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postgraduate thesis: Characterization of ATP-binding cassette sub-family F member 1 (ABCF1) in liver cancer and fetal liver
Title | Characterization of ATP-binding cassette sub-family F member 1 (ABCF1) in liver cancer and fetal liver |
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Authors | |
Advisors | |
Issue Date | 2018 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Fung, S. [馮思慧]. (2018). Characterization of ATP-binding cassette sub-family F member 1 (ABCF1) in liver cancer and fetal liver. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. |
Abstract | Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal malignancy worldwide. Diagnosis at the advanced stage, tumor recurrence and treatment inefficacy are the major causes of HCC mortality, and the latter has been attributed to metastasis and chemoresistance. The importance of developmental biology in carcinogenesis has been highlighted by their resemblance in multiple aspects, including the expression and the involvement of similar molecules, which have been identified as oncofetal molecules with expression in stem cells and cancer stem cells (CSC); and the transition of cells between epithelial and mesenchymal states by the epithelial-mesenchymal transition (EMT) program. The aim of our study is to explore novel molecules, especially those involved in developmental processes and that promote tumorigenesis.
ATP-binding cassette (ABC) transporters mediate multidrug resistance and stemness properties in model systems. Yet, their clinical relevance remained controversial. Little has been known on ABCF1, especially with the lack of transmembrane domain, it has not been considered to have transporter function. In this study, we characterized the expression pattern and the involvement of ABCF1 in HCC. The expression profiles of ABC genes in HCC samples have been retrieved from published datasets and analyzed systemically. Independent clinical cohort has been used and validated on paired HCC tissues and cell lines. ABCF1 was significantly upregulated in HCCs compared to adjacent non-tumor and normal liver tissues. High ABCF1 levels associated with poor recurrence-free survival after partial hepatectomy and aggressive clinico-pathological features including tumor size, tumor stage and venous infiltration. Evaluation of ABCF1 expression in fetal, neonatal and adult mouse livers by qPCR, western blot and immunohistochemistry revealed strong expression of ABCF1 in liver during early embryonic stages but limited expression in neonates and adult livers. Our results demonstrated the oncofetal expression pattern of ABCF1 and suggested the significance of ABCF1 in promoting HCC progression.
Consistently, functional assays showed that stable overexpression of ABCF1 enhanced chemoresistance and the drug efflux ability of HCC cells. Subcellular fractionation analysis and confocal microscopy concordantly demonstrated ABCF1 on plasma membrane and cytoplasm in HCC cells. Upregulated ABCF1 expression augmented cell migratory potential and induced lamellipodia/ filopodia in HCC cells. Concurrently, ABCF1 elevated the expression of the mesenchymal marker neural (N)-cadherin. The molecular impact of modulated ABCF1 expression in HCC cells was further delineated by whole transcriptome RNA sequencing analysis. Ectopic ABCF1 expression was demonstrated to result in stimulated expression of known EMT inducers, including hypoxia inducible factor 1 alpha subunit (HIF1A), interleukin 8 (IL8) and SRY-box 4 (SOX4); and CSC markers aldehyde dehydrogenase 1 family member A1 (ALDH1A1). Our findings indicated that ABCF1 plays a pro-metastatic role and facilitate chemoresistance in HCC which may be mediated through activation of the EMT program thereby promoting the acquisition of mesenchymal phenotypes.
In summary, we revealed the significance of ABCF1 as a hepatic oncofetal protein which played an important role in HCC progression and chemoresistance.
