MicroRNAs (miRNAs or miRs) are the most characterized class of non-coding RNAs and are engaged in many cellular processes, including cell differentiation, development, and homeostasis. MicroRNA dysregulation was observed in several diseases, cancer included. Epitranscriptomics is a branch of epigenomics that embraces all RNA modifications occurring after DNA transcription and RNA synthesis and involving coding and non-coding RNAs. The development of new high-throughput technologies, especially deep RNA sequencing, has facilitated the discovery of miRNA isoforms (named isomiRs) resulting from RNA modifications mediated by enzymes, such as deaminases and exonucleases, and differing from the canonical ones in length, sequence, or both. In this review, we summarize the distinct classes of isomiRs, their regulation and biogenesis, and the active role of these newly discovered molecules in cancer and other diseases.

RNA editing in microRNAs has been recently proposed as a novel biomarker in cancer. Here, we investigated RNA editing by leveraging small-RNA sequencing data from 87 NSCLC (Non-Small Cell Lung Cancer) samples paired with normal lung tissues from The Cancer Genome Atlas (TCGA) combined with 26 plasma-derived exosome samples from an independent cohort. Using both the editing levels and microRNA editing expression, we detected deregulated microRNA editing events between NSCLC tumor and normal tissues. Interestingly, and for the first time, we also detected editing sites in the microRNA cargo of circulating exosomes, providing the potential to non-invasively discriminate between normal and tumor samples. Of note, miR-411-5p edited in position 5 was significantly dysregulated in tissues as well as in exosomes of NSCLC patients, suggesting a potential targetome shift relevant to lung cancer biology.

MicroRNAs (miRNAs) have been extensively reported to be associated with hematological malignancies. The loss of miR-15a/16-1 at chromosome 13q14 is a hallmark of most of human chronic lymphocytic leukemia (CLL). Deletion of murine miR-15a/16-1 and miR-15b/ 16-2 has been demonstrated to promote B cell malignancies. Here, we evaluate the biological role of miR-15/16 clusters, crossbreeding miR-15a/16-1 and miR-15b/16-2 knockout mice. Unexpectedly, the complete deletion of both clusters promoted myeloproliferative disorders in the majority of the mice by the age of 5 months with a penetrance of 70%. These mice showed a significant enlargement of spleen and abnormal swelling of lymph nodes. Flow cytometry characterization demonstrated an expanded CD11b/Gr-1 double-positive myeloid population both in spleen and in bone marrow. The transplantation of splenocytes harvested from double-KO mice into wildtype recipient mice resulted in the development of myeloproliferative disorders, as observed in the donors. In vivo, miR-15/16 cluster deletion up-regulated the expression of Cyclin D1, Cyclin D2, and Bcl-2. Taken together, our findings identify a driver oncogenic role for miR-15/16 cluster deletion in different leukocytic cell lineages. miR-15/16 cluster | acute myeloid leukemia | mouse model T he loss of miR-15a/16-1 at chromosome 13q14, encoding two miRNAs residing in the same polycistrocnic RNA, is a hallmark of most of human chronic lymphocytic leukemias (CLL) (1). This dysregulation has been proved as the first evidence that genetic alteration in noncoding genes can cause malignancy (1).Most of CLLs are indolent but may progress to an aggressive disease. Analysis for mutations in many CLL showed that germline mutations just seven nucleotides 3′ of miR-16-1 are present in familial CLL (2), and this region was found to be necessary for processing of the miRNA precursor (3). Furthermore, the mouse strain NZB that develops an indolent CLL late in life carries a mutation six nucleotides 3′ of miR-16-1 affecting miR-15/16 processing, indicating that loss of function of miR-15a/16-1 leads to the development of indolent CLL (4). The frequency of loss of one or both miR-15a/16-1 clusters on chromosome 13q14 occurs in over 70% of the CLL patients and is the most common genetic alteration in CLL (1). Klein et al. (5) knocked out the miR-15a/16-1 locus in the mouse, and the knockout (KO) mice developed late in life the indolent form of CLL, as in human patients (6). Thus, loss of miR-15a/16-1 leads to the development of indolent CLL both in humans and mice. Since an additional locus of miR-15/16 exists on chromosome 3 (3q25), we have knocked out this second miR-15b/16-2 locus in the mouse (7). These mice developed mainly CLL and few diffuse large B cell lymphoma at higher penetrance (60%) and earlier age at 15-18 months (7) than the miR-15a/16-1 KO mice described by Klein et al. (5). Here, we evaluated the biological role of two different miR-15/16 clusters, crossbreeding miR-15a/16-1 and miR-15b/16-2 knockout (KO) mice. Unexpec...

Triple-negative breast cancer (TNBC) is a heterogeneous, highly aggressive, and difficult to treat tumor type. The tumor suppressor WWOX spans FRA16D, a common fragile site that is commonly altered in breast cancer. Despite recent progress, the role of WWOX in TNBC metastasis is unknown. Here we report that WWOX inactivation correlates with advanced stages of TNBC and that its levels are frequently altered in TNBC cells. Ectopic restoration of WWOX in WWOX-negative TNBC cells inhibited metastasis while its depletion in WWOXpositive TNBC cells promoted metastasis. WWOX was a negative regulator of c-MYC, which regulated miR-146a expression and consequently fibronectin levels, contributing to an epithelial status of the cell. Treatment of TNBC cells with anti-miR-146a rescued the WWOX antimetastatic phenotype. Moreover, overexpression of MYC in WWOX-expressing TNBC cells overrode WWOX effects on miR-146a and fibronectin levels. Altogether, our data uncover an essential role for WWOX in antagonizing TNBC progression and highlight its potential use as a biomarker for metastasis.Significance: These findings highlight the mechanism by which the tumor suppressor WWOX regulates metastasis of triple-negative breast cancer.