DCLK1 Regulates Pluripotency and Angiogenic Factors via microRNA-Dependent Mechanisms in Pancreatic Cancer

摘要: Stem cell pluripotency, angiogenesis and epithelial-mesenchymal transition (EMT) have been shown to be significantly upregulated in pancreatic ductal adenocarcinoma (PDAC) many other aggressive cancers. The dysregulation of these processes is believed play key roles tumor initiation, progression, metastasis, contributory PDAC being the fourth leading cause cancer-related deaths US. suppressor miRNA miR-145 downregulates critical pluripotency factors oncogenes results repressed metastatic potential PDAC. Additionally, miR-200 family regulates several angiogenic which linked metastasis solid tumors. We previously demonstrated that downregulation DCLK1 can upregulate miRNAs both vitro vivo cancer models c-MYC, KRAS, NOTCH1 EMT-related transcription factors. A recent report has also Dclk1 distinguish between normal stem cells Apcmin/+ mice ablation Dclk1+ resulted regression intestinal polyps without affecting homeostasis. Here we demonstrate knockdown using poly(lactide-co-glycolide)-encapsulated-DCLK1-siRNA AsPC1 growth arrest. Examination xenograft tumors revealed, (a) increased decreased maintenance OCT4, SOX2, NANOG, KLF4 as well KRAS RREB1; (b) let-7a factor LIN28B; (c) VEGFR1, VEGFR2 ZEB1, ZEB2, SNAIL SLUG. Specificity post-transcriptional regulation downstream targets miR-145, was accomplished utilizing a luciferase-based reporter assay. conclude plays significant master regulatory role tumorigenesis through multiple their pro-tumorigenic pathways. This novel concept targeting alone advantages over single pathway or miRNA-based therapies for