BACH1 Promotes Pancreatic Cancer Metastasis by Repressing Epithelial Genes and Enhancing Epithelial-Mesenchymal Transition
BACH1 Promotes Pancreatic Cancer Metastasis by Repressing Epithelial Genes and Enhancing Epithelial-Mesenchymal Transition
复制标题
DOI：
10.1158/0008-5472.can-18-4099
复制
发表时间：
2020-03-15
期刊：
影响因子：
11.2
通讯作者：
Igarashi, Kazuhiko
中科院分区：
文献类型：
--
作者：
Sato, Masaki;Matsumoto, Mitsuyo;Igarashi, Kazuhiko
胰腺导管腺癌（PDAC）由于其高度恶性特征而成为预后最差的癌症之一。 BTB和CNC同源性1（BACH1）已与RAS驱动的肿瘤形成有关。我们专注于Bach1在PDAC中的作用，其中90％以上具有KRAS突变。 Bach1在PDAC细胞系中的敲低，部分通过增加E-钙粘蛋白的表达来减少细胞迁移和侵袭，而其过表达却显示出相反的作用。 Bach1直接抑制了FOXA1的表达，该表达已激活编码E-钙粘着蛋白并抑制上皮到间质转变的CDH1表达。 Bach1还直接抑制了包括CLDN3和CLDN4在内的上皮细胞粘附重要的基因表达。在小鼠的原位植入模型中，ASPC-1细胞的高转移能力需要BACH1。 IHC对具有新开发的抗Bach1 mAb的临床标本的IHC分析表明，Bach1的高表达是不良的预后因素。这些结果表明，BACH1和下游基因的基因调节网络（包括CDH1）通过调节上皮到间质转变而促进了PDAC的恶性特征。对胰腺上皮层次向上质的基因调节网络的更大了解癌细胞将提供新颖的治疗靶标和诊断标记。
Pancreatic ductal adenocarcinoma (PDAC) is among the cancers with the poorest prognoses due to its highly malignant features. BTB and CNC homology 1 (BACH1) has been implicated in RAS-driven tumor formation. We focused on the role of BACH1 in PDAC, more than 90% of which have KRAS mutation. Knockdown of BACH1 in PDAC cell lines reduced cell migration and invasion, in part, by increasing E-cadherin expression, whereas its overexpression showed opposite effects. BACH1 directly repressed the expression of FOXA1 that is known to activate the expression of CDH1 encoding E-cadherin and to inhibit epithelial-to-mesenchymal transition. BACH1 also directly repressed the expression of genes important for epithelial cell adhesion including CLDN3 and CLDN4. In a mouse orthotopic implantation model, BACH1 was required for the high metastatic ability of AsPC-1 cells. IHC analysis of clinical specimens with a newly developed anti-BACH1 mAb revealed that high expression of BACH1 is a poor prognostic factor. These results suggest that the gene regulatory network of BACH1 and downstream genes including CDH1 contribute to the malignant features of PDAC by regulating epithelial-to-mesenchymal transition.Significance: Greater understanding of the gene regulatory network involved in epithelial-to-mesenchymal transition of pancreatic cancer cells will provide novel therapeutic targets and diagnostic markers.