Cadherins play an important role in tissue homeostasis, as they are responsible for cell-cell adhesion during embryogenesis, tissue morphogenesis, differentiation and carcinogenesis. Cadherins are inseparably connected with catenins, forming cadherin-catenin complexes, which are crucial for cell-to-cell adherence. Any dysfunction or destabilization of cadherin-catenin complex may result in tumor progression. Epithelial mesenchymal transition (EMT) is a mechanism in which epithelial cadherin (E-cadherin) expression is lost during tumor progression. However, during tumorigenesis, many processes take place, and downregulation of E-cadherin, nuclear β-catenin and p120 catenin (p120) signaling are among the most critical. Additional signaling pathways, such as Receptor tyrosine kinase (RTK), Rho GTPases, phosphoinositide 3-kinase (PI3K) and Hippo affect cadherin cell-cell adhesion and also contribute to tumor progression and metastasis. Many signaling pathways may be activated during tumorigenesis; thus, cadherin-targeting drugs seem to limit the progression of malignant tumor. This review discusses the role of cadherins in selected signaling mechanisms involved in tumor growth. The clinical importance of cadherin will be discussed in cases of human and animal cancers.

Acute pancreatitis (AP) is an inflammatory disorder of pancreatic tissue initiated in injured acinar cells. Severe AP remains a significant challenge due to the lack of effective treatment. The widely-accepted autodigestion theory of AP is now facing challenges, since inhibiting protease activation has negligible effectiveness for AP treatment despite numerous efforts. Furthermore, accumulating evidence supports a new concept that malfunction of a self-protective mechanism, the unfolded protein response (UPR), is the driving force behind the pathogenesis of AP. The UPR is induced by endoplasmic reticulum (ER) stress, a disturbance frequently found in acinar cells, to prevent the aggravation of ER stress that can otherwise lead to cell injury. In addition, the UPR’s signaling pathways control NFκB activation and autophagy flux, and these dysregulations cause acinar cell inflammatory injury in AP, but with poorly understood mechanisms. We therefore summarize the protective role of the UPR in AP, propose mechanistic models of how inadequate UPR could promote NFκB’s pro-inflammatory activity and impair autophagy’s protective function in acinar cells, and discuss its relevance to current AP treatment. We hope that insight provided in this review will help facilitate the research and management of AP.

INTRODUCTION: AKT is a major cell survival mediator in pancreatic cancer. Clarifying the mechanism of its activation in response to chemotherapy is desirable for designing strategies to overcome pancreatic cancer chemoresistance. Recently, REG3A was identified as an extracellular activator of AKT in psoriatic keratinocytes. This finding implies that AKT in pancreatic cancer cells could be activated by REG1, a REG3A family member, which is mainly secreted by acinar cells and has promoting effects on pancreatic cancer. Furthermore, we found that in pancreatic cancer cells, gemcitabine treatment significantly increased expression of EXTL3, a receptor shared by REG1 and REG3A. Therefore, we hypothesized that acinar cell-derived REG1 promotes the development of chemoresistance in pancreatic cancer. In this study, we investigated REG1-mediated gemcitabine resistance in Panc-1 and MIA-paca-2 pancreatic cancer cells.METHODS: Expression of EXTL3 in gemcitabine-treated cells was evaluated by Western blot and RT-PCR. REG1-induced activation of AKT and AKT-regulated p21Cip/Waf1 cellular location were analyzed by Western blot and immunofluorescence staining, respectively. Survival of gemcitabine-treated cells with/without REG1 stimulation and AKT inhibition was quantified by measuring cellular dehydrogenase activity.RESULTS: REG1 supplementation significantly increased AKT phosphorylation and AKT-mediated cytoplasmic location of p21Cip/Waf1 in cultured pancreatic cancer cells. These effects resulted in the enhanced resistance to gemcitabine that could be reversed by AKT inhibition.CONCLUSIONS: REG1 is an AKT activator that increases chemoresistance in pancreatic cancer cells, suggesting an adverse role of acinar cells during pancreatic cancer chemotherapy. Targeting REG1 to overcome chemoresistance is being investigated in our REG1-deficient orthotopic mouse model of human pancreatic cancers.