Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world, especially in Asia and Africa countries. The distribution pattern shows geographical variation and pathogesis in multifactors as environment, infection, nutrition, metabolism, and endocrine contribute to hepatocarcinogenesis. Alpha fetal protein (AFP), the major tumor marker used at present accounts only 50% HCC diagnostic efficiency. This study aims to identify potential tumor markers or suppressor genes for further application in early HCC diagnoses and treatments. Therefore we utilized available cDNA microarray databases in conjunction with other bioinformatic resources to identify our candidate genes related to HCCs. cDNA microarray technology and bioinformatic resources which enable investigators to obtain comprehensive data with respect to gene-expression profiles, is progressing rapidly. The Okabe¡¦s and Stanford¡¦s HCC database were our major data-mining material. A total of 85 potential tumor markers and 106 potential tumor suppressors were found via preliminary in silico datamining. We furthermore narrowed down to 14 candidate tumor markers and 7 candidate tumor suppressor genes by the way of quantitative RT-PCR technologies were applied in various HCC cancer cell lines and 21 patient¡¦s in pair, tumor/non-tumor tissues to confirm gene expression profile. The results revealed that 6 genes (PRO2000, PYGB, STMN1, AFM, C8FW, NNMT) conformed to our data-mining studies.

Thesis (Ph. D.)--University of Missouri-Columbia, 2003. / Typescript. Vita. Includes bibliographical references (leaves 164-183). Also available on the Internet.

Thesis (Ph. D.)--University of Missouri-Columbia, 2003. / Typescript. Vita. Includes bibliographical references (leaves 164-183). Also available on the Internet.

Dissertation (MSc)--University of Stellenbosch, 2008. / Bibliography. Also available via the Internet.

Thesis (Ph. D.)--University of Chicago, Committee on Immunology, August 2001. / Includes bibliographical references. Also available on the Internet.

published_or_final_version / Medicine / Master / Master of Medical Sciences

published_or_final_version / Medicine / Master / Master of Medical Sciences

published_or_final_version / Obstetrics and Gynaecology / Doctoral / Doctor of Philosophy

published_or_final_version / Clinical Oncology / Doctoral / Doctor of Philosophy

Hepatocellular carcinoma (HCC) is the most common tumors worldwide. In contrast to other cancers, the prognosis of HCC is extremely poor, with less that 5% of 5-year survival rate worldwide. From our previous studies, we isolated Chromodomain Helicases/ATPase DNA binding protein1-Like (CHD1L) gene from chromosome 1q21, and characterized it as a specific oncogene in HCC. By using 2D-PAGE and MALDI-TOF mass spectrometry approach, Translationally Controlled Tumor Protein (TCTP) was identified as a CHD1L target, which was preferentially expressed in CHD1L-transfected cells. TCTP is a highly conserved protein and expressed in almost all mammalian tissues. It has been reported that TCTP interacts with microtubules in a cell-cycle-dependent manner, and functions as a prosurvival factor and inhibiting apoptosis. To better understand the molecular mechanisms of HCC progression, the effect of TCTP overexpression in HCC and the mechanism by which TCTP regulated cell-cycle progression were elucidated in this study. CHD1L is a unique oncogene belongs to SNF2-like subfamily. Mechanistic studies found that CHD1L protein directly binds to the promoter region (nt -733 to -1,027) of TCTP and activated TCTP transcription. Investigation of clinical HCC specimens found that overexpression of TCTP was not only significantly associated with the advanced tumor stage (P = 0.037) and overall survival time of HCC patients (P = 0.034), but also an independent marker associated with poor prognostic outcomes. Functional studies demonstrated that TCTP has tumorigenic abilities and overexpression of TCTP contributed to the mitotic defects of tumor cells. Further mechanistic studies demonstrated that TCTP promoted the ubiquitin-proteasome degradation of Cdc25c during mitotic progression, which caused the failure in the dephosphorylation of Cdk1 on Tyr 15 and decreased Cdk1 activity. The consequence of chromosome missegregation and mitotic catastrophe results in aneuploidy, which is frequently observed in cancer. In addition, the correlation between TCTP overexpression and metastatic potential of HCC was elucidated by examined the expression levels of TCTP using a tissue microarray (TMA) containing 60 pairs of primary HCCs and their matched metastases. Further studies demonstrated that overexpression of TCTP shows high incidence of extrahepatic metastasis and positive correlation was found between TCTP and MMP-2 or MMP-9 (Spearmen correlation coefficient=0.466, and 0.352, respectively, P<0.001 for both). In vitro functional studies showed that TCTP protein associated with promoter regions of MMP-2 and MMP-9 and activates their transcriptions. Molecular analyses revealed that TCTP served as a JunD coactivator and formed complexes with JunD and bind with consensus AP-1 sites on MMP-2 and MMP-9 promoters to enhance their expression in HCC cells. More importantly, high co-expression of TCTP and MMP-2 or MMP-9 was significantly associated with poor disease-free survival (log rank= 8.146, and 11.677 respectively, P =0.017 and 0.003 respectively). In summary, two novel molecular mechanisms (CDH1L/TCTP/Cdc25C/Cdk1) and (TCTP/JunD/MMP-2, MMP-9) were revealed during HCC progression and metastasis. Also, the prognostic value of TCTP and MMP-2 or MMP-9 coexpression for HCC was highlight in this study. / published_or_final_version / Clinical Oncology / Doctoral / Doctor of Philosophy