Abstract
The hallmarks of pancreatic cancer are limitless replicative potential as well as tissue invasion and metastasis, leading to an extremely aggressive disease with shockingly high lethality. However, the molecular mechanisms underlying these characteristics remain largely unclear. Herein, we report the results of a differential miRNA expression screen that compared pancreatic cancer tissues and normal pancreatic tissues, where the pancreatic cancer tissues had highly downregulated miR-29c with relative Wnt cascade hyperactivation. MiR-29c directly suppressed the following Wnt upstream regulators: frequently rearranged in advanced T-cell lymphomas 2 (FRAT2), low-density lipoprotein receptor-related protein 6 (LRP6), Frizzled-4 (FZD4) and Frizzled-5 (FZD5). Furthermore, transforming growth factor-β (TGF-β) inhibited miR-29c expression, leading to Wnt activation. Significantly, our results were consistent with an important correlation between miR-29c levels and TGF-β hyperactivation and the activated Wnt cascade in human pancreatic cancer specimens. These findings reveal a novel mechanism for Wnt hyperactivation in pancreatic cancer and may suggest a new target for clinical intervention in pancreatic cancer.
Highlights
Pancreatic cancer (PANC), which caused 330,000 deaths globally in 2012 [1], has the worst 1- and 5-year survival rates of all cancers
These findings suggest a possible link between miR-29c reduction and human PANC progression
An increasing amount of evidence shows that cancer treatments that fail to eradicate cancer stem cells (CSC) may lead to tumor recurrence, and these CSCs are implicated in tumor progression and metastasis, the critical causes of death in patients with cancer
Summary
Pancreatic cancer (PANC), which caused 330,000 deaths globally in 2012 [1], has the worst 1- and 5-year survival rates of all cancers. A series of studies has proven the cancer stem cell hypothesis in PANC [11,12,13,14,15], the precise molecular mechanisms underlying the stem cell-like properties of PANC cells remain largely unknown. Undercover molecular mechanisms that collaboratively regulate PANC cell metastasis and stemness are expected to provide new insights into the development of novel and effective therapy for PANC. In this context, identifying genetic and/or epigenetic factors that modulate the stem cell-like phenotype of PANC cells is of significant importance in the clinic
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