Modulating the ERK1/2–MMP1 Axis through Corosolic Acid Inhibits Metastasis of Human Oral Squamous Cell Carcinoma Cells

Abstract

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.

Identity of MMP1 and its effects on tumor progression in head and neck squamous cell carcinoma

“…36 A research about human oral squamous cell carcinoma showed that MMP1 was expressed higher in tumor than normal tissue and its higher expression was positively correlated with a shorter overall survival rate. 37 Wang et al also found that MMP1 3'UTR can sponge miR-188-5p to facilitate the proliferation and migration of human oral squamous cell carcinoma. 38 Consistently, our results showed that MMP1 was significantly increased in HNSCCs and its high expression was positively correlated with poor prognosis.…”

“…Lallemant et al reported that MMP1 shows high sensitivity and specificity for serving as a diagnostic marker in HNSCC 36 . A research about human oral squamous cell carcinoma showed that MMP1 was expressed higher in tumor than normal tissue and its higher expression was positively correlated with a shorter overall survival rate 37 . Wang et al also found that MMP1 3’UTR can sponge miR‐188‐5p to facilitate the proliferation and migration of human oral squamous cell carcinoma 38 .…”

Protein tyrosine phosphatase nonreceptor type 2 exerts antimetastatic functions in pancreatic ductal adenocarcinoma

“…The above analysis supported the role of PTPN2 in suppressing PDAC metastasis in vitro experiments. Therefore, we chose MMP‐1 (Matrix Metallopeptidase 1) as the target gene, because MMP‐1 has been reported to promote cancer metastasis in various cancer types 29–31 (Figure 4F). Besides, MMP‐1 belonged to the most enriched three GO terms in Figure 5D.…”

“…Also, GO-Biological Process analysis showed that the enriched genes were subjected to cell migration, such as extracellular structure organization, extracellular matrix organization, and positive regulation of cell adhesion (Figure 4C). Moreover, we carried out GSEA enrichment analysis (http://www.linkedomics.org/login.php) based on all the PDAC patients from TCGA databases, indicating that PTPN2 was inversely correlated with terms associated with cell invasion, including cell-cell adhesion and cell projection membrane (Figure 4D,E [29][30][31] (Figure 4F). Besides, MMP-1 belonged to the most enriched three GO terms in Figure 5D.…”

Molecular Mechanisms of Inhibitory Effects of Bovine Lactoferrin on Invasion of Oral Squamous Cell Carcinoma

“…Recently, our group found that bLF reversed the programing of epithelial-to- mesenchymal transition (EMT) to mesenchymal-to-epithelial transition (MET) in OSCC by decreasing the ERK signaling pathway, reducing the expression of TWIST, and improving membrane bound E-Cadherin [ 11 ]. Currently, evidence is accumulating that the ERK1/2/MMP-1 axis could inhibit metastasis of human oral squamous cells [ 45 ], and that knocking down of MMP-1 could suppress the PI3K/Akt/c-myc signaling pathway and EMT in colorectal cancer [ 46 ]. In addition, MMP-3 directly mediated EMT by upregulating TWIST, thereby disrupting E-cadherin expression [ 47 , 48 ].…”