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Title: Novel FOXM1 transcription factor target genes in oesophageal cancer
Author: Wiseman, Elizabeth Fiona
ISNI:       0000 0004 5359 3700
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2014
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The prognosis of oesophageal cancer remains poor, with <10% 5-year survival. Delineating the molecular pathogenesis of oesophageal cancer could inform future research into targeted therapies and may uncover novel biomarkers to aid management decisions. As a transcription factor with important roles in the control of cell cycle transcription, FOXM1 regulates cellular proliferation and chromosome stability. FOXM1 is frequently overexpressed in human cancers and this has recently been described in oesophageal adenocarcinoma (OAC) tissues. We have sought to identify novel gene targets of FOXM1 to better understand the molecular pathogenesis of OAC. Using chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) in OE33 OAC cells we investigated the genome-wide DNA binding regions of FOXM1, identifying a shortlist of putative FOXM1 target genes. We then identified those genes with evidence of transcriptional regulation by FOXM1 in primary oesophageal tissue specimens and in OE33 OAC cells subjected to FOXM1-directed RNA interference, using the Nanostring mRNA quantification technique. True direct FOXM1 target genes were defined as those genes that are bound by FOXM1 at their regulatory regions in OE33 cells, significantly downregulated in FOXM1-depleted OE33 cells and significantly overexpressed in primary oesophageal tissues expressing high FOXM1 mRNA levels. We identified the following genes as direct FOXM1 transcriptional targets: CDKN3, CCNB1, CCNF, KIF14, KPNA2, UBE2C, MKI67, GTSE1, TPX2, KIF23, FAM64A, UHRF1, MAD2L1, ANLN, DBF4, ETV4 and ZNF367. All of these genes have functions in cell cycle-related processes, apart from ETV4 and ZNF367 which function as transcriptional activators. The expression levels of ETV4 and UHRF1 were significantly associated with locally advanced disease (advanced T stage) and metastatic disease respectively. Identification of these new FOXM1 transcriptional targets in oesophageal tissues provides further insights into the molecular pathobiology of OAC, by identifying new gene pathways that are upregulated as a result of FOXM1 overexpression in OAC.
Supervisor: Sharrocks, Andrew; Ang, Yeng Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available