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The DNA damage response pathway in oral squamous cell carcinoma

Parikh, Rahul Atul (2006) The DNA damage response pathway in oral squamous cell carcinoma. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Nearly 45% of oral squamous cell carcinomas (OSCC) are characterized by amplification of chromosomal band 11q13, which occurs by breakage-fusion-bridge (BFB) cycle mechanism. The first step in this cycle involves loss of distal 11q. Consequently, critical genes involved in the DNA damage response pathway, MRE11A, ATM, H2AFX and CHEK1 are lost in the step preceding 11q13 amplification. We hypothesized that this loss on distal 11q may lead to a diminished DNA damage response in OSCC. Characterization of OSCC using fluorescence in situ hybridization revealed partial loss of MRE11A, ATM, H2AFX and CHEK1 in all cell lines with 11q13 amplification and in additional cell lines without 11q13 amplification. Quantitative microsatellite analysis and loss of heterozygosity studies confirmed this loss. Quantitative PCR and immunoblotting revealed reductions in RNA and protein expression of MRE11A, ATM and H2AX. All cell lines with distal 11q loss exhibited aberrant gamma-H2AX foci and increased chromosomal instability to ionizing radiation. Surprisingly, distal 11q loss also correlated with reduced sensitivity to ionizing radiation. Although the literature attributes poor prognosis in OSCC to 11q13 gene amplification, our results suggest that distal 11q deletions may be equally if not more significant.We observed an upregulation of the ATR-CHEK1 pathway in a subset of OSCC with loss of the G1 cell cycle checkpoint. We hypothesized that this upregulation protects OSCC from premature chromatin condensation or mitotic catastrophe (cell death) by enhancing the S phase and G2 phase checkpoints. In OSCC, we observed a gain in ATR gene copy number; whereas CHEK1 is partially lost at the gene level. However, we observed that both ATR and CHEK1 are overexpressed in a subset of OSCC with loss of the G1 cell cycle checkpoint. Inhibition of ATR or CHEK1 with caffeine or with the respective siRNAs results in an increased susceptibility of OSCC to DNA damaging agents. Thus, inhibition of the ATR-CHEK1 pathway in OSCC may aid the current therapeutic modalities used in the treatment of OSCC. The public health significance of our studies involves the development and use of distal 11q loss and ATR-CHEK1 upregulation as biomarkers for OSCC.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Parikh, Rahul Atulrahul.parikh@gmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairGollin, Susanne Msusanne.gollin@hgen.pitt.eduGOLLIN
Committee MemberRajasekaran, Baskaranbask@mgb.pitt.edu
Committee MemberZhang, LinZhangLx@upmc.eduLIZ22
Committee MemberFerrell, Robert Erobert.ferrell@hgen.pitt.eduRFERRELL
Committee MemberSaunders, William Swsaund@pitt.eduWSAUND
Date: 9 October 2006
Date Type: Completion
Defense Date: 20 June 2006
Approval Date: 9 October 2006
Submission Date: 1 August 2006
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: ATM; ATR; gene amplification; HNSCC; isochromosome 3q; OSCC
Other ID: http://etd.library.pitt.edu/ETD/available/etd-08012006-195439/, etd-08012006-195439
Date Deposited: 10 Nov 2011 19:55
Last Modified: 19 Dec 2016 14:36
URI: http://d-scholarship.pitt.edu/id/eprint/8789

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