The activation of hepatic stellate cells (HSCs) is a prominent event in liver fibrogenesis. However, how HSCs are activated in the hypoxic microenvironment remains unclear. Here, we found that hypoxia increased autophagy in rat HSCs. Moreover, hypoxia induced an elevation of the intracellular calcium concentration ([Ca 2+ ] i ), which was abolished by the cytosolic Ca 2+ chelator or the phospholipase C (PLC)-specific inhibitor. Furthermore, hypoxia-induced autophagy involved the calcium-dependent activation of the 5ʹ-adenosine monophosphate-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) and protein kinase C-theta (PKCh) pathways. In addition, hypoxia-mediated activation of HSCs depended on autophagy.Our results suggest that autophagy induction via the calcium-dependent AMPK-mTOR and PKCh pathways might lead to the activation of HSCs during hypoxic stress.

The hedgehog signaling pathway was first discovered in the 1980s. It is a stem cell-related pathway that plays a crucial role in embryonic development, tissue regeneration, and organogenesis. Aberrant activation of hedgehog signaling leads to pathological consequences, including a variety of human tumors such as pancreatic cancer. Multiple lines of evidence indicate that blockade of this pathway with several small-molecule inhibitors can inhibit the development of pancreatic neoplasm. In addition, activated hedgehog signaling has been reported to be involved in fibrogenesis in many tissues, including the pancreas. Therefore, new therapeutic targets based on hedgehog signaling have attracted a great deal of attention to alleviate pancreatic diseases. In this review, we briefly discuss the recent advances in hedgehog signaling in pancreatic fibrogenesis and carcinogenesis and highlight new insights on their potential relationship with respect to the development of novel targeted therapies.