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postgraduate thesis: The functional roles and therapeutic implications of FOXM1 and CENPF in hepatocellular carcinoma

TitleThe functional roles and therapeutic implications of FOXM1 and CENPF in hepatocellular carcinoma
Authors
Issue Date2017
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Lam, W. M. [林瑋羚]. (2017). The functional roles and therapeutic implications of FOXM1 and CENPF in hepatocellular carcinoma. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR.
AbstractHepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Deregulation of cell cycle progression underlies aberrant cell growth that characterizes the malignant phenotype of cancer cells. The deregulated cell cycle machinery is therefore believed to be a convergence point for cellular transformation. In the previous RNA-sequencing study performed by our group, we have identified Forkhead Box M1 (FOXM1) and Centromere Protein F (CENPF) as the top-listing upregulated genes in HCC by analyzing the Cancer Genome Atlas (TCGA) whole-transcriptome sequencing data. Both FOXM1 and CENPF are essential components in cell-cycle progression. FOXM1 encodes for the cell-cycle-dependent forkhead box M1 transcription factor that regulates genes for DNA replication and mitosis in cell cycle; whereas CENPF encodes for centromere protein F for chromosome alignment and segregation during mitosis. Interestingly, previous study on prostate cancer has suggested that FOXM1 and CENPF function as a synergistic master regulator that drive its malignant phenotype. Nonetheless, the underlying mechanistic principles of FOXM1 and CENPF remains elusive. In this study, we demonstrated that the upregulation of FOXM1-CENPF axis may drive hepatocarcinogenesis. We aimed to study their clinical relevance, potential synergistic mechanistic role and therapeutic implication in HCC. We demonstrated the significant roles of FOXM1 and CENPF in hepatocarcinogenesis. In respect of clinical relevance, we found the co-overexpression of FOXM1 and CENPF was associated with more aggressive tumor behaviors, including the presence of venous invasion, tumor microsatellite formation, chronic liver diseases and the absence of tumor encapsulation. Functionally, we demonstrated the essential roles of FOXM1 and CENPF in HCC cell proliferation, cell migration and cell invasion in both in vitro and in vivo models. Mechanistically, our study has provided new insight into the synergistic regulatory role of FOXM1 and CENPF in HCC. By RNA-sequencing and differential gene expression analysis, we uncovered a list of candidate genes co-regulated by FOXM1 and CENPF. Among the differentially expressed genes, POLD1 was ranked as the top downstream target co-regulated by FOXM1 and CENPF. Intriguingly, POLD1 is also an indispensable component in cell cycle progression. It encodes for the catalytic subunit of DNA polymerase δ, which is responsible for DNA replication during S-phase of cell cycle. In addition, we revealed FOXM1 and CENPF co-regulated a set of genes in cell cycle processes, cell metabolism, RNA processing and oncogenic signaling pathways. In respect of translational significance, we found thiostrepton (a potential inhibitor of FOXM1) and zoledronic acid (a potential inhibitor of CENPF) inhibited FOXM1 and CENPF protein expression respectively in HCC cells but not in immortalized normal liver cells. Remarkably, we demonstrated that a combined treatment of thiostrepton and zoledronic acid would further suppressed HCC cell proliferative, migratory and invasive abilities. Taken together, our study provided novel insight into the synergistic regulatory role of FOXM1 and CENPF in HCC. More importantly, we manifested the translational significance of targeting FOXM1 and CENPF in HCC, of which FOXM1 and CENPF may represent new vulnerabilities to novel drug-based therapy in HCC.
DegreeMaster of Philosophy
SubjectCentromere
Forkhead transcription factors
Pathogenesis - Liver - Cancer
Dept/ProgramPathology
Persistent Identifierhttp://hdl.handle.net/10722/264730

 

