{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T20:15:13Z","timestamp":1792008913278,"version":"4.4.0"},"reference-count":34,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2011,6,7]],"date-time":"2011-06-07T00:00:00Z","timestamp":1307404800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Cellular Biochemistry"],"published-print":{"date-parts":[[2011,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Since claudin\u201018 (Cldn18) is overexpressed in precursor lesion PanIN and pancreatic duct carcinoma, it serves as a diagnostic marker and a target of immunotherapy. The stomach isoform of Cldn18, Cldn18a2 is regulated via a PKC\/MAPK\/AP\u20101\u2010dependent pathway in PKC activator 12\u2010\n                    <jats:italic>O<\/jats:italic>\n                    \u2010tetradecanoylphorbol 13\u2010acetate (TPA)\u2010stimulated gastric cancer cells. However, little is known about how Cldn18 is regulated, not only in pancreatic duct carcinoma but also in normal human pancreatic duct epithelial cells (HPDE cells). In the present study, four pancreatic cancer cell lines, HPAF\u2010II, HPAC, PANC\u20101 and BXPC3, and hTERT\u2010HPDE cells in which the hTERT gene was introduced into HPDE cells in primary culture, were treated with TPA. In all human pancreatic cancer cell lines and hTERT\u2010HPDE cells, Cldn18 mRNA indicated as Cldn18a2 was markedly induced by TPA and in well\u2010 or moderately differentiated human pancreatic cancer cells HPAF\u2010II and HPAC and hTERT\u2010HPDE cells, the protein was also strongly increased. The upregulation of Cldn18 by TPA in human pancreatic cancer cell lines was prevented by inhibitors of PKC\u03b4, PKC\u03b5, and PKC\u03b1, whereas the upregulation of Cldn18 by TPA in hTERT\u2010HPDE cells was prevented by inhibitors of PKC\u03b4, PKC\u03b8, and PKC\u03b1. Furthermore, a CpG island was identified within the coding sequence of the Cldn18 gene and treatment with the demethylating agent 5\u2010azadeoxycytidine enhanced upregulation of Cldn18 by TPA in HPAF\u2010II and HPAC, but not hTERT\u2010HPDE cells. Our findings suggest that in human pancreatic cancer cells, Cldn18 is primarily regulated at the transcriptional level via specific PKC signaling pathways and modified by DNA methylation. J. Cell. Biochem. 112: 1761\u20131772, 2011. \u00a9 2011 Wiley\u2010Liss, Inc.\n                  <\/jats:p>","DOI":"10.1002\/jcb.23095","type":"journal-article","created":{"date-parts":[[2011,3,4]],"date-time":"2011-03-04T10:29:37Z","timestamp":1299234577000},"page":"1761-1772","source":"Crossref","is-referenced-by-count":58,"title":["Transcriptional regulation of claudin\u201018 via specific protein kinase C signaling pathways and modification of DNA methylation in human pancreatic cancer 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