Inactivation of mouse tumor susceptibility gene tsg101 leads to neoplastic transformation which could reversed by restoration of tsg101 protein activity. In the varieties of human malignancies, no genomic defect could be identified questioning the role of TSG101as a classical tumor suppressor. Subsequent studies revealed presence of abnormal TSG101 transcripts in both tumor tissues and its normal counter parts, as well as in embryonic tissues. Hence, the relationship between TSG101 and human cancer development remains unclear. The previous studies have demonstrated that TSG101 has multiple biological functions, including regulations of protein degradation through ubiquitination, transcriptional, protein trafficking, cell survival and proliferation and epithelial cell differentiation. To further investigate the role of TSG101 in tumorigenesis, we employed immunohistochemistry and in situ hybridization analysis to study the expressions of TSG101 protein and mRNA in squamous cell carcinomas of different differentiation status. In addition, we scrutinized the relationship between TSG101 expression and the changs of cell cycle-related tumor suppressors and markers of epithelial differentiation, cell growth, tumor metastasis and apoptosis. The results reveal that TSG101 protein and mRNA are consistently expressed in the epidermal cells residing in the suprabasal, granular and cornified layers, but only weakly expressed in the cells of basal layer. The expressions of TSG101 are down regulated in poorly differentiated squamous cell carcinomas of various organs. Furthermore, TSG101 is also expressed in the tissue of squamous metaplasia, and the expression of TSG101 is positively related to that of cytokeratin. In addition, while TSG101 is down regulated, the expressions of p21Cip1/WAF1, p14ARF and MDM2 are also decreased ehereas that of p53 is conversely increased. Phospho-Rb and E-Cadherin were found to be down regulated in advanced cancers, but we failed to find their correlation with TSG101 on cell proliferation and tumor metastasis. Taken together, we hypothesize that TSG101 expression may influence and promote cell differentiation by regulating keratin expression, being involved in the MDM2-p53 circuit and interacting with p21Cip1/WAF1. Besides, by the integration of the studies of TSG101, keratin 10, and Rb protein expression, we infer that TSG101 may indirectly suppress expression of Rb by up-regulating keratin 10 in epithelial cells. The detailed mechanisms of the observation require further investigation. Nevertheless, our results have provided evidences to support the role of TSG101 on differentiation of squamous epithelial cells in addition to tumorigenesis.

No description available.

Thesis (M.S.)--University of Missouri-Columbia, 2007. / "May 2007" The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Vita. Includes bibliographical references.

Penile squamous cell carcinoma (PSCC) is rare; hence little is known about its aetiology and pathogenesis. Two challenges exist in the clinical management of PSCC patients. Firstly, finding a non-invasive method to aid the detection of occult lymph node metastasis to improve patient selection for inguinal lymphadenectomy. Secondly, the development of novel treatment strategies for those with advanced PSCC, as current treatment options are limited. A high prevalence of copy number gain in the chromosome 3q arm has been identified and linked to poor cancer-specific and disease-free survival in PSCC. Within this region lies the PIK3CA oncogene, which is mutated/amplified/gained and results in the activation of the PI3K-AKT-mTOR pathway. PIK3CA copy number gain has not been fully investigated in PSCC and it has the potential to be a driver gene in penile carcinogenesis and the PI3K-AKT-mTOR pathway presents an opportunity for targeted therapeutics in PSCC. I demonstrated an increasing frequency of PIK3CA copy number gain with evolving PSCC disease state (penile intraepithelial neoplasia (10/58; 17%), primary PSCC (83/199; 42%), advanced primary PSCC (20/26; 77%); p < 0.0001) with few PIK3CA mutations in PSCC (3/51; 6%). PIK3CA copy number gain correlated with more aggressive PSCC subtypes (p=0.0028), higher tumour grade (p < 0.0001) and stage (p=0.0043) and thus could be used as a marker of high-risk disease. However, it shows no significant association with lymph node metastasis or prognostic value for cancer-specific survival in PSCC. Overall, I confirmed that the PI3K-AKT-mTOR pathway activity is primarily involved in early penile carcinogenesis and based on these findings the therapeutic targeting of this pathway in those with advanced PSCC disease is unlikely to produce significant clinical benefit. Future studies will need to focus on the identification of new clinically relevant candidate genes and signalling pathways, which offer prognostic value and the potential for targeted therapeutics in this rare cancer.

Thesis (Ph.D.)--University of Hong Kong, 2003. / Also available in print.

Thesis (Ph.D.)--University of Hong Kong, 2003. / Also available in print.

Thesis (Ph. D.)--University of Hong Kong, 2001. / Includes bibliographical references (leaves 143-163).

Thesis (Ph.D.)--University of California, San Francisco, 2004. / Includes bibliographical references. Also available online.

Thesis (M. Med. Sc.)--University of Hong Kong, 2006.

Thesis (M. Res.)--University of Hong Kong, 2006.