DC FieldValueLanguage
dc.contributor.authorLam, Wai-ling, Macrina-
dc.contributor.author林瑋羚-
dc.date.accessioned2018-10-25T04:12:05Z-
dc.date.available2018-10-25T04:12:05Z-
dc.date.issued2017-
dc.identifier.citationLam, W. M. [林瑋羚]. (2017). The functional roles and therapeutic implications of FOXM1 and CENPF in hepatocellular carcinoma. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR.-
dc.identifier.urihttp://hdl.handle.net/10722/264730-
dc.description.abstractHepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Deregulation of cell cycle progression underlies aberrant cell growth that characterizes the malignant phenotype of cancer cells. The deregulated cell cycle machinery is therefore believed to be a convergence point for cellular transformation. In the previous RNA-sequencing study performed by our group, we have identified Forkhead Box M1 (FOXM1) and Centromere Protein F (CENPF) as the top-listing upregulated genes in HCC by analyzing the Cancer Genome Atlas (TCGA) whole-transcriptome sequencing data. Both FOXM1 and CENPF are essential components in cell-cycle progression. FOXM1 encodes for the cell-cycle-dependent forkhead box M1 transcription factor that regulates genes for DNA replication and mitosis in cell cycle; whereas CENPF encodes for centromere protein F for chromosome alignment and segregation during mitosis. Interestingly, previous study on prostate cancer has suggested that FOXM1 and CENPF function as a synergistic master regulator that drive its malignant phenotype. Nonetheless, the underlying mechanistic principles of FOXM1 and CENPF remains elusive. In this study, we demonstrated that the upregulation of FOXM1-CENPF axis may drive hepatocarcinogenesis. We aimed to study their clinical relevance, potential synergistic mechanistic role and therapeutic implication in HCC. We demonstrated the significant roles of FOXM1 and CENPF in hepatocarcinogenesis. In respect of clinical relevance, we found the co-overexpression of FOXM1 and CENPF was associated with more aggressive tumor behaviors, including the presence of venous invasion, tumor microsatellite formation, chronic liver diseases and the absence of tumor encapsulation. Functionally, we demonstrated the essential roles of FOXM1 and CENPF in HCC cell proliferation, cell migration and cell invasion in both in vitro and in vivo models. Mechanistically, our study has provided new insight into the synergistic regulatory role of FOXM1 and CENPF in HCC. By RNA-sequencing and differential gene expression analysis, we uncovered a list of candidate genes co-regulated by FOXM1 and CENPF. Among the differentially expressed genes, POLD1 was ranked as the top downstream target co-regulated by FOXM1 and CENPF. Intriguingly, POLD1 is also an indispensable component in cell cycle progression. It encodes for the catalytic subunit of DNA polymerase δ, which is responsible for DNA replication during S-phase of cell cycle. In addition, we revealed FOXM1 and CENPF co-regulated a set of genes in cell cycle processes, cell metabolism, RNA processing and oncogenic signaling pathways. In respect of translational significance, we found thiostrepton (a potential inhibitor of FOXM1) and zoledronic acid (a potential inhibitor of CENPF) inhibited FOXM1 and CENPF protein expression respectively in HCC cells but not in immortalized normal liver cells. Remarkably, we demonstrated that a combined treatment of thiostrepton and zoledronic acid would further suppressed HCC cell proliferative, migratory and invasive abilities. Taken together, our study provided novel insight into the synergistic regulatory role of FOXM1 and CENPF in HCC. More importantly, we manifested the translational significance of targeting FOXM1 and CENPF in HCC, of which FOXM1 and CENPF may represent new vulnerabilities to novel drug-based therapy in HCC. -
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subject.lcshCentromere-
dc.subject.lcshForkhead transcription factors-
dc.subject.lcshPathogenesis - Liver - Cancer-
dc.titleThe functional roles and therapeutic implications of FOXM1 and CENPF in hepatocellular carcinoma-
dc.typePG_Thesis-
dc.description.thesisnameMaster of Philosophy-
dc.description.thesislevelMaster-
dc.description.thesisdisciplinePathology-
dc.description.naturepublished_or_final_version-
dc.date.hkucongregation2017-
dc.identifier.mmsid991043982880803414-

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