Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
Laboratório de Vetores Virais, Centro de Investigação Translacional em Oncologia/LIM24, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina, Universidade de São Paulo, SP, Brazil; Current address: Cristalia, Biotecnologia Unidade 1, Rodoviária SP 147, Itapira, SP, Brasil.
Neoplasia. 2021 Aug;23(8):823-834. doi: 10.1016/j.neo.2021.05.015. Epub 2021 Jul 8.
Deregulation of miRNAs contributes to the development of distinct cancer types, including melanoma, an aggressive form of skin cancer characterized by high metastatic potential and poor prognosis. The expression of a set of 580 miRNAs was investigated in a model of murine melanoma progression, comprising non-metastatic (4C11-) and metastatic melanoma (4C11+) cells. A significant increase in miR-138-5p expression was found in the metastatic 4C11+ melanoma cells compared to 4C11-, which prompted us to investigate its role in melanoma aggressiveness. Functional assays, including anoikis resistance, colony formation, collective migration, serum-deprived growth capacity, as well as in vivo tumor growth and experimental metastasis were performed in 4C11- cells stably overexpressing miR-138-5p. miR-138-5p induced an aggressive phenotype in mouse melanoma cell lines leading to increased proliferation, migration and cell viability under stress conditions. Moreover, by overexpressing miR-138-5p, low-growing and non-metastatic 4C11- cells became highly proliferative and metastatic in vivo, similar to the metastatic 4C11+ cells. Luciferase reporter analysis identified the tumor suppressor Trp53 as a direct target of miR-138-5p. Using data sets from independent melanoma cohorts, miR-138-5p and P53 expression were also found deregulated in human melanoma samples, with their levels negatively and positively correlated with prognosis, respectively. Our data shows that the overexpression of miR-138-5p contributes to melanoma metastasis through the direct suppression of Trp53.
miRNA 的失调导致了不同癌症类型的发生，包括黑色素瘤，这是一种侵袭性皮肤癌，具有高转移潜能和不良预后。在一个包含非转移性（4C11-）和转移性黑色素瘤（4C11+）细胞的小鼠黑色素瘤进展模型中，研究了一组 580 种 miRNA 的表达情况。在转移性 4C11+黑色素瘤细胞中发现 miR-138-5p 的表达显著增加，与 4C11-相比，这促使我们研究其在黑色素瘤侵袭性中的作用。在稳定过表达 miR-138-5p 的 4C11-细胞中进行了包括凋亡抵抗、集落形成、集体迁移、血清剥夺生长能力以及体内肿瘤生长和实验性转移在内的功能测定。miR-138-5p 在小鼠黑色素瘤细胞系中诱导侵袭表型，导致在应激条件下增殖、迁移和细胞活力增加。此外，通过过表达 miR-138-5p，低生长和非转移性 4C11-细胞在体内变得高度增殖和转移性，类似于转移性 4C11+细胞。荧光素酶报告分析鉴定出肿瘤抑制因子 Trp53 是 miR-138-5p 的直接靶标。使用来自独立黑色素瘤队列的数据集，还发现 miR-138-5p 和 P53 的表达在人类黑色素瘤样本中失调，其水平分别与预后呈负相关和正相关。我们的数据表明，miR-138-5p 的过表达通过直接抑制 Trp53 促进黑色素瘤转移。
