GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer.
GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer.
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DOI：
10.1136/gutjnl-2015-311256
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发表时间：
2017-09
期刊：
影响因子：
24.5
通讯作者：
Real FX
中科院分区：
文献类型：
--
作者：
Martinelli P;Carrillo-de Santa Pau E;Cox T;Sainz B Jr;Dusetti N;Greenhalf W;Rinaldi L;Costello E;Ghaneh P;Malats N;Büchler M;Pajic M;Biankin AV;Iovanna J;Neoptolemos J;Real FX
加塔因子在肿瘤中的作用近年来受到越来越多的关注，但GATA 6在胰腺导管腺癌（PDAC）中的作用仍存在争议。GATA 6在一个肿瘤子集中扩增，并被认为是致癌的，但高GATA 6水平在分化良好的肿瘤中发现，并与更好的患者预后相关。相比之下，使用遗传小鼠模型证明了GATA 6的肿瘤抑制功能。我们的目的是阐明GATA 6在PDAC中的功能。我们将PDAC细胞系中GATA 6沉默和过表达与GATA 6 ChIP-Seq和RNA-Seq数据相结合，以了解GATA 6功能的机制。然后，我们在主要患者样本中证实了我们的一些观察结果，其中一些被纳入ESPAC-3随机临床试验用于辅助治疗。GATA 6在体外抑制上皮-间充质转化（EMT），在体内抑制细胞播散。GATA 6具有独特的促上皮细胞和抗间充质细胞功能，其转录调控是直接的，并间接地暗示着参与EMT的其他转录因子的调节。GATA 6在肿瘤中丢失，与改变的分化和基底样分子表型的获得相关，与上皮-上皮（ET 2）转变一致。基底细胞样GATA 6low肿瘤患者的生存期较短，并且对5-氟尿嘧啶（5-FU）/亚叶酸的辅助反应明显较差。然而，培养细胞中GATA 6表达的调节并不直接调节对5-FU的应答。我们提供了GATA 6肿瘤抑制功能的机制，其作为典型上皮细胞分化的调节剂的作用，并提出GATA 6表达的丧失是对辅助治疗反应的预后和预测。
The role of GATA factors in cancer has gained increasing attention recently, but the function of GATA6 in pancreatic ductal adenocarcinoma (PDAC) is controversial. GATA6 is amplified in a subset of tumours and was proposed to be oncogenic, but high GATA6 levels are found in well-differentiated tumours and are associated with better patient outcome. By contrast, a tumour-suppressive function of GATA6 was demonstrated using genetic mouse models. We aimed at clarifying GATA6 function in PDAC. We combined GATA6 silencing and overexpression in PDAC cell lines with GATA6 ChIP-Seq and RNA-Seq data, in order to understand the mechanism of GATA6 functions. We then confirmed some of our observations in primary patient samples, some of which were included in the ESPAC-3 randomised clinical trial for adjuvant therapy. GATA6 inhibits the epithelial–mesenchymal transition (EMT) in vitro and cell dissemination in vivo. GATA6 has a unique proepithelial and antimesenchymal function, and its transcriptional regulation is direct and implies, indirectly, the regulation of other transcription factors involved in EMT. GATA6 is lost in tumours, in association with altered differentiation and the acquisition of a basal-like molecular phenotype, consistent with an epithelial-to-epithelial (ET2) transition. Patients with basal-like GATA6low tumours have a shorter survival and have a distinctly poor response to adjuvant 5-fluorouracil (5-FU)/leucovorin. However, modulation of GATA6 expression in cultured cells does not directly regulate response to 5-FU. We provide mechanistic insight into GATA6 tumour-suppressive function, its role as a regulator of canonical epithelial differentiation, and propose that loss of GATA6 expression is both prognostic and predictive of response to adjuvant therapy.
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影响因子：
10.3
作者：
Greenhalf, William;Ghaneh, Paula;Buechler, Markus W.
通讯作者：
Buechler, Markus W.
DOI：
10.3233/blc-150037
发表时间：
2016-01-07
期刊：
Bladder cancer (Amsterdam, Netherlands)
影响因子：
--
作者：
Lerner SP;McConkey DJ;Hoadley KA;Chan KS;Kim WY;Radvanyi F;Höglund M;Real FX
通讯作者：
Real FX
影响因子：
4.5
作者：
Kwei KA;Bashyam MD;Kao J;Ratheesh R;Reddy EC;Kim YH;Montgomery K;Giacomini CP;Choi YL;Chatterjee S;Karikari CA;Salari K;Wang P;Hernandez-Boussard T;Swarnalata G;van de Rijn M;Maitra A;Pollack JR
通讯作者：
Pollack JR
影响因子：
64.8
作者：
Bailey, Peter;Chang, David K.;Grimmond, Sean M.
通讯作者：
Grimmond, Sean M.
影响因子：
3.7
作者：
Birnbaum, David J.;Adelaide, Jose;Chaffanet, Max
通讯作者：
Chaffanet, Max