Oncogenic Role of Fusion-circRNAs Derived from Cancer-Associated Chromosomal Translocations

Abstract

Chromosomal translocations encode oncogenic fusion proteins that have been proven to be causally involved in tumorigenesis. Our understanding of whether such genomic alterations also affect non-coding RNAs is limited, and their impact on circular RNAs (circRNAs) has not been explored. Here, we show that well-established cancer-associated chromosomal translocations give rise to fusion circRNAs (f-circRNA) that are produced from transcribed exons of distinct genes affected by the translocations. F-circRNAs contribute to cellular transformation, promote cell viability and resistance upon therapy, and have tumor-promoting properties in in vivo models. Our work expands the current knowledge regarding molecular mechanisms involved in cancer onset and progression, with potential diagnostic and therapeutic implications.

The emerging role and clinical implication of human exonic circular RNA

“…16,29,30 Moreover, some potentially unique circRNAs (such as f-circRNAs) were found to be expressed only in pathological conditions. 27 For example, a circRNA named circ_101222 was found to be more significantly enriched in the blood corpuscles of patients with pre-eclampsia than in those of corresponding healthy controls. 54 Using the plasma protein factor endoglin (ENG) in combination with circ_101222 resulted in a sensitivity of 0.7073, a specificity of 0.8049, and overall area under the curve of 0.876 (95% confidence interval 0.816-0.922) for the prediction of pre-eclampsia.…”

“…Because the expression of f-circRNAs in cancer cells is essential for their maintenance and confers resistance to chemotherapy, it has been suggested that pharmaceutical interventions that are aimed at blocking f-circRNAs or their down-stream effectors could prove to be beneficial as therapeutic targets to eradicate diseases. 27 Another study that employed in vivo delivery of siRNA-targeting endogenous circ-Foxo3 showed that it abrogated the effect of doxorubicin-induced cardiomyopathy, suggesting a potential therapeutic approach for myocardial protection. 25 …”

“…Although they are generally expressed at low levels, increasing evidence has shown that circRNAs are linked to physiological development 15 and different diseases, such as neurological dystrophy, 21 cardiovascular diseases, [22][23][24][25] and cancer. [26][27][28] Recently, circRNAs have also been shown to be enriched and stable in plasma, 29 saliva, 30 and even in serum exosomes, 31 indicating the potential of circRNAs as readable biomarkers.…”

Circular RNAs: Unexpected outputs of many protein-coding genes

“…Recent work by Guarnerio and colleagues revealed that the PML/RARa translocation in acute promyelocytic leukemia (APL), MLL/ AF9 translocation in acute myeloid leukemia (AML), EWSR1/ FL1 translocation in Ewing sarcoma, and EML4/ALK1 translocation in lung cancer all generate aberrant circular RNAs via this mechanism. 78 These fusion circular RNAs, which are not expressed in normal cells, promote cancer development in part by contributing to cellular transformation and protecting cancer cells from drug-induced apoptosis. Circular RNAs may thus represent promising new therapeutic targets.…”

A circular twist on microRNA regulation

“…Second, many circRNAs have been linked to cancer development and progression. Notably, aberrant circRNAs have been also identified in cancer as proto-tumorigenic products of chromosomal translocations [11]. Thus, the opposite outcome, in terms of gene expression, that is observed in acute vs chronic targeting of Cdr1as could have tremendous therapeutic implications, and it will be critical to test multiple treatment strategies in pre-clinical settings (e.g., metronomic vs continuous administration of the RNA medicine of interest) (Figure 1).…”