The modulation of Dicer regulates tumor immunogenicity in melanoma

Abstract

MicroRNAs (miRs) are small non-coding RNAs that regulate most cellular protein networks by targeting mRNAs for translational inhibition or degradation. Dicer, a type III endoribonuclease, is a critical component in microRNA biogenesis and is required for mature microRNA production. Abnormal Dicer expression occurs in numerous cancer types and correlates with poor patient prognosis. For example, increased Dicer expression in melanoma is associated with more aggressive tumors (higher tumor mitotic index and depth of invasion) and poor patient prognosis. However, the role that Dicer plays in melanoma development and immune evasion remains unclear. Here, we report on a newly discovered relationship between Dicer expression and tumor immunogenicity. To investigate Dicer's role in regulating melanoma immunogenicity, Dicer knockdown studies were performed. We found that B16F0-Dicer deficient cells exhibited decreased tumor growth compared to control cells and were capable of inducing anti-tumor immunity. The decrease in tumor growth was abrogated in immunodeficient NSG mice and was shown to be dependent upon CD8+ T cells. Dicer knockdown also induced a more responsive immune gene profile in melanoma cells. Further studies demonstrated that CD8+ T cells preferentially killed Dicer knockdown tumor cells compared to control cells. Taken together, we present evidence which links Dicer expression to tumor immunogenicity in melanoma.

New susceptibility loci for cutaneous melanoma risk and progression revealed using a porcine model

“…Both genes could represent appealing candidates for melanoma and would deserve further description. For example, as detailed thereafter, DICER1 is currently considered as a pivotal actor in melanoma biology [ 73 ].…”

“…DICER1 (SSC7), associated with ulceration is a key player of miRNA synthesis and responsible for the DICER1 syndrome, a condition that increases the risk of developing various types of tumours in families of patients. In their article, Hoffend and colleagues [ 73 ] report an unexpected role for DICER in inducing anti-tumor immunity. Indeed, DICER knocked-down tumors had a slower growth than controls, due to a more immunogenic phenotype of cells.…”

Role of the Ribonuclease ONCONASE in miRNA Biogenesis and tRNA Processing: Focus on Cancer and Viral Infections

“…To reach the inhibitory effect on mRNA translation, mature miRNAs generally bind to their mRNA targets in the mRNA’s 3′untranslated region (UTR) site, although noncanonical binding sites also exist [ 12 ]. However, the cellular miRNA effects depend on the functions of the target genes they repress.…”