Cross-presentation of antigens is critical for the induction of adaptive immunity against tumor cells and infectious pathogens. Currently, it is not known how cross-presentation of tumor antigens is regulated by autophagy. Using both HEK 293T cells that expressed the model antigen OVA and melanoma cells as antigen donors, we show that macroautophagy in tumor cells is essential for cross-presentation by dendritic cells both in vitro and in vivo. Inhibition of autophagy abolished cross-presentation almost completely, whereas induction of autophagy dramatically enhanced the cross-presentation of tumor antigens. Moreover, purified autophagosomes were found to be efficient antigen carriers for cross-presentation. Our findings not only identified a novel role for autophagy as an active process in antigen sequestration and delivery to dendritic cells for cross-presentation, but also suggested, for the first time, that isolated autophagosomes may have potential as potent vaccines for immunotherapy against cancer and infectious diseases. [Cancer Res 2008;68(17):6889-95]

Alcoholic liver disease (ALD) is a major cause of acute and chronic liver injury. Extensive evidence has been accumulated on the pathological process of ALD during the past decades. However, effective treatment options for ALD are very limited due to the lack of suitable in vivo models that recapitulate the full spectrum of ALD. Experimental animal models of ALD, particularly rodents, have been used extensively to mimic human ALD. An ideal animal model should recapitulate all aspects of the ALD process, including significant steatosis, hepatic neutrophil infiltration, and liver injury. A better strategy against ALD depends on clear diagnostic biomarkers, accurate predictor(s) of its progression and new therapeutic approaches to modulate stop or even reverse the disease. Numerous models employing rodent animals have been established in the last decades to investigate the effects of acute and chronic alcohol exposure on the initiation and progression of ALD. Although significant progress has been made in gaining better knowledge on the mechanisms and pathology of ALD, many features of ALD are unknown, and require further investigation, ideally with improved animal models that more effectively mimic human ALD. Although differences in the degree and stages of alcoholic liver injury inevitably exist between animal models and human ALD, the acquisition and translational relevance will be greatly enhanced with the development of new and improved animal models of ALD.

We examined the impact of crosstalk between the insulin receptor (INSR) and G protein-coupled receptor (GPCR) signaling pathways on the regulation of Yes-associated Protein (YAP) localization, phosphorylation and transcriptional activity in the context of human pancreatic ductal adenocarcinoma (PDAC). Stimulation of PANC-1 or MiaPaCa-2 cells with insulin and neurotensin, a potent mitogenic combination of agonists for these cells, promoted striking YAP nuclear localization and decreased YAP phosphorylation at Ser127 and Ser397. Challenging PDAC cells with either insulin or neurotensin alone modestly induced the expression of YAP/TEAD-regulated genes, including Connective Tissue Growth Factor (CTGF), Cysteine-rich angiogenic inducer 61 (CYR61) and CXCL5 whereas the combination of neurotensin and insulin induced a marked increase in the level of expression of these genes. In addition, siRNA-mediated knockdown of YAP/TAZ prevented the increase in the expression of these genes. A small-molecule inhibitor (A66), selective for the p110α subunit of PI3K, abrogated the increase in phosphatidylinositol 3,4,5-trisphosphate (PIP3) production and the expression of CTGF, CYR61 and CXCL5 induced by neurotensin and insulin. Furthermore, treatment of PDAC cells with protein kinase D (PKD) family inhibitors (CRT0066101 or kb NB 142-70) or with siRNAs targeting the PKD family prevented the increase of CTGF, CYR61 and CXCL5 mRNA levels in response to insulin and neurotensin stimulation. Thus, PI3K and PKD mediate YAP activation in response to insulin and neurotensin in pancreatic cancer cells.

miR-155 expression is altered in both liver tissue and circulating inflammatory cells during liver injury, thus regulating inflammatory cell recruitment and liver damage; these results suggest that maintaining miR-155 expression in inflammatory cells might be a potential strategy to modulate liver injury. (Hepatology 2018).