Matrix metalloproteinases and the upstream Toll-like receptor 3 signaling as decisive factors in invasiveness of oral squamous cell carcinoma

• Main Authors: Hui Ching Chuang, 莊蕙青
• Other Authors: J. H. Chuang
• Format: Others
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/54879628718127651375

博士 === 長庚大學 === 臨床醫學研究所 === 100 === Head and neck cancer (HNC) is one of the most important malignancies worldwide, and among these malignancies, the incidence of oral cancer ranks fourth in male patients in Taiwan. Oral squamous cell carcinoma (OSCC) grows rapidly, with distant and regional lymph node metastasis, resulting in high mortality in patients. Numerous studies have provided evidence that chronic inflammation can lead to cancer formation. The oral cavity is vulnerable to pathogens that can induce inflammation and eventually lead to tumorigenesis. Toll-like receptors (TLRs) are a particular group of receptors in the host that recognize exogenous or endogenous pathogens and induce immediate immune and inflammatory reactions. Increasing evidence suggests that TLRs are expressed in tumor cells, and that TLR-signaling in tumor cells is associated with tumor cell proliferation, apoptosis, enhancement of tumor cell invasion, and distant metastasis. Matrix metalloproteinases (MMPs) are zinc-dependent proteinases that play an important role in tumor development, migration, angiogenesis, and immune modulation. In this study, we explored the role of active MMP-7 expression in oral cancers, and correlated this expression with clinicopathologic factors in patients. Immunoreactivity for active MMP-7 was present only in cancer tissue and was correlated with tumor size and tumor invasion of the adjacent skin and mandible, suggesting that MMP-7 is activated in tumor cells and is associated with aggressive tumor behavior in buccal cancer. In addition, we examined the expression of TLR3 in OSCC cells and the effect of a TLR3 agonist in the TLR3-signaling pathway in HNC cell lines. We found that TLR3 overexpression in OSCC cells was associated with high-risk tumor histopathological features, such as poor differentiation and perineural invasion. Using the TLR3 agonist polyinosinic:polycytidylic acid (poly I:C) to trigger TLR3-expressing OC2 cells, poly I:C induced the phosphorylation of interferon regulatory factor 3 and IB, as well as the secretion of interleukin-6 (IL-6) and chemokine (C–C motif) ligand 5 (CCL5) in a dose- and time-dependent manner. Poly I:C also induced dose-dependent MMP-9 activation. Moreover, poly I:C stimulation promoted CCL5-mediated migration in OC2 cells. In summary, these results show that MMPs and upstream TLR3 signaling are correlated with the invasiveness of OSCC. TLR3 activation via increasing MMPs activation and proinflammatory cytokine expression in OSCC contributes to tumor invasiveness. These findings provide new molecular insight into the correlation between oral cancer and innate immunity.