Abstract
The cancer mortality rate of oral cancer has risen from the sixth to the fifth place in the past decade in Taiwan. More than 90% of oral cancers are oral squamous cell carcinomas (OSCC). Currently, patients with malignant oral cancer are treated with surgery to remove a large proportion of tumor, followed by radiation therapy or chemotherapy to destroy any remaining cancer cells. However, many patients developed recurrence after treatment, especially for those who suffered from lymphatic metastasis and distant metastasis. Thus, preventing metastasis is a way to reduce recurrence. In this thesis, we investigated the possible mechanism that promotes metastasis of OSCC. To this end, we used an OSCC cell line, OC3, which was derived from a betel nut-chewing oral cancer patient, and a more invasive line, IV2, to study the mechanism of OSCC invasion. We found that the expression of EZH2, a histone methyltransferase responsible for tri-methylation of histone H3 at lysine 27 (H3K27me3), was lower in the more invasive IV2 cells compared to that in OC3 cells. Consistent with this finding, knocking down EZH2 in OC3 cells enhanced migration and invasion. Several target genes of EZH2 have been identified, including ADAMTS1, MMP3, ROS1, CXCL1 and GLI1. To determine what leads to reduced EZH2 in IV2 cells, chromatin immunoprecipitation (ChIP) analysis suggests the involvement of STAT3 in the transcriptional expression of EZH2. In fact, STAT3 level was reduced in IV2 cells compared to OC3 cells. Knocking down STAT3 or inhibiting STAT3 decreased EZH2 expression and increased EZH2 target genes, ADAMTS1, ROS1, CXCL1 and GLI1, to regulate cell migration, invasion and proliferation. We also determined the feedback regulation between STAT3 and IL8 signaling, an upstream of STAT3. Taken together, these findings implicate that EZH2 may serve as a tumor suppressor by inhibiting metastasis-related genes in OSCC cells.