|CSC-DC000254||Panoply™ Human ADAMTS15 Knockdown Stable Cell Line||Inquiry|
|CSC-SC000254||Panoply™ Human ADAMTS15 Over-expressing Stable Cell Line||Inquiry|
|CDCB191798||Rabbit ADAMTS15 ORF clone (XM_002708592.2)||Inquiry|
|CDCL182590||Mouse ADAMTS15 ORF clone(NM_001024139.1)||Inquiry|
|CDCR373549||Rat Adamts15 ORF Clone(NM_001106810.1)||Inquiry|
|CDCS416844||Human ADAMTS15 ORF Clone (BC109114)||Inquiry|
|CDFR006538||Rat Adamts15 cDNA Clone(NM_001106810.1)||Inquiry|
|MiUTR1M-01198||ADAMTS15 miRNA 3'UTR clone||Inquiry|
|MiUTR4H-TG10494||ADAMTS15 miRNA 3'UTR clone||Inquiry|
A disintegrin and metalloproteinase with thrombospondin motifs 15 are abbreviated as ADAMTS15. ADAMTS15 has a predicted molecular weight of 104 kDa and a domain structure consisting of a signal peptide, a prodomain, a metalloproteinase domain, and a disintegrin-like domain. The central TSR domain, a cysteine-rich region, and a spacer region, followed by two TSRs at the C-terminus. Amino acid sequence alignment showed 46% identity to ADAMTS1 and ADAMTS5, and 44% was consistent with ADAMTS8.
ADAMTS15 is a disintegrin with a thrombospondin motif (ADAMTS) and a metalloproteinase is a secretory member of a zinc-dependent metalloproteinase that contains one or more thrombospondin type 1 repeats (TSP1) as a helper domain. Tissue inhibitors of metalloproteinases (inhibitors) are endogenous inhibitors of matrix metalloproteinases, and studies by Guo et al. show that ADAMTS 13 and 15 are not inhibited by N-TIMP-1 to -4, a metalloenzyme inhibitor.
ADAMTS15 and Angiogenesis
ADAMTS15 can cause migration of MDA-MB-231 and MCF-7 cells but is not metallopeptidase dependent. This transfer is more likely due to the involvement of syndecan-4 since syndecan-4 will increase in expression and signal in this case. In contrast to its effect on cell migration, only wild-type ADAMTS15 showed anti-angiogenic effects in both in vivo and in vitro models. During cell transfer, ADAMTS15 is able to reduce the metastasis of MDA-MB-231 cells to the liver.
Intracranial aneurysm rupture (IAs) causes subarachnoid hemorrhage, leading to direct death or severe disability. Yan et al. showed that silencing ADAMTS15 and overexpressing ADAMTS15 p.E133Q accelerated endothelial cell migration, suggesting that ADAMTS15 may have anti-angiogenic activity. ADAMTS15 removes the integrin domain and releases the C-terminal fragment, which is similar to the fragment of ADAMTS1 for anti-angiogenesis. These studies suggest a possible role for ADAMTS15 in angiogenesis.
ADAMTS15 and Tumor
ADAMTS15 and breast cancerADAMTS15 is a potential tumor suppressor. Only a limited number of in-depth studies have been conducted on this enzyme; however, expression and analysis studies have shown that the ADAMTS15 gene is genetically inactivated in colon and breast cancer. ADAMTS15 alone was used as a predictor of prolonged survival and showed significant down-regulation in grade 3 breast cancer compared to grade 1 and grade 2 breast cancer.
Figure 1. Schematic representation of the protumor effects mediated by ADAMTS metalloproteases. (Cal S., et al. 2015)
Many studies have described the dysregulated expression of many ADAMTS genes in breast cancer. Among them, ADAMTS15 alone was used as a predictor of prolonged event-free survival and showed significant down-regulation in grade 3 breast cancer compared with grade 1 and grade 2 breast cancer. Using the PyMT model (a robust transgenic model of highly metastatic breast cancer), this model is very similar to human breast cancer with high-grade and high-invasive disease outcomes, with the same level of expression found in ADAMTS15, with high expression of ADAMTS8. These are associated with poor clinical outcomes.
