Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Department of Oncology and Hemato-oncology, University of Milan, 20133 Milan, Italy.
Cells. 2020 Feb 13;9(2):435. doi: 10.3390/cells9020435.
The development of novel therapies or the improvement of currently used approaches to treat prostate cancer (PCa), the most frequently diagnosed male tumor in developed countries, is an urgent need. In this regard, the functional characterization of microRNAs, molecules shown to regulate a number of cancer-related pathways, is instrumental to their possible clinical exploitation. Here, we demonstrate the tumor-suppressive role of the so far uncharacterized , which we found to be significantly down-modulated in PCa clinical specimens compared to normal tissues. Through a gain-of-function approach using miRNA mimics, we showed that supplementation in two PCa cell models (DU145 and 22Rv1) reverted the mesenchymal phenotype by affecting migratory and invasive properties, and reduced cell growth in vitro and in vivo in SCID mice. Additionally, by targeting encoding the endocytic protein HIP1, balanced EGFR membrane turnover, thus affecting the downstream AKT/ERK pathways, and, ultimately, increasing PCa cell response to ionizing radiation. Overall, our results show that reconstitution can affect several tumor traits, thus suggesting this approach as a potential novel therapeutic strategy to be pursued for PCa, with the multiple aim of reducing tumor growth, enhancing response to radiotherapy and limiting metastatic dissemination.
开发新的治疗方法或改进目前用于治疗前列腺癌 (PCa) 的方法是当务之急,PCa 是发达国家男性最常见的肿瘤。在这方面,对 microRNAs 的功能特征进行鉴定对于其可能的临床应用至关重要,这些分子被证明可以调节许多与癌症相关的途径。在这里,我们证明了 的肿瘤抑制作用,我们发现与正常组织相比,该分子在 PCa 临床标本中显著下调。通过使用 miRNA 模拟物的功能获得方法,我们表明在两种 PCa 细胞模型 (DU145 和 22Rv1) 中补充 可以通过影响迁移和侵袭特性来逆转间充质表型,并减少体外和体内 SCID 小鼠中的细胞生长。此外,通过靶向编码内吞蛋白 HIP1 的 , 平衡了 EGFR 膜周转,从而影响下游 AKT/ERK 途径,最终增加了 PCa 细胞对电离辐射的反应。总的来说,我们的结果表明, 重建可以影响几种肿瘤特征,因此表明这种方法是一种有前途的新型治疗策略,可以用于治疗 PCa,其多个目标是减少肿瘤生长、增强对放疗的反应和限制转移扩散。