microRNA-378a-5p iS a novel positive regulator of melanoma progression.,Oncogenesis

当前位置： X-MOL 学术 › Oncogenesis › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

microRNA-378a-5p iS a novel positive regulator of melanoma progression.
Oncogenesis ( IF 5.9 ) Pub Date : 2020-02-14 , DOI: 10.1038/s41389-020-0203-6
Maria Grazia Tupone _{1,

2} , Simona D'Aguanno ₁ , Marta Di Martile ₁ , Elisabetta Valentini ₁ , Marianna Desideri ₁ , Daniela Trisciuoglio _{1,

3} , Sara Donzelli ₄ , Andrea Sacconi ₅ , Simonetta Buglioni ₆ , Cristiana Ercolani ₆ , Alessio Biagioni ₇ , Gabriella Fibbi ₇ , Luigi Fattore ₈ , Rita Mancini ₉ , Gennaro Ciliberto ₁₀ , Giovanni Blandino ₄ , Donatella Del Bufalo ₁

Affiliation

Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.
Institute of Molecular Biology and Pathology, National Research Council, Rome, Italy.
Oncogenomics and Epigenetics Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
Clinical Trial Center, Biostatistics and Bioinformatics Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
Pathology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
Department of Melanoma, Oncologic Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori IRCCS, "Fondazione G. Pascale", Naples, Italy.
Department of Molecular and Clinical Medicine, Risk Management Q&A, Sant'Andrea Hospital, "Sapienza" University, Rome, Italy.
Scientific Direction, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Evaluating the expression levels of miR-378a-5p both in a large melanoma patient cohort from The Cancer Genome Atlas database and in melanoma patients from our Institute, we found that miR-378a-5p is upregulated in metastatic melanoma specimens. miR-378a-5p expression was also increased in melanoma cells resistant to target therapy, and decreased in response to drug treatment. We also demonstrated that overexpression of miR-378a-5p enhances in vitro cell invasion and migration, and facilitates the ability of melanoma cells to form de novo vasculogenic structures. While performing downstream targeting studies, we confirmed the ability of miR-378a-5p to modulate the expression of known target genes, such as SUFU, FUS-1, and KLF9. Luciferase-3'UTR experiments also identified STAMBP and HOXD10 as new miR-378a-5p target genes. MMP2 and uPAR, two HOXD10 target genes, were positively regulated by miR-378a-5p. Genetic and pharmacologic approaches inhibiting uPAR expression and activity evidenced that the in vitro tumor-promoting functions of miR-378a-5p, were in part mediated by uPAR. Of note miR-378a-5p was also able to increase VEGF, as well as in vitro and in vivo angiogenesis. Finally, genetic and pharmacologic modulation of Bcl-2 evidenced Bcl-2 ability to regulate miR-378a-5p expression. In conclusion, to the best of our knowledge, this is the first study demonstrating that miR-378a-5p acts as an oncogenic microRNA in melanoma.

中文翻译：

microRNA-378a-5p是黑色素瘤进展的新型阳性调节剂。

从癌症基因组图谱数据库中的大型黑色素瘤患者队列和我们研究所的黑色素瘤患者中评估miR-378a-5p的表达水平，我们发现miR-378a-5p在转移性黑色素瘤标本中上调。在对靶标治疗有抗性的黑素瘤细胞中，miR-378a-5p表达也有所增加，而对药物治疗的反应则有所降低。我们还证明了miR-378a-5p的过表达增强了体外细胞的侵袭和迁移，并促进了黑色素瘤细胞形成新生血管生成结构的能力。在进行下游靶向研究时，我们证实了miR-378a-5p能够调节已知目标基因（例如SUFU，FUS-1和KLF9）的表达。荧光素酶3'UTR实验还确定了STAMBP和HOXD10是新的miR-378a-5p靶基因。MMP2和uPAR，两个HOXD10靶基因受到miR-378a-5p的正调控。抑制uPAR表达和活性的遗传和药理学方法证明，miR-378a-5p的体外肿瘤促进功能部分由uPAR介导。值得注意的是，miR-378a-5p还能够增加VEGF，以及体外和体内血管生成。最后，Bcl-2的遗传和药理学调节证明了Bcl-2调节miR-378a-5p表达的能力。总而言之，就我们所知，这是第一项证明miR-378a-5p在黑色素瘤中起致癌作用的微小RNA的研究。值得注意的是，miR-378a-5p还能够增加VEGF，以及体外和体内血管生成。最后，Bcl-2的遗传和药理学调节证明了Bcl-2调节miR-378a-5p表达的能力。总而言之，就我们所知，这是第一项证明miR-378a-5p在黑色素瘤中起致癌作用的微小RNA的研究。值得注意的是，miR-378a-5p还能够增加VEGF，以及体外和体内血管生成。最后，Bcl-2的遗传和药理学调节证明了Bcl-2调节miR-378a-5p表达的能力。总而言之，就我们所知，这是第一项证明miR-378a-5p在黑色素瘤中起致癌作用的微小RNA的研究。

更新日期：2020-02-14

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11