ADAMTS15 has an inhibitory effect on angiogenesis, and existing experimental data indicates that it also has a tumor suppressor function. By observing the expression of 19 ADAMTS family members in breast cancer, although the expression levels of each member in normal tissues and cancer tissues are different, the level of expression is inversely proportional to the patient's living state. In a large number of population trials, the more ADAMTS15 expression, the less recurrence, indicating that ADAMTS15 has metastatic inhibition. Patients with low expression of ADAMTS15 had a poorer prognosis, a 5-fold increased risk of recurrence and a 3-fold increased risk of death.
ADAMTS15 and Colon Cancer
Expression of ADAMTS15 in prostate cancer and related stromal cells has been reported. Studies have shown that in response to TGF-β stimulation, the level of underlying ADAMTS15 is decreased in prostate stromal cells with an increase in versican, which is an indicator of poor prognosis in prostate cancer. Frequent mutations in ADAMTS15 were found in colorectal cancer. Studies have shown that overexpression of ADAMTS15 results in reduced colony forming ability and reduced invasive ability using two different colon cancer cell lines (HCT-116 and SW-480). In contrast, siRNA-mediated gene knockdown results in increased clonality, ability to form, and invasion of these cells.
In vitro and in vivo studies of colon cancer cell lines and severe combined immunodeficiency disease (SCID) mice revealed that expression of wild-type ADAMTS15 inhibited tumor growth and invasion. Immunohistochemistry was used to detect the expression of ADAMTS15 in colorectal cancer tissues. It was found that ADAMTS15 was highly expressed in normal tissues and low in cancer tissues. This expression was negatively correlated with the pathological grade in colorectal cancer. Cal et al. believe that ADAMTS15 is also indirectly involved in androgen-mediated prostate cancer growth and proliferation, depending on the detoxification activity of ADAMTS15 function. The study used immunostaining to observe colorectal cancer and normal human epithelial cells, respectively and found that the expression of ADAMTS15 is inversely proportional to the grade of human colorectal cancer.
The study also found that the knockdown of the ADAMTS15 gene showed a reduced effect on colony formation or tumor cell invasion in G849fs mutant cells. However, the effect of knockdown of the ADAMTS15 gene on the motility of wild-type or G849fs mutant overexpressing cells was not observed in the wound healing assay. Since the catalytically inactive form of ADAMTS15 also showed similar inhibition, the study concluded that the terminal TSR is responsible for the anti-tumor function of ADAMTS15. Furthermore, overexpression of the G849fs mutant form or knockdown of ADAMTS15 in HCT-116 cells caused dramatic morphological changes in these cells. Compared to the more rounded, smaller control cells, ADAMTS15 overexpressing cells are larger, flatter, and spindle-shaped. This indicates that the invasive ability has been obtained.
ADAMTS15 depleted cells show enhanced in vivo tumor growth. In addition, immunohistochemical analysis of normal and tumor colorectal samples showed that ADAMTS15 expression was preferentially located in normal tissues. Furthermore, the expression of ADAMTS15 was inversely correlated with the histopathological grade of colorectal tumors, indicating its utility as an effective marker of differentiation. The anti-tumor function of ADAMTS15 is associated with the ability of this protein to modulate the Ras-dependent ERK pathway. Tumor cells expressing wild-type of ADAMTS15 showed very low levels of phospho-ERK. In contrast, cells expressing the G849fs mutant form of ADAMTS15 retain the ability to phosphorylate ERK compared to cells. Therefore, the C-terminal TSR domain is required for ADAMTS15 to effectively inhibit ERK activity. Therefore, ADAMTS15 acts as a tumor suppressor in colorectal cancer and does not rely on its metalloproteinase activity.
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