MicroRNA-497 impairs the growth of chemoresistant neuroblastoma cells by targeting cell cycle, survival and vascular permeability genes

Abstract

Despite multimodal therapies, a high percentage of high-risk neuroblastoma (NB) become refractory to current treatments, most of which interfere with cell cycle and DNA synthesis or function, activating the DNA damage response (DDR). In cancer, this process is frequently altered by deregulated expression or function of several genes which contribute to multidrug resistance (MDR). MicroRNAs are outstanding candidates for therapy since a single microRNA can modulate the expression of multiple genes of the same or different pathways, thus hindering the development of resistance mechanisms by the tumor. We found several genes implicated in the MDR to be overexpressed in high-risk NB which could be targeted by microRNAs simultaneously. Our functional screening identified several of those microRNAs that reduced proliferation of chemoresistant NB cell lines, the best of which was miR-497. Low expression of miR-497 correlated with poor patient outcome. The overexpression of miR-497 reduced the proliferation of multiple chemoresistant NB cell lines and induced apoptosis in MYCN-amplified cell lines. Moreover, the conditional expression of miR-497 in NB xenografts reduced tumor growth and inhibited vascular permeabilization. MiR-497 targets multiple genes related to the DDR, cell cycle, survival and angiogenesis, which renders this molecule a promising candidate for NB therapy.

MicroRNA‐194 reduces inflammatory response and human dermal microvascular endothelial cells permeability through suppression of TGF‐β/SMAD pathway by inhibiting THBS1 in chronic idiopathic urticaria

“…Proinflammatory cytokines like TNF-α and IL-6 are implicated in inflammation in autoimmune and infectious disease initiation and progression including CIU by activating inflammatory cells and regulating cell differentiation and apoptosis. 43 Another study demonstrated that upregulated miR-21 could decrease vascular permeability in mouse kidneys. 41 TNF-α was upregulated in endothelial and perivascular cells of the upper dermis in CIU inducing neuroendocrine disturbance and susceptibility to CIU, which may be induced by environmental stimulus.…”

MicroRNAs in neuroblastoma differentiation and differentiation therapy

“…This study found that miRNA-34a mimic treatment resulted in a significant decrease in tumor growth, an increase in tumor cell apoptosis and a significant reduction of angiogenesis, suggesting the therapeutic potential of miR-34a mimic in neuroblastoma [77] . A study on the tumor suppressive miR-497 showed that the overexpression of miR-497 reduces tumor growth and inhibits vascular permeabilization in neuroblastoma xenograft model, supporting a potential therapeutic strategy by overexpressing miR-497 [78] .…”

Neuroblastoma: Genetic, Epigenetic Mechanisms and Targeted Therapy Approaches: Review

“…34 miR-497, proliferasyon, metastaz ve direnç ile ilişkili genleri düzenleyen, hedefe yönelik nöroblastom tedavisi için yeni bir aday molekül-dür. 85 Epigenetik düzenleyici miR-506, TGF-β sinyal yolağında bulunan ROCK1' i inhibe ederek nöroblastom hücrelerinin metastazını baskılamak-tadır. 86 ncRNA 45A'nın upregülasyonu, FE65L1 ve GTSE1 genlerinin ekspresyonunu düzenleyerek tümör proliferasyonu ve metastazında kritik bir rol oynamaktadır.…”