Functional dynamic modulation of colorectal cancer initiation and metastatic capacity by a novel MiR-7974 regulatory...

Colorectal cancer (CRC) is one of the most prevalently diagnosed malignancies. Frequent metastasis and recurrence render treatments ineffective. The accumulation of omics data has helped develop a comprehensive functional regulatory network underlying tumorigenesis, causing significant breakthroughs in cancer therapy.

Systematic transcriptomic analysis of CRC tissues and matched normal samples identified miR-7974 as a novel miRNA with distinct expression pattern in CRC. Independent RT-qPCR assays further validated its tumor-biased expression. To investigate the role of miR-7974 in tumor progression, a series of cell-based assays and xenograft models were conducted. Additionally, RNA sequencing, reporter assays, and functional rescue experiments were performed to delineate the downstream regulatory network, with specific focuses on the miR-7974/CDKN1A and miR-7974/MYO1E axes involved in tumor growth and metastasis.

MiR-7974 demonstrated high expression in early CRC but decreased abundance in later stages. We uncover that miR-7974 augments cancer growth by mitigating the expression of the cell cycle regulator, CDKN1A, through in vitro assays. Concurrently, miR-7974 reduces cellular migration and invasion by targeting MYO1E. In-depth transcriptomic investigations revealed miR-7974's role in repressing the epithelial-to-mesenchymal transition (EMT) in CRC cells, thereby maintaining the tumor in a highly proliferative epithelial state. This result is congruent with miR-7974's pronounced expression in early-stage CRC and its attenuation in advanced, metastatic stages. Such dynamic changes in expression patterns elucidate miR-7974's prognostic significance. Despite its abundant expression in CRC tissues, patients with heightened miR-7974 levels achieved more favorable survival outcomes.

Our findings demonstrate that miR-7974 regulates EMT plasticity, promoting a rapidly proliferating epithelial phenotype while reducing metastatic potential in CRC. Dynamic miR-7974 expression, coupled with its associated target gene regulation, provides the mechanistic foundation for understanding the acquisition of metastatic potential. This emphasizes the functional effect of miR-7974 on CRC growth and provides a deeper understanding of miRNome dynamics during cancer development.