MiR-744 increases tumorigenicity of pancreatic cancer by activating Wnt/β-catenin pathway

Abstract

The Wnt/β-catenin signaling pathway, commonly hyperactivated in pancreatic cancer, has been reported to play an important role in the maintenance of stemness of cancer stem cells (CSCs), which is closely related to the progression of pancreatic cancer. Therefore, exploring the regulatory mechanism in Wnt/β-catenin signaling may provide valuable clinical targets for cancer therapy. In the current study, we demonstrated that upregulation of miR-744 in pancreatic cancer promoted Wnt/β-catenin signaling by directly targeting secreted frizzled-related protein 1 (SFRP1), glycogen synthase kinase 3β (GSK3β), and transducin-like enhancer of split 3 (TLE3), important negative modulators of Wnt/β-catenin signaling. Expression of miR-744 was markedly upregulated in pancreatic cancer and positively correlated with poor patient survival. Furthermore, we found that overexpressing miR-744 enhanced, while inhibiting miR-744 reduced, the stem cell-like phenotype of pancreatic cancer cells in vitro. Importantly, in vivo model of human-derived pancreatic xenografts showed that miR-744 upregulation enhanced the tumorigenicity of pancreatic cancer cells. These findings suggest that miR-744 plays a vital role in promoting the stem cell-like phenotype of pancreatic cancer cells, and may represent a novel prognostic biomarker and therapeutic target.

Identification of novel genes associated with a poor prognosis in pancreatic ductal adenocarcinoma via a bioinformatics analysis

“…In the current study, the survival analysis demonstrated that the up-regulated expression of miR-455-3p in PDAC patients was associated with prolonged OS. miR-744 was found to be significantly up-regulated in PC and increased tumorigenicity by inhibiting multiple negative regulators of the Wnt/β-catenin pathway [54]. Furthermore, a high level of plasma miR-744 contributed to the poor progression-free survival of nonoperable PC patients [55].…”

Clinical Relevance of microRNA Expressions in Breast Cancer Validated Using the Cancer Genome Atlas (TCGA)

“…Animal models of miRNA-744 high expression revealed a decrease in the size of the tumors, and in vitro experiments showed impaired proliferation of cervical cancers. On the other hand, miRNA-744 appeared to demonstrate an oncogenic phenotype in pancreatic cancer, where its high expression was associated with increased recurrences, lymph node metastasis and poor survival 1323 . We do not have a good explanation for this conflicting result other than the fact that miRNA-744 may function differently in different cancers.…”

“…Similarly, in cervical cancer cells high expression of miRNA-744 decreases the expression of B-cell lymphoma 2 (Bcl2) leading to reduced cellular proliferation in vitro and decreased tumor growth in mice 12 . Contrastingly, miRNA-744 is an “oncogenic” miRNA in pancreatic cancer 13 . MiRNA-744 high expression is found to target important negative modulators of the Wnt/β-catenin signaling pathway and leads to an increase in the stem cell-like phenotype in pancreatic cancer cells 13 .…”

“…Contrastingly, miRNA-744 is an “oncogenic” miRNA in pancreatic cancer 13 . MiRNA-744 high expression is found to target important negative modulators of the Wnt/β-catenin signaling pathway and leads to an increase in the stem cell-like phenotype in pancreatic cancer cells 13 .…”

Roles of GSK-3 and microRNAs on epithelial mesenchymal transition and cancer stem cells

“…This occurred by miR-744 targeting SFRP1, GSK-3beta and the transducin-like enhancer of Split-3 (TLE3) [22]. miR-744 overexpression also increased the tumorigenicity of the pancreatic cells.…”