The role of GATA4 and GATA6 as putative tumor suppressors and co-modulators in astrocytes

372 Introduction: Astrocytomas compromise over 60% of all primary human adult central nervous system neoplasms, with Glioblastoma Multiforme (GBM) being the most common and malignant. Our group has previously used an oncogenic V12Ha-Ras mouse model (GEM) for astrocytomas as a “gene-discovery” reagent to screen for genetic modifiers, and identified GATA6 as a late progression tumor suppressor gene (TSG) in both murine and human astrocytomas. Furthermore, using a candidate gene approach, we identified GATA4, a member of the same GATA family of transcription factors, as a possible TSG in gliomas. Our overall objective was to examine the function and expression of both GATA4 and GATA6 in normal and transformed human and murine astrocytes. Methods-Results: Using Real time RT-PCR and western blot analysis, we identified GATA4 as a positive regulator of GATA6 expression, and vice versa in newborn (P0) murine astrocytes but not in adult normal human astrocytes (immortalized with TERT) and in transformed astrocytes (glioma cell lines). The expression of effector genes such as DAB2, WNT7a and BMP2 were regulated positively by both GATA4 and GATA6, unlike some genes such as HNF4a that is regulated only by GATA6. We studied our oncogenic V12Ha-Ras GEM for gliomas and identified both GATA4 and GATA6 as expressed in the low grade astrocytomas (LGA) but with absent expression in high grade astrocytomas (HGA). We next examined panels of human glioma specimens (glioma cell lines, GBM xenografts explants, surgical specimens) using western blot analysis, RT-PCR and immunohistochemistry. We noted the majority of HGAs (60-85%) but only 10-33% of LGAs, with loss of GATA4 and GATA6 expression. We did not find any statistically significant correlation between concurrent altered expression of GATA4 and GATA6, however while more LGAs had loss of GATA4 expression, more HGAs had loss of GATA6 expression. Discussion: Both GATA4 and GATA6 have been implicated as TSGs in cancers such as adrenocortical, gastric and ovarian. We are the first to demonstrate transcriptional regulatory cross talks between GATA4 and GATA6 in astrocytes, with roles as late progression factors in gliomas. Both GATA4 and GATA6 plus their effectors can therefore serve as excellent therapeutic targets in the treatment of gliomas.

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