Functional role of BTB and CNC Homology 1 gene in pancreatic cancer and its association with survival in patients treated with gemcitabine

Abstract

Genetic variation (rs372883C/T) in the 3'-untranslated region of BTB and CNC homology 1 (<i>BACH1</i>) has been associated with pancreatic ductal adenocarcinoma (PDAC) risk in our previous genome-wide association study; however, the action roles of this genetic variation in PDAC remains unknown. <b>Methods:</b><i>BACH1</i> expression was measured by quantitative real-time PCR, Western blot and immunohistochemistry. The effects of <i>BACH1</i> on cell proliferation and sensitivity to gemcitabine were examined by alteration of <i>BACH1</i> expression in PDAC cells. Angiogenesis was determined in vitro using a human umbilical vein endothelial cell model. Reporter gene assays were conducted to compare the effects of microRNA-1257 on rs372883 variation. The associations between rs372883 variants and survival time in patients treated with gemcitabine were estimated by logistic regression. <b>Results:</b> We found substantially lower <i>BACH1</i> expression in PDAC compared with normal pancreatic tissues and the rs372883T allele had significantly lower <i>BACH1</i> levels than the rs372883C allele in both tumor and normal tissues. Knockdown of <i>BACH1</i> expression provoked proliferation of PDAC cells and angiogenesis, which might result from upregulation of hemeoxygenase-1 that evokes oncogenic AKT and ERK signaling. The rs372883T>C change inhibits interaction of <i>BACH1</i> with microRNA-1257, resulting in increased <i>BACH1</i> expression. PDAC patients with the rs372883T allele were more resistant to gemcitabine and had shorter survival time compared with those with the rs372883C allele. <b>Conclusion:</b> These results shed light on the mechanism underlying the associations of <i>BACH1</i> rs372883 variation with risk of developing PDAC and differential gemcitabine sensitivity in patients.