Thesis (M.S.)--West Virginia University, 2002. / Title from document title page. Document formatted into pages; contains viii, 56 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 50-54).

Thesis (M.S.)--Rutgers University, 2009. / "Graduate Program in Biomedical Engineering." Includes bibliographical references (p. 53-55).

Thesis (M. Phil.)--University of Hong Kong, 2001. / Includes bibliographical references (leaves 133-138).

Thesis (M. Phil.)--University of Hong Kong, 2001. / Includes bibliographical references (leaves 87-102).

published_or_final_version / Obstetrics and Gynaecology / 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

Background Esophageal carcinoma mainly affects middle aged to elderly males. It ranks the ninth most common cancer world-wide. The main histological types are squamous cell carcinoma and adenocarcinoma. In Hong Kong, esophagus squamous cell carcinoma (ESCC) is by far the more common. BARX2 is a human homeobox gene located at 11q24-q25, encoding a protein of 254 amino acids. Recent researches show that its expression in breast cancer promotes cellular invasion. Objectives The study aimed to test the hypothesis that BARX2 is a prognostic marker in ESCC. BARX2 expression in ESCC was correlated with patient survival and other clinicopathologic parameters in a cohort of patients. Material and Methods Records of ESCC patients were obtained retrospectively from the computerized database of Queen Mary Hospital. ESCC patients, who underwent esophagectomy in the hospital from 1998 to 2005 but without receiving prior chemotherapy or radiotherapy directed to the tumor, were selected. Tumor staging was done according to the 6th edition of AJCC Cancer Staging Manual. Immunohistochemical staining for BARX2 expression was performed on paraffin sections of the primary ESCC tissues sampled in a tissue microarray constructed for research purposes. The pattern of BARX2 expression in nucleus and cell cytoplasm of tumor cells was recorded and the staining intensity scored on a 4-point scale. The scores were statistically analyzed together with the various clinicopathologic parameters. BARX2 expression and patient survival time were analyzed by the log-rank test. Results A total of 78 ESCC patients were recruited. At the time of data analysis, 52 (66.7%) patients were dead. The overall median survival of patients was 14.3 months. BARX2 was found to be mainly expressed in the cytoplasm of tumor cells while non-tumor epithelium showed strong nuclear expression. Patients with high level BARX2 expression had short survival time, though the difference did not reach statistical significance (p=0.075). Within the subgroup of lower T-stage ESCC (T1-3), high level BARX2 expression was significantly associated with shorter survival time (p=0.042). However, differential BARX2 expression did not affect survival time within the group of patients who had advanced stage (T4) disease (p=0.525). In patients who had no regional lymph node metastasis (N0), high level BARX2 expression was associated with shorter survival time (p=0.023). However, when patients had regional lymph node metastases (N1), BARX2 expression did not affect patient survival time (p=0.533). Patients whose ESCC showed moderate differentiation in a three-tier tumor grading system, when accompanied with low level BARX2 expression, had longer survival time (p=0.029). However, BARX2 expression did not affect survival time when ESCC showed either well differentiation (p=0.462) or poor differentiation (p=0.637). Multivariate analysis showed patient age and T-stage to be the only two independent parameters of prognostic significance (p=0.025 and p=0.036 respectively). Conclusions BARX2 expression in ESCC was aberrant and mainly cytoplasmic. It was inversely correlated with patient survival time in early ESCC disease (T1-T3 or N0). BARX2 expression evaluated by immunohistochemistry could be a useful and practical prognostic marker of ESCC in its early stages, when the proper decision on treatment would be critical for the patients. / published_or_final_version / Pathology / Master / Master of Medical Sciences

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Biochemistry / Master / Master of Philosophy

No description available.