AUTHOR=Alvarez Secord Angeles , Bernardini Marcus Q., Broadwater Gloria , Grace Lisa A., Huang Zhiqing , Baba Tsukasa , Kondo Eiji , Sfakianos Gregory , Havrilesky Laura J., Murphy Susan K.

TITLE=TP53 Status is Associated with Thrombospondin1 Expression In vitro

JOURNAL=Frontiers in Oncology

VOLUME=3

YEAR=2013

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2013.00269

DOI=10.3389/fonc.2013.00269

ISSN=2234-943X

ABSTRACT=<p><bold>Objectives:</bold> To elucidate the association between thrombospondin1 (THBS1) expression and <italic>TP53</italic> status and <italic>THBS1</italic> promoter methylation in epithelial ovarian cancer (EOC).</p><p><bold>Methods:</bold> Epithelial ovarian cancer cell lines with known <italic>TP53</italic> status were analyzed for <italic>THBS1</italic> gene expression using Affymetrix U133 microarrays and promoter methylation by pyrosequencing. <italic>THBS1</italic> mRNA expression was obtained pre- and post-exposure to radiation and hypoxia treatment in A2780 parent wild-type (wt) and mutant (m)<italic>TP53</italic> cells. <italic>THBS1</italic> expression was compared to tumor growth properties.</p><p><bold>Results:</bold><italic>THBS1</italic> gene expression was higher in cells containing a wt<italic>TP53</italic> gene or null <italic>TP53</italic> mutation (<italic>p</italic> = 0.005) and low or absent p53 protein expression (<italic>p</italic> = 0.008) compared to those harboring a missense <italic>TP53</italic> gene mutation and exhibiting high p53 protein expression. Following exposure to radiation, there was a 3.4-fold increase in <italic>THBS1</italic> mRNA levels in the m<italic>TP53</italic> versus wt<italic>TP53</italic> A2780 cells. After exposure to hypoxia, <italic>THBS1</italic> mRNA levels increased approximately fourfold in both wt<italic>TP53</italic> and m<italic>TP53</italic> A2780 cells. Promoter methylation levels were low (median = 8.6%; range = 3.5–88.8%). There was a non-significant inverse correlation between <italic>THBS1</italic> methylation and transcript levels. There was no association between <italic>THBS1</italic> expression and population doubling time, invasive capacity, or anchorage-independent growth.</p><p><bold>Conclusion:</bold><italic>THBS1</italic> expression may be regulated via the <italic>TP53</italic> pathway, and induced by hypoxic tumor microenvironment conditions. Overall low levels of <italic>THBS1</italic> promoter methylation imply that methylation is not the primary driver of <italic>THBS1</italic> expression in EOC.</p>