AUTHOR=Davidson Brittany Anne , Rubatt Jennifer M. , Corcoran David L. , Teoh Deanna K. , Bernardini Marcus Q. , Grace Lisa A. , Soper William John , Berchuck Andrew , Siamakpour-Reihani Sharareh , Chen Wei , Owzar Kouros , Murphy Susan K. , Secord Angeles Alvarez 

TITLE=Differential Angiogenic Gene Expression in TP53 Wild-Type and Mutant Ovarian Cancer Cell Lines

JOURNAL=Frontiers in Oncology

VOLUME=4

YEAR=2014

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2014.00163

DOI=10.3389/fonc.2014.00163

ISSN=2234-943X

ABSTRACT=<p><bold>Objectives:</bold> Underlying mechanisms regulating angiogenesis in ovarian cancer have not been completely elucidated. Evidence suggests that the <italic>TP53</italic> tumor suppressor pathway and tumor microenvironment play integral roles. We utilized microarray technology to study the interaction between <italic>TP53</italic> mutational status and hypoxia on angiogenic gene expression.</p><p><bold>Methods:</bold> Affymetrix U133A arrays were analyzed for angiogenic gene expression in 19 ovarian cancer cell lines stratified both by <italic>TP53</italic> mutation status and A2780 wild-type (wt) <italic>TP53</italic> vs. mutated (m) <italic>TP53</italic> cell lines after treatment under hypoxic conditions or with ionizing radiation.</p><p><bold>Results:</bold> Twenty-eight differentially expressed angiogenic genes were identified in the m<italic>TP53</italic> cell lines compared to wt<italic>TP53</italic> lines. Five genes were upregulated in m<italic>TP53</italic> cells: 40% involved in extracellular matrix (ECM) degradation [matrix metalloproteinase 10 (MMP10)/15] and 60% in angiogenesis (fibroblast growth factor receptor 3/VEGFA/ephrin receptor-B4). Twenty-three genes were upregulated in wt<italic>TP53</italic>: nearly 22% were ECM constituents or involved in ECM degradation; over 40% were growth factors or mediators of angiogenesis. Five genes were upregulated in the <italic>A</italic>2780m<italic>TP53</italic> cells: 40% involved in ECM remodeling (MMP10, ADAMTS1), 40% with pro-angiogenic activity (EFNB2, factor 2 receptor), and 20% with anti-angiogenic properties (ADAMTS1). Three genes were upregulated in hypoxia treated cells compared to controls: one with anti-angiogenic activity (angiopoietin-like 4) and two with pro-angiogenic activity (VEGFA, EFNA3). No significant gene fold changes were noted after exposure to radiation. Four genes continued to demonstrate significant differential expression (<italic>p</italic> ≤ 0.05) after adjusting for multiple comparisons. These genes included <italic>endoglin</italic> upregulation in wt lines (pro-angiogenesis) and upregulation of <italic>FGF20</italic> (growth factor), <italic>ADAMTS1</italic> (anti-angiogenesis) and <italic>MMP10</italic> (ECM degradation) in m<italic>TP53</italic> cell lines.</p><p><bold>Conclusion:</bold> Our exploratory findings indicate that non-overlapping angiogenic pathways may be altered by <italic>TP53</italic> mutations and hypoxic conditions in the tumor microenvironment. Further evaluation is needed for confirmation.</p>