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Degree | Doctor of Philosophy |
Subject | Liver - Cancer ATP-binding cassette transporters |
Dept/Program | Biomedical Sciences |
Persistent Identifier | http://hdl.handle.net/10722/268140 |
DC Field | Value | Language |
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dc.contributor.advisor | Tsao, GSW | - |
dc.contributor.advisor | Cheung, ST | - |
dc.contributor.author | Fung, Sze-wai | - |
dc.contributor.author | 馮思慧 | - |
dc.date.accessioned | 2019-03-18T03:31:29Z | - |
dc.date.available | 2019-03-18T03:31:29Z | - |
dc.date.issued | 2018 | - |
dc.identifier.citation | Fung, S. [馮思慧]. (2018). Characterization of ATP-binding cassette sub-family F member 1 (ABCF1) in liver cancer and fetal liver. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. | - |
dc.identifier.uri | http://hdl.handle.net/10722/268140 | - |
dc.description.abstract | Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal malignancy worldwide. Diagnosis at the advanced stage, tumor recurrence and treatment inefficacy are the major causes of HCC mortality, and the latter has been attributed to metastasis and chemoresistance. The importance of developmental biology in carcinogenesis has been highlighted by their resemblance in multiple aspects, including the expression and the involvement of similar molecules, which have been identified as oncofetal molecules with expression in stem cells and cancer stem cells (CSC); and the transition of cells between epithelial and mesenchymal states by the epithelial-mesenchymal transition (EMT) program. The aim of our study is to explore novel molecules, especially those involved in developmental processes and that promote tumorigenesis. ATP-binding cassette (ABC) transporters mediate multidrug resistance and stemness properties in model systems. Yet, their clinical relevance remained controversial. Little has been known on ABCF1, especially with the lack of transmembrane domain, it has not been considered to have transporter function. In this study, we characterized the expression pattern and the involvement of ABCF1 in HCC. The expression profiles of ABC genes in HCC samples have been retrieved from published datasets and analyzed systemically. Independent clinical cohort has been used and validated on paired HCC tissues and cell lines. ABCF1 was significantly upregulated in HCCs compared to adjacent non-tumor and normal liver tissues. High ABCF1 levels associated with poor recurrence-free survival after partial hepatectomy and aggressive clinico-pathological features including tumor size, tumor stage and venous infiltration. Evaluation of ABCF1 expression in fetal, neonatal and adult mouse livers by qPCR, western blot and immunohistochemistry revealed strong expression of ABCF1 in liver during early embryonic stages but limited expression in neonates and adult livers. Our results demonstrated the oncofetal expression pattern of ABCF1 and suggested the significance of ABCF1 in promoting HCC progression. Consistently, functional assays showed that stable overexpression of ABCF1 enhanced chemoresistance and the drug efflux ability of HCC cells. Subcellular fractionation analysis and confocal microscopy concordantly demonstrated ABCF1 on plasma membrane and cytoplasm in HCC cells. Upregulated ABCF1 expression augmented cell migratory potential and induced lamellipodia/ filopodia in HCC cells. Concurrently, ABCF1 elevated the expression of the mesenchymal marker neural (N)-cadherin. The molecular impact of modulated ABCF1 expression in HCC cells was further delineated by whole transcriptome RNA sequencing analysis. Ectopic ABCF1 expression was demonstrated to result in stimulated expression of known EMT inducers, including hypoxia inducible factor 1 alpha subunit (HIF1A), interleukin 8 (IL8) and SRY-box 4 (SOX4); and CSC markers aldehyde dehydrogenase 1 family member A1 (ALDH1A1). Our findings indicated that ABCF1 plays a pro-metastatic role and facilitate chemoresistance in HCC which may be mediated through activation of the EMT program thereby promoting the acquisition of mesenchymal phenotypes. In summary, we revealed the significance of ABCF1 as a hepatic oncofetal protein which played an important role in HCC progression and chemoresistance. | - |
dc.language | eng | - |
dc.publisher | The University of Hong Kong (Pokfulam, Hong Kong) | - |
dc.relation.ispartof | HKU Theses Online (HKUTO) | - |
dc.rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject.lcsh | Liver - Cancer | - |
dc.subject.lcsh | ATP-binding cassette transporters | - |
dc.title | Characterization of ATP-binding cassette sub-family F member 1 (ABCF1) in liver cancer and fetal liver | - |
dc.type | PG_Thesis | - |
dc.description.thesisname | Doctor of Philosophy | - |
dc.description.thesislevel | Doctoral | - |
dc.description.thesisdiscipline | Biomedical Sciences | - |
dc.description.nature | published_or_final_version | - |
dc.identifier.doi | 10.5353/th_991044040584003414 | - |
dc.date.hkucongregation | 2018 | - |
dc.identifier.mmsid | 991044040584003414 | - |