| Summary: | 碩士 === 國立成功大學 === 口腔醫學研究所 === 101 === Oral squamous cell carcinoma (OSCC) is a common neoplasm worldwide. In Taiwan, that is also one of the top ten malignancies, and ranked the fourth leading cause of cancer death in Taiwanese male. Neuropilin-1 (NRP1) has been known to be highly expressed in high grade and metastatic tumors. Signal transducers and activator of transcription 3 (Stat3) is a cytoplasmic transcription factor which is constitutively activated in cancer cells and tumor microenvironment and implicates tumor metastasis, proliferation and apoptosis. Our preliminary results showed that Stat3 activation may positively regulate NRP1 expression in lung cancer cells. In this study, we aim to figure out the role of NRP1 and Stat3 in oral cancer. Above all, we used immunohistochemistry to examine the clinical OSCC specimens and found that NRP1/Stat3/p-Stat3 were higher expression in tumors compared to normal tissues and had positive correlation in tumor tissue. The expression level of NRP1 is positively correlated with tumor stage in clinical OSCC specimens. Moreover, the expression of NRP1 and p-Stat3 was higher and positively correlated in highly malignant OSCC cell lines. To investigate the influence of NRP1 in OSCC, we knocked down the expression of NRP1 and found the cell migration, invasion, and proliferation was all decreased in NRP1 silencing cells. In addition, we found that silencing the expression of Stat3 leads to a significant reduction in the expression level of NRP1 and IL-6. We analyzed the promoter region of NRP1 and found a potential Stat3 binding site may involve in transcriptional regulation of NRP1. Next, we use luciferase report assays to verify the regulation of stat3 in NRP1 expression, and then we finding that Stat3 could regulate NRP1 expression by drive on it’s promoter region. In animal models, we established tumor xenografts by subcutaneously implanting SCC15 cells with knockdown of NRP1, stat3 and shLuci (control) respectively. The result show that knockdown of NRP1 or Stat3 could effectively reduce tumor volume and tumor weight, especially in the shNRP1 group. However, analysis for angiogenesis and proliferative effect in the outcome. Tumors from the shNRP1 and shStat3 groups showed significantly lower CD31 and Ki67 staining than the shLuci groups. According to these results, the correlation of NRP1 expression levels and Stat3 activation is a novel finding in oral cancer development. In the future, NRP1/stat3 axis can be a new prognosis marker and therapeutic target in oral cancer.
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