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postgraduate thesis: Identification and characterization of microRNA-135A in cervical carcinogenesis

TitleIdentification and characterization of microRNA-135A in cervical carcinogenesis
Authors
Advisors
Issue Date2013
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Leung, O. [梁靄嬣]. (2013). Identification and characterization of microRNA-135A in cervical carcinogenesis. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5066208
AbstractCervical cancer is the second major cancer among women worldwide and is associated with persistent infection of human papillomaviruses (HPVs). However, exposure to high-risk type HPVs alone is insufficient for tumor formation. Additional factors are required for the HPV-infected cervical cells to become tumorigenic. Activation of ß-catenin/TCF signaling is essential for transformation of HPV-immortalized keratinocyte into cancer. ß-catenin is excessively expressed in cervical cancer. Dysregulation of microRNAs is profoundly observed in various cancers but their roles in cervical cancer are obscure. MicroRNA-135a (miR-135a) regulates one of the negative regulators of ß-catenin signaling, E3 ubiquitin ligase Seven In Absentia Human Homolog 1 (SIAH1). A 39-fold increase in the expression of miR-135a occurs in early stage cervical cancer. This study hypothesized that over-expression of miR-135a transformed HPV-infected cervical cells to cancer by activating ß-catenin/TCF signaling through down-regulation of SIAH1. In this study, miR-135a was confirmed to be specifically up-regulated in cervical cancer tissues when compared with precancerous lesions. Force-expression of miR-135a induced tumorigenic properties (anchorage independent growth and metastatic abilities) in vitro of a non-tumorigenic cervical epithelial cell line NC104 immortalized by HPV-16 E6 and E7 oncoproteins (NC104 E6/E7). The metastatic activities induced by miR-135a required the presence of E6 and E7 proteins as the activities were not observed in another immortalized cervical cell-line from the same parental cells but without the oncoproteins. The observations were confirmed by the observations that miR-135a knockdown did not impair the above tumorigenic properties in a HPV-negative cervical cancer cell line, but suppressed them in HPV-positive cervical cancer cell lines. The mechanism of action of miR-135a in cervical cancer was evaluated. The tumorigenic effects was due to the inhibitory action of miR-135a on SIAH1 leading to up-regulation of ß-catenin/TCF signaling. MiR-135a force-expression enhanced the growth of the cervical cancer cell line HeLa and NC104 E6/E7-derived tumor in vivo. The effect of miR-135a was partially nullified by SIAH1 force-expression. These observations were in line with expression analyses in cervical biopsies, in which SIAH1 immunoreactivities were inversely correlated, whereas ß-catenin was positively correlated with the expression of miR-135a. The data illustrated an oncogenic role of miR-135a/SIAH1/ß-catenin signaling in cervical cancer formation. The role of miR-135a in the formation of cancer stem cells (CSCs) was also elucidated. The number of CD133+ cells was significantly higher in the miR-135a-transformed NC104 E6/E7 cells than the untreated group. The CD133+ cells isolated from the miR-135a-transformed NC104 E6/E7 possessed self-renewal, differentiation and multidrug resistance properties, up-regulation of miR-135a. They also expressed ß-catenin and the stemness genes OCT4, SSEA-4. CD133+ cells were also identified sporadically in fresh cervical tumors. The observations indicate that CD133+ cervical cancer cells possesses CSC properties. In conclusion, this thesis was the first to identify and characterize the functions of miR-135a as an oncomiR in cervical carcinogenesis. MiR-135a played a pivotal role in malignant transformation and cancer progression in HPV-infected cervical cells through miR-135a/SIAH1/ß-catenin signaling. The microRNA also enhanced the proportion of CD133-expressing cervical CSCs.
DegreeDoctor of Philosophy
SubjectSmall interfering RNA
Cervix uteri - Cancer - Genetic aspects
Dept/ProgramObstetrics and Gynaecology
Persistent Identifierhttp://hdl.handle.net/10722/202234

 

