FOXA1通过染色质重塑重编程SMAD顺反组差异化调节TGF-β靶基因群抑制鼻咽癌的机制研究

鼻咽癌发生过程中TGF-β/SMAD活化水平增高，并且由抑制生长转变为促进肿瘤发生、进展，与疾病复发和不良预后相关。我们发现先导转录因子FOXA1具有抑制鼻咽癌细胞恶性行为的作用，在鼻咽癌组织中表达降低。基因芯片分析显示FOXA1影响了TGF-β/SMAD信号通路靶分子群表达。FOXA1促进了TGF-β抑瘤性靶基因BAMBI、PMEPA1等表达，抑制了TGF-β对促瘤性靶基因L1CAM、PTHLH、Vimentin、HMGA2等分子的诱导作用，并恢复了鼻咽癌细胞对TGF-β生长抑制作用的敏感性。我们推测FOXA1通过引起靶基因染色质重塑，重编程SMAD顺反组和转录组；FOXA1缺失是引起鼻咽癌细胞TGF-β/SMAD信号失常的主导因素。本项目拟深入研究FOXA1通过染色质重塑，差异化调节抑瘤性或促瘤性TGF-β靶基因群表达，抑制鼻咽癌恶性行为的机制，并探索其临床价值。

Abnormal activation of TGF-β/SMAD signaling pathway in nasopharyngeal carcinoma(NPC) was associated with relapse and poor prognosis. TGF-β signaling switches from tumor suppression to promoting cancer progression, invasion, and tumor metastasis during cancer development, but the molecular mechanism underlying this function switch of TGF-β in human cancer is not clear. We found the pioneering factor FOXA1 decreased in NPC samples. Re-expression of FOXA1 suppresses the malignant behaviors of NPC cells. Microarray analysis indicates that FOXA1 differentially regulates TGF-β/SMAD signaling targets expression in NPC cells. Characteristically, FOXA1 facilitates the induction of tumor suppressors such as BAMBI and PMEPA1, but attenuates the expression of that molecules with tumor promotive function induced by TGF-β, including L1CAM, PTHLH, Vimentin and HMGA2 et al. Functionally, FOXA1 expression enhances the sensitivity of NPC cells to the cytostatic effects of TGF-β. We hypothized that FOXA1 expression in NPC cells reprogrammed TGF-β stimulated SMAD cistrome via induction of chromatin remodeling on the targets locus. Loss of FOXA1 leads to the dysregulation of TGF-β/SMAD signaling pathway in NPC development. In this study, we aim to determine the tumor suppressive role of FOXA1 on NPC cells, and to determine the effect of FOXA1 on physiological functions of TGF-β. We also aim to decipher the detail mechanisms underlying the inhibition of TGF-β/SMAD activation via induction of BAMBI by FOXA1 cooperating with SMAD complex. By using ChIP-Seq and RNA-Seq，the association of FOXA1 mediated chromating remodeling with reprogramming of TGF-β stimulated SMAD cistrome and transcriptome would be studied. We also plan to measure the expression level of FOXA1 and TGF-β targets in NPC samples and to study the association of these molecules with the clinical characteristics.