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postgraduate thesis: Characterization of the extracellular matrix tumor suppressor protein, latent transforming growth factor-beta binding protein 2 (LTBP2), and in-depth mechanistic studies of its signaling pathway in nasopharyngeal carcinoma

TitleCharacterization of the extracellular matrix tumor suppressor protein, latent transforming growth factor-beta binding protein 2 (LTBP2), and in-depth mechanistic studies of its signaling pathway in nasopharyngeal carcinoma
Authors
Issue Date2016
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Kan, P. R. [簡珮琪]. (2016). Characterization of the extracellular matrix tumor suppressor protein, latent transforming growth factor-beta binding protein 2 (LTBP2), and in-depth mechanistic studies of its signaling pathway in nasopharyngeal carcinoma. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5774068.
AbstractNasopharyngeal carcinoma, poised as one of the top ten most common cancers in Hong Kong, displays a disproportionate clustering in specific ethnic groups and demonstrates a unique geographical distribution. As a subset of head and neck cancers, the pathogenesis of this disease is attributed to three major etiological factors: Epstein-Barr virus infection, non-viral environmental risk factors, and host genetic predisposition. By screening for novel candidate tumor suppressor genes (TSGs) in NPC using microcell-mediated chromosome transfer, gene mapping, microarray approaches, and functional studies, a plethora of candidate genes implicated in NPC was identified. From evidence-based research, LTBP2, mapped to chromosome 14q24, was selected for further investigation due to its high allelic loss in NPC tumors. The LTBP2 gene encodes a 5.5kb secreted extracellular matrix (ECM) protein that was significantly down-regulated in all seven NPC cell lines and in a majority of the patient biopsies. To evaluate the functional role of LTBP2, the lentiviral transduction system was employed to restore the expression of LTBP2 in NPC cell lines. In vivo and in vitro functional studies on LTBP2 revealed its multi-faceted role in the maintenance of tumor cell dormancy, growth, migration, and survival. Aberrancy in the ECM triggers pro-tumorigenic alterations in the intracellular circuitry of NPC cells. Hence, the intrinsic biochemical pathway(s) implicated by LTBP2 was also scrutinized. LTBP2 was able to reduce p65 phosphorylation and modulate nuclear translocation of the active protein in HONE1 and HK1 cells. This result translates to a suppression of cell proliferation, migration, invasion, and angiogenesis, suggesting that its anti-tumorigenic characteristics are mediated via the regulation of the canonical NF-κB transcription factor. Moreover, silencing of the p65 expression corresponds to LTBP2 re-expression in NPC cells. NF-κB was found to be up-regulated in NPC tumor biopsies. Biochemical and molecular studies of the canonical NF-κB pathway were conducted using p65 mutants that elicit differential transcriptional activity and binding affinity to DNA. Since the degree of p65-related gene expression and the severity of the oncogenic traits vary with the magnitude of p65 mutant activities, these observations suggest that the NF-κB p65 subunit is one of the key oncogenic drivers in NPC. Despite being highly conserved and well-regulated at least in HONE1 cells, the NF-κB signaling cascade was postulated to behave in a cell-type and stimulus-dependent manner that differs between NPC cell lines. Also, there needs to be a stimulatory event, such as TNFα production, to induce a constitutive autocrine or paracrine NF-κB signaling in the NPC cells, as the NF-κB components do not show any gain-of-function mutations. Finally, to prove that NF-κB is a critical oncogene in NPC, the use of an IKKβ small molecule inhibitor, PS-1145, provided sound evidence to support the abrogation of this signaling pathway leading to significant global inhibition of tumor development. Targeted drug therapies should definitely be considered as adjuvants to the current conventional treatments for NPC. Therefore, the overarching issue of the crosstalk between extracellular and intracellular molecular signaling should be further studied, with emphasis on the significance of the canonical NF-κB pathway in NPC.
DegreeDoctor of Philosophy
SubjectNasopharynx - Cancer - Pathogenesis
Tumor suppressor proteins
Dept/ProgramClinical Oncology
Persistent Identifierhttp://hdl.handle.net/10722/238188
HKU Library Item IDb5774068

 