DC FieldValueLanguage
dc.contributor.advisorYeung, WSB-
dc.contributor.advisorPang, RTK-
dc.contributor.authorLeung, Oi-ning-
dc.contributor.author梁靄嬣-
dc.date.accessioned2014-08-22T23:13:21Z-
dc.date.available2014-08-22T23:13:21Z-
dc.date.issued2013-
dc.identifier.citationLeung, O. [梁靄嬣]. (2013). Identification and characterization of microRNA-135A in cervical carcinogenesis. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5066208-
dc.identifier.urihttp://hdl.handle.net/10722/202234-
dc.description.abstractCervical cancer is the second major cancer among women worldwide and is associated with persistent infection of human papillomaviruses (HPVs). However, exposure to high-risk type HPVs alone is insufficient for tumor formation. Additional factors are required for the HPV-infected cervical cells to become tumorigenic. Activation of ß-catenin/TCF signaling is essential for transformation of HPV-immortalized keratinocyte into cancer. ß-catenin is excessively expressed in cervical cancer. Dysregulation of microRNAs is profoundly observed in various cancers but their roles in cervical cancer are obscure. MicroRNA-135a (miR-135a) regulates one of the negative regulators of ß-catenin signaling, E3 ubiquitin ligase Seven In Absentia Human Homolog 1 (SIAH1). A 39-fold increase in the expression of miR-135a occurs in early stage cervical cancer. This study hypothesized that over-expression of miR-135a transformed HPV-infected cervical cells to cancer by activating ß-catenin/TCF signaling through down-regulation of SIAH1. In this study, miR-135a was confirmed to be specifically up-regulated in cervical cancer tissues when compared with precancerous lesions. Force-expression of miR-135a induced tumorigenic properties (anchorage independent growth and metastatic abilities) in vitro of a non-tumorigenic cervical epithelial cell line NC104 immortalized by HPV-16 E6 and E7 oncoproteins (NC104 E6/E7). The metastatic activities induced by miR-135a required the presence of E6 and E7 proteins as the activities were not observed in another immortalized cervical cell-line from the same parental cells but without the oncoproteins. The observations were confirmed by the observations that miR-135a knockdown did not impair the above tumorigenic properties in a HPV-negative cervical cancer cell line, but suppressed them in HPV-positive cervical cancer cell lines. The mechanism of action of miR-135a in cervical cancer was evaluated. The tumorigenic effects was due to the inhibitory action of miR-135a on SIAH1 leading to up-regulation of ß-catenin/TCF signaling. MiR-135a force-expression enhanced the growth of the cervical cancer cell line HeLa and NC104 E6/E7-derived tumor in vivo. The effect of miR-135a was partially nullified by SIAH1 force-expression. These observations were in line with expression analyses in cervical biopsies, in which SIAH1 immunoreactivities were inversely correlated, whereas ß-catenin was positively correlated with the expression of miR-135a. The data illustrated an oncogenic role of miR-135a/SIAH1/ß-catenin signaling in cervical cancer formation. The role of miR-135a in the formation of cancer stem cells (CSCs) was also elucidated. The number of CD133+ cells was significantly higher in the miR-135a-transformed NC104 E6/E7 cells than the untreated group. The CD133+ cells isolated from the miR-135a-transformed NC104 E6/E7 possessed self-renewal, differentiation and multidrug resistance properties, up-regulation of miR-135a. They also expressed ß-catenin and the stemness genes OCT4, SSEA-4. CD133+ cells were also identified sporadically in fresh cervical tumors. The observations indicate that CD133+ cervical cancer cells possesses CSC properties. In conclusion, this thesis was the first to identify and characterize the functions of miR-135a as an oncomiR in cervical carcinogenesis. MiR-135a played a pivotal role in malignant transformation and cancer progression in HPV-infected cervical cells through miR-135a/SIAH1/ß-catenin signaling. The microRNA also enhanced the proportion of CD133-expressing cervical CSCs.-
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.lcshSmall interfering RNA-
dc.subject.lcshCervix uteri - Cancer - Genetic aspects-
dc.titleIdentification and characterization of microRNA-135A in cervical carcinogenesis-
dc.typePG_Thesis-
dc.identifier.hkulb5066208-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplineObstetrics and Gynaecology-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b5066208-
dc.date.hkucongregation2013-

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