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Targeting MYCN IRES in MYCN-amplified neuroblastoma with miR-375 inhibits tumor growth and sensitizes tumor cells to radiation.

ABSTRACT: The MYCN oncogene is amplified in 20% of neuroblastomas, leading to its overexpression at both the mRNA and protein levels. MYCN overexpression is strongly associated with advanced disease stage, rapid tumor progression and a worse prognosis. In the present study, we identified microRNA-375 (miR-375) as a negative regulator of MYCN: enforced expression of miR-375 inhibited MYCN-amplified neuroblastoma in vitro and in vivo. Upon searching the website miRbase for possible miR-375 binding sites within the whole MYCN mRNA, we found that the MYCN 5'-UTR had significant sequence complementarity to miR-375, yet no complementary sequences existed within the MYCN 3'-UTR and coding regions. Enforced overexpression of miR-375 efficiently inhibited MYCN mRNA translation and protein synthesis, via an IRES-dependent mechanism. In athymic nude mouse model with human MYCN-amplified neuroblastoma, MYCN downregulation by miR-375 led to inhibition of tumor cell growth and tumorigenicity. In particular, miR-375-regulated inhibition of MYCN translation was enhanced when MYCN-amplified neuroblastoma cells were exposed to stress stimulation, such as ionizing irradiation (IR), resulting in a remarkable increase in the neuroblastoma's sensitivity to IR-induced cell death. Our results identified a novel mechanism by which IRES-dependent translation of MYCN is repressed by miR-375, particularly during cellular stress, highlighting a potential anticancer strategy: the development of miR-375 as a novel therapeutic agent to treat MYCN-amplified neuroblastoma.

SUBMITTER: Zhang H

PROVIDER: S-EPMC4523463 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Purpose:In a previous study, we demonstrated that the combination of fenretinide with lenalidomide, administered by a novel nanomicellar formulation (FLM), provided a strong antitumor effect in a neuroblastoma TrkB-expressing tumor. In this study, we tested the nanomicellar combination in an MYCN amplified neuroblastoma xenograft to assess its efficacy in different tumor genotypes and evaluate the interactions of the nanomicelles with the tumor cells. Experimental Design:FLM was administered to mice bearing human NLF xenografts to evaluate its efficacy in comparison with the nanomicelles containing fenretinide alone (FM). Confocal laser-scanning fluorescence microscopy images of the NLF cells treated with FLM and FM allowed us to estimate the nanomicelle ability to transport the encapsulated drugs inside the tumor cells. Flow cytometric analysis of the cells from treated tumors was performed to assess the effect of treatment on GD2 expression and NK cell infiltration. Results:FLM and FM decreased the growth of NLF xenografts at comparable extents during the treatment period. Afterwards, FLM induced a progressive tumor regression without regrowth, while FM treatment was followed by regrowth within 15-20 days after the end of treatment. Both FLM and FM were able to penetrate the tumor cells transporting the encapsulated drugs. FLM transported higher amount of fenretinide inside the cells. Also, FLM treatment strongly increased GD2 expression in treated tumors and slightly decreased the NK infiltration compared to FM. Conclusion:FLM treatment induced a superior antitumor response than FM in NLF xenografts, presumably due to the combined effects of fenretinide cytotoxicity and lenalidomide antiangiogenic activity. The ability of FLM to penetrate tumor cells, transporting the encapsulated drugs, substantially improved the therapeutic efficiency of this system. Moreover, the enhancement of GD2 expression in FLM treated tumors offers the possibility to further increase the antitumor effect by the use of anti-GD2 CAR-T cells and anti-GD2 antibodies in combination with FLM in multimodal therapies.

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Targeting MYCN IRES in MYCN-amplified neuroblastoma with miR-375 inhibits tumor growth and sensitizes tumor cells to radiation.

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