Retinoic acid-dependent transforming growth factor-β2-mediated induction of MUC4 mucin expression in human pancreatic tumor cells follows retinoic acid receptor-α signaling pathway

The MUC4 mucin is considered as the homologue of rat sialomucin complex (SMC, rat Muc4) due to its similar structural organization. Like SMC, MUC4 may also exist as two subunits: A mucin type unit known as MUC4α and a growth factor-like transmembrane subunit, MUC4β. The expression of MUC4 in normal human pancreas is not detectable, but it is highly expressed in pancreatic tumor cells. In the present study, we investigated the regulation of MUC4 expression in human pancreatic tumor cells CD18/HPAF, exhibiting a high level of MUC4 transcripts and protein. When these cells were adapted to grow in the serum-free medium (CD18/HPAFSF), the MUC4 expression was undetectable. Among several serum constituents, all-trans-retinoic acid (RA) induced the expression of MUC4 transcripts in a concentration- and time-dependent manner. The RA-mediated increase in the level of the MUC4 transcript coincided with an increased expression of transforming growth factor-β2 (TGF-β2) transcript. The antagonist of the retinoic acid receptor (RAR)-α (Ro41-5253) abrogated the expression of MUC4 and TGF-β2 induced by RA. The exogenous addition of TGF-β2 also increased the MUC4 expression. The TGF-β-neutralizing antibody blocked the RA-induced as well as TGF-β2-mediated MUC4 expression. In conclusion, induction of MUC4 expression in pancreatic carcinoma by RA is mediated through the RAR-α signaling pathway, and TGF-β2 may serve as an interim mediator of this regulated expression.