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ID1-induced activation of PI3K/AKT/NFkB pathway: mechanisms and significance in esophageal cancerLi, Bin, 李斌 January 2009 (has links)
published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy
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Role of DNAJB6 in esophageal squamous cell carcinomaYu, Zhuoyou, 余卓由 January 2013 (has links)
Esophageal cancer (EC), which is geographically diverse, has only a 10.7% five-year survival rate. One of the histologic forms, esophageal squamous cell carcinoma (ESCC), in Hong Kong accounts for 81.5% of the total EC cases and its five-year survival rate is only ~14%, due to its high frequency of metastasis.
In our previous studies, functional complementation study of chromosome 9 defects led to the discovery of a novel tumor suppressor gene, Deleted in Esophageal Cancer 1 (DEC1), mapping to 9q32. DEC1 was shown to reduce tumorigenicity in a mouse model and its expression was shown to be associated with lymph node metastasis, early onset of ESCC, and familial ESCC development in a tissue microarray (TMA) study. Moreover, DNAJ (Hsp40) homologue subfamily B member 6 (DNAJB6), a molecular co-chaperone protein and the focus of the current study, was identified as a DEC1-interacting protein through a yeast two-hybrid screening. The interaction was further confirmed by the GST pull-down assay and co-localization studies. Using a TMA constructed with ESCC tissues from Hong Kong, the clinical relevance of DNAJB6 expression was demonstrated.
In the present study, the role of DNAJB6 in ESCC was investigated using cell line-based in vivo and in vitro studies. DNAJB6 was shown to be down-regulated in ESCC cell lines. The two isoforms of DNAJB6 have distinct subcellular localizations, with DNAJB6a mainly localized to the nucleus and DNAJB6b diffused throughout the cell. Existence of a functional nuclear localization signal peptide and a functional nuclear export signal peptide was verified in DNAJB6a and DNAJB6b, respectively. In vitro evidence of possible DNAJB6a truncation was found.
In vivo subcutaneous nude mice tumorigenicity assays showed that over-expression of DNAJB6a, but not DNAJB6b, suppresses tumor growth at the primary site, while DNAJB6a silencing enhances tumor growth. The suppressive effect of DNAJB6a depends on nuclear localization of the protein and the HPD tripeptide motif in the N-terminal J domain. In vitro function studies show that DNAJB6a over-expression impairs cell proliferation by suppressing G1/S transition.
AKT1 phosphorylation is down-regulated in DNAJB6a over-expressed cells, leading to up-regulation of p27KIP1 protein expression and down-regulation of cyclin E1 protein expression, the G1/S transition promoter, in an AKT1-dependent manner. DNAJB6a silencing results in the opposite effect.
Over-expression of DNAJB6b, but not DNAJB6a, instead suppresses lung colonization in an experimental metastasis assay, and prolongs survival of the mice.
Silencing of DNAJB6a in immortalized normal esophageal epithelial cells initially induces a senescence-like phenotype with greatly reduced proliferation possibly due to oncogenic stress from up-regulation of AKT1 phosphorylation and cyclin E1 protein expression, but promotes EMT-like molecular alterations by up-regulating STAT3 phosphorylation and TWIST1 protein expression and resumes proliferation after prolonged culture.
In summary, these results suggest that DNAJB6 plays a critical role in ESCC initiation, development, and metastasis and provides valuable insight into the understanding of ESCC tumorigenesis and metastasis. This suggests its usefulness as a biomarker candidate for detecting early ESCC tumor initiation. / published_or_final_version / Clinical Oncology / Doctoral / Doctor of Philosophy
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Evaluation of chemoresistance in oesophagogastric cancers : identification of candidate novel therapeutic targetsMatula, Katarzyna Monika January 2013 (has links)
Development of resistance is the major hindrance to successful chemotherapy treatment in oesophago-gastric (OEG) cancers. Platinum based chemotherapy prolong the survival however only 20 - 30 % of patients survive 5- years since diagnosis of the disease. Therefore understanding of the mechanisms that underlie this phenomenon and identification of novel biomarkers/targets that could predict the response to the treatment and sensitize these tumours to current therapy is needed. We established a panel of human cancer cell lines of oesophagus (OE21 and OE33) and gastric cardia (AGS) resistant to oxaliplatin, cisplatin and docetaxel. To study mechanisms of drug resistance we performed gene expression profiling on resistant and parental lines and differentially expressed genes involved in sphingolipids / lysosomes metabolism have been shown as associated with drug resistance. Selected markers were validated on mRNA and protein levels among the panel of OEG cell lines and clinical specimens. Cellular levels of sphingolipid species were determined in drug sensitive and resistant lines using mass spectrometry. This study revealed a positive correlation between over-expression of sphingosine kinase 1 (SPHK1) and increased levels of sphingosine -1-phosphate (S1P) associated with drug resistance in gastric cancer cell lines. Moreover it showed the predictive value of SPHK1 as high level of this protein correlates with poor survival of OEG cancer patients treated with cisplatin based chemotherapy, in contrast to those patients that received surgery alone. Additionally, lipidomic profiling data showed possibly distinct mechanisms of drug resistance between gastric and oesophageal tumours, indicating that mechanisms of drug resistance are likely cell type, rather than drug specific. In conclusions, this study proofs the clinical relevance of our in vitro experimental models to study mechanisms of drug resistance in OEG tumours and provides the source of novel biomarkers for targeted therapy strategies in this disease.
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The role of p16 gene in oesophageal carcinomaLaw, Bic-fai, Fian., 羅璧輝. January 2001 (has links)
published_or_final_version / Medical Sciences / Master / Master of Medical Sciences
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Epigenetic inactivation of RASSF1 candidate tumor suppressor gene on 3p21.3 locus in esophageal cancer王洛儀, Wong, Lok-yee, Michelle. January 2003 (has links)
published_or_final_version / Medical Sciences / Master / Master of Medical Sciences
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Integrative analysis of array comparative genomic hybridisation and microarray gene expression profiles in oesophageal adenocarcinomaGoh, Xin Yi January 2012 (has links)
No description available.
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Identification of a novel therapeutic strategy from molecular stratification of oesophageal adenocarcinomaOng, Chin-Ann Johnny January 2013 (has links)
No description available.
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Identification and characterization of cancer-related genes in esophageal squamous cell carcinomaFu, Li, January 2007 (has links)
Thesis (Ph. D.)--University of Hong Kong, 2007. / Also available in print.
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Proteomic identification and characterization of proteins that are associated with malignancy of esophageal cancer cellsCai, Zhen, January 2007 (has links)
Thesis (Ph. D.)--University of Hong Kong, 2008. / Also available in print.
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Oesophageal mucosal injury by acid and bile salt /Kiroff, George Kosta. January 1986 (has links) (PDF)
Thesis (M.S.)--University of Adelaide, Dept. of Surgery, 1989. / The experimental work described was performed in the Department of Surgery of the University of Adelaide during 1982-1983. Typescript (photocopy). Includes bibliographical references (leaves 191-211).
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