Dataset Information

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

ABSTRACT: The Wnt/?-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/?-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/?-catenin signaling by directly targeting secreted frizzled-related protein 1 (SFRP1), glycogen synthase kinase 3? (GSK3?), and transducin-like enhancer of split 3 (TLE3), important negative modulators of Wnt/?-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.

SUBMITTER: Zhou W

PROVIDER: S-EPMC4741948 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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

Zhou Wei W Li Yongfeng Y Gou Shanmiao S Xiong Jiongxin J Wu Heshui H Wang Chunyou C Yan Haijiao H Liu Tao T

Oncotarget 20151101 35

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 signa ...[more]

PMID: 26485754

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Project description:BACKGROUND:Pancreatic cancer is one of the most lethal malignancies and has an extremely poor diagnosis and prognosis. The development of resistance to gemcitabine is still a major challenge. The long noncoding RNA PVT1 was reported to be involved in carcinogenesis and chemoresistance; however, the mechanism by which PVT1 regulates the sensitivity of pancreatic cancer to gemcitabine remains poorly understood. METHODS:The viability of pancreatic cancer cells was assessed by MTT assay in vitro and xenograft tumor formation assay in vivo. The expression levels of PVT1 and miR-619-5p were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Western blotting analysis and qRT-PCR were performed to assess the protein and mRNA levels of Pygo2 and ATG14, respectively. Autophagy was explored via autophagic flux detection under confocal microscopy and autophagic vacuole investigation under transmission electron microscopy (TEM). The functional role and mechanism of PVT1 were further investigated by gain- and loss-of-function assays in vitro. RESULTS:In the present study, we demonstrated that PVT1 was up-regulated in gemcitabine-resistant pancreatic cancer cell lines. Gain- and loss-of-function assays revealed that PVT1 impaired sensitivity to gemcitabine in vitro and in vivo. We further found that PVT1 up-regulated the expression of both Pygo2 and ATG14 and thus regulated Wnt/?-catenin signaling and autophagic activity to overcome gemcitabine resistance through sponging miR-619-5p. Moreover, we discovered three TCF/LEF binding elements (TBEs) in the promoter region of PVT1, and activation of Wnt/?-catenin signaling mediated by the up-regulation of Pygo2 increased PVT1 expression by direct binding to the TBE region. Furthermore, PVT1 was discovered to interact with ATG14, thus promoting assembly of the autophagy specific complex I (PtdIns3K-C1) and ATG14-dependent class III PtdIns3K activity. CONCLUSIONS:These data indicate that PVT1 plays a critical role in the sensitivity of pancreatic cancer to gemcitabine and highlight its potential as a valuable target for pancreatic cancer therapy.

Dataset Information

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

Publications

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

Similar Datasets

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