Department of Gastrointestinal Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510275, China.
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510275, China.
Biomolecules. 2021 Apr 12;11(4):561. doi: 10.3390/biom11040561.
A Disintegrin and Metalloproteinase with Thrombospondin motifs 19 (ADAMTS19) has been reported to participate in the pathogenesis of solid cancers. However, its role in gastric cancer (GC) remains undocumented. Using immunohistochemistry (IHC) staining and quantitative real-time polymerase chain reaction (qRT-PCR) on GC tissues and adjacent normal tissues, we found that ADAMTS19 was downregulated in GC tissues (IHC: < 0.001; qRT-PCR: = 0.017). Further investigation revealed that ADAMTS19 correlated with distant metastasis ( = 0.008) and perineural invasion ( = 0.018) and that patients with low ADAMTS19 had worse overall survival ( = 0.021). Gain- and loss-of-function assays showed that ADAMTS19 suppressed cell migration and invasion in vitro. Using bioinformatics analysis and co-immunoprecipitation, immunofluorescence, and dual-luciferase reporter gene assays, we confirmed that ADAMTS19 binds with cytoplasm P65, decreasing the nucleus phosphorylation of P65, a crucial transcription factor in the nuclear factor kappa-B (NF-κB) pathway, thereby downregulating S100 calcium-binding protein A16 (S100A16) expression. S100A16 acted as the downstream of ADAMTS19, reversing the suppression of cell migration and invasion by ADAMTS19 in vitro. A combination of ADAMTS19 and S100A16 expression provided the optimal prognostic indicator for GC. Patients with ADAMTS19-S100A16 had better overall survival than ADAMTS19-S100A16 patients ( = 0.006). These results suggest that ADAMTS19 suppresses cell migration and invasion by targeting S100A16 via the NF-κB pathway and that ADAMTS19 and S100A16 are potential metastasis and survival biomarkers for GC.
一种含有解整合素和金属蛋白酶域的蛋白 19（ADAMTS19）已被报道参与实体瘤的发病机制。然而，其在胃癌（GC）中的作用仍未被记录。我们通过免疫组织化学（IHC）染色和定量实时聚合酶链反应（qRT-PCR）检测 GC 组织和相邻正常组织，发现 ADAMTS19 在 GC 组织中下调（IHC：<0.001；qRT-PCR：=0.017）。进一步研究表明，ADAMTS19 与远处转移（=0.008）和神经周围侵犯（=0.018）相关，并且 ADAMTS19 低表达的患者总生存期更差（=0.021）。增益和缺失功能试验表明，ADAMTS19 抑制细胞迁移和侵袭。通过生物信息学分析、共免疫沉淀、免疫荧光和双荧光素酶报告基因试验，我们证实 ADAMTS19 与细胞质 P65 结合，降低核因子 kappa-B（NF-κB）通路中关键转录因子 P65 的核磷酸化，从而下调 S100 钙结合蛋白 A16（S100A16）的表达。S100A16 作为 ADAMTS19 的下游靶点，逆转了 ADAMTS19 对体外细胞迁移和侵袭的抑制作用。ADAMTS19 和 S100A16 表达的组合为 GC 提供了最佳的预后指标。ADAMTS19-S100A16 患者的总生存期优于 ADAMTS19-S100A16 患者（=0.006）。这些结果表明，ADAMTS19 通过 NF-κB 通路靶向 S100A16 抑制细胞迁移和侵袭，ADAMTS19 和 S100A16 是 GC 转移和生存的潜在标志物。
