published_or_final_version / Pathology / Doctoral / Doctor of Philosophy

published_or_final_version / Biological Sciences / Master / Master of Philosophy

published_or_final_version / Biochemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Clinical Oncology / Doctoral / Doctor of Philosophy

published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

published_or_final_version / Pathology / Master / Master of Medical Sciences

published_or_final_version / Pathology / Master / Master of Medical Sciences

published_or_final_version / Obstetrics and Gynaecology / Master / Master of Philosophy

 Squamous cell carcinoma of the tongue has a low survival rate, with cure rate reduced by half if cervical lymph node metastasis is present. Standard treatment regimen includes surgical resection of the tumor, radiotherapy and chemotherapy. These treatment modalities, however, can result in irreversible side effects including loss of form and function of the tongue. So far, there is no efficient treatment regime targeting migration and invasion of tongue carcinoma. Curcumin is a natural polyphenol extracted from Curcuma longa. Recent studies indicated that curcumin is a potential anti-cancer agent. The anticancer effects have been demonstrated in numerous cancers including lung cancer, liver cancer, breast cancer, prostate cancer and melanoma. In head and neck cancers, the number studies is limited and its inhibitory effects in migration and invasion is rarely explored. To explore the global expression changes in tongue cancer, we used microarray to evaluate the genes responsive to curcumin treatment and focused on genes related to migration and invasion of tongue cancer cell line HN21B. The genes down-regulated by curcumin were validated in HN21B and two other tongue cancer cell line CAL27 and HN96 using qRT-PCR, Western blotting and immunostaining. The identified genes were quantified in tongue carcinoma tissues to examine whether it was up-regulated in human tongue tissues. Scratch wound assay and radial-migration assay were used to assess the degree of inhibition on migration. Adhesion and invasion assays were also performed to assess the adhesion and invasion ability. Transcriptomic analyses showed that MMP-10 was 2.36 fold down-regulated in HN21B in response to curcumin. Curcumin treatment resulted in down-regulation of MMP-10 gene in all the 3 tongue carcinoma cell lines at mRNA and protein levels. Out of 24 tongue carcinoma cases, 55% tumor tissue had obvious up-regulation of MMP-10 expression in comparison with the normal counterpart. Adhesion, migration and invasion ability of tongue carcinoma cell lines was significantly reduced upon IC50 of curcumin treatment in all TSCC cell lines. In conclusion, our results indicated that curcumin could reduce migration, adhesion and invasion in tongue carcinoma cells partly through reducing MMP-10 expression. Further investigations are warranted to explore the potential therapeutic use of curcumin to inhibit migration and invasion of tongue carcinoma cells. / published_or_final_version / Surgery / Master / Master of Philosophy

Emerging evidences have documented that aberrant expression of FOXM1 is closely associated with human cancers. A recent comprehensive genome analysis has revealed that FOXM1 signaling is one of the major pathways involved in ovarian cancer oncogenesis. However, the regulatory network of FOXM1 in exerting the metastatic phenotypes remains unknown. Therefore, the identification of FOXM1 downstream targets will assist in understanding of its molecular mechanism in ovarian cancer oncogenesis. In this study, by bioinformatics and a series of functional analyses, we identified DLX1 as a novel target of FOXM1. Our results clearly demonstrated that enforced expression of FOXM1 (FOXM1B and FOXM1C) could increase DLX1 in mRNA and protein levels. Conversely, depletion of FOXM1 by Thiostrepton (FOXM1 specific inhibitor) or RNAi knockdown could reduce DLX1 expression. Importantly, we demonstrated that the changes of DLX1 expression were in concomitant with the expression of a positive control gene, Cyclin-D1. Additionally, the luciferase promoter assay further showed that there are two conserved FOXM1 binding sites TFBS1 and TFBS2 which located at -61~-52bp upstream and -737~727bp upstream of the transcription factor binding sites (TSS) of DLX1 promoter respectively. In comparison of two binding sites, the more conserved binding site, TFBS1, seems have higher importance of FOXM1 binding in DLX1 transcriptional activation. Furthermore, our study using immunohistochemical and Q-PCR analyses showed that DLX1 was frequently up-regulated in ovarian cancer samples. Noticeably, clinicopathological analysis revealed that the upregulated DLX1 was significantly associated with not only the overexpressed FOXM1 (P=0.001) but also high grade ovarian cancer (P<0.001). Previous studies have reported that DLX1 is a homeobox transcription factor controlling neuron migration and proliferation in embryogenesis. However, the oncogenic functions of DLX1 are rarely reported. In this study, we revealed that DLX1 could promote ovarian cancer cell proliferation and cell migration which are the main phenomena found in high grade tumors. To the best of our knowledge, this is the first report showing the regulation of FOXM1 on DLX1 and the metastatic functions exerted by DLX1 in ovarian cancer cells. Although ovarian cancer cells are epithelial cell type which is different from neurons, the similar cell functions derived from DLX1 reflecting that both cell types share the similar signaling pathway of DLX1. However, further investigation on the downstream network of DLX1 and the in vivo tumorigenic capacities in ovarian cancer cells are warranted. To conclude, we have identified DLX1 as a novel target of FOXM1 and frequently up-regulated in high grade ovarian cancer. The in vitro tumorigenic assay demonstrated DLX1 could promote cell proliferation and cell migration which are the metastatic properties usually found in high grade ovarian cancer. Therefore, these data highlight the possibilities of using DLX1 as a biomarker and therapeutic target in combating ovarian cancer in the future. / published_or_final_version / Obstetrics and Gynaecology / Master / Master of Philosophy