RNA-binding protein QKI suppresses breast cancer via RASA1/MAPK signaling pathway

Background: RNA-binding protein Quaking (QKI) has been linked with the pathogenesis and development of various human malignancies. Herein, we explored the particular role of QKI in breast cancer (BC) progression. Methods: The methods employed in the study included public dataset analysis, western blot, quantitative real-time PCR (qRT-PCR), cell count kit-8 (CCK8) assay, colony formation assay, flow cytometric analysis, RNA immunoprecipitation (RIP), messenger RNA (mRNA) stability assay, QKI overexpression and knockdown, and Ras p21 protein activator 1 (RASA1) knockdown. Results: Aberrant expression levels of QKI and RASA1 were detected in BC and compared with those in noncancerous tissues. A moderately positive correlation between QKI and RASA1 was verified within BC tissues. Low expression of QKI was associated with positive estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status, non-triple-negative breast cancer (TNBC), non-basal-like BC, and poor clinical outcomes in BC patients. QKI overexpression suppressed BC cell proliferation and colony formation, and arrested cell cycle at G1 phase. RIP assay and mRNA stability assay confirmed that QKI directly bound to RASA1 transcript and increased its stability, thus inactivating the MAPK pathway and inhibiting BC progression. RASA1 knockdown could partly attenuate the inhibitory effect of QKI on BC cell proliferation via activating the mitogen-activated protein kinase (MAPK) pathway. Conclusions: QKI, which was frequently downregulated in BC, could significantly inhibit cell proliferation and arrest cell cycle at G1 phase by binding and enhancing RASA1 mRNA expression. Low expression of QKI was prominently associated with unfavorable clinical outcomes in BC patients, indicating the prognostic value of QKI in BC.