The epigenetic regulators Bmi1 and Ring1B are differentially regulated in pancreatitis and pancreatic ductal adenocarcinoma

Abstract

Chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC) are associated with major changes in cell differentiation. These changes may be at the basis of the increased risk for PDAC among patients with chronic pancreatitis. Polycomb proteins are epigenetic silencers expressed in adult stem cells; up-regulation of Polycomb proteins has been reported to occur in a variety of solid tumours such as colon and breast cancer. We hypothesized that Polycomb might play a role in preneoplastic states in the pancreas and in tumour development/progression. To test these ideas, we determined the expression of PRC1 complex proteins (Bmi1 and Ring1b) during pancreatic development and in pancreatic tissue from mouse models of disease: acute and chronic pancreatic injury, duct ligation, and in K-Ras(G12V) conditional knock-in and caerulein-treated K-Ras(G12V) mice. The study was extended to human pancreatic tissue samples. To obtain mechanistic insights, Bmi1 expression in cells undergoing in vitro exocrine cell metaplasia and the effects of Bmi1 depletion in an acinar cancer cell line were studied. We found that Bmi1 and Ring1B are expressed in pancreatic exocrine precursor cells during early development and in ductal and islet cells-but not acinar cells-in the adult pancreas. Bmi1 expression was induced in acinar cells during acute injury, in acinar-ductal metaplastic lesions, as well as in pancreatic intraepithelial neoplasia (PanIN) and PDAC. In contrast, Ring1B expression was only significantly and persistently up-regulated in high-grade PanINs and in PDAC. Bmi1 knockdown in cultured acinar tumour cells led to changes in the expression of various digestive enzymes. Our results suggest that Bmi1 and Ring1B are modulated in pancreatic diseases and could contribute differently to tumour development.

Long-term evolution of acinar-to-ductal metaplasia and β-cell mass after radiofrequency-assisted transection of the pancreas in a controlled large animal model

“…PDL has been extensively used to study the conversion of ADM into PDAC [1,3] as well as a method of duct-to-islet differentiation [6,[8][9][10][11][12] in order to increase beta-cell mass. However, contradictory results have been obtained from the conventional mouse models [6,7,11,26].…”

“…Pancreatic duct ligation (PDL) in mouse models has been extensively used as a model of chronic pancreatitis in order to study the evolution of ADM into PDAC [1,3,7], and also as a model of duct-to-islet differentiation [6,[8][9][10][11][12] to increase beta-cell mass. However, the validity of PDL as a model of endocrine regeneration has now been called into question [5][6][7]11,13,14].…”

“…Since ADM is characterized by a switch from acinar to ductal phenotype with active proliferation, and since metaplasic ductal lesions are frequently seen in chronic pancreatitis as well as in specimens of pancreatic ductal adenocarcinoma (PDAC), ADM is thought to represent a preneoplastic condition [1,3,4]. Even though some areas of ADM could revert to normal acinar morphology [5,6] in the absence of oncogenic Kras mutations or in the presence of acute pancreatitis, the transition of acinar cells into a duct-like state (as in ADM) has been recognized as an important early event in tumor initiation.…”

“…The conversion of exocrine acinar tissue into tubular or ductal complexes, usually known as acinar-toductal metaplasia (ADM), is common in various pancreatic diseases including pancreatitis and cancer [1][2][3]. Since ADM is characterized by a switch from acinar to ductal phenotype with active proliferation, and since metaplasic ductal lesions are frequently seen in chronic pancreatitis as well as in specimens of pancreatic ductal adenocarcinoma (PDAC), ADM is thought to represent a preneoplastic condition [1,3,4].…”

New insights into pancreatic cancer stem cells

“…During this process of early tumorigenesis after Kras mutations, several of the transcription factors like Oct4 and Nanog gets overexpressed linearly with the PanIN progression to PDAC [53] . Oncogenic Kras mutations in the pancreas activate important signaling pathways such as sonic hedgehog, Wnt, PI3K/AKT, Notch and PTEN, Bmi1 that lead the transformation of the normal pancreas to the malignant PanINs and PDAC [54][55][56][57][58][59] .…”