ADAMTS9 is a functional tumor suppressor through inhibiting AKT/mTOR pathway and associated with poor survival in gastric cancer

Abstract

Using genome-wide promoter methylation analysis, we identified a disintegrin-like and metalloprotease with thrombospondin type 1 motif 9 (ADAMTS9) is methylated in cancer. We aim to clarify its epigenetic inactivation, biological function and clinical implication in gastric cancer. ADAMTS9 was silenced in 6 out of 8 gastric cancer cell lines. The loss of ADAMTS9 expression was regulated by promoter hypermethylation and could be restored by demethylation agent. Ectopic expression of ADAMTS9 in gastric cancer cell lines (AGS, BGC823) inhibited cell growth curve in both the cell lines (P<0.0001), suppressed colony formation (P<0.01) and induced apoptosis (P<0.001 in AGS, P<0.01 in BGC823). Moreover, conditioned culture medium from ADAMTS9-transfected cell lines significantly disrupted the human umbilical vein endothelial cell tube formation capacity on Matrigel (P<0.01 in AGS, P<0.001 in BGC823). The in vivo growth of ADAMTS9 cells in nude mice was also markedly diminished after stable expression of ADAMTS9 (P<0.001). On the other hand, ADAMTS9 knockdown promoted cell proliferation (P<0.001). We further revealed that ADAMTS9 inhibited tumor growth by blocking activation of Akt and its downstream target the mammalian target of rapamycin (mTOR). ADAMTS9 also reduced phosphorylation of mTOR downstream targets p70 ribosomal S6 kinase, eIF4E-binding protein and downregulated hypoxia-inducible factor-1α. Therefore, this is the first demonstration that ADAMTS9 is a critical tumor suppressor of gastric cancer progression at least in part through suppression of oncogenic AKT/mTOR signaling. Moreover, promoter methylation of ADAMTS9 was detected in 29.2% (21/72) of primary gastric tumors. Multivariate analysis showed that patients with ADAMTS9 methylation had a poorer overall survival (relative risk (RR)=2.788; 95% confidence interval, 1.474-5.274; P=0.002). Kaplan-Meier survival curves showed that ADAMTS9 methylation was significantly associated with shortened survival in gastric cancer patients (P=0.001, log-rank test). In conclusion, ADAMTS9 acts as a functional tumor suppressor in gastric cancer through inhibiting oncogenic AKT/mTOR signaling pathway. Methylation of ADAMTS9 is an independent prognostic factor of gastric cancer.

Hydrogen Peroxide-Induced Oxidative Damage in Human Chondrocytes: The Prophylactic Effects of Hypericum Perforatum Linn Extract on Deoxyribonucleic acid Damage, Apoptosis and Matrix Remodeling by a Disintegrin-Like and Metalloproteinase With Thrombospondin Motifs Proteinases

“…ADAMTS9 has been found to be a critical tumor suppressor of gastric cancer progression through suppression of oncogenic AKT/mTOR signaling. 51 In accordance with our findings, ectopic expression of ADAMTS9 in gastric cancer cell lines (AGS, BGC823) was found to induce apoptosis. The mechanism of the action of ADAMTS is required to be understood more comprehensively.…”

“…Therefore, we can suggest that H 2 O 2 may trigger oxidative damage and ADAMTSinduced apoptosis in chondrocytes (Figure 8). 51 Our findings demonstrated that the applied concentration of H 2 O 2 caused cellular damage in OUMS-27 cells in two hours. Additionally, HPL was observed to protect OUMS-27 against oxidative damage, inhibit the damage of ECM by decreasing ADAMTS5 level, and protect cartilage tissue from the secondary damage upon abnormal and pathological cell death at a dose of 400 μg/ml.…”

Matricellular protein SPARCL1 regulates tumor microenvironment–dependent endothelial cell heterogeneity in colorectal carcinoma

“…For example, antiangiogenic genes included septin 9 (SEPT9) and protein tyrosine phosphatase, nonreceptor type 23 (PTPN23), which inhibit EC proliferation and migration, respectively (28,30). The antitumorigenic genes included ADAMTS9, which blocks tumor growth by inhibition of Akt activation (25); DYRK1A, which inhibits the growth of AML cells (26), and CAMK2N1, which inhibits prostate cancer progression through androgen receptor-dependent signaling (27). These activities were in line with the originating tumors, suggesting that TECs derived from CRC with a Th1-TME express a set of "memory genes."…”

Long non‐coding RNAs in brain tumours: Focus on recent epigenetic findings in glioma

“…The ADAMTS9‐AS2 antisense transcript of ADAMTS9 gene was shown to be significantly down‐regulated in glioma tissues and was negatively correlated with tumour grade and prognosis. The ADAMTS9 gene is widely expressed in foetal and adult tissues, functioning as a tumour suppressor gene in diverse cancer types 75. Overexpression of ADAMTS9‐S2 in glioma cells inhibited cell migration and invasion, while ADAMTS9‐S2 silencing increased the malignancy of GBM cells, validating its tumour suppressor activity 76…”