The versatile nature of miR-9/9* in human cancer

Abstract

miR-9 and miR-9* (miR-9/9*) were first shown to be expressed in the nervous system and to function as versatile regulators of neurogenesis. The variable expression levels of miR-9/9* in human cancer prompted researchers to investigate whether these small RNAs may also have an important role in the deregulation of physiological and biochemical networks in human disease. In this review, we present a comprehensive overview of the involvement of miR-9/9* in various human malignancies focusing on their opposing roles in supporting or suppressing tumor development and metastasis. Importantly, it is shown that the capacity of miR-9/9* to impact tumor formation is independent from their influence on the metastatic potential of tumor cells. Moreover, data suggest that miR-9/9* may increase malignancy of one cancer cell population at the expense of another. The functional versatility of miR-9/9* emphasizes the complexity of studying miRNA function and the importance to perform functional studies of both miRNA strands in a relevant cellular context. The possible application of miR-9/9* as targets for miRNA-based therapies is discussed, emphasizing the need to obtain a better understanding of the functional properties of these miRNAs and to develop safe delivery methods to target specific cell populations.

MicroRNA-9-5p-CDX2 Axis: A Useful Prognostic Biomarker for Patients with Stage II/III Colorectal Cancer

“…Recent studies showed that CDX2 targets the multidrug resistance gene MDR1 (ABCB1) and CFTR (ABCC7), coding for two ATP-dependent drug efflet pumps [36][37][38]. These genes are significantly down-regulated in CDX2-negative cell lines and CDX2-negative patient tumors and have also been reported to promote the response to chemotherapy [24,38]. This supports our results showing that CDX2-positive cases show a poor response to chemotherapy which may be effective in patients with CDX2-negative CRC.…”

“…The mature miR-9 transcript is produced by three independent genes: miR-9-1, miR-9-2, and miR-9-3. Of miR-9-5p and miR-9-3p which are mature miR-9s, miR-9-5p is dominant in humans [24] (Figure 4a). We performed cell proliferation, cell cycle, and cytotoxicity assays using DLD-1 cells overexpressing miR-9-1 (DLD-1-miR-9-1) which stably expresses miR-9-5p ( Figure 4b).…”

“…Formalin-fixed, paraffin-embedded human colorectal tissues were stained with an anti-CDX2 mouse monoclonal antibody (Clone: CDX2-88, 1:50, BioGenex, San Ramon, CA, USA) using the avidin-biotin immunoperoxidase method. A scoring system described in a previous report [24] was used to quantify CDX2 expression levels. All IHC samples were evaluated independently by two researchers.…”

Single cell visualisation ofmir-9aandSenselessco-expression duringDrosophila melanogasterembryonic and larval peripheral nervous system development

“…These studies demonstrate clear similarities between miR-9 expression and function in Drosophila and vertebrates. Disrupted miR-9 function has also been linked with some human pathologies, including cancer progression (Nowek et al 2018) and neurodegenerative amyloid diseases (Packer et al 2008). For instance tumorigenic cells from medulloblastoma appear to have decreased expression of miR-9, while a subclass of glioblastoma tumour cells express miR-9 at a higher level (Ferretti et al 2009;Kim et al 2011).…”

Structural differences between pri-miRNA paralogs promotes alternative Drosha cleavage and expands target repertoires

“…MiR-9 is highly expressed in brain, where it is involved in neural stem cell self-renewal and differentiation (Zhao et al, 2009) , and synaptic plasticity (Sim et al, 2016) . Mir-9 levels are also dysregulated in many human cancers Nowek et al, 2018) . Consistent with a role for Drosha cleavage fidelity in driving function, an isomiR of miR-9 with an altered 5' end was detected in human embryonic stem cells and neural cells and shown to affect target site selection of several reporter constructs (Tan et al, 2014.).…”