Abstract
Simple SummaryOncolytic adenoviruses are replication-competent viruses engineered for use in cancer treatment. However, the transformation of cancer cells defines a scenario in which the viruses are not adapted to replicate. During tumorigenesis, a large number of miRNAs are deregulated, modulating the expression of genes with essential roles in carcinogenesis and with potential effects on adenoviral propagation. Here we show how OncomiRs can impact adenoviral activity, identifying miR-222 as a limiting factor. Of notice, by genetically engineering a therapeutic adenovirus with miR-222 sponges (AdNuPAR-E-miR222-S), we reduced the latter miRNA content, while enhancing adenoviral fitness, increasing cytotoxicity, and sustaining tumor growth control in xenografts.Oncolytic adenoviruses (OA) are envisioned as a therapeutic option for patients with cancer, designed to preferentially replicate in cancer cells. However, the high number of genetic alterations in tumors can generate a context in which adenoviruses have difficulties replicating. Abnormal miRNAs expression is a trademark of pancreatic cancer, with several oncogenic miRNAs playing essential roles in cancer-associated pathways. The perturbed miRNome induces reprogramming of gene expression in host cells that can impact the complex interplay between cellular processes and viral replication. We have studied the effects of overexpressed miRNAs on oncolytic adenoviral activity and identified miRNAs modulators of adenoviral oncolysis in pancreatic cancer cells. Inhibition of the highly upregulated miR-222 sensitized cancer cells to oncolysis. To provide a therapeutic application to this insight, we engineered the oncolytic adenovirus AdNuPARmE1A with miR-222 binding sites, working as sponges to withdraw the miRNA from the cellular environment. AdNuPAR-E-miR222-S mediated-decrease of miR-222 expression in pancreatic cancer cells strongly improved the viral yield and enhanced the adenoviral cytotoxic effects. Antitumoral studies confirmed a high activity for AdNuPARmE1A-miR222-S in vivo, controlling tumor progression more effectively than the scrambled control virus in xenografts. We demonstrated that the increased antitumor potency of the novel oncolytic virus resulted from the combinatory effects of miR-222 oncomiR inhibition and the restoration of miR-222 target genes activity enhancing viral fitness.
Highlights
Licensee MDPI, Basel, Switzerland.Oncolytic adenoviruses are a promising class of anticancer agents, designed to selectively target and replicate within malignant cells, inducing their lysis and evoking a consistent antitumor immune response [1]
We studied the role of pancreatic ductal adenocarcinoma (PDAC) OncomiRs on the oncolytic adenoviral activity, identifying miR-222 as a limiting factor for viral propagation
The absence of interferon signaling permits the activation of the E1A adenoviral gene transcription, which in turn triggers the expression of the remaining viral genes, promoting the adenoviral replication cycle [35]. c-GAS is a cytosolic protein acting as a first-line sensor for viral and microbial infections, which upon detection of exogenous dsDNA activates a signaling cascade that leads to the activation of interferon-stimulated genes (ISGs), to restrain host invasion. miR-93 negatively regulates c-GAS, repressing the production of interferon and creating the conditions to facilitate viral propagation [36]
Summary
Oncolytic adenoviruses are a promising class of anticancer agents, designed to selectively target and replicate within malignant cells, inducing their lysis and evoking a consistent antitumor immune response [1]. Some attention has been placed on microRNAs (miRNAs) These molecules are small single-stranded (20–25 nt), non-coding RNA sequences, that regulate gene expression at the post-transcriptional level, either by triggering the degradation of target mRNAs, or inhibiting their translation. They participate in a plethora of processes balancing the correct cellular homeostasis and having a key role in carcinogenesis. Deregulation of miRNAs expression is a constant characteristic in cancers, which generally show an upregulation of the oncogenic miRNAs (OncomiRs), and a downregulation of the tumor-suppressive ones, favoring the acquisition of cancer hallmarks [3,4]
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