Molecular Regulations and Functional Properties of MYB NFIB in Human Adenoid Cystic Cancer

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Material Information

Title:
Molecular Regulations and Functional Properties of MYB NFIB in Human Adenoid Cystic Cancer
Physical Description:
1 online resource (130 p.)
Language:
english
Creator:
Gao, Ruli
Publisher:
University of Florida
Place of Publication:
Gainesville, Fla.
Publication Date:

Thesis/Dissertation Information

Degree:
Doctorate ( Ph.D.)
Degree Grantor:
University of Florida
Degree Disciplines:
Genetics and Genomics
Committee Chair:
KAYE,FREDERIC JOSEPH
Committee Co-Chair:
BUNGERT,JORG
Committee Members:
LU,JIAN RONG
RENNE,ROLF FRIEDRICH
ZAJAC-KAYE,MARIA

Subjects

Subjects / Keywords:
adenoid-cystic-cancer -- extracellular -- hapln1 -- microarray -- myb-nfib -- vcan
Genetics and Genomics -- Dissertations, Academic -- UF
Genre:
Genetics and Genomics thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract:
Salivary gland tumors (SGT) comprise a heterogeneous group of tumors. The common benign subtype is pleomorphic adenoma (PA), and most common malignant tumors are mucoepidermoid carcinomas (MEC), adenoid cystic cancer (ACC), and adenocarcinoma (ADC)-not otherwise specified. Interestingly, PA, MEC, and ACC are now known to usually arise due to somatic chromosomal translocations. Our laboratory previously cloned and characterized the CRTC1-MAML2 fusion oncogene in MEC. We have now focused on studying the genetics and biology of the MYB:NFIB fusion oncogene in ACC, which is the most lethal subtype of SGT with no known systemic treatment for nonresectable disease. We focused on studying the whole transcriptome expression profile as well as the global miRNA pattern for this lethal disease to define the key molecular alterations, to discover new tumor signaling pathways and to identify novel treatment targets for ACC. Our data demonstrated that MYB was the key molecular alteration in ACC and was the top activated gene. We initially hypothesized that MYB:NFIB translocation offers a novel mechanism for oncogene activation via deletion of regulatory microRNA (miRNA) binding sites within the MYB 3-untranslated region (3-UTR). However, we did not detect any changes in the mRNA and miRNA profiles of ACC tumors that deleted or retained the MYB 3-UTR miRNA binding sites. I also discovered several cases of ACC with low to undetectable MYB expression. Analysis of these samples identified both MYB-dependent and independent gene targets that encoded related components of extracellular matrix (ECM) complex. Integration of ACC signature with exome mutational data suggests that RUNX1, a MYB binding oncogene, participates in ACC tumorigenesis to activate ECM elements including HAPLN1/VCAN. We also observed forced MYB-NFIB expression in immortalized human salivary gland cells alters cell morphology and cell adhesion in vitro. Further, we successfully generated validated human ACC tumor cell line and demonstrated that depletion of HAPLN1/VCAN, blocked tumor cell viability. In summary, we have identified an important ACC signature that is distinct from matched normal samples and from other types of SGTs. We have also discovered MYB-dependent and independent signals and identified HAPLN1/VCAN extracellular complexes as new druggable targets for human ACC.
General Note:
In the series University of Florida Digital Collections.
General Note:
Includes vita.
Bibliography:
Includes bibliographical references.
Source of Description:
Description based on online resource; title from PDF title page.
Source of Description:
This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility:
by Ruli Gao.
Thesis:
Thesis (Ph.D.)--University of Florida, 2014.
Local:
Adviser: KAYE,FREDERIC JOSEPH.
Local:
Co-adviser: BUNGERT,JORG.
Electronic Access:
RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2016-05-31

Record Information

Source Institution:
UFRGP
Rights Management:
Applicable rights reserved.
Classification:
lcc - LD1780 2014
System ID:
UFE0046113:00001