Emerging Role of isomiRs in Cancer: State of the Art and Recent Advances

Abstract

The advent of Next Generation Sequencing technologies brought with it the discovery of several microRNA (miRNA) variants of heterogeneous lengths and/or sequences. Initially ascribed to sequencing errors/artifacts, these isoforms, named isomiRs, are now considered non-canonical variants that originate from physiological processes affecting the canonical miRNA biogenesis. To date, accurate IsomiRs abundance, biological activity, and functions are not completely understood; however, the study of isomiR biology is an area of great interest due to their high frequency in the human miRNome, their putative functions in cooperating with the canonical miRNAs, and potential for exhibiting novel functional roles. The discovery of isomiRs highlighted the complexity of the small RNA transcriptional landscape in several diseases, including cancer. In this field, the study of isomiRs could provide further insights into the miRNA biology and its implication in oncogenesis, possibly providing putative new cancer diagnostic, prognostic, and predictive biomarkers as well. In this review, a comprehensive overview of the state of research on isomiRs in different cancer types, including the most common tumors such as breast cancer, colorectal cancer, melanoma, and prostate cancer, as well as in the less frequent tumors, as for example brain tumors and hematological malignancies, will be summarized and discussed.

One locus, several functional RNAs—emerging roles of the mechanisms responsible for the sequence variability of microRNAs

“…An earlier attempt to classify 32 cancer types using isomiR profiling was surprisingly successful: even if a "binary" (present or absent) approach was applied, this method could label different tumor types with high (90%) sensitivity and with a very low (3%) false discovery rate (Telonis et al 2017). A recent meta-analysis of available cancer datasets and publications not only supported this approach but could identify specific miRNA isomiRs that can be used as biomarkers for certain tumor types (Zelli et al 2021). A further deep analysis of isomiR datasets could differentiate even among breast cancer subtypes (Nersisyan et al 2022), whereas a recent study provided evidence that the heterogeneous nuclear ribonucleoprotein C (hnRNPC) induced 5' isomiR shift of miR-21-5p could lead to liver cancer (Park et al 2022).…”

“…The mechanisms behind isomiR formation have, in general, been revealed: beside the subtle regulation of the main miRNA processing enzymes (Drosha and Dicer), the action of terminal nucleotidyl transferases, exoribonucleases and RNA editing enzymes are also responsible for the existence of certain isomiR groups (Tomasello et al 2021). On the other hand, the regulation of cell-type specific isomiR distribution is still not completely understood and this aspect is currently in the focus of intensive investigations (Zelli et al 2021;Aparicio-Puerta et al 2023). Nevertheless, isomiRs should definitely be considered in miRNA target predictions (Ahmed et al 2014), as well as in the development of new diagnostic tools and in planned therapy applications (Nikolova et al 2021;Scheper et al 2022).…”

Circulating Exosome Cargoes Contain Functionally Diverse Cancer Biomarkers: From Biogenesis and Function to Purification and Potential Translational Utility

“…In this fashion it does not allow discovery of IsomiR (i.e., miRNA variants of the same miRNA, which can differ in sequence and/or length composition and will bind to different mRNA targets than the original miRNA sequence [ 306 ]) expression ratio differences for a specific miRNA in exosome sub-populations. The study of isomiRs is relevant in cancer, as their expression ratio has been shown to be affected by and can elicit changes in tumor cell migration and invasion [ 307 ]. (2) qPCR assays typically require large inputs of RNAs for global evaluation and may still require a pre-amplification step (i.e., typically ~14 cycles) before the 40-cycle amplification for fluorescent quantification, which leaves room for potential amplification bias or errors.…”

The dual role of microRNA (miR)-20b in cancers: Friend or foe?

“…Besides, based on the origin of sequence from opposite arms of pre-miRNA, mature miRNA is annotated with a -5p or -3p, such as miR-20b-5p [ 16 ]. The most important of these findings is that the functions and biological activity of isomiRs are diverse from each other and canonical miRNA [ 17 ].…”