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Adenosine modification may be preferred for reducing siRNA immune stimulation.

ABSTRACT: The immune stimulation induced by short interfering RNAs (siRNAs) has been reported to be quieted or abrogated by methoxy or fluoro modifications of the 2' position of the ribose sugar. However, variables such as the type of modification, nucleotide preference, and strand bias have not been systematically evaluated. Here, we report the results of a screen of several modified siRNAs via a human peripheral blood monocyte cytokine induction assay. Unlike corresponding modifications of guanosine, cytidine, or uridine, 2'-fluoro modification of adenosine significantly reduced cytokine induction while retaining siRNA knockdown activity. The results of this study suggest adenosine as an optimal target for modification.

SUBMITTER: Fucini RV

PROVIDER: S-EPMC4047996 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Adenosine modification may be preferred for reducing siRNA immune stimulation.

Fucini Raymond V RV Haringsma Henry J HJ Deng Patricia P Flanagan W Michael WM Willingham Aarron T AT

Nucleic acid therapeutics 20120420 3

The immune stimulation induced by short interfering RNAs (siRNAs) has been reported to be quieted or abrogated by methoxy or fluoro modifications of the 2' position of the ribose sugar. However, variables such as the type of modification, nucleotide preference, and strand bias have not been systematically evaluated. Here, we report the results of a screen of several modified siRNAs via a human peripheral blood monocyte cytokine induction assay. Unlike corresponding modifications of guanosine, cy ...[more]

PMID: 22519815

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Project description:BackgroundFour RNA adenosine modifications, including m6A, m1A, alternative polyadenylation, and adenosine-to-inosine RNA editing, have been identified as potentially valuable in influencing colorectal carcinogenesis, immune infiltration, and response to drug therapy. However, the regulatory mechanisms and clinical significance of these four RNA modifications in ovarian cancer (OC) remain unknown.MethodsWe comprehensively described the transcriptional and genetic modifications of 26 RNA modification "writers" in OC and assessed the expression patterns. We identified two RNA modification subtypes using an unsupervised clustering approach. Subsequently, using differentially expressed genes (DEGs) in both subtypes, we calculated RNA modification "writer" scores (RMW scores) to characterize the RNA modifications of single OC patients. RMW score-related gene expression was investigated by qRT-PCR. We explored the correlation between RMW score and clinical features, immune infiltration, and drug sensitivity. We drew a nomogram to more intuitively and accurately describe the application value of the RMW score.ResultsWe found that molecular alterations in "writers" are strongly related to prognostic and immune-infiltrating features in OC patients. We identified two different clusters of RNA modifications. According to the immune infiltration characteristics in the two RNA modification isoforms, cluster A and cluster B can correspond to "hot" and "cold" tumors, respectively. With the median RMW score, we classified the patients into high- and low-score subgroups. A low RMW score was associated with good patient prognosis and lower immune infiltration. In addition, a low RMW score equated with a higher cancer stem cell index and a lower tumor mutation burden, which to some extent affected the sensitivity of patients to therapeutic drugs. Seven RMW score-related gene expressions were investigated by qRT-PCR in three OC cell lines. Compared to previously known models, our established RMW score has higher accuracy in predicting patient survival.ConclusionA comprehensive analysis of four RNA modification patterns in OC reveals their potential value in OC prognosis, immune microenvironment, and drug sensitivity. These results could deepen our knowledge of RNA modification and yield fresh insights for new personalized therapeutic strategies.

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Adenosine modification may be preferred for reducing siRNA immune stimulation.

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Adenosine modification may be preferred for reducing siRNA immune stimulation.

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