miR-300 regulates the epithelial-mesenchymal transition and invasion of hepatocellular carcinoma by targeting the FAK/PI3K/AKT signaling pathway

Wang, Rongchang; Yu, Zhenzhen; Chen, Fan; Xu, Hongxu; Shen, Shunli; Chen, Wei; Chen, Lianzhou; Qiao, Shan; Zhang, Longjuan; Bi, Jiong; Zeng, Wei; Li, Wen; Huang, Xiaohui; Wang, Qian

doi:10.1016/j.biopha.2018.03.005

Cited by 39 publications

(32 citation statements)

References 28 publications

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“… 50 – 56 MiRs are important regulators of HCC proliferation and metastasis. 57 – 63 In the present work, we firstly identified miR-140-3p as a potential miRNA target for PXR. Then, the regulatory effect of miR-140-3p on PXR was identified.…”

Section: Discussionmentioning

confidence: 97%

MicroRNA-140-3p enhances the sensitivity of hepatocellular carcinoma cells to sorafenib by targeting pregnenolone X receptor

Zhao²,

Wang³

et al. 2018

OTT

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BackgroundPregnane X receptor (PXR), which is a member of the nuclear receptor protein family (nuclear receptor subfamily 1 group I member 2 [NR 1I2]), mediates the drug-resistance in the hepatocellular carcinoma (HCC) via enhancing the expression of drug-resistance-related genes which accelerate the clearance of antitumor drugs, eg, sorafenib. However, there are few reports on miRNA targeting PXR participating in the epigenetic regulation of PXR in HCC cells.Materials and methodsTargetScan 7.2, an online method, was used to predict the miRNAs potentially targeting PXR. The expression of PXR and PXR downstream genes was detected by quantitative real-time PCR (qPCR) and Western blot. The clearance of sorafenib in HCC cells was monitored by liquid chromatograph-mass spectrometer/mass spectrometer (LC-MS/MS). The effects of miRNA on sorafenib’s efficacy were examined by in vitro methods, eg, MTT, and in vivo methods, eg, subcutaneous or intrahepatic tumor model.ResultsBy virtual screening, we identified that miR-140-3p possibly targets PXR and then confirmed that the overexpression of miR-140-3p via lentiviral particles inhibited the expression of PXR in HCC cells. The downregulation of PXR’s expression by miR-140-3p led to the reduction of PXR downstream genes’ expression, which finally resulted in the decelerating clearance of sorafenib in HCC cells and enhanced the sensitivity of HCC cells to sorafenib. The effect of miR-140-3p could not modulate the expression of mutated PXR and the effect of miR-140-3p could also be inhibited by miR-140-3p’s inhibitor. Moreover, miR-140-3p enhanced the anti-tumor effect of sorafenib in both the subcutaneous and intrahepatic HCC tumor models.ConclusionOur study suggests that targeting PXR by miR-140-3p is a promising strategy for enhancing sorafenib’s efficacy during HCC treatment.

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Section: Discussionmentioning

confidence: 97%

MicroRNA-140-3p enhances the sensitivity of hepatocellular carcinoma cells to sorafenib by targeting pregnenolone X receptor

Zhao²,

Wang³

et al. 2018

OTT

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“…The let-7 family of miRNA have also been studied as treatment for non-small cell lung cancer in the pre-clinical setting 15 . Loss of miR-300 has been previously correlated with development and aggressiveness of hepatocellular carcinoma 49 as well as in oncogenesis of pituitary tumors 50 . Reduced expression of miR-424-5p and miR-4282 have each been implicated in the development of basal-like breast cancer 51 , 52 .…”

Section: Discussionmentioning

confidence: 97%

Network potential identifies therapeutic miRNA cocktails in Ewing sarcoma

Weaver

Pishas

Williamson

et al. 2019

Preprint

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Introduction:Micro-RNA (miRNA)-based therapies are an emerging class of cancer therapies with many potential applications in the field owing to their ability to repress multiple, predictable targets and cause widespread changes in a cell signaling network. New miRNA-based oligonucleotide drugs have have shown significant promise for the treatment of cancer in pre-clinical studies. Because of the broad effects miRNAs can have on different cells and tissues, a network science-based approach is well-equipped to evaluate and identify miRNA candidates and combinations of candidates for the repression of key oncogenic targets. Methods: In this work, we present a novel network science-based approach for identification of potential miRNA therapies, using Ewings Sarcoma as a model system. We first characterized 6 EW cell lines using paired mRNA and miRNA sequencing. We then estimated a measure of tumor state, which we term network potential, based on both the mRNA gene expression and the underlying protein-protein interaction network in the tumor. Next, we ranked mRNA targets based on their contribution to network potential, aiming to approximate the relative importance of each protein to network stability in decreasing the network potential. After identifying these mRNA targets, we sought to identify miRNAs and combinations of miRNAs that preferentially act to repress these targets, with the aim of defining synthetic miRNA-based therapy for down-regulation of these targets. Results: We identified TRIM25, APP, ELAV1, RNF4, XPO1 as ideal protein targets for therapy for each of the six cell lines based on the degree of network disruption induced when each gene was modeled as repressed. The expanded list of targets was enriched for genes involved in the canonical miRNA biogenesis pathway, suggesting a link between signaling network disruption and miRNA production. Using miRNA-mRNA target mappings, we identified miR-3613-3p, let-7a-3p, miR-300, miR-424-5p, and let-7b-3p as the optimal miRNAs for preferential repression of these targets. Discussion: In this work, we applied a novel pipeline for identification of miRNAs candidates for cancer therapy. Using a measure of network state, network potential, we identified potential mRNA targets crucial to the stability of the Ewings Sarcoma signaling network, including known drivers of tumor progression and genes involved in miRNA biogenesis. Applying mRNA-miRNA mappings, we successfully identified miRNAs and combinations of miRNAs that, if introduced synthetically, are predicted to preferentially and dramatically disrupt the Ewings Sarcoma signaling network. 1 MicroRNA (miRNA)-based treatments, including anti-sense oligonucleotides, are an emerging class of cancer therapies 1 .2 Recent work has highlighted the critical importance of miRNAs in the development and maintenance of the cancer phenotype 1-3 . 3 MiRNA deregulation has been implicated in the development of each of the hallmark features of cancer, and restoration of 4 expression of some of these critical downregulated miR...

