miR-577 Regulates TGF-β Induced Cancer Progression through a SDPR-Modulated Positive-Feedback Loop with ERK-NF-κB in Gastric Cancer

Abstract

Transforming growth factor β (TGF-β) drives epithelial-mesenchymal transition (EMT), playing vital roles in cancer metastasis. The crosstalk between microRNAs (miRNAs) and TGF-β are frequently observed and involved in TGF-β-induced EMT. Here, we determine that miR-577 is significantly upregulated in gastric cancer (GC). miR-577 expression is positively correlated with GC metastasis status and poor patient prognosis. Functional assays demonstrate that miR-577 promotes metastasis and chemoresistance by inducing EMT and stemness-like properties. Moreover, TGF-β promotes the expression of miR-577, and miR-577 participates TGF-β-mediated cancer metastasis. Mechanistically, TGF-β activates miR-577 via NF-κB-mediated transcription, and miR-577 enhances TGF-β signaling by targeting the serum deprivation protein response (SDPR), which directly interacts with ERK to inactivate the ERK-NF-κB pathway, hence forming a feedback loop to drive tumor metastasis. A plausible mechanism of EMT induction by the TGF-β network is elucidated. Our findings suggest that the TGF-β-miR-577-SDPR axis may be a potential prognostic marker and therapeutic target against cancer metastasis in GC.

Keywords: TGF-β; feedback loop; gastric cancer; metastasis; miR-577-SDPR axis.