Loss of miR-122 promotes cell migration and poor prognosis in triple-negative breast cancer treated by neoadjuvant chemotherapy

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BACKGROUND: MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression post-transcriptionally. miR-122 is abnormally expressed in breast cancer, functioning as both a tumor suppressor and oncomiR, however, its role in triple-negative breast cancer (TNBC) remains unclear. PURPOSE: In this study we investigate the molecular mechanism of miR-122 in TNBC patients undergoing neoadjuvant chemotherapy (NAC). METHODS: We analyzed the expression of miR-122 and its clinical association in TNBC patients from TCGA and KM-plotter datasets. Functional analysis was performed by modulating miR-122 levels in TNBC cells through antagomiR transfections for knockdown assays, and mimic-miR-122 assays, followed by RT-qPCR, immunoblotting, cell viability and migration assays. RESULTS: Downregulation of miR-122 in TNBC patients is associated with tumor recurrence but not with pathologic complete response after NAC. Low miR-122 levels in rapid-relapse TNBC patients activate a gene co-expression network enriched in genes linked to migration, invasion, and cell differentiation. Among these, DNA-binding protein BORIS was identified as a target of miR-122. Overexpression of miR-122 inhibited cell migration and BORIS expression. Additionally, BORIS promoted a gene expression profile related to cell differentiation and cytoskeletal components in TNBC tumors deficient of miR-122. CONCLUSION: The loss of miR-122 in TNBC tumors is associated with rapid relapse after chemotherapy in patients and allows cell migration by promoting a metastatic-related transcriptomic landscape, including positive modulation of BORIS expression.

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