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postgraduate thesis: Tumor suppressor genes associated with deletion in short arm of chromosome 3 in nasopharyngeal carcinoma

TitleTumor suppressor genes associated with deletion in short arm of chromosome 3 in nasopharyngeal carcinoma
Authors
Issue Date2014
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Chen, J. C. [陈娟]. (2014). Tumor suppressor genes associated with deletion in short arm of chromosome 3 in nasopharyngeal carcinoma. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5312309
AbstractNasopharyngeal carcinoma (NPC) is one of the most common malignancies in southern China. Deletion of genomic DNA, which occurs during the complex pathogenesis process for NPC, represents a pivotal mechanism in the inactivation of tumor suppressor genes (TSGs). In many circumstances, loss of TSGs can be detected as diagnostic and prognostic markers in cancer treatment. It is found that the short arm of chromosome 3 (3p) is frequently deleted in NPC, with two most frequently minimally deleted regions at 3p21.1-21.2 and 3p25.2-26.1. Recently, our research group and others have focused on the identification and characterization of novel TSGs in the 3p deleted region. Three new tumor suppressor genes, CACNA2D3, RBMS3 and CHL1 were identified by our group. In this thesis, I found thatRBMS3at3p24was down-regulated in 3/3 NPC cell lines and 13/15 (86.7%) primary NPC tissues, compared with corresponding non-tumor tissues. Functional study demonstrated that RBMS3hadstrong tumor suppressive function in NPC cells, including inhibiting the cell growth rate, colony formation in soft-agar and tumor formation in nude mice. Moreover, the tumor suppressive mechanism of RBMS3was involved with the cell cycle arrest at the G1/S checkpoint.RBMS3 also had a pro-apoptotic role in a mitochondrial-dependent manner. Finally, RBMS3 could inhibit microvessel formation. Located at the important tumor suppressor locus 3p26.1, CHL1encodes a one-pass trans-membrane cell adhesion molecule (CAM). I identified CHL1as a tumor suppressor gene in nasopharyngeal carcinoma through expression profiling and epigenetic characterization. In this study, down-regulation of CHL1 was detected in 3/3of NPC cell lines and 12/15 (80.0%) of NPC tissues. Expression of CHL1could be reversed by pharmacological demethylation with 5-aza, indicating that promoter methylation might play an important role inCHL1down-regulation. Functional study showed that ectopic expression of CHL1 in NPC cells could dramatically inhibit clonogenicity and cell motility, possibly through cell cycle arrest. Further study found that CHL1 was able to induce mesenchymal-epithelial transition (MET), a key event to prevent tumor invasion and metastasis, by up-regulating epithelial markers and down-regulating mesenchymal markers. In addition, CHL1could inactivate RhoA/Rac1/Cdc42 signaling pathway to decrease the formation of stress fiber, lamellipodia and filopodia. In conclusion, these findings demonstrate thatCHL1is an important tumor suppressor gene in NPC. Later, I identified CHL1 could co-localize with integrin-beta1, an adhesion molecular, and expression of CHL1 was positively correlated with integrin-beta1. Moreover, CHL1 could interact with integrin-beta1 by using pull-down assay. Also, the tumor suppressor merlin could interact with CHL1. However, when CHL1 is lost, integrin beta1-AKT pathway would be activated and merlin will be phosphorylated and become inactivated, then it could not function as a tumor suppressor anymore. In this thesis, I summarize my recent work on two TSGs at 3p, RBMS3and CHL1, in the development and progression of NPC. Better understanding of TSGs at 3p will greatly improve our knowledge on pathogenesis of NPC, diagnosis and treatment.
DegreeDoctor of Philosophy
SubjectNasopharynx - Cancer
Antioncogenes
Dept/ProgramClinical Oncology
Persistent Identifierhttp://hdl.handle.net/10722/210237

 

