Glucocorticoid-induced pancreatic-hepatic trans-differentiation in a human cell line in vitro

Differentiation. Jul-Aug 2018;102:10-18. doi: 10.1016/j.diff.2018.05.003. Epub 2018 May 22.

Abstract

The rodent pancreatic AR42J-B13 (B-13) cell line differentiates into non-replicative hepatocyte-like cells in response to glucocorticoid mediated via the glucocorticoid receptor (GR). The aims of this study were to identify a human cell line that responds similarly and investigate the mechanisms underpinning any alteration in differentiation. Exposing the human pancreatic adenocarcinoma (HPAC) cell line to 1-10 µM concentrations of dexamethasone (DEX) resulted an inhibition of proliferation, suppressed carcinoembryonic antigen expression, limited expression of pancreatic acinar and hepatic gene expression and significant induction of the constitutively-expressed hepatic CYP3A5 mRNA transcript. These changes were associated with a pulse of genomic DNA methylation and suppressed notch signalling activity. HPAC cells expressed high levels of GR transcript in contrast to other nuclear receptors - such as the glucocorticoid-activated pregnane X receptor (PXR) - and GR transcriptional function was activated by DEX in HPAC cells. Expression of selected hepatocyte transcripts in response to DEX was blocked by co-treatment with the GR antagonist RU486. These data indicate that the HPAC response to glucocorticoid exposure includes an inhibition in proliferation, alterations in notch signalling and a limited change in the expression of genes associated with an acinar and hepatic phenotype. This is the first demonstration of a human cell responding to similarly to the rodent B-13 cell regarding formation of hepatocyte-like cells in response to glucocorticoid. Identifying and modulating the ablating factor(s) may enhance the hepatocyte-like forming capacity of HPAC cells after exposure to glucocorticoid and generate an unlimited in vitro supply of human hepatocytes for toxicology studies and a variety of clinical applications.

Keywords: AR42J; AR42J-B13; B-13; HPAC; Liver; NR3C1; Pancreas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation / drug effects*
  • Cell Line
  • Dexamethasone / pharmacology
  • Glucocorticoids / pharmacology*
  • Hepatocytes / cytology
  • Hepatocytes / drug effects*
  • Humans
  • Liver / metabolism
  • Pancreas / cytology*
  • Pancreatic Neoplasms / drug therapy
  • Receptors, Glucocorticoid / drug effects

Substances

  • Glucocorticoids
  • Receptors, Glucocorticoid
  • Dexamethasone

Supplementary concepts

  • Pancreatic Carcinoma