Department of Pathology and Anatomical Science, University of Missouri School of Medicine, Columbia, Missouri 65212, USA.
J Biol Chem. 2011 Mar 18;286(11):9127-35. doi: 10.1074/jbc.M110.191361. Epub 2010 Dec 16.
Oral squamous cell carcinoma (OSCC) ranks among the top 8 causes of cancer death worldwide, with only a 60% 5-year survival rate, highlighting the need for discovery of novel biomarkers and therapeutic targets. We have previously reported that expression of a panel of serine proteinase kallikreins (KLK 5, 7, 8, and 10) is correlated with formation of more aggressive OSCC tumors in a murine orthotopic OSCC model and is elevated in human OSCC. Current studies focus on understanding the potential role of KLK5 in OSCC progression. In initial studies, KLK levels in malignant OSCC cells (SCC25) were compared with cells from normal oral mucosa (OKF/6) and pre-malignant oral keratinocytes (pp126) using qPCR. A marked elevation of all KLKs was observed in aggressive SCC25 cells relative to OKF/6 cells. In normal skin, KLKs are involved in desquamation during epidermal differentiation via proteolytic cleavage of the desmosomal cadherin component desmoglein 1 (Dsg1). As loss of cell-cell cohesion is prevalent in tumor metastasis, Dsg1 integrity was evaluated. Results show that SCC25 cells exhibit cleavage of Dsg1, which is blocked by proteinase inhibitor treatment as well as by siRNA silencing of KLK5 expression. Furthermore, cell-cell aggregation assays demonstrate that silencing of KLK5 enforces cell-cell adhesion; conversely, overexpression of KLK5 in normal oral mucosal cells (OKF/6) enhances cell dispersal. These data suggest that KLK5 may promote metastatic dissemination of OSCC by promoting loss of junctional integrity through cleavage of desmoglein 1.
口腔鳞状细胞癌（OSCC）是全球癌症死亡的前 8 大原因之一，其 5 年生存率仅为 60%，这突出表明需要发现新的生物标志物和治疗靶标。我们之前曾报道过，一组丝氨酸蛋白酶激肽原（KLK5、7、8 和 10）的表达与在鼠原位 OSCC 模型中形成侵袭性更高的 OSCC 肿瘤相关，并且在人 OSCC 中升高。目前的研究集中在理解 KLK5 在 OSCC 进展中的潜在作用。在初步研究中，使用 qPCR 比较了恶性 OSCC 细胞（SCC25）与正常口腔粘膜细胞（OKF/6）和前恶性口腔角质形成细胞（pp126）中的 KLK 水平。与 OKF/6 细胞相比，侵袭性 SCC25 细胞中所有 KLK 的水平均明显升高。在正常皮肤中，KLKs 通过对桥粒钙粘蛋白成分桥粒蛋白 1（Dsg1）的蛋白水解切割参与表皮分化中的脱屑。由于肿瘤转移中普遍存在细胞-细胞黏附丧失，因此评估了 Dsg1 的完整性。结果表明，SCC25 细胞显示出 Dsg1 的裂解，该裂解可通过蛋白酶抑制剂处理以及 KLK5 表达的 siRNA 沉默来阻断。此外，细胞-细胞聚集测定表明 KLK5 的沉默增强了细胞-细胞黏附；相反，在正常口腔粘膜细胞（OKF/6）中过表达 KLK5 增强了细胞分散。这些数据表明 KLK5 可能通过切割桥粒蛋白 1 促进 OSCC 的转移扩散，从而破坏连接完整性。
