Piras Sabrina, Furfaro Anna L, Caggiano Rocco, Brondolo Lorenzo, Garibaldi Silvano, Ivaldo Caterina, Marinari Umberto M, Pronzato Maria A, Faraonio Raffaella, Nitti Mariapaola
Department of Experimental Medicine, University of Genoa, Genoa, Italy.
Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", Naples, Italy.
Front Oncol. 2018 Jun 13;8:199. doi: 10.3389/fonc.2018.00199. eCollection 2018.
Heme oxygenase 1 (HO-1) is crucially involved in cell adaptation to oxidative stress and has been demonstrated to play an important role in cancer progression and resistance to therapies. We recently highlighted that undifferentiated neuroblastoma (NB) cells are prone to counteract oxidative stress through the induction of HO-1. Conversely, differentiated NB cells were more sensitive to oxidative stress since HO-1 was scarcely upregulated. In this work, we investigated the role played by miR-494, which has been proved to be involved in cancer biology and in the modulation of oxidative stress, in the upregulation of HO-1. We showed that NB differentiation downregulates miR-494 level. In addition, endogenous miR-494 inhibition in undifferentiated cells impairs HO-1 induction in response to exposure to 500 µM HO, reducing the number of viable cells. The analysis of Bach1 expression did not reveal any significant modifications in any experimental conditions tested, proving that the impairment of HO-1 induction observed in cells treated with miR-494 inhibitor and exposed to HO is independent from Bach1. Our results underline the role played by miR-494 in favoring HO-1 induction and cell adaptation to oxidative stress and contribute to the discovery of new potential pharmacological targets to improve anticancer therapies.
血红素加氧酶1（HO-1）在细胞适应氧化应激过程中起关键作用，并且已被证明在癌症进展和对治疗的抗性中发挥重要作用。我们最近强调，未分化的神经母细胞瘤（NB）细胞易于通过诱导HO-1来对抗氧化应激。相反，分化的NB细胞对氧化应激更敏感，因为HO-1几乎不被上调。在这项工作中，我们研究了已被证明参与癌症生物学和氧化应激调节的miR-494在HO-1上调中所起的作用。我们表明NB分化会下调miR-494水平。此外，未分化细胞中内源性miR-494的抑制会损害其在暴露于500μM血红素（HO）时对HO-1的诱导，减少活细胞数量。对Bach1表达的分析未发现在任何测试实验条件下有任何显著变化，证明在用miR-494抑制剂处理并暴露于HO的细胞中观察到的HO-1诱导受损与Bach1无关。我们的结果强调了miR-494在促进HO-1诱导和细胞适应氧化应激中所起的作用，并有助于发现新的潜在药理学靶点以改善抗癌治疗。
