Reexpression of Let-7g MicroRNA Inhibits the Proliferation and Migration via K-Ras/HMGA2/Snail Axis in Hepatocellular Carcinoma

Chen, Ke-ji; Hou, Ying; Wang, Kui; Li, Jun; Xia, Yong; Yang, Xiaoyu; Liu, Gang; Xing, Xiang-Lei; Shen, Feng

doi:10.1155/2014/742417

Cited by 47 publications

(55 citation statements)

References 25 publications

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“…39,40 Not much is known about the different roles of NOTCH family members in cancer, although there is speculation that they have different roles in brain tumor development. 41 There exists evidence that each of the NOTCH family members contributes to hepatocarcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Combinatorial interventions inhibit TGFβ-driven epithelial-to-mesenchymal transition and support hybrid cellular phenotypes

et al. 2015

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Epithelial-to-mesenchymal transition (EMT) is a developmental process hijacked by cancer cells to leave the primary tumor site, invade surrounding tissue and establish distant metastases. A hallmark of EMT is the loss of E-cadherin expression, and one major signal for the induction of EMT is transforming growth factor beta (TGFβ), which is dysregulated in up to 40% of hepatocellular carcinoma (HCC). We aim to identify network perturbations that suppress TGFβ-driven EMT, with the goal of suppressing invasive properties of cancer cells. We use a systems-level Boolean dynamic model of EMT to systematically screen individual and combination perturbations (inhibition or constitutive activation of up to four nodes). We use a recently developed network control approach to understand the mechanism through which the combinatorial interventions suppress EMT. We test the results of our in silico analysis using siRNA. Our model predicts that targeting key elements of feedback loops in combination with the SMAD complex is more effective than suppressing the SMAD complex alone. We demonstrate experimentally that expression of a majority of these elements is enriched in mesenchymal relative to epithelial phenotype HCC cell lines. An siRNA screen of the predicted combinations confirms that many targeting strategies suppress TGFβ-driven EMT measured by E-cadherin expression and cell migration. Our analysis reveals that some perturbations give rise to hybrid states intermediate to the epithelial and mesenchymal states. Our results indicate that EMT is driven by an interconnected signaling network and many apparently successful single interventions may lead to steady states that are in-between epithelial and mesenchymal states. As these putative hybrid or partial EMT states may retain invasive properties, our results suggest that combinatorial therapies are necessary to fully suppress invasive properties of tumor cells.

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Section: Discussionmentioning

confidence: 99%

Combinatorial interventions inhibit TGFβ-driven epithelial-to-mesenchymal transition and support hybrid cellular phenotypes

et al. 2015

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“…Hsa-let-7g miRNA has been described to inhibit proliferation and migration of hepatocellular carcinoma by targeting diverse genes (Lan et al, 2011;Chen et al, 2014). Instead, let-7g induced the increase of proliferation and reduction of apoptosis in normal cells by targeting antiangiogenic genes or apoptotic genes .…”

Section: Discussionmentioning

confidence: 99%

Hsa-let-7g miRNA regulates the anti-tumor effects of gastric cancer cells under oxidative stress through the expression of DDR genes

Hu¹,

Zhao

Jin

et al. 2015

J. Toxicol. Sci.

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-Oxidative stress is linked to increased risk of gastric cancer (GC). Recent reports have found that hsa-let-7g microRNA (miRNA) has properties of anti-tumor and resistance to damages induced by oxidized low-density lipoprotein (ox-LDL). Dysregulation of hsa-let-7g was present in GC in vivo and in vitro under exogenous stress. However, we didn't know whether there are regulatory mechanisms of hsa-let-7g in GC under oxidative stress. This study was aimed at investigating the effects of hsa-let-7g microRNA (miRNA) on GC under oxidative stress. The results showed that H 2 O 2 induced the increase of DNA damage response (DDR) genes (ATM, H2AX and Chk1) and downregulation of hsa-let-7g in GC cells. Further study confirmed Hsa-let-7g caused the apoptosis and loss of proliferation in GC cells exposed to H 2 O 2 associated with repression of DDR system. Yet, we found let-7g didn't target DDR genes (ATM, H2AX and Chk1) directly. In addition, data revealed hsa-let-7g miRNA increased the sensitivity of GC to X-rays involving in ATM regulation as well according to application of X-rays (another DDR inducer). In conclusion, Hsa-let-7g miRNA increased the sensitivity of GC to oxidative stress by repression activation of DDR indirectly. Let-7g improved the effects of X-rays on GC cells involving in DDR regulation as well.

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“…The highly conserved let-7 miRNAs have also been shown to have suppressive effects in cancers with overexpression of RAS proteins and RAS oncogenes with lesser mutations, such as hepatocellular carcinoma [4,[16][17][18]. We previously verified the presence of let-7a target wild-type RAS genes in humans through luciferase activity.…”

Section: Introductionmentioning

confidence: 89%

Vector-Based let-7a miRNAs Function as Suppressors of Multiple Oncogenes in SK-N-MC and SHEP Neuroblastoma Cells

Guan¹,

Guo²,

Zhang³

et al. 2016

J Carcinog Mutagene

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Objective: This study was designed to determine the anti-tumor effect of vector-based let-7a miRNA in neuroblastoma cell lines. Methods:A tetracycline (tet)-inducible let-7a expression vector was constructed and used to stably transfect SK-N-MC and SHEP neuroblastoma cells. The effects of let-7a overexpression induced by tetracycline on cell proliferation and adhesion were analyzed in vitro by MTT assays and adhesion assays. The mRNA expression of the let-7 target oncogenes NRAS, KRAS, c-myc, and HMGA2 was examined by quantitative real-time reverse transcription polymerase chain reaction. Protein expression of N-RAS, K-RAS, c-Myc, HMGA2, NeuN, and β3-tubulin was analyzed using western blot and immunocytochemistry. Morphology of SK-N-MC and SHEP cells was also observed. Additionally, the let-7a-inducible vector-transfected SHEP cells were subcutaneously injected in nude mice, and tumor growth in vivo was also evaluated. Conclusion:Taken together, our data demonstrate the anti-tumor effects of vector-based let-7a miRNA overexpression in SK-N-MC and SHEP neuroblastoma cells against multioncogenes. Let-7a miRNA is a potential therapeutic molecule for the treatment of neuroblastoma.

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Reexpression of Let-7g MicroRNA Inhibits the Proliferation and Migration via K-Ras/HMGA2/Snail Axis in Hepatocellular Carcinoma

Cited by 47 publications

References 25 publications

Combinatorial interventions inhibit TGFβ-driven epithelial-to-mesenchymal transition and support hybrid cellular phenotypes

Combinatorial interventions inhibit TGFβ-driven epithelial-to-mesenchymal transition and support hybrid cellular phenotypes

Hsa-let-7g miRNA regulates the anti-tumor effects of gastric cancer cells under oxidative stress through the expression of DDR genes

Vector-Based let-7a miRNAs Function as Suppressors of Multiple Oncogenes in SK-N-MC and SHEP Neuroblastoma Cells

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