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New Approaches and Gene Targets in Molecular Pathogenesis of Colorectal Cancer

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New approaches and gene targets in molecular pathogenesis of colorectal cancer Author Lee, Katherine Published 2018-11 Thesis Type Thesis (PhD Doctorate) School School of Medicine DOI https://doi.org/10.25904/1912/1616 Copyright Statement The author owns the copyright in this thesis, unless stated otherwise. Downloaded from http://hdl.handle.net/10072/384291 Griffith Research Online https://research-repository.griffith.edu.au New approaches and gene targets in molecular pathogenesis of colorectal cancer Katherine Ting-Wei Lee Master of Science in Medical and Health Sciences (By Research) School of Medicine Griffith University A dissertation submitted in fulfilment of the requirements for the degree of Doctor of Philosophy November 2018 Abstract Two genes namely GAEC1 (gene amplified in oesophageal carcinoma one) and FAM134B (family with sequence similarity 143, member B) were first identified in 2001. Subsequently, further characterisation of their biological function in colorectal adenocarcinoma was done. While knock down of GAEC1 dampened cancer progression by inhibiting cellular functions such as proliferation and increasing apoptosis, knock down of FAM134B enhanced these cellular functions and drove the progression of colon adenocarcinoma. These results were further supported with in vivo studies by xenotransplanting colon adenocarcinoma cells containing with either knock down GAEC1 or FAM134B into immunodeficient mice. Results showed that mice xenotransplanted with colon adenocarcinoma cells with knock down GAEC1, lost the ability to form tumour whereas, mice xenotransplanted with colon adenocarcinoma cells with knock down FAM134B¸ formed larger tumour compared to the control mice. Thus, these studies confirm GAEC1 as a transforming oncogene and FAM134B as a tumour suppressor gene. Nonetheless, current literature lacks knowledge on the absolute copy number aberration (CNA) and ploidy number of GAEC1, in depth genetic and epigenetic regulation, functional insights, interacting signalling pathways and molecular partners of GAEC1 and FAM134B. This study first developed a duplex DNA binding dye chemistry-based droplet digital PCR (ddPCR) method and compared the efficiency with real-time PCR (qPCR), the current gold standard method for accurate detection of CNA and ploidy determination. Results showed that ddPCR has better reproducibility compared to qPCR. Both assays were comparable at 96.5% of the time. In addition, the run-time and cost per sample was greatly reduce, thus, providing a better option for use in clinical settings. Following on, this study was the first to attempt identifying mutations of GAEC1. The ddPCR assay was first used to determine the GAEC1 CNA and its ploidy number in patients 2 with colorectal adenocarcinoma. Mutations within the exon sequence of GAEC1 was called using Sanger sequencing and the mRNA and protein expression were determined using qPCR and western blot (confirmed with immunofluorescence assay). To this end, 24% of patients with colorectal adenocarcinoma also have GAEC1 amplification. Additionally, GAEC1 mutations were observed in 10% of patients with colorectal adenocarcinoma including one missense mutation, four loss of heterozygosity and two substitutions. Increased GAEC1 copy and GAEC1 mutations were significantly associated with biological aggressiveness of the adenocarcinoma (P<0.05). Furthermore, GAEC1 mutations were frequently associated with GAEC1 protein expression and is associated with poorer clinical outcomes, thus, indicating the oncogenic potential of GAEC1. Subsequently, GAEC1 was overexpressed in colon adenocarcinoma and non-neoplastic colonic epithelial cells to confirm the oncogenic effects of GAEC1. Multiple in vitro assays including cell proliferation wound healing, clonogenic, apoptosis, cell cycle and extracellular flux were performed. In addition, several potential transcriptional factors that interact with GAEC1 were identified using western blot analysis. Functional studies revealed that GAEC1 overexpression significantly enhance cell proliferation, migration and clonogenic potential (P<0.05) of colon adenocarcinoma cells of the early stage. Moreover, GAEC1 also affected the mitochondrial respiration of colon adenocarcinoma through reducing cell coupling efficiency. A further look into the molecular mechanism of GAEC1 showed that when GAEC1 is overexpressed, increase in the expression of pAkt, FOXO3 and MMP9 were noted. These findings indicate that GAEC1 may interact with these protein molecules and may perhaps play a role in regulating gene pathways such as the Akt pathway. Later, FAM134B overexpression was used to confirm the tumour suppressive effects of FAM134B on colon