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-tomesenchymal 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.

Abstract-Bach1 is a stress-responsive transcriptional factor that is thought to control the expression levels of cytoprotective factors, including heme-oxygenase (HO)-1. In the present study, we investigated the roles of Bach1 in the development of left ventricular (LV) hypertrophy and remodeling induced by transverse aortic constriction (TAC) in vivo using Bach1 gene-deficient (Bach1 Ϫ/Ϫ ) mice. TAC for 3 weeks in wild-type control (Bach1 ϩ/ϩ ) mice produced LV hypertrophy and remodeling manifested by increased heart weight, histological findings showing increased myocyte cross-sectional area (CSA) and interstitial fibrosis (picro Sirius red staining), reexpressions of ANP, BNP, and ␤MHC genes, and echocardiographic findings showing wall thickening, LV dilatation, and reduced LV contraction. Deletion of Bach1 caused significant reductions in heart weight (by 16%), CSA (by 36%), tissue collagen content (by 38%), and gene expression levels of ANP (by 75%), BNP (by 45%), and ␤MHC (by 74%). Echocardiography revealed reduced LV dimension and ameliorated LV contractile function. Deletion of Bach1 in the LV caused marked upregulation of HO-1 protein accompanied by elevated HO activity in both basal or TAC-stimulated conditions. Treatment of Bach1 Ϫ/Ϫ mice with tin-protoporphyrin, an inhibitor of HO, abolished the antihypertrophic and antiremodeling effects of Bach1 gene ablation. These results suggest that deletion of Bach1 caused upregulation of cytoprotective HO-1, thereby inhibiting TAC-induced LV hypertrophy and remodeling, at least in part, through activation of HO. Bach1 repressively controls myocardial HO-1 expression both in basal and stressed conditions, inhibition of Bach1 may be a novel therapeutic strategy to protect the myocardium from pressure overload. Key Words: hypertrophy Ⅲ HO-1 Ⅲ mice Ⅲ oxidative stress Ⅲ Bach1 Ⅲ remodeling C ardiac hypertrophy has been regarded as a compensatory mechanism of the heart to maintain cardiac output during pathological states with sustained increases in hemodynamic load, but it is associated with a high risk of cardiac mortality because of its established role in the development of cardiac failure. Heme-oxygenase (HO) is an enzyme that degrades prooxidant heme to carbon monoxide and biliverdin/bilirubin. HO-1 is an inducible form and HO-2 is a constitutive form of the enzyme. 1 HO-1, the activity of which is 10-fold greater than that of HO-2, is considered to be a stress-induced cytoprotective factor because (1) it is swiftly upregulated on exposure to cellular stress and (2) the catalytic products, carbon monoxide and biliverdin/bilirubin, have antiinflammatory 2 and antioxidant 3 actions, respectively. In the left ventricle (LV), stresses such as pressure overload cause generation of reactive oxygen species (ROS) and inflammatory reaction, which are thought to be involved in the underlying mechanisms of LV hypertrophy and the subsequent process of LV remodeling. 4 HO-1 may be activated in the LV in such stressed conditions, attenuating the effects of prohypertrophic R...

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