Garcinol downregulates Notch1 signaling via modulating miR‐200c and suppresses oncogenic properties of PANC‐1 cancer stem‐like cells

Huang, Chi Cheng; Lin, Chien Min; Huang, Yan; Li, Wei; Ting, Lei Li; Kuo, Chian Jue; Hsu, Chun-Yao; Chiou, Jeng Fong; Wu, Alexander T.H.; Lee, Wei Hwa

doi:10.1002/bab.1446

Cited by 29 publications

(15 citation statements)

References 42 publications

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“…Enhanced chemosensitivity by miR-200c was also reported to occur through the Akt [ 19 , 20 ] and JNK2/c-Jun [ 21 ] signaling pathways. Notch signaling activation was also reported to be regulated by miR-200c in human cancer cell lines [ 22 , 23 ]. Notch genes are responsible for the expression of transmembrane receptors involved in communication between cells that are in contact.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-200c increases radiosensitivity of human cancer cells with activated EGFR-associated signaling

et al. 2017

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MicroRNA-200c (miR-200c) recently was found to have tumor-suppressive properties by inhibiting the epithelial-mesenchymal transition (EMT) in several cancers. miR-200c also interacts with various cellular signaling molecules and regulates many important signaling pathways. In this study, we investigated the radiosensitizing effect of miR-200c and its mechanism in a panel of human cancer cell lines. Malignant glioma (U251, T98G), breast cancer (MDA-MB-468), and lung carcinoma (A549) cells were transfected with control pre-microRNA, pre-miR-200c, or anti-miR-200c. Then, RT-PCR, clonogenic assays, immunoblotting, and immunocytochemisty were performed. To predict the potential targets of miR-200c, microRNA databases were used for bioinformatics analysis. Ectopic overexpression of miR-200c downregulated p-EGFR and p-AKT and increased the radiosensitivity of U251, T98G, A549, and MDA-MB-468 cells. In contrast, miR-200c inhibition upregulated p-EGFR and p-AKT, and decreased radiation-induced cell killing. miR-200c led to persistent γH2AX focus formation and downregulated pDNA-PKc expression. Autophagy and apoptosis were major modes of cell death. Bioinformatics analysis predicted that miR-200c may be associated with EGFR, AKT2, MAPK1, VEGFA, and HIF1AN. We also confirmed that miR-200c downregulated the expression of VEGF, HIF-1α, and MMP2 in U251 and A549 cells. In these cells, overexpressing miR-200c inhibited invasion, migration, and vascular tube formation. These phenotypic changes were associated with E-cadherin and EphA2 downregulation and N-cadherin upregulation. miR-200c showed no observable cytotoxic effect on normal human fibroblasts and astrocytes. Taken together, our data suggest that miR-200c is an attractive target for improving the efficacy of radiotherapy via a unique modulation of the complex regulatory network controlling cancer pro-survival signaling and EMT.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-200c increases radiosensitivity of human cancer cells with activated EGFR-associated signaling

et al. 2017

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“…Similarly, DCAMKL-1 (a putative pancreatic stem cell marker) knockdown resulted in down-regulation of Notch-1 expression in a miR-144-dependent mechanism (44). Garcinol, a known plant-derived antioxidant, could downregulate Notch-1 signaling via up-regulation of miR-200c, thereby suppressing oncogenic properties of PANC-1 cancer stem-like cells (45). Notably, quercetin-induced let-7c was shown to decrease pancreatic cancer initiating cell growth by posttranscriptional activation of Numbl and indirect inhibition of Notch in a fertilized chick egg tumor xenotransplant model (46).…”

mentioning

confidence: 99%

microRNA regulation of human pancreatic cancer stem cells

Hannafon

Ding

2017

Stem Cell Investig.

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microRNAs (miRNAs) are a group of small non-coding RNAs that function primarily in the post transcriptional regulation of gene expression in plants and animals. Deregulation of miRNA expression in cancer cells, including pancreatic cancer cells, is well documented, and the involvement of miRNAs in orchestrating tumor genesis and cancer progression has been recognized. This review focuses on recent reports demonstrating that miRNAs are involved in regulation of pancreatic cancer stem cells (CSCs). A number of miRNA species have been identified to be involved in regulating pancreatic CSCs, including miR-21, miR-34, miR-1246, miR-221, the miR-17-92 cluster, the miR-200 and let-7 families. Furthermore, the Notch-signaling pathway and epithelial-mesenchymal transition (EMT) process are associated with miRNA regulation of pancreatic CSCs. Given the significant contribution of CSCs to chemo-resistance and tumor progression, a better understanding of how miRNAs function in pancreatic CSCs could provide novel strategies for the development of therapeutics and diagnostics for this devastating disease.

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“…Another investigation showed aberrantly low expressions of miR-200c in PCSCs isolated from PANC-1 cells and is associated with the enhanced potential of proliferation, metastasis, and drug resistance while induced overexpression of miR-200c in PCSCs attenuated the stemness features [174]. Further, another mechanistic investigation reveals that the modulation of miR-200c expression inhibits the stemness of PCSCs via targeting Notch1 [105].…”

Section: Pancreatic Cancermentioning

confidence: 99%

Role of miRNA-Regulated Cancer Stem Cells in the Pathogenesis of Human Malignancies

Khan

Ahmed

Elareer

et al. 2019

Cells

238

168

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Recent biomedical discoveries have revolutionized the concept and understanding of carcinogenesis, a complex and multistep phenomenon which involves accretion of genetic, epigenetic, biochemical, and histological changes, with special reference to MicroRNAs (miRNAs) and cancer stem cells (CSCs). miRNAs are small noncoding molecules known to regulate expression of more than 60% of the human genes, and their aberrant expression has been associated with the pathogenesis of human cancers and the regulation of stemness features of CSCs. CSCs are the small population of cells present in human malignancies well-known for cancer resistance, relapse, tumorigenesis, and poor clinical outcome which compels the development of novel and effective therapeutic protocols for better clinical outcome. Interestingly, the role of miRNAs in maintaining and regulating the functioning of CSCs through targeting various oncogenic signaling pathways, such as Notch, wingless (WNT)/β-Catenin, janus kinases/ signal transducer and activator of transcription (JAK/STAT), phosphatidylinositol 3-kinase/ protein kinase B (PI3/AKT), and nuclear factor kappa-light-chain-enhancer of activated B (NF-kB), is critical and poses a huge challenge to cancer treatment. Based on recent findings, here, we have documented the regulatory action or the underlying mechanisms of how miRNAs affect the signaling pathways attributed to stemness features of CSCs, such as self-renewal, differentiation, epithelial to mesenchymal transition (EMT), metastasis, resistance and recurrence etc., associated with the pathogenesis of various types of human malignancies including colorectal cancer, lung cancer, breast cancer, head and neck cancer, prostate cancer, liver cancer, etc. We also shed light on the fact that the targeted attenuation of deregulated functioning of miRNA related to stemness in human carcinogenesis could be a viable approach for cancer treatment.

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Garcinol downregulates Notch1 signaling via modulating miR‐200c and suppresses oncogenic properties of PANC‐1 cancer stem‐like cells

Cited by 29 publications

References 42 publications

MicroRNA-200c increases radiosensitivity of human cancer cells with activated EGFR-associated signaling

MicroRNA-200c increases radiosensitivity of human cancer cells with activated EGFR-associated signaling

microRNA regulation of human pancreatic cancer stem cells

Role of miRNA-Regulated Cancer Stem Cells in the Pathogenesis of Human Malignancies

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