Department of Hematology & Oncology, Chung-Kang Branch, Cheng Ching Hospital, Taichung 40764, Taiwan.
Director of Surgery Department, Chung-Kang Branch, Cheng Ching General Hospital, Taichung 40764, Taiwan.
Int J Mol Sci. 2021 Aug 11;22(16):8641. doi: 10.3390/ijms22168641.
Corosolic acid (CA; 2α-hydroxyursolic acid) is a natural pentacyclic triterpenoid with antioxidant, antitumour and antimetastatic activities against various tumour cells during tumourigenesis. However, CA's antitumour effect and functional roles on human oral squamous cell carcinoma (OSCC) cells are utterly unknown. In this study, our results demonstrated that CA significantly exerted an inhibitory effect on matrix metalloproteinase (MMP)1 expression, cell migration and invasion without influencing cell growth or the cell cycle of human OSCC cells. The critical role of MMP1 was confirmed using the GEPIA database and showed that patients have a high expression of MMP1 and have a shorter overall survival rate, confirmed on the Kaplan-Meier curve assay. In the synergistic inhibitory analysis, CA and siMMP1 co-treatment showed a synergically inhibitory influence on MMP1 expression and invasion of human OSCC cells. The ERK1/2 pathway plays an essential role in mediating tumour progression. We found that CA significantly inhibits the phosphorylation of ERK1/2 dose-dependently. The ERK1/2 pathway played an essential role in the CA-mediated downregulation of MMP1 expression and in invasive motility in human OSCC cells. These findings first demonstrated the inhibitory effects of CA on OSCC cells' progression through inhibition of the ERK1/2-MMP1 axis. Therefore, CA might represent a novel strategy for treating OSCC.
熊果酸（CA；2α-羟基乌苏酸）是一种天然的五环三萜，具有抗氧化、抗肿瘤和抗转移活性，可抑制肿瘤发生过程中的各种肿瘤细胞。然而，CA 对人口腔鳞状细胞癌（OSCC）细胞的抗肿瘤作用和功能作用尚不清楚。在本研究中，我们的结果表明 CA 可显著抑制基质金属蛋白酶（MMP）1 的表达，对人 OSCC 细胞的迁移和侵袭具有抑制作用，而对细胞生长或细胞周期无影响。GEPIA 数据库证实了 MMP1 的关键作用，并显示高 MMP1 表达的患者总生存率较低，这在 Kaplan-Meier 曲线分析中得到了证实。在协同抑制分析中，CA 和 siMMP1 联合处理对人 OSCC 细胞中 MMP1 的表达和侵袭具有协同抑制作用。ERK1/2 通路在介导肿瘤进展中起关键作用。我们发现 CA 可显著抑制 ERK1/2 的磷酸化，呈剂量依赖性。ERK1/2 通路在 CA 介导的 MMP1 表达下调和人 OSCC 细胞侵袭性运动中起关键作用。这些发现首次证明 CA 通过抑制 ERK1/2-MMP1 轴抑制 OSCC 细胞的进展。因此，CA 可能代表治疗 OSCC 的一种新策略。
