- Title Information
- Title
- Identification and Characterization of T Cell Factor-4 (TCF-4) Isoforms of Wnt Signaling in Hepatocellular Carcinoma (HCC)
- Name:
Personal
- Name Part
- Tsedensodnom, Orkhontuya
- Role
- Role Term:
Text
- creator
- Origin Information
- Copyright Date
- 2010
- Physical Description
- Extent
- xxi, 199 p.
- digitalOrigin
- born digital
- Note
- Thesis (Ph.D. -- Brown University (2010)
- Name:
Personal
- Name Part
- Wands, Jack
- Role
- Role Term:
Text
- Director
- Name:
Personal
- Name Part
- Kim, Miran
- Role
- Role Term:
Text
- Director
- Name:
Personal
- Name Part
- Freiman, Richard
- Role
- Role Term:
Text
- Reader
- Name:
Personal
- Name Part
- Gruppuso, Philip
- Role
- Role Term:
Text
- Reader
- Name:
Personal
- Name Part
- Wessel, Gary
- Role
- Role Term:
Text
- Reader
- Name:
Personal
- Name Part
- Baffy, Gyorgy
- Role
- Role Term:
Text
- Reader
- Name:
Corporate
- Name Part
- Brown University. BIOMED: Molecular Biology, Cell Biology, and Biochemistry
- Role
- Role Term:
Text
- sponsor
- Genre (aat)
- theses
- Abstract
- Background and Aims: The canonical Wnt signaling pathway is frequently activated in hepatocellular carcinoma (HCC). Although b-catenin is the principle effector protein of Wnt pathway, the success of relaying signals to the nucleus depends on the T Cell Factor (TCF) family of transcription factors that bind to promoters of Wnt-responsive target genes. The human TCF-4 gene is composed of 17 exons with multiple alternative splicing sites. In spite of theoretical possibility of constructing more than 500 isoforms, only two TCF-4 splice variants have been identified so far. Therefore, the objective of this thesis is to identify TCF-4 isoforms in HCC, and to evaluate their role in hepatocarcinogenesis.Methods: Reverse transcription polymerase chain reaction (RT-PCR) was employed to identify distinct TCF-4 isoforms and to determine expression profiles of TCF-4 isoforms in HCC cell lines and human HCC tissues. The function of TCF-4 isoforms in HCC cell lines was examined by TCF transcriptional activity, cell proliferation, wound healing, trans-well motility, and colony formation assays.Results: I identified 17 different TCF-4 isoforms including two previously known forms TCF-4B (short) and TCF-4E (long) from four HCC cell lines. The 15 new isotypes were named in alphabetical order according to increasing size of their protein products. Functional analysis of these isoforms revealed distinct effects on the phenotype of HCC cells. The TCF-4J isoform produced characteristic features of the malignant phenotype since it generated the highest cell proliferation rate, cell migration and colony formation. In contrast, the TCF-4K isoform displayed the lowest TCF transcriptional activity, cell proliferation rate, and colony formation. Interestingly, TCF-4J and TCF-4K differed by only five amino acids (the SxxSS motif). Moreover, TCF-4J expression was upregulated in HCC tumors compared to peritumor and normal liver, whereas TCF-4K was downregulated in tumors.Conclusions: Conserved splicing motifs in TCF-4 may have a major influence on the function of TCF-4 isoforms and alter the characteristics of the malignant phenotype in HCC.
- Subject
- Topic
- Wnt
- Subject
- Topic
- b-catenin
- Subject
- Topic
- HCC
- Subject
- Topic
- TCF-4
- Subject
- Topic
- Record Information
- Record Content Source (marcorg)
- RPB
- Record Creation Date
(encoding="iso8601")
- 20111003
- Language
- Language Term:
Code (ISO639-2B)
- eng
- Language Term:
Text
- English
- Identifier:
DOI
- 10.7301/Z0K072HJ
- Access Condition:
rights statement
(href="http://rightsstatements.org/vocab/InC/1.0/")
- In Copyright
- Access Condition:
restriction on access
- Collection is open for research.
- Type of Resource (primo)
- dissertations