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

published_or_final_version / Clinical Oncology / Doctoral / Doctor of Philosophy

published_or_final_version / Clinical Oncology / Doctoral / Doctor of Philosophy

published_or_final_version / Clinical Oncology / Doctoral / Doctor of Philosophy

Esophageal squamous cell carcinoma (ESCC) is a common cancer worldwide with a high mortality rate. High occurrence of ESCC is observed in Southeast Asia. Identification and characterization of ESCC important tumor suppressor genes will be highly beneficial to the understanding of the disease and for the early diagnosis and improvement of therapy for the cancer. In our previous microcell-mediated chromosome transfer (MMCT) studies, the transfer of an intact chromosome 13 into the recipient ESCC cell line revealed the tumor suppressive ability and putative tumor suppressive function of chromosome 13 in ESCC. One candidate gene, Plant-Homeodomain Finger Protein 11(PHF11), was identified from the study and selected for further functional studies in this current study. PHF11, located on chromosomal region 13q14, contains two plant homeodomain fingers and is a member of the PHD finger protein family. PHF11was reported to be associated with asthma and atopic diseases, yet no studies of PHF11havebeen reported in cancer to date. This study is the first to report the functional role of PHF11in tumor suppression. In this current study, two isoforms of PHF11, PHF11aand b, were reintroduced into ESCC cell lines by methods of transient tranfection and lentiviral-infection. In vitro studies showed both isoforms have cell proliferation and colony-formation inhibition abilities. In the nude mouse tumorigenicity assay, however, it was revealed that only thePHF11aisoform was tumor suppressive in vivo. No differences in angiogenesis-related factors and apoptosis-related factors were observed in PHF11a-and b-expressing cells. Further studies by Western blotting analysis and flow cytometry analysis showed that PHF11amay play a role in delaying cell cycle progression by the down-regulation of cyclin expression, while the PHF11bmay be functionally inactive, The results of this current study further confirm the tumor suppressive role of PHF11ain ESCC, whereas the PHF11b isoform was unable to suppress tumor formation in vivo. Further study of the PHF11 isoforms to identify their differential functions and interacting partners will provide a better understanding of the mechanism by which PHF11a suppressestumor growth. / published_or_final_version / Clinical Oncology / Master / Master of Philosophy

abstract / Anatomy / Master / Master of Philosophy

Introduction: Gastro-oesophageal disease (GORD) is a common disease affecting 20% of adults in the Western world (Dexter 2004) and occurs when the anti-reflux barrier is compromised. Anti-reflux surgery can be recommended to patients with GORD as an alternate to long-term medical therapy. Aim: Laparoscopic anterior fundoplication (LAF) is the preferred type of anti-reflux surgery in our institution. This study aimed to determine the long-term effectiveness of LAF by means of quality of life (QOL) and acid reflux level assessment. Methods: After applying exclusion criteria, patients were sent an invitation for the study along with a QOL questionnaire (QOLRAD) to complete. Selected patients were also invited to undergo 24-hour pH studies. These patients were also asked to complete another QOL questionnaire (Reflux questionnaire (RQ)). Results: QOLRAD questionnaires were analysed (n = 126) and mean scores were calculated for each dimension in addition to an overall QOL score. Over 75% of patients in both the medium-term (2-4 years) and long-term groups (5-14 years) had a good QOL (score 5-7). The median QOL score for the long-term group was 5.89 (±1.36). In addition, Reflux Questionnaire QOL scores (n = 20) (RQLS) indicated that patients were well with a median score of 87.7 out of 100 at long-term. By comparing our post-operative results to published baseline result, our patients QOL had improved since surgery. Most dimensions (QOLRAD) and all symptoms scores (RQ) suggested improvement from baseline. Post-operative 24-hour pH testing (n = 22 0) showed that 55% of patients had a normal TFT pH<4 and that a further 18% had better TFT pH <4 than pre-operatively at long-term follow-up Conclusion: This study suggests that LAF is effective in the long-term by maintaining a good QOL and controlling acid reflux levels. However, larger numbers of participants and pre-operative data are required to confirm these findings.

Over the last three decades, there has been a sharp rise in the incidence of oesophageal adenocracinoma (OA) in the UK. The cause of this rising trend remains unknown. Chronic symptomatic Gastro-Oesophageal Reflux Disease (GORD) has been associated with Barrett's oesophagus (BO), a premalignant stage of OA. The process how acid exposure drives the metaplasia-dysplasia-neoplasia sequence is not known. Oxidative stress plays vital role in carcinogenesis. Selenium is a trace metal element in our diet essential for anti-oxidant selenoproteins synthesis, such as glutathione peroxidases (GPxs). GPxs play a vital role in humans to fight oxidative stress. Epidemiological studies showed that high serum selenium levels are associated with a lower incidence of oesophageal and gastric cardia cancer. This thesis hypothesised that chronic GORD is an initiator of OA pathogenesis by exposing the lower oesophagus to chronic pulse acid, which results in radical oxygen species (ROS) production and oxidative stress damage. GORD patients with suboptimal selenium status are more susceptible to pulse-acid induced oxidative damage because of poor anti-oxidative defence system. The combination of pulse acid exposure and low selenium status potentially drives the OA pathogenesis. The study aims to investigate the effect of pulse-acid exposure, selenium status and its supplementation on cellular proliferation and apoptosis, key processes in carcinogenesis. The study also further investigated the potential pathways through which the pulse acid and low selenium could trigger the carcinogenesis. Ex vivo study was also conducted to examine the selenium status among BO and OA patients, including analysis of single nucleotide polymorphism (SNP) of GPx4 among these patients. The results showed that pulse-acid exposure increased cellular survival and suppressed apoptosis. This result was consistent with previous studies conducted by other researchers. Selenium supplementation at supra-optimal level (100 nM) was shown to potentially mitigate the proliferative effect induced by pulse-acid exposure. Pulse acid exposure was shown to induce ROS production in vitro. This could be mitigated by selenium supplementation. The mitigating effect was likely to be mediated by GPx1, and GPx4, selenoenzymes that are capable of reducing ROS. The study also revealed that apoptosis suppression by selenium supplementation was probably mediated by p53 tumour suppressor gene, but not via Bcl-2 protein. Ex vivo study results showed that OA patients have a 54% significant lower GPx4 mRNA expressions compared to the normal subjects, while the Barrett's subjects were in between OA and Normal. This is in line with the hypothesis that the severity of the disease is closely linked with the levels of anti-oxidant enzymes expression. Expectantly, patients with BO have higher, although not statistically significant, serum selenium compared to the control group. Single nucleotide polymorphism (SNP) of GPx4 could be an explanation for the reason OA and BO patients were unable to synthesise GPx despite an adequate serum selenium level, this rendered them more susceptible to ROS induced oxidative damage. These findings might have potential therapeutic implications for BO and OA. Targeted selenium supplementation could be a cost effective way of OA cancer prevention. Target screening to identify subjects with certain Genotype or SNP, could ensure early intervention to prevent cancer development. A long term, well designed, randomised, placebo controlled selenium supplementation trial to examine the clinical efficacy of selenium supplementation in OA prevention is warrant.

No description available.

Thesis (Ph. D.)--Rutgers University, 2007. / "Graduate Program in Food Science." Includes bibliographical references (p. 65-78).