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postgraduate thesis: Oncogene EIF5A2 promotes cell growth and proliferation by reprograming cellular metabolism in hepatocellular carcinoma

TitleOncogene EIF5A2 promotes cell growth and proliferation by reprograming cellular metabolism in hepatocellular carcinoma
Authors
Issue Date2014
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Cao, T. [曹婷婷]. (2014). Oncogene EIF5A2 promotes cell growth and proliferation by reprograming cellular metabolism in hepatocellular carcinoma. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5350995
AbstractHuman Eukaryotic translation initiation factor 5A2 (eIF5A2), a novel oncogene located at chromosome 3q26.2, is frequently up-regulated in many human solid tumors including hepatocellular carcinoma (HCC). It has been reported that EIF5A2 can promote cell growth in hypoxia condition, in which the metabolism pathways (e.g. glucose metabolism) are disordered, suggesting that EIF5A2 may play a crucial role in regulating cancer cell metabolic activities. The aim of this study is to find out how EIF5A2 promotes cancer cell growth and proliferation from the perspective of cellular metabolism. Previous studies have shown that the aberrant metabolic alterations play a crucial role in the initiation and progression of HCC. The poor vascularization in tumor tissues leads to nutrient deprivation and limited oxygen supply, which attenuates cell proliferation. However, tumor cells could adapt the environmental stress via altered metabolic pathways. For example, tumor cells are inclined to utilize glucose through glycolysis rather than tricarboxylic acid cycle (TCA cycle) for energy generation and metabolite production, in despite of high oxygen availability, which is termed as Warburg Effect. In this study, the functional study and metabolic analysis were performed on liver cell line models with EIF5A2 overexpression or knockdown. It was observed that overexpression of EIF5A2 accelerated cell growth rate under normoxic condition, and high EIF5A2 expression level enabled the cells to survive better in the absence of oxygen. The cell cycle analysis indicated that overexpression of EIF5A2 accelerated the G2 entry. With the application of non-targeted metabolic analysis and metabolite detection assays, it was found that the glucose utilization and lipogenesis rates in EIF5A2-overexpressing cells increased significantly both under normoxic and hypoxic condition. The high rates of glucose uptake and lactate secretion in EIF5A2-overexpressing cells revealed the turnover from TCA cycle to aerobic glycolysis. In addition, the increased Glycerophospholipids in cells, an important component of cellular block building, was a solid proof that EIF5A2 promoted cell proliferation. Furthermore, a series of key enzymes in both glycolysis and de novo lipid biosynthesis were screened using qPCR and Western Blot analysis. The results showed that EIF5A2 up-regulated several key enzymes in glycolysis process such as Glucose Transporter type 1 and 2 (GLUT1/2), Hexokinase 1 and 2 (HK1/2), Glyceraldehyde 3-phoshpate dehydrogenase (GAPDH), pyruvate kinase muscle type (PKM), and Lactate dehydrogenase A (LDHA). In addition, EIF5A2 reprogrammed fatty acid de novo biosynthesis and lipogenesis by up-regulating fatty acid synthase (FASN) and cytosolic acetyl-CoA synthetase 2 (ACSS2). Conversely, these enzymes mentioned above were all down-regulated in cells transduced with shRNAs targeted at EIF5A2. In summary, this study provided evidence that EIF5A2 could promote cell growth and proliferation in liver cell lines through reprogramming cellular metabolism, including glucose metabolism and fatty aid biosynthesis. Due to the great diversity of cancer cells, our perspective in this study may be not universal, but could provide a framework about the metabolic function of EIF5A2 in HCC, as well as a novel insight for how to manipulate cancer cell metabolism.
DegreeDoctor of Philosophy
SubjectLiver - Cancer - Genetic aspects
Oncogenes
Dept/ProgramClinical Oncology
Persistent Identifierhttp://hdl.handle.net/10722/220005

 

