SPOCK1 is a novel inducer of epithelial to mesenchymal transition in drug-induced gingival overgrowth
SPOCK1 is a novel inducer of epithelial to mesenchymal transition in drug-induced gingival overgrowth
复制标题
DOI：
10.1038/s41598-020-66660-z
复制
发表时间：
2020-06-17
影响因子：
4.6
通讯作者：
Nishimura, Fusanori
中科院分区：
文献类型：
--
作者：
Alshargabi, Rehab;Sano, Tomomi;Nishimura, Fusanori
很少有研究调查的作用，细胞外基质蛋白多糖的发病机制中的药物诱导的牙龈增生（DIGO）。SPOCK 1是一种细胞外蛋白聚糖，在几种癌细胞系中诱导上皮向间质转化（EMT），并表现出蛋白酶抑制活性。然而，SPOCK 1在非癌性疾病如DIGO中的作用尚未得到很好的解决。我们发现，钙通道阻滞剂诱导的牙龈过度生长中SPOCK 1、TGF-β 1和MMP-9的表达高于非过度生长组织。过表达Spock 1的转基因小鼠出现明显的牙龈过度生长和纤维化表型，并与EMT样改变呈正相关。此外，体外数据表明SPOCK 1、TGF-β 1和MMP-9之间存在三向相互作用，导致牙龈过度生长。我们的研究表明，在非癌性疾病和牙龈过度生长的SPOCK 1诱导EMT的SPOCK 1上调发生通过几个潜在的信号通路之间的合作和串扰。因此，SPOCK 1是牙龈过度生长的一个新的治疗靶点，其表达是癌性病变中诱导EMT的潜在风险。
Few studies have investigated the role of extracellular-matrix proteoglycans in the pathogenesis of drug-induced gingival overgrowth (DIGO). SPOCK1 is an extracellular proteoglycan that induces epithelial to mesenchymal transition (EMT) in several cancer cell lines and exhibits protease-inhibitory activity. However, the role of SPOCK1 in non-cancerous diseases such as DIGO has not been well-addressed. We demonstrated that the expression of SPOCK1, TGF-beta 1, and MMP-9 in calcium channel blocker-induced gingival overgrowth is higher than that in non-overgrowth tissues. Transgenic mice overexpressing Spock1 developed obvious gingival-overgrowth and fibrosis phenotypes, and positively correlated with EMT-like changes. Furthermore, in vitro data indicated a tri-directional interaction between SPOCK1, TGF-beta 1, and MMP-9 that led to gingival overgrowth. Our study shows that SPOCK1 up-regulation in a noncancerous disease and SPOCK1-induced EMT in gingival overgrowth occurs via cooperation and crosstalk between several potential signaling pathways. Therefore, SPOCK1 is a novel therapeutic target for gingival overgrowth and its expression is a potential risk of EMT induction in cancerous lesions.