RESUMEN
Background: Medullary thyroid carcinoma (MTC) presents a disproportionate number of thyroid cancer deaths due to limited treatment options beyond surgery. Gain-of-function mutations of the human REarranged during Transfection (RET) proto-oncogene have been well-established as the key driver of MTC tumorigenesis. RET has been targeted by tyrosine kinase inhibitors (TKIs), such as cabozantinib and vandetanib. However, clinical results have been disappointing, with regular dose reductions and inevitable progression. This study aimed to identify RET-regulated microRNAs (miRNAs) and explore their potential as novel therapeutic targets. Methods: Small RNA sequencing was performed in MTC TT cells before and after RET inhibition to identify RET-regulated miRNAs of significance. In vitro gain-of-function studies were performed to investigate cellular and molecular effects of potential miRNAs on cell phenotypes. Systemic delivery of miRNA in MTC xenografts using EDV™ nanocells, targeted to epidermal growth factor receptor on tumor cells, was employed to assess the therapeutic potential and possible modulation of TKI responses. Results: The study demonstrates the tumor suppressive role of a specific RET-regulated miRNA, microRNA-153-3p (miR-153-3p), in MTC. Targeted intravenous delivery of miR-153-3p impeded the tumor growth in MTC xenografts. Furthermore, combined treatment with miR-153-3p plus cabozantinib caused greater growth inhibition and appeared to reverse cabozantinib resistance. Mechanistically, miR-153-3p targets ribosomal protein S6 kinase B1 (RPS6KB1) of mTOR signaling and reduced downstream phosphorylation of Bcl-2 associated death promoter. Conclusion: This study provides evidence to establish systemic miRNA replacement plus TKIs as a novel therapeutic for patients with metastatic, progressive MTC.
Asunto(s)
Carcinoma Medular/metabolismo , MicroARNs/metabolismo , Proteínas Proto-Oncogénicas c-ret/metabolismo , Neoplasias de la Tiroides/metabolismo , Anilidas/farmacología , Animales , Apoptosis/efectos de los fármacos , Carcinoma Medular/genética , Carcinoma Medular/patología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular , Humanos , Ratones , MicroARNs/genética , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas c-ret/genética , Piridinas/farmacología , Proteínas Tirosina Quinasas Receptoras/farmacología , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patologíaRESUMEN
Medullary thyroid carcinoma (MTC) is an aggressive and rare cancer with limited treatment options for metastatic disease. Due to this, there is a need for a better understanding of MTC biology in the hope of improved treatments. One area of improved understanding of cancer biology is epigenetics. Epigenetics is defined as cellular processes which alter gene expression independent of changes in the primary DNA sequence. These processes include modifications such as DNA methylation, microRNA deregulation and post-translational histone modifications, all of which have been implicated in tumorigenesis of MTC. Transcription of the main driver of MTC - the REarranged during Transfection (RET) proto-oncogene can also be modulated by epigenetic alterations. This review will present a review of MTC and its epigenetic links with a particular focus on targeting epigenetic mechanisms as novel therapeutic strategies.