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Distinguishing the immunostimulatory properties of noncoding RNAs expressed in cancer cells

Significance Using an approach derived from statistical physics, we quantify transcriptome-wide motif usage in human and murine noncoding RNAs (ncRNAs), determining that most have motif usage consistent with the coding genome. However, an outlier subset of tumor-associated ncRNAs comprises repetitive elements whose motif usage patterns are more typically associated with the genomes of inflammatory pathogens. We demonstrate that a key subset of these elements directly activates the cellular innate immune response. We propose that the innate response in tumors partially originates from direct interaction of immunogenic ncRNAs preferentially expressed in cancer cells with innate pattern recognition receptors. Recent studies have demonstrated abundant transcription of a set of noncoding RNAs (ncRNAs) preferentially within tumors as opposed to normal tissue. Using an approach from statistical physics, we quantify global transcriptome-wide motif use for the first time, to our knowledge, in human and murine ncRNAs, determining that most have motif use consistent with the coding genome. However, an outlier subset of tumor-associated ncRNAs, typically of recent evolutionary origin, has motif use that is often indicative of pathogen-associated RNA. For instance, we show that the tumor-associated human repeat human satellite repeat II (HSATII) is enriched in motifs containing CpG dinucleotides in AU-rich contexts that most of the human genome and human adapted viruses have evolved to avoid. We demonstrate that a key subset of these ncRNAs functions as immunostimulatory “self-agonists” and directly activates cells of the mononuclear phagocytic system to produce proinflammatory cytokines. These ncRNAs arise from endogenous repetitive elements that are normally silenced, yet are often very highly expressed in cancers. We propose that the innate response in tumors may partially originate from direct interaction of immunogenic ncRNAs expressed in cancer cells with innate pattern recognition receptors, and thereby assign a previously unidentified danger-associated function to a set of dark matter repetitive elements. These findings potentially reconcile several observations concerning the role of ncRNA expression in cancers and their relationship to the tumor microenvironment.