CDR1as' role in tumorigenesis and metastasis of melanoma by miR-7 regulation

Abstract

Circular RNAs (circRNAs) are a large class of particularly stable RNAs which are conserved in animals and have complex stage and tissue-specific expression patterns. CircRNAs are generated by a back-splicing reaction, in which a 5' splice site covalently ligates to an upstream 3' splice site. Recent studies have demonstrated novel capabilities of circRNAs as gene regulators in mammals mainly by microRNAs (miRNA) regulation, working as miRNAs sponges. Alterations in the expression levels of miRNAs are strongly associated with the development of cancer, modulating tumorigenic processes through the regulation of tumor-suppressors or oncogenes. The Cerebellar Degeneration Related 1 Antisense (CDR1as) has over 70 binding sites for a single miRNA, miR-7. Consequently, CDR1as works as a sponge for miR-7 stabilizing miR-7 molecules but also preventing its interaction with cognate messenger RNA (mRNA) targets. CDR1as can also bind to miR-671, which results in CDR1as cleavage. Several studies have documented important roles for miR-7 in melanoma through the targeting of IRS-2, EGFR, IGF-1R, and indirect regulation of PI3K/AKT and MAPK pathways; however the impact of CDR1as expression and its effects on miR-7 function in melanoma have not been reported. The present study will explore the role of CDR1as as miR-7 sponge in melanoma. Cutaneous melanomas are malignant neoplasms found predominantly in sun-exposed skin. Melanoma is a particularly aggressive tumor type, as melanoma cells frequently disseminate or metastasize from the site of primary tumor to other tissues. In general, metastases appear first in the lymph nodes near the primary tumor area, before spreading distally to visceral organs. Activating BRAF mutations, which drive aberrant MAPK signaling, are the most-common oncogenic event in melanomas, comprising approximately 50% of Cutaneous melanoma. Recent therapeutic advances, including MAPK pathway inhibitors (BRAF and MEK inhibitors) and immunotherapy (checkpoint inhibitors), have dramatically altered the treatment landscape for many metastatic melanoma patients. Both approaches have improved the overall survival of patients with advanced-stage melanoma, however some patients' tumors are treatment refractory and many others develop therapeutic resistance. In this context, the investigation of the molecular mechanisms underlying melanoma development and progression, and the identification of novel therapeutic targets are still necessary. Since CDR1as was characterized as a miR-7 sponge and the involvement of this miRNA in melanoma has already been demonstrated, the aim of this study is to evaluate the role of CDR1as by miR-7 regulation in melanoma in vitro and in vivo models.