Abstract
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-β1, 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-β1, 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.
Highlights
Few studies have investigated the role of extracellular-matrix proteoglycans in the pathogenesis of drug-induced gingival overgrowth (DIGO)
SPOCK1, TGF-β1, and matrix metalloproteinases (MMPs)-9 are associated with the epithelial to mesenchymal transition (EMT) process in several cancer types so, we asked if these molecules are involved in EMTrelated Drug-induced gingival overgrowth (DIGO)
We found that SPOCK1, TGF-β1, and MMP-9 mRNA (Fig. 1a) and their protein products (Fig. 1b) were significantly higher in gingival overgrowth (GO) samples compared to non-overgrowth controls
Summary
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. In vitro studies revealed phenotypic changes in both keratinocytes and fibroblasts[3] and at the histopathological level, all forms of DIGO share similar features, including parakeratinized squamous epithelium with elongated rete pegs that extend deep into the connective tissue, and collagen accumulation within lamina propria[4,5]. Previous studies suggested that the elongated rete pegs in gingival overgrowth may result from increased epithelial plasticity, which leads to a phenotypic transition known as epithelial to mesenchymal transition (EMT)[18,19,20,21]. SPOCK1 has been shown to induce EMT through the TGF-β1 pathway[25,29] and was reported to exert an anti-apoptotic effect by activating the PI3K/AKT pathway[22,30,31,32,33]
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