colorectal cancer cell lines and human CRC tissue samples, suggesting that ADAMTS9 may be a potential TSG and that its inactivation may play a role in the development of colorectal cancer. Our results indicate that expression of exogenous ADAMTS9 in CaCo2 and HCT116 cells induces apoptosis, inhibits cell growth and cell migration, and induces G0/G1 cell cycle arrest. On the other hand, knockdown of ADAMTS9 in SW480 cells significantly promoted cell proliferation.
Chen et al. showed that ADAMTS9 can also reverse the epithelial-mesenchymal transition (EMT). In addition, the mesenchymal marker vimentin is inhibited, and E-cadherin is up-regulated by the ADAMTS9Akt pathway. It plays an important role in the development and progression of cancer by regulating cell proliferation and apoptosis. We analyzed the relationship between ADAMTS9 and Akt signaling pathways in colorectal cancer. ADAMTS9 inhibits the expression of p-Akt and VEGFA but up-regulates the expression of p53 in CRC. P53, another downstream target gene of Akt, is a very important tumor suppressor gene in many oncogenes. These results suggest that ADAMTS9 may play a role as a tumor suppressor gene in colorectal cancer.