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postgraduate thesis: Functional study of suppressor of variegation 3-9 homolog 1 in hepatocellular carcinoma

TitleFunctional study of suppressor of variegation 3-9 homolog 1 in hepatocellular carcinoma
Authors
Advisors
Advisor(s):Wong, CMNg, IOL
Issue Date2012
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Fan, N. [樊傲賢]. (2012). Functional study of suppressor of variegation 3-9 homolog 1 in hepatocellular carcinoma. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b4961792
AbstractHepatocellular carcinoma (HCC) is the major type of primary liver cancer which is well-known for its high heterogenicity and metastatic potential. Despite of the current advancement in surgical resection and the availability of targeted therapy, HCC remains a barely curable and fatal disease. We previously demonstrated that deregulation of epigenetic regulators is a common event in human HCC. Herein, we identified the frequent up-regulation of the prototype of H3K9 tri-methyltransferase SUV39H1 in clinical HCCs. SUV39H1 over-expression was also significantly associated with increased Ki67 expression and the presence of venous invasion. By using both SUV39H1 over-expression and knockdown model, we consistently demonstrated that SUV39H1 contributed to HCC tumor growth and migration. Most importantly, SUV39H1 knockdown drastically suppressed in vivo tumorigenicity and extra-hepatic metastasis of HCC cells in nude mice model. These findings evidently demonstrated the oncogenic role of SUV39H1 in HCC and implied potential therapeutic targeting of SUV39H1 for HCC treatment. Molecularly, SUV39H1 knockdown HCC cell underwent morphological changes and accompanied with increased lysosomal β-galactosidase activity and elevated p21 protein and γH2AX level. This data suggested senescence induction in SUV39H1 knockdown HCC cells. SUV39H1 has been implicated in telomere regulation and transcriptional control. However, neither telomere length nor expression of tumor suppressor genes was altered in SUV39H1 knockdown HCC cells. Interestingly, we demonstrated a novel observation that SUV39H1 may potentially methylate non-histone substrates that are yet to be identified, which may contribute to the pro-tumorigenic function of SUV39H1 in HCC. We also investigated the upstream regulation of SUV39H1 and identified miR-125b as the negative post-transcriptional regulator of SUV39H1. Ectopic expression of miR-125b abolished SUV39H1 3’UTR-coupled luciferase activity and suppressed endogenous SUV39H1 at both mRNA and protein level. Clinically, miR-125b level was found inversely correlated with SUV39H1 expression. We have previously reported the frequent under-expression of miR-125b in HCC. Collectively, our data suggested that SUV39H1 up-regulation in HCC may be the sequential outcome of miR-125b down-regulation. In conclusion, we demonstrated for the first time that SUV39H1 up-regulation contributed to HCC development and metastasis, potentially via senescence evasion. SUV39H1 elevation in HCC was attributed to the loss of its negative regulator, the tumor suppressive miR-125b.
DegreeDoctor of Philosophy
SubjectLiver - Cancer - Genetic aspects.
Dept/ProgramPathology
Persistent Identifierhttp://hdl.handle.net/10722/180972

 

DC FieldValueLanguage
dc.contributor.advisorWong, CM-
dc.contributor.advisorNg, IOL-
dc.contributor.authorFan, Ngo-yin.-
dc.contributor.author樊傲賢.-
dc.date.accessioned2013-02-07T06:21:48Z-
dc.date.available2013-02-07T06:21:48Z-
dc.date.issued2012-
dc.identifier.citationFan, N. [樊傲賢]. (2012). Functional study of suppressor of variegation 3-9 homolog 1 in hepatocellular carcinoma. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b4961792-
dc.identifier.urihttp://hdl.handle.net/10722/180972-
dc.description.abstractHepatocellular carcinoma (HCC) is the major type of primary liver cancer which is well-known for its high heterogenicity and metastatic potential. Despite of the current advancement in surgical resection and the availability of targeted therapy, HCC remains a barely curable and fatal disease. We previously demonstrated that deregulation of epigenetic regulators is a common event in human HCC. Herein, we identified the frequent up-regulation of the prototype of H3K9 tri-methyltransferase SUV39H1 in clinical HCCs. SUV39H1 over-expression was also significantly associated with increased Ki67 expression and the presence of venous invasion. By using both SUV39H1 over-expression and knockdown model, we consistently demonstrated that SUV39H1 contributed to HCC tumor growth and migration. Most importantly, SUV39H1 knockdown drastically suppressed in vivo tumorigenicity and extra-hepatic metastasis of HCC cells in nude mice model. These findings evidently demonstrated the oncogenic role of SUV39H1 in HCC and implied potential therapeutic targeting of SUV39H1 for HCC treatment. Molecularly, SUV39H1 knockdown HCC cell underwent morphological changes and accompanied with increased lysosomal β-galactosidase activity and elevated p21 protein and γH2AX level. This data suggested senescence induction in SUV39H1 knockdown HCC cells. SUV39H1 has been implicated in telomere regulation and transcriptional control. However, neither telomere length nor expression of tumor suppressor genes was altered in SUV39H1 knockdown HCC cells. Interestingly, we demonstrated a novel observation that SUV39H1 may potentially methylate non-histone substrates that are yet to be identified, which may contribute to the pro-tumorigenic function of SUV39H1 in HCC. We also investigated the upstream regulation of SUV39H1 and identified miR-125b as the negative post-transcriptional regulator of SUV39H1. Ectopic expression of miR-125b abolished SUV39H1 3’UTR-coupled luciferase activity and suppressed endogenous SUV39H1 at both mRNA and protein level. Clinically, miR-125b level was found inversely correlated with SUV39H1 expression. We have previously reported the frequent under-expression of miR-125b in HCC. Collectively, our data suggested that SUV39H1 up-regulation in HCC may be the sequential outcome of miR-125b down-regulation. In conclusion, we demonstrated for the first time that SUV39H1 up-regulation contributed to HCC development and metastasis, potentially via senescence evasion. SUV39H1 elevation in HCC was attributed to the loss of its negative regulator, the tumor suppressive miR-125b.-
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.source.urihttp://hub.hku.hk/bib/B49617928-
dc.subject.lcshLiver - Cancer - Genetic aspects.-
dc.titleFunctional study of suppressor of variegation 3-9 homolog 1 in hepatocellular carcinoma-
dc.typePG_Thesis-
dc.identifier.hkulb4961792-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplinePathology-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b4961792-
dc.date.hkucongregation2013-

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