title: Loss of HNF6 expression correlates with human pancreatic cancer progression.
abstract: Normal pancreatic epithelium progresses through various stages of pancreatic intraepithelial neoplasms (PanINs) in the development of pancreatic ductal adenocarcinoma (PDAC). Transcriptional regulation of this progression is poorly understood. In mouse, the hepatic nuclear factor 6 (Hnf6) transcription factor is expressed in ductal cells and at lower levels in acinar cells of the adult pancreas, but not in mature endocrine cells. Hnf6 is critical for terminal differentiation of the ductal epithelium during embryonic development and for pancreatic endocrine cell specification. We previously showed that, in mice, loss of Hnf6 from the pancreatic epithelium during organogenesis results in increased duct proliferation and altered duct architecture, increased periductal fibrosis and acinar-to-ductal metaplasia. Here we show that decreased expression of HNF6 is strongly correlated with increased severity of PanIN lesions in samples of human pancreata and is absent from >90% of PDAC. Mouse models in which cancer progression can be analyzed from the earliest stages that are seldom accessible in humans support a role for Hnf6 loss in progression from early- to late-stage PanIN and PDAC. In addition, gene expression analyses of human pancreatic cancer reveal decreased expression of HNF6 and its direct and indirect target genes compared with normal tissue and upregulation of genes that act in opposition to HNF6 and its targets. The negative correlation between HNF6 expression and pancreatic cancer progression suggests that HNF6 maintains pancreatic epithelial homeostasis in humans, and that its loss contributes to the progression from PanIN to ductal adenocarcinoma. Insight on the role of HNF6 in pancreatic cancer development could lead to its use as a biomarker for early detection and prognosis.
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Pekala
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Xidi
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Kropp
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Christine P
authors.initials: CP
authors.lastname: Petersen
authors.affiliation: 1] Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA [2] VA Medical Center, Nashville, TN, USA.
authors.forename: Courtney W
authors.initials: CW
authors.lastname: Hudgens
authors.affiliation: Department of Oncology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Christine H
authors.initials: CH
authors.lastname: Chung
authors.affiliation: Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Chanjuan
authors.initials: C
authors.lastname: Shi
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Nipun B
authors.initials: NB
authors.lastname: Merchant
authors.affiliation: 1] Department of Oncology, Johns Hopkins University, Baltimore, MD, USA [2] Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.affiliation: 1] Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Means
authors.affiliation: 1] Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, USA [3] VA Medical Center, Nashville, TN, USA [4] Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Gannon
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D051559:Hepatocyte Nuclear Factor 6 / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D051559:Hepatocyte Nuclear Factor 6