Nuclear Roles of Spliceosome-Associated microRNAs in Neuronal Cancer Cells

MicroRNAs (miRNAs) are well known for regulating translation in the cytoplasm, yet their nuclear roles remain poorly understood. Previously, we identified spliceosome-associated miRNAs implicated in tumorigenesis and metastasis in breast cancer models. Here, we investigate their nuclear functions in the immortalized human cortical neuron (HCN) cell line, along with glioblastoma (U87MG) and neuroblastoma (SH-SY5Y) cell lines, both widely used as models for brain cancer research. Our findings reveal that spliceosome-associated miRNAs mark neuronal cancer cells and uncover novel nuclear targets. Notably, some spliceosomal miRNAs exhibit opposing regulatory effects in the nucleus compared to the cytoplasm, while others demonstrate potential novel nuclear functions. A prominent example is miR-99b, which overlaps the 5′ splice junction of the poorly characterized long non-coding RNA (lncRNA) sperm acrosome-associated 6 antisense RNA1 (SPACA6-AS1) and, through base pairing, enhances SPACA6-AS1 pre-mRNA levels. These results highlight the diverse and context-dependent functions of nuclear miRNAs in gene regulation and cancer progression, broadening our understanding of their regulatory potential beyond the cytoplasm.