DC FieldValueLanguage
dc.contributor.authorCao, Tingting-
dc.contributor.author曹婷婷-
dc.date.accessioned2015-10-09T23:12:30Z-
dc.date.available2015-10-09T23:12:30Z-
dc.date.issued2014-
dc.identifier.citationCao, T. [曹婷婷]. (2014). Oncogene EIF5A2 promotes cell growth and proliferation by reprograming cellular metabolism in hepatocellular carcinoma. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5350995-
dc.identifier.urihttp://hdl.handle.net/10722/220005-
dc.description.abstractHuman Eukaryotic translation initiation factor 5A2 (eIF5A2), a novel oncogene located at chromosome 3q26.2, is frequently up-regulated in many human solid tumors including hepatocellular carcinoma (HCC). It has been reported that EIF5A2 can promote cell growth in hypoxia condition, in which the metabolism pathways (e.g. glucose metabolism) are disordered, suggesting that EIF5A2 may play a crucial role in regulating cancer cell metabolic activities. The aim of this study is to find out how EIF5A2 promotes cancer cell growth and proliferation from the perspective of cellular metabolism. Previous studies have shown that the aberrant metabolic alterations play a crucial role in the initiation and progression of HCC. The poor vascularization in tumor tissues leads to nutrient deprivation and limited oxygen supply, which attenuates cell proliferation. However, tumor cells could adapt the environmental stress via altered metabolic pathways. For example, tumor cells are inclined to utilize glucose through glycolysis rather than tricarboxylic acid cycle (TCA cycle) for energy generation and metabolite production, in despite of high oxygen availability, which is termed as Warburg Effect. In this study, the functional study and metabolic analysis were performed on liver cell line models with EIF5A2 overexpression or knockdown. It was observed that overexpression of EIF5A2 accelerated cell growth rate under normoxic condition, and high EIF5A2 expression level enabled the cells to survive better in the absence of oxygen. The cell cycle analysis indicated that overexpression of EIF5A2 accelerated the G2 entry. With the application of non-targeted metabolic analysis and metabolite detection assays, it was found that the glucose utilization and lipogenesis rates in EIF5A2-overexpressing cells increased significantly both under normoxic and hypoxic condition. The high rates of glucose uptake and lactate secretion in EIF5A2-overexpressing cells revealed the turnover from TCA cycle to aerobic glycolysis. In addition, the increased Glycerophospholipids in cells, an important component of cellular block building, was a solid proof that EIF5A2 promoted cell proliferation. Furthermore, a series of key enzymes in both glycolysis and de novo lipid biosynthesis were screened using qPCR and Western Blot analysis. The results showed that EIF5A2 up-regulated several key enzymes in glycolysis process such as Glucose Transporter type 1 and 2 (GLUT1/2), Hexokinase 1 and 2 (HK1/2), Glyceraldehyde 3-phoshpate dehydrogenase (GAPDH), pyruvate kinase muscle type (PKM), and Lactate dehydrogenase A (LDHA). In addition, EIF5A2 reprogrammed fatty acid de novo biosynthesis and lipogenesis by up-regulating fatty acid synthase (FASN) and cytosolic acetyl-CoA synthetase 2 (ACSS2). Conversely, these enzymes mentioned above were all down-regulated in cells transduced with shRNAs targeted at EIF5A2. In summary, this study provided evidence that EIF5A2 could promote cell growth and proliferation in liver cell lines through reprogramming cellular metabolism, including glucose metabolism and fatty aid biosynthesis. Due to the great diversity of cancer cells, our perspective in this study may be not universal, but could provide a framework about the metabolic function of EIF5A2 in HCC, as well as a novel insight for how to manipulate cancer cell metabolism.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.subject.lcshLiver - Cancer - Genetic aspects-
dc.subject.lcshOncogenes-
dc.titleOncogene EIF5A2 promotes cell growth and proliferation by reprograming cellular metabolism in hepatocellular carcinoma-
dc.typePG_Thesis-
dc.identifier.hkulb5350995-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplineClinical Oncology-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b5350995-

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