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postgraduate thesis: The identification of 14-3-3 [sigma] as a contributor to cisplatin resistance in esophageal squamous cell carcinoma

TitleThe identification of 14-3-3 [sigma] as a contributor to cisplatin resistance in esophageal squamous cell carcinoma
Authors
Issue Date2014
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Lai, K. [賴景然]. (2014). The identification of 14-3-3 [sigma] as a contributor to cisplatin resistance in esophageal squamous cell carcinoma. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5387973
AbstractEsophageal squamous cell carcinoma (ESCC) is the predominant type of esophageal cancer in Asia. Cisplatin is commonly used as an agent for treating ESCC patients undergoing chemotherapy. However establishment of resistance over the course of treatment diminishes the clinical usefulness and is one reason explaining poor prognosis of ESCC patients. In order to gain insights into the mechanism of cisplatin resistance in ESCC, HPLC/nESI-MS/MS proteomic profiling was employed to examine the global protein alterations of cisplatin-resistant ESCC cell line HKESC2/CDDP comparing with its parental cisplatin-sensitive cell line HKESC2. Stable over-expression and knocked-down cell lines were established for pathway analysis and functional studies. Seventeen proteins were identified with more than 2-fold difference in expression levels. These proteins are involved in endoplasmic reticulum stress response, metabolic processes, DNA replication and repair, nucleotide binding and cell cycle control, while some of them are components of cytoskeletal proteins. Among them, 14-3-3σ was one of the most significantly upregulated proteins found in HKESC2/CDDP cells and its differential expression levels were validated using western blotting and real-time quantitative polymerase chain reaction. Pathway analysis revealed that ectopic overexpression of 14-3-3σ caused a general upregulation in DNA repairing genes. Furthermore, functional validation showed that elevated 14-3-3σ expression contributed considerably to the observed cisplatin resistance in HKESC2/CDDP cells. While knocking down 14-3-3σ expression reversed the above situations in SLMT1 cells. I conclude that up-regulation in 14-3-3σ, together with DNA repairing genes, contributes to the establishment of cisplatin resistance in HKESC2/CDDP cells. Knocking down 14-3-3σ expression sensitized ESCC cells to cisplatin treatment, and hence, opens a therapeutic opportunity for ESCC cisplatin resistance.
DegreeDoctor of Philosophy
SubjectDrug resistance in cancer cells
Cisplatin
Esophagus - Cancer - Chemotherapy
Squamous cell carcinoma - Chemotherapy
Dept/ProgramSurgery
Persistent Identifierhttp://hdl.handle.net/10722/208627

 

DC FieldValueLanguage
dc.contributor.authorLai, King-yin-
dc.contributor.author賴景然-
dc.date.accessioned2015-03-13T01:44:12Z-
dc.date.available2015-03-13T01:44:12Z-
dc.date.issued2014-
dc.identifier.citationLai, K. [賴景然]. (2014). The identification of 14-3-3 [sigma] as a contributor to cisplatin resistance in esophageal squamous cell carcinoma. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5387973-
dc.identifier.urihttp://hdl.handle.net/10722/208627-
dc.description.abstractEsophageal squamous cell carcinoma (ESCC) is the predominant type of esophageal cancer in Asia. Cisplatin is commonly used as an agent for treating ESCC patients undergoing chemotherapy. However establishment of resistance over the course of treatment diminishes the clinical usefulness and is one reason explaining poor prognosis of ESCC patients. In order to gain insights into the mechanism of cisplatin resistance in ESCC, HPLC/nESI-MS/MS proteomic profiling was employed to examine the global protein alterations of cisplatin-resistant ESCC cell line HKESC2/CDDP comparing with its parental cisplatin-sensitive cell line HKESC2. Stable over-expression and knocked-down cell lines were established for pathway analysis and functional studies. Seventeen proteins were identified with more than 2-fold difference in expression levels. These proteins are involved in endoplasmic reticulum stress response, metabolic processes, DNA replication and repair, nucleotide binding and cell cycle control, while some of them are components of cytoskeletal proteins. Among them, 14-3-3σ was one of the most significantly upregulated proteins found in HKESC2/CDDP cells and its differential expression levels were validated using western blotting and real-time quantitative polymerase chain reaction. Pathway analysis revealed that ectopic overexpression of 14-3-3σ caused a general upregulation in DNA repairing genes. Furthermore, functional validation showed that elevated 14-3-3σ expression contributed considerably to the observed cisplatin resistance in HKESC2/CDDP cells. While knocking down 14-3-3σ expression reversed the above situations in SLMT1 cells. I conclude that up-regulation in 14-3-3σ, together with DNA repairing genes, contributes to the establishment of cisplatin resistance in HKESC2/CDDP cells. Knocking down 14-3-3σ expression sensitized ESCC cells to cisplatin treatment, and hence, opens a therapeutic opportunity for ESCC cisplatin resistance.-
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.lcshDrug resistance in cancer cells-
dc.subject.lcshCisplatin-
dc.subject.lcshEsophagus - Cancer - Chemotherapy-
dc.subject.lcshSquamous cell carcinoma - Chemotherapy-
dc.titleThe identification of 14-3-3 [sigma] as a contributor to cisplatin resistance in esophageal squamous cell carcinoma-
dc.typePG_Thesis-
dc.identifier.hkulb5387973-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplineSurgery-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b5387973-

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