RESUMO
Ovarian cancer (OC) causes more deaths than any other gynecological cancer. Many cellular pathways have been elucidated to be associated with OC development and progression. Specifically, the insulin-like growth factor 1 receptor/insulin receptor substrate 1 (IGF1R/IRS1) pathway participates in OC development. Moreover, accumulating evidence has shown that microRNA deregulation contributes to tumor initiation and progression. Here, our study aimed to investigate the molecular functions and regulatory mechanisms of miR-150, specifically, in OC. We found that the expression of miR-150-5p/3p and their precursor, mir-150, was downregulated in OC tissues; lower mir-150 levels were associated with poor OC patient outcomes. Ectopic mir-150 expression inhibited OC cell growth and metastasis in vitro and in vivo. Furthermore, both IRS1 and IGF1R were confirmed as direct targets of miR-150-5p/3p, and the miR-150-IGF1R/IRS1 axis exerted antitumor effects via the PI3K/AKT/mTOR pathway. Forkhead box protein 3 (FoxP3) positively regulated the expression of miR-150-5p/3p by binding to the mir-150 promoter. In turn, the PI3K/AKT/mTOR pathway downregulated FoxP3 and miR-150-5p/3p. Taken together, these findings indicate that a complex FoxP3-miR-150-IGF1R/IRS1-PI3K/AKT/mTOR feedback loop regulates OC pathogenesis, providing a novel mechanism for miR-150 as a tumor suppressor miRNA in OC.
Assuntos
Movimento Celular , Proliferação de Células , Fatores de Transcrição Forkhead/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , MicroRNAs/metabolismo , Neoplasias Ovarianas/metabolismo , Receptor IGF Tipo 1/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Retroalimentação Fisiológica , Feminino , Fatores de Transcrição Forkhead/genética , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Invasividade Neoplásica , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor IGF Tipo 1/genética , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Carga TumoralRESUMO
MicroRNAs (miRNAs) are a class of short non-coding RNAs of approximately 22 nucleotides in length, which function by binding to the 3' UTR sequences of their target mRNAs. It has been reported that dysregulated miRNAs play pivotal roles in numerous diseases, including cancers, such as gastric, breast, colorectal, ovarian, and other cancers. Recent research efforts have been devoted to translating these basic discoveries into clinical applications that could improve the therapeutic outcome in patients with cancer. Early studies have shown that miR-340 may act either as an oncogene or a tumor suppressor by targeting genes related to proliferation, apoptosis, and metastasis, as well as those associated with diagnosis, treatment, chemoresistance, and prognosis. miR-340 has been shown to have a role in other diseases, such as autoimmune diseases, acute stroke, and alcoholic steatohepatitis. Nevertheless, the roles of miR-340 in human malignancies are still unclear, and the associated mechanisms are complex, involving a variety of signaling pathways, such as Wnt/ß-catenin and the JAK-STAT pathways. Herein, we review the crucial roles of miR-340 in human cancers through the analysis of the latest research studies, with the aim of clarifying miR-340 function in malignant disease diagnosis, treatment, and prognosis, and to propose further investigations.
