Giovannini Catia, Fornari Francesca, Dallo Rossella, Gagliardi Martina, Nipoti Elisa, Vasuri Francesco, Coadă Camelia Alexandra, Ravaioli Matteo, Bolondi Luigi, Gramantieri Laura
Center for Applied Biomedical Research (CRBa), St. Orsola-Malpighi University Hospital, 40138, Bologna, Italy; Department of Medical and Surgical Sciences (DIMEC), Bologna University, 40138, Bologna, Italy.
Center for Applied Biomedical Research (CRBa), St. Orsola-Malpighi University Hospital, 40138, Bologna, Italy; Department of Biological, Geological and Environmental Sciences (BiGea), University of Bologna, 40126, Bologna, Italy.
Acta Histochem. 2018 Feb;120(2):95-102. doi: 10.1016/j.acthis.2017.12.004. Epub 2017 Dec 15.
Hepatocellular carcinoma (HCC) represents the second cause of cancer-related mortality worldwide and is associated with poor prognosis, due to a high recurrence rate after curative treatments and a drug resistance phenotype. In this scenario, the identification of innovative and effective therapeutic strategies is an unmet clinical need. The safety and efficacy of microRNA (miRNA) mediated approaches in preclinical models and clinical trials have been widely described in cancer. MicroRNA-199a downregulation is a common feature of HCC where its reduced expression contributes to mTOR and c-Met pathways activation. Notch1 activation is also a common event in HCC, influencing epithelial-to-mesenchymal transition, tumor invasion and recurrence at least in part through E-cadherin regulation. Here we identified a negative correlation between miR-199a-3p and Notch1 or E-cadherin protein levels in HCC patients and demonstrated that miR-199a-3p regulates E-cadherin expression through Notch1 direct targeting in in vitro models. Moreover, we showed that a strong correlation exists between miR-199a-5p and miR-199a-3p in HCC specimens and that miR-199a-5p contributes to E-cadherin regulation as well, underlying the complex network of interaction carried out by miR-199a and its influence on tumor aggressiveness. In conclusion, our findings suggest the restoration of miR-199a-3p physiologic levels as a possible therapeutic strategy for the treatment of HCC.
肝细胞癌（HCC）是全球癌症相关死亡的第二大原因，且预后较差，这是由于根治性治疗后复发率高以及存在耐药表型。在这种情况下，识别创新且有效的治疗策略是一项尚未满足的临床需求。微小RNA（miRNA）介导的方法在临床前模型和临床试验中的安全性和有效性在癌症领域已被广泛描述。MicroRNA-199a下调是HCC的一个常见特征，其表达降低会导致mTOR和c-Met通路激活。Notch1激活在HCC中也是一个常见事件，至少部分通过E-钙黏蛋白调节影响上皮-间质转化、肿瘤侵袭和复发。在这里，我们在HCC患者中发现miR-199a-3p与Notch1或E-钙黏蛋白蛋白水平呈负相关，并在体外模型中证明miR-199a-3p通过直接靶向Notch1来调节E-钙黏蛋白的表达。此外，我们表明在HCC标本中miR-199a-5p与miR-199a-3p之间存在强相关性，并且miR-199a-5p也有助于E-钙黏蛋白的调节，这揭示了miR-199a所构建的复杂相互作用网络及其对肿瘤侵袭性的影响。总之，我们的研究结果表明恢复miR-199a-3p的生理水平可能是治疗HCC的一种治疗策略。