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“…A previous study demonstrated that blockade of the FAK/AKT signaling pathway inhibits head and neck cancer metastasis (37). Another study demonstrated that activating the FAK/AKT pathway promotes the epithelial-mesenchymal transition and invasion of HCC (38). Consequently, identifying the crosstalk between Gli1 and FAK/AKT pathway may provide a further understanding of the molecular mechanism of HCC invasion and metastasis.…”

Section: Discussionmentioning

confidence: 98%

Silencing glioma‑associated oncogene homolog 1 suppresses the migration and invasion of hepatocellular carcinoma <em>in vitro</em>

Xie

et al. 2020

Oncol Lett

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Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-associated death worldwide. Glioma-associated oncogene homolog 1 (Gli1) is a key component and functions as a reliable marker of Hedgehog signaling pathway activation. Previous studies have demonstrated that Gli1 serves important roles in the progression of various types of cancer, including HCC. However, its effect on HCC invasion and metastasis and the underlying mechanism remain to be elucidated. Small interference RNA was employed to silence the Gli1 gene in liver cancer cells. Reverse transcription-quantitative PCR and western blot analysis were performed to evaluate the mRNA and protein expression of Gli1, respectively. A series of assays, including Cell Counting Kit-8, adhesion, wound healing and Matrigel invasion were performed to investigate cell viability, adhesive, migratory and invasive capabilities of liver cancer cells, respectively. In addition, immunofluorescence staining was performed to determine the cellular localization of focal adhesion kinase (FAK), phosphorylated (p-)FAK and p-AKT. The mRNA and protein expression of Gli1 in liver cancer cells (HepG2 and SK-Hep1) were markedly decreased in a dose-dependent manner following Gli1-knockdown. Gli1 silencing significantly inhibited the adhesion, migration and invasion of SK-Hep1 cells. Additionally, knockdown of Gli1 markedly suppressed the expression of metalloproteinase (MMP)-2 and MMP-9. Furthermore, downregulation of Gli1 blocked the FAK/AKT signaling pathway. Gli1 serves significant roles in the migration and invasion of HCC cells through activation of the FAK/AKT signaling pathway and subsequent upregulation of MMP-2 and MMP-9 expression. Thus, Gli1 may be a potential protein target for the regulation of HCC migration and invasion.

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miR-300 regulates the epithelial-mesenchymal transition and invasion of hepatocellular carcinoma by targeting the FAK/PI3K/AKT signaling pathway

Cited by 39 publications

References 28 publications

MicroRNA-140-3p enhances the sensitivity of hepatocellular carcinoma cells to sorafenib by targeting pregnenolone X receptor

MicroRNA-140-3p enhances the sensitivity of hepatocellular carcinoma cells to sorafenib by targeting pregnenolone X receptor

Network potential identifies therapeutic miRNA cocktails in Ewing sarcoma

Silencing glioma‑associated oncogene homolog 1 suppresses the migration and invasion of hepatocellular carcinoma <em>in vitro</em>

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miR-300 regulates the epithelial-mesenchymal transition and invasion of hepatocellular carcinoma by targeting the FAK/PI3K/AKT signaling pathway

Cited by 39 publications

References 28 publications

MicroRNA-140-3p enhances the sensitivity of hepatocellular carcinoma cells to sorafenib by targeting pregnenolone X receptor

MicroRNA-140-3p enhances the sensitivity of hepatocellular carcinoma cells to sorafenib by targeting pregnenolone X receptor

Network potential identifies therapeutic miRNA cocktails in Ewing sarcoma

Silencing glioma‑associated oncogene homolog 1 suppresses the migration and invasion of hepatocellular carcinoma <em>in&nbsp;vitro</em>

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Silencing glioma‑associated oncogene homolog 1 suppresses the migration and invasion of hepatocellular carcinoma <em>in vitro</em>