Abstract
Stem cell pluripotency, angiogenesis and epithelial-mesenchymal transition (EMT) have been shown to be significantly upregulated in pancreatic ductal adenocarcinoma (PDAC) and many other aggressive cancers. The dysregulation of these processes is believed to play key roles in tumor initiation, progression, and metastasis, and is contributory to PDAC being the fourth leading cause of cancer-related deaths in the US. The tumor suppressor miRNA miR-145 downregulates critical pluripotency factors and oncogenes and results in repressed metastatic potential in PDAC. Additionally, the miR-200 family regulates several angiogenic factors which have been linked to metastasis in many solid tumors. We have previously demonstrated that downregulation of DCLK1 can upregulate critical miRNAs in both in vitro and in vivo cancer models and results in downregulation of c-MYC, KRAS, NOTCH1 and EMT-related transcription factors. A recent report has also shown that Dclk1 can distinguish between normal and tumor stem cells in Apc min/+ mice and that ablation of Dclk1+ cells resulted in regression of intestinal polyps without affecting homeostasis. Here we demonstrate that the knockdown of DCLK1 using poly(lactide-co-glycolide)-encapsulated-DCLK1-siRNA results in AsPC1 tumor growth arrest. Examination of xenograft tumors revealed, (a) increased miR-145 which results in decreased pluripotency maintenance factors OCT4, SOX2, NANOG, KLF4 as well as KRAS and RREB1; (b) increased let-7a which results in decreased pluripotency factor LIN28B; and (c) increased miR-200 which results in decreased VEGFR1, VEGFR2 and EMT-related transcription factors ZEB1, ZEB2, SNAIL and SLUG. Specificity of DCLK1 post-transcriptional regulation of the downstream targets of miR-145, miR-200 and let-7a was accomplished utilizing a luciferase-based reporter assay. We conclude that DCLK1 plays a significant master regulatory role in pancreatic tumorigenesis through the regulation of multiple tumor suppressor miRNAs and their downstream pro-tumorigenic pathways. This novel concept of targeting DCLK1 alone has several advantages over targeting single pathway or miRNA-based therapies for PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the U.S annually with a 5% 5-year survival rate
A subset of cells with cancer stem-cell (CSC) properties has been identified in PDAC [2] that are capable of unlimited self-renewal and give rise to more-differentiated and more-aggressive progeny, which are often resistant to conventional chemotherapy and radiotherapy [2,3]
This heterogeneity is further complicated by epithelial to mesenchymal transition (EMT), a process that plays a key role in cancer invasion and metastasis [7,8]
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the U.S annually with a 5% 5-year survival rate. The inability to eradicate these CSCs is postulated to be a reason for tumor relapse, metastasis and death following initial responses to treatment [4]. Another critical obstacle in combating solid tumor cancers in general is the heterogeneity of cell types within the tumor microenvironment [5] and the highly desmoplastic tumor niche [6]. This heterogeneity is further complicated by epithelial to mesenchymal transition (EMT), a process that plays a key role in cancer invasion and metastasis [7,8]. The precise regulatory features that tip the balance towards a cancer phenotype with respect to tumor suppressor versus oncogenic miRNA expression are poorly understood
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