Arosarena Oneida A, Barr Eric W, Thorpe Ryan, Yankey Hilary, Tarr Joseph T, Safadi Fayez F
Department of Otolaryngology-Head and Neck Surgery, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania.
Department of Anatomy and Cell Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania.
J Cell Physiol. 2018 Jan;233(1):409-421. doi: 10.1002/jcp.25900. Epub 2017 Apr 25.
Nearly 60% of patients with head and neck squamous cell carcinoma (HNSCC) die of metastases or locoregional recurrence. Metastasis is mediated by cancer cell migration and invasion, which are in part dependent on extracellular matrix degradation by matrix metalloproteinases. Osteoactivin (OA) overexpression plays a role in metastases in several malignancies, and has been shown to upregulate matrix metalloproteinase (MMP) expression and activity. To determine how OA modulates MMP expression and activity in HNSCC, and to investigate OA effects on cell invasion, we assessed effects of OA treatment on MMP mRNA and protein expression, as well as gelatinase and caseinolytic activity in HNSCC cell lines. We assessed the effects of OA gene silencing on MMP expression, gelatinase and caseinolytic activity, and cell invasion. OA treatment had differential effects on MMP mRNA expression. OA treatment upregulated MMP-10 expression in UMSCC14a (p = 0.0431) and SCC15 (p < 0.0001) cells, but decreased MMP-9 expression in UMSCC14a cells (p = 0.0002). OA gene silencing decreased MMP-10 expression in UMSCC12 cells (p = 0.0001), and MMP-3 (p = 0.0005) and -9 (p = 0.0036) expression in SCC25 cells. In SCC15 and SCC25 cells, OA treatment increased MMP-2 (p = 0.0408) and MMP-9 gelatinase activity (p < 0.0001), respectively. OA depletion decreased MMP-2 (p = 0.0023) and -9 (p < 0.0001) activity in SCC25 cells. OA treatment increased 70 kDa caseinolytic activity in UMSCC12 cells consistent with tissue type plasminogen activator (p = 0.0078). OA depletion decreased invasive capacity of UMSCC12 cells (p < 0.0001). OA's effects on MMP expression in HNSCC are variable, and may promote cancer cell invasion.
近60%的头颈部鳞状细胞癌（HNSCC）患者死于转移或局部区域复发。转移由癌细胞迁移和侵袭介导，这部分依赖于基质金属蛋白酶对细胞外基质的降解。骨激活素（OA）过表达在多种恶性肿瘤的转移中起作用，并且已被证明可上调基质金属蛋白酶（MMP）的表达和活性。为了确定OA如何调节HNSCC中MMP的表达和活性，并研究OA对细胞侵袭的影响，我们评估了OA处理对HNSCC细胞系中MMP mRNA和蛋白表达以及明胶酶和酪蛋白溶解活性的影响。我们评估了OA基因沉默对MMP表达、明胶酶和酪蛋白溶解活性以及细胞侵袭的影响。OA处理对MMP mRNA表达有不同影响。OA处理上调了UMSCC14a（p = 0.0431）和SCC15（p < 0.0001）细胞中MMP-10的表达，但降低了UMSCC14a细胞中MMP-9的表达（p = 0.0002）。OA基因沉默降低了UMSCC12细胞中MMP-10的表达（p = 0.0001），以及SCC25细胞中MMP-3（p = 0.0005）和-9（p = 0.0036）的表达。在SCC15和SCC25细胞中，OA处理分别增加了MMP-2（p = 0.0408）和MMP-9明胶酶活性（p < 0.0001）。OA缺失降低了SCC25细胞中MMP-2（p = 0.0023）和-9（p < 0.0001）的活性。OA处理增加了UMSCC12细胞中与组织型纤溶酶原激活剂一致的70 kDa酪蛋白溶解活性（p = 0.0078）。OA缺失降低了UMSCC12细胞的侵袭能力（p < 0.0001）。OA对HNSCC中MMP表达的影响是可变的，并且可能促进癌细胞侵袭。