adenocarcinoma. Various in vitro assays were done, several potential transcriptional factors that interact with FAM134B were identified using western blot analysis 3 and correlated with immunohistochemistry staining in cancer tissues of patients with colorectal adenocarcinoma. This study found that FAM134B is involved in the apoptosis and mitochondrial function of colon adenocarcinoma. FAM134B overexpression significantly increased the expression of EB1, p53 and MIF. While 70% of patients with colorectal adenocarcinoma showed that low expression of FAM134B was significantly correlated with increased expression of MIF, 30% of these patients showed concurrent expressions of MIF and FAM134B expression (P<0.05). Low expression of FAM134B coupled with high expression of MIF is significantly associated with microsatellite instability (P<0.05). Taken together, chapter proves for the first time that FAM134B overexpression affects mitochondrial functionality and potentially interacts with MIF, EB1 and p53 to affect colon adenocarcinoma progression. Collectively, from clinical studies to molecular studies, this study has provided critical knowledge towards further understanding the oncogenic properties of GAEC1 and tumour suppressive properties of FAM134B in colorectal adenocarcinoma. Both GAEC1 and FAM134B portrayed significant correlation in patients with colorectal adenocarcinoma. Likewise, mutations in both GAEC1 and FAM134B has been determined for the first time. Overexpression of GAEC1 or FAM134B showed significant impact on colon adenocarcinoma in vitro. Consequently, potential interacting partners were identified with the manipulation of the expression of GAEC1 or FAM134B. These findings act as a basis for further studies on validating these genes as potential biomarkers for the detection of colorectal cancer or as potential therapeutic options. 4 Statement of Originality This work has not previously been submitted for a degree or diploma in any university. To the best of my knowledge and belief, the thesis contains no material previously published or written by another person except where due reference is made in the thesis itself. (Signed)_____________________________ Katherine Ting-Wei Lee 5 Acknowledgement The completion of this dissertation would not be possible without the tremendous support of multiple individuals and organisation. I would like to express my utmost gratitude and sincere thanks to all of them. To begin with, I would like to thank my dedicated supervisors Professor Alfred Lam, Dr. Vinod Gopalan and Dr. Robert Smith for their continual support, mentoring, guidance and critical input throughout my postgraduate degree. Without their expertise and timely feedback and suggestions, it would not have been possible for me to complete this dissertation. I would also like to thank Dr. Johnny Tang for his kind donation of the GAEC1 plasmid and constructive input during my candidature. In addition, I would like to thank Griffith University, Griffith Graduate Research School, Griffith Health and Menzies Health Institute of Queensland (MHIQ) for awarding me the scholarship and support to carry out this research. Special thanks Dr. Cu Tai Lu from Gold Coast University Hospital for the recruitment of the clinical samples used in this study, Melissa Leung for keeping the tissue biomarker database well organised and up to date and for organising monthly group meetings and Christmas celebrations. Not to forget, the NH Diagnostic Laboratory team that helped the preparation of formalin-fixed paraffin-embedded tissue specimens. I would also like to portray my sincere thanks to Dr. Jelena Vider who have kindly provided her expert advice and training for the use of flow cytometry, immunofluorescence microscope and Seahorse analyser. Her relentless help in obtaining consumables at crucial stages. My heartfelt thanks also go to Dr. Cameron Flegg for his experienced advices in immunofluorescence staining, confocal microscopy and his ever willingness to provide help and advice when requested. Sincere gratitude to Institute of Health and Biomedical Innovation 6 at the Queensland University of Technology for providing the droplet digital system so I could carry out my experiments. Special thanks to the great support and encouragement that I have received from the whole team at the Cancer Molecular Pathology Group, School of Medicine, Griffith University throughout my candidature. Their ever willingness to lend a helping hand, share their wealth of knowledge and provide mental support has helped me come this far. These wonderful individuals that I would love to thanks includes Anna Chruścik, Dr. Farhadul Islam, Dr. S.M. Raijul Wahab, Dr. Suja Pillai, Dr. Md. Hakimul Haque, Dr. Nassim Saremi, Tracie Cheng, Jeremy Martin, Dr. Haleh Vogha, Dr. Afraa Mahdi Jawad Mamoori, Dr. Faeza Ebrahimi, Faysal-Bin
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