DC FieldValueLanguage
dc.contributor.authorKan, Pei-qi, Rebecca-
dc.contributor.author簡珮琪-
dc.date.accessioned2017-02-04T00:18:16Z-
dc.date.available2017-02-04T00:18:16Z-
dc.date.issued2016-
dc.identifier.citationKan, P. R. [簡珮琪]. (2016). Characterization of the extracellular matrix tumor suppressor protein, latent transforming growth factor-beta binding protein 2 (LTBP2), and in-depth mechanistic studies of its signaling pathway in nasopharyngeal carcinoma. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5774068.-
dc.identifier.urihttp://hdl.handle.net/10722/238188-
dc.description.abstractNasopharyngeal carcinoma, poised as one of the top ten most common cancers in Hong Kong, displays a disproportionate clustering in specific ethnic groups and demonstrates a unique geographical distribution. As a subset of head and neck cancers, the pathogenesis of this disease is attributed to three major etiological factors: Epstein-Barr virus infection, non-viral environmental risk factors, and host genetic predisposition. By screening for novel candidate tumor suppressor genes (TSGs) in NPC using microcell-mediated chromosome transfer, gene mapping, microarray approaches, and functional studies, a plethora of candidate genes implicated in NPC was identified. From evidence-based research, LTBP2, mapped to chromosome 14q24, was selected for further investigation due to its high allelic loss in NPC tumors. The LTBP2 gene encodes a 5.5kb secreted extracellular matrix (ECM) protein that was significantly down-regulated in all seven NPC cell lines and in a majority of the patient biopsies. To evaluate the functional role of LTBP2, the lentiviral transduction system was employed to restore the expression of LTBP2 in NPC cell lines. In vivo and in vitro functional studies on LTBP2 revealed its multi-faceted role in the maintenance of tumor cell dormancy, growth, migration, and survival. Aberrancy in the ECM triggers pro-tumorigenic alterations in the intracellular circuitry of NPC cells. Hence, the intrinsic biochemical pathway(s) implicated by LTBP2 was also scrutinized. LTBP2 was able to reduce p65 phosphorylation and modulate nuclear translocation of the active protein in HONE1 and HK1 cells. This result translates to a suppression of cell proliferation, migration, invasion, and angiogenesis, suggesting that its anti-tumorigenic characteristics are mediated via the regulation of the canonical NF-κB transcription factor. Moreover, silencing of the p65 expression corresponds to LTBP2 re-expression in NPC cells. NF-κB was found to be up-regulated in NPC tumor biopsies. Biochemical and molecular studies of the canonical NF-κB pathway were conducted using p65 mutants that elicit differential transcriptional activity and binding affinity to DNA. Since the degree of p65-related gene expression and the severity of the oncogenic traits vary with the magnitude of p65 mutant activities, these observations suggest that the NF-κB p65 subunit is one of the key oncogenic drivers in NPC. Despite being highly conserved and well-regulated at least in HONE1 cells, the NF-κB signaling cascade was postulated to behave in a cell-type and stimulus-dependent manner that differs between NPC cell lines. Also, there needs to be a stimulatory event, such as TNFα production, to induce a constitutive autocrine or paracrine NF-κB signaling in the NPC cells, as the NF-κB components do not show any gain-of-function mutations. Finally, to prove that NF-κB is a critical oncogene in NPC, the use of an IKKβ small molecule inhibitor, PS-1145, provided sound evidence to support the abrogation of this signaling pathway leading to significant global inhibition of tumor development. Targeted drug therapies should definitely be considered as adjuvants to the current conventional treatments for NPC. Therefore, the overarching issue of the crosstalk between extracellular and intracellular molecular signaling should be further studied, with emphasis on the significance of the canonical NF-κB pathway in NPC.-
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.lcshNasopharynx - Cancer - Pathogenesis-
dc.subject.lcshTumor suppressor proteins-
dc.titleCharacterization of the extracellular matrix tumor suppressor protein, latent transforming growth factor-beta binding protein 2 (LTBP2), and in-depth mechanistic studies of its signaling pathway in nasopharyngeal carcinoma-
dc.typePG_Thesis-
dc.identifier.hkulb5774068-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplineClinical Oncology-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b5774068-

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