DC FieldValueLanguage
dc.contributor.authorChen, Juan, Catherine-
dc.contributor.author陈娟-
dc.date.accessioned2015-05-29T23:09:37Z-
dc.date.available2015-05-29T23:09:37Z-
dc.date.issued2014-
dc.identifier.citationChen, J. C. [陈娟]. (2014). Tumor suppressor genes associated with deletion in short arm of chromosome 3 in nasopharyngeal carcinoma. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5312309-
dc.identifier.urihttp://hdl.handle.net/10722/210237-
dc.description.abstractNasopharyngeal carcinoma (NPC) is one of the most common malignancies in southern China. Deletion of genomic DNA, which occurs during the complex pathogenesis process for NPC, represents a pivotal mechanism in the inactivation of tumor suppressor genes (TSGs). In many circumstances, loss of TSGs can be detected as diagnostic and prognostic markers in cancer treatment. It is found that the short arm of chromosome 3 (3p) is frequently deleted in NPC, with two most frequently minimally deleted regions at 3p21.1-21.2 and 3p25.2-26.1. Recently, our research group and others have focused on the identification and characterization of novel TSGs in the 3p deleted region. Three new tumor suppressor genes, CACNA2D3, RBMS3 and CHL1 were identified by our group. In this thesis, I found thatRBMS3at3p24was down-regulated in 3/3 NPC cell lines and 13/15 (86.7%) primary NPC tissues, compared with corresponding non-tumor tissues. Functional study demonstrated that RBMS3hadstrong tumor suppressive function in NPC cells, including inhibiting the cell growth rate, colony formation in soft-agar and tumor formation in nude mice. Moreover, the tumor suppressive mechanism of RBMS3was involved with the cell cycle arrest at the G1/S checkpoint.RBMS3 also had a pro-apoptotic role in a mitochondrial-dependent manner. Finally, RBMS3 could inhibit microvessel formation. Located at the important tumor suppressor locus 3p26.1, CHL1encodes a one-pass trans-membrane cell adhesion molecule (CAM). I identified CHL1as a tumor suppressor gene in nasopharyngeal carcinoma through expression profiling and epigenetic characterization. In this study, down-regulation of CHL1 was detected in 3/3of NPC cell lines and 12/15 (80.0%) of NPC tissues. Expression of CHL1could be reversed by pharmacological demethylation with 5-aza, indicating that promoter methylation might play an important role inCHL1down-regulation. Functional study showed that ectopic expression of CHL1 in NPC cells could dramatically inhibit clonogenicity and cell motility, possibly through cell cycle arrest. Further study found that CHL1 was able to induce mesenchymal-epithelial transition (MET), a key event to prevent tumor invasion and metastasis, by up-regulating epithelial markers and down-regulating mesenchymal markers. In addition, CHL1could inactivate RhoA/Rac1/Cdc42 signaling pathway to decrease the formation of stress fiber, lamellipodia and filopodia. In conclusion, these findings demonstrate thatCHL1is an important tumor suppressor gene in NPC. Later, I identified CHL1 could co-localize with integrin-beta1, an adhesion molecular, and expression of CHL1 was positively correlated with integrin-beta1. Moreover, CHL1 could interact with integrin-beta1 by using pull-down assay. Also, the tumor suppressor merlin could interact with CHL1. However, when CHL1 is lost, integrin beta1-AKT pathway would be activated and merlin will be phosphorylated and become inactivated, then it could not function as a tumor suppressor anymore. In this thesis, I summarize my recent work on two TSGs at 3p, RBMS3and CHL1, in the development and progression of NPC. Better understanding of TSGs at 3p will greatly improve our knowledge on pathogenesis of NPC, diagnosis and treatment.-
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.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.lcshNasopharynx - Cancer-
dc.subject.lcshAntioncogenes-
dc.titleTumor suppressor genes associated with deletion in short arm of chromosome 3 in nasopharyngeal carcinoma-
dc.typePG_Thesis-
dc.identifier.hkulb5312309-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplineClinical Oncology-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b5312309-

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