Fig. 5: Concordant or discordant impact of the coding and non-coding products derived from the same bifunctional gene in cancer.

Graphical representation of the possible combinations of cancer-related functions of coding (orange) and non-coding (blue) partners. Upper left panel: both the coding and the non-coding products have tumor-suppressive properties. PTEN mRNA encodes the tumor suppressor PTEN protein and, due to its 3′UTR, it can sponge oncogenic miRNAs. Upper right panel: the coding product is a tumor suppressor, while the non-coding product is an oncogene. Zbtb7a pre-mRNA undergoes canonical splicing and generates a mature mRNA that encodes the Pokémon protein with tumor suppressor properties; the same pre-mRNA also undergoes back-splicing of exon 2, leading to the formation of oncogenic circPOK. Bottom left panel: the coding product is an oncogene, while the non-coding product is a tumor suppressor. AKT3 pre-mRNA is translated into AKT3 oncogenic protein, but exons 3–7 undergo back-splicing, leading to the production of a circRNA (hsa_circ_0017250) that exerts tumor-suppressive effects through its translation into the AKT3-174aa ncPEP. Bottom right panel: both the coding and the non-coding products have oncogenic properties. MCM7 pre-mRNA is spliced to produce a mature mRNA that is translated into the oncogenic MCM7 protein; in addition, intron 13 hosts oncogenic miR-106b~25 cluster. From a therapeutic point of view, the optimal approach is to enhance/restore tumor-suppressive activities (green “plus” symbol) and/or, on the other hand, abolish/inhibit oncogenic activities (red “minus” symbol). This is easier in the case of bifunctional genes whose products have concordant outputs, while it can be ineffective or even deleterious in the case of a discordant output.