MicroRNA regulation of glucocorticoid-induced autophagy and progression of pancreatic ductal adenocarcinoma

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Pancreatic ductal adenocarcinoma (PDA) is one of the most aggressive malignancies with poor prognosis. Glucocorticoids (GCs), such as dexamethasone (DEX), are administered as co-treatment to limit side effects and for palliative reasons. Accumulating evidence indicates that GCs induce progression and therapy resistance of epithelial tumor cells involving PDA. This is similar to other steroid hormones, such as estrogen or androgen, whose receptors are blocked for therapeutic reasons in breast and prostate cancer. The first in vivo report about the induction of chemotherapy resistance by pharmacological doses of DEX in a lung and cervical cancer cell line came from our group in 2003. Meanwhile these data were confirmed by several other researchers and are supported by patient studies. Our latest data demonstrate that signaling by glucocorticoid receptor and kinases activate TGFβ, which mediates therapy resistance and epithelial-mesenchymal transition (EMT) in PDA. Our unpublished results indicate that autophagy and GC-induced microRNA (miRNA) signaling are also involved. By miRNA array analysis, bioinformatic evaluation and in silico computational prediction we identified miR-132, miR-378a-3p, miR-10b-5p, and their target genes TGFβ, ATG12, RAS/ERK and JNK/AP-1 as key players.The aim of the requested project is the molecular analysis of GC-induced miRNA signaling, the verification of the most significant miRNAs with their target genes and to examine the function of GC-induced EMT and autophagy in malignant progression. We will examine whether (1) not only DEX, but also other commonly prescribed GC medicaments induce PDA progression, (2) GC pre-medication prior to Whipple OP influences the expression of candidate miRNAs and their target genes in patient tissue, (3) the miRNA candidates and their target genes are functionally involved in DEX-induced autophagy and EMT, (4) DEX-induced autophagy and EMT are cross-regulated, and (5) the strongest miRNA candidate and it´s target gene are effective in vivo using tumorxenograft models. This project contributes to a better understanding of the complex molecular mechanisms, by which GC medicaments mediate beneficial but also harmful effects in PDA. The involvement of commonly prescribed GC medicaments and the examination of patient tissues underline the translational character and the clinical relevance. Considering that GCs are frequently used and that severe stress, chronic pancreatitis, depression, protein-rich meals, and acute smoking raise endogenous GC levels, the expected results may also contribute to understand the development of pancreatic cancer, but also of other epithelial tumor entities.