Inhibition of TGFβRI as a therapy for GATA4 deficient lung cancers [RNA-seq]

GATA4 is frequently epigenetically silenced in lung cancers. However, the impact of GATA4 inactivation on tumorigenesis and related therapeutic strategy remain to be determined. Through the genome-wide screening of tumor suppressing transcription factors, we demonstrate that GATA4 functions as an essential tumor suppressor in lung cancer in vitro and in vitro. Interestingly, ectopic GATA4 expression resulted in cellular senescence. Mechanistically, GATA4 up-regulates multiple miRNAs (miRNA-32, miRNA-301b, miR-320a, and miR-590) targeting TGFB2 mRNA and causes ensuing downregulation of WNT7B level to induce senescence. TGFBRI inhibitor synergizes with MEK1/2 inhibitor to promote lung cancer regression in Kras G12D/GATA4-/- mouse models. Decreased GATA4 level in clinical specimens negatively correlates with WNT7B or TGFB2 level and is significantly associated with poor prognosis.

GATA4在肺癌中常发生表观遗传沉默。然而，GATA4失活对肿瘤发生及相关治疗策略的影响仍有待阐明。通过全基因组筛选抑癌转录因子，我们证实GATA4在肺癌中作为关键抑癌因子发挥作用，且该效应在体外及体内均得到验证。有趣的是，异位表达GATA4可诱导细胞衰老。从机制层面来看，GATA4可上调多种靶向TGFB2 mRNA的微小RNA(miRNA)，具体包括miRNA-32、miRNA-301b、miR-320a及miR-590，继而下调WNT7B的表达水平，最终诱导细胞衰老。转化生长因子β受体I(TGFBRI)抑制剂与丝裂原活化蛋白激酶激酶1/2(MEK1/2)抑制剂协同作用，可在Kras G12D/GATA4-/-小鼠模型中促进肺癌消退。临床标本中GATA4的表达水平降低与WNT7B或TGFB2的表达水平呈负相关，且与不良预后显著相关。