| Summary: | 博士 === 國立陽明大學 === 臨床醫學研究所 === 100 === Head and neck squamous cell carcinoma (HNSCC) represents the sixth most common frequent cancer worldwide. It is one of the major cancers in Taiwan especially for male, and it is the fourth leading cause for male cancer death in Taiwan. Understanding the mechanisms of head and neck cancer metastasis will greatly improve diagnostic or interceptive strategies. EMT was demonstrated to be one of the major mechanisms responsible for mediating invasiveness and metastasis of late-stage cancers. In HNSCC, the hypoxic tumor environment has been shown to be critical to promote HNSCC metastasis through inducing angiogenesis, epithelial-mesenchymal transition (EMT), and invasiveness. However, the EMT-independent metastatic mechanism of HNSCC under hypoxic environment is unclear. In this study, we aim to elucidate the EMT-independent mechanism for hypoxic HNSCC metastasis. In the first part of the study, we demonstrated that activation of Slug, a transcriptional factor regulating the EMT process of human cancers, by hypoxia-inducible factor-1α (HIF-1α) was critical for the EMT independent induction of Membrane-type 4 matrix metalloproteinase (MT4-MMP) under hypoxia. This study establishes a novel signaling pathway for hypoxia-mediated metastasis and explains the EMT independent role of Slug in cancer metastasis. The past results in our laboratory demonstrated that the critical role and the regulatory mechanism of the EMT regulator Twist1 in hypoxia-mediated metastasis is responsible for promoting metastasis and stem-like properties of cancer cells. However, dissociation of cellular aggregates is not sufficient to explain why cancer cells move, and the motile nature of cancer cells undergoing EMT remains elusive. In the second part of the study, we focused on the role of Twist1 in the individual cell movements. We identified a novel mechanism in which the EMT regulator Twist1 promotes individual cancer cell movement through activation of ras-related C3 botulinum toxin substrate 1 (RAC1). Twist1 cooperates with BMI1 to suppress microRNA let-7i expression. The suppression of let-7i results in upregulation of the RAC1 co-activators neural precursor cell expressed developmentally down-regulated 9 (NEDD9) and dedicator of cytokinesis 3 (DOCK3), which leads to activating RAC1 and generating mesenchymal-mode movement in three-dimensional environments. Meanwhile, suppression of let-7i contributes to Twist1-induced stem-like properties. Clinically, activation of Twist1-let-7i- NEDD9 axis in head and neck cancer patients correlates with tumor invasiveness and a worse outcome. Our researches find an essential mechanism for interpreting how Twist1 generates the motile stem-like cancer cells beyond the suppression of E-cadherin. In summary, our study identifies critical EMT-independent metastatic mechanisms in hypoxic HNSCC, which will provide valuable information for developing novel therapies against advanced HNSCC.
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