Department of Genetics, Federal University of Paraná, Curitiba 80060-000, Brazil.
Laboratory of Applied Science and Technology in Health, Carlos Chagas Institute, Oswaldo Cruz Foundation (Fiocruz), Curitiba 81350-010, Brazil.
Genes (Basel). 2022 Dec 16;13(12):2375. doi: 10.3390/genes13122375.
Over the last decades, accumulating evidence has shown tumor-dependent profiles of miR-708, being either up- or downregulated, and thus, acting as a "Janus" regulator of oncogenic pathways. Herein, its functional duality was assessed through a thorough review of the literature and further validation in silico using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. In the literature, miR-708 was found with an oncogenic role in eight tumor types, while a suppressor tumor role was described in seven cancers. This double profile was also found in TCGA and GEO databases, with some tumor types having a high expression of miR-708 and others with low expression compared with non-tumor counterparts. The investigation of validated targets using miRBase, miRTarBase, and miRecords platforms, identified a total of 572 genes that appeared enriched for PI3K-Akt signaling, followed by cell cycle control, p53, Apellin and Hippo signaling, endocrine resistance, focal adhesion, and cell senescence regulations, which are all recognized contributors of tumoral phenotypes. Among these targets, a set of 15 genes shared by at least two platforms was identified, most of which have important roles in cancer cells that influence either tumor suppression or progression. In a clinical scenario, miR-708 has shown to be a good diagnostic and prognosis marker. However, its multitarget nature and opposing roles in diverse human tumors, aligned with insufficient experimental data and the lack of proper delivery strategies, hamper its potential as a sequence-directed therapeutic.
在过去的几十年中，越来越多的证据表明 miR-708 与肿瘤相关，其表达水平要么上调，要么下调，因此作为致癌途径的“两面神”调节剂发挥作用。本文通过对文献的全面回顾，并进一步在 TCGA 和 GEO 数据库中进行计算机模拟验证，评估了其功能的双重性。在文献中，miR-708 在八种肿瘤类型中被发现具有致癌作用，而在七种癌症中被描述为抑制肿瘤作用。这种双重作用模式也在 TCGA 和 GEO 数据库中得到了验证，一些肿瘤类型的 miR-708 表达较高，而另一些肿瘤类型的 miR-708 表达较低，与非肿瘤对照相比。使用 miRBase、miRTarBase 和 miRecords 平台对验证靶点进行研究，共鉴定出 572 个基因，这些基因与 PI3K-Akt 信号通路、细胞周期调控、p53、Apellin 和 Hippo 信号通路、内分泌抵抗、焦点黏附和细胞衰老调节等有关，这些都是公认的肿瘤表型贡献者。在这些靶点中，至少有两个平台共享的一组 15 个基因被鉴定出来，其中大多数在癌细胞中具有重要作用，影响肿瘤的抑制或进展。在临床情况下，miR-708 已被证明是一种良好的诊断和预后标志物。然而，其多靶点性质及其在多种人类肿瘤中的相反作用，加上实验数据不足和缺乏适当的递送策略，阻碍了其作为序列导向治疗的潜力。
