科研之友
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摘要
Protein kinase C (PKC) is highly expressed in pancreatic cancer. However, the effects of PKC on Snail and claudin-1, which play crucial roles in epithelial cell polarity during epithelialmesenchymal transition (EMT), remain unclear. In this study, we investigated the mechanisms of regulation of Snail and claudin-1 via a PKC signal pathway during EMT in pancreatic cancer cells and in normal human pancreatic duct epithelial cells (HPDEs). By immunostaining, overexpression of PKC and downregulation of claudin-1 were observed in poorly differentiated human pancreatic cancer tissues and the pancreatic cancer cell line PANC-1. Treatment with the PKC inhibitor G6976 transcriptionally decreased Snail and increased claudin-1 in PANC-1 cells. The PKC inhibitor prevented upregulation of Snail and downregulation of claudin-1 during EMT induced by transforming growth factor-1 (TGF-1) treatment and under hypoxia in PANC-1 cells. The effects of the PKC inhibitor were in part regulated via an extracellular signal-regulated kinase (ERK) signaling pathway. The PKC inhibitor also prevented downregulation of the barrier function and fence function during EMT in well-differentiated pancreatic cancer cell line HPAC. In normal HPDEs, the PKC inhibitor transcriptionally induced not only claudin-1 but also claudin-4, -7 and occludin without a change of Snail. Treatment with the PKC inhibitor in normal HPDEs prevented downregulation of claudin-1 and occludin by TGF-1 treatment and enhanced upregulation of claudin-1, -4, -7 and occludin under hypoxia. These findings suggest that PKC regulates claudin-1 via Snail- and mitogen-activated protein kinase/ERK-dependent pathways during EMT in pancreatic cancer. Thus, PKC inhibitors may be potential therapeutic agents against the malignancy of human pancreatic cancer cells.
- 出版日期2013-6
