KRT14 Drives Basal Muscle-Invasive Bladder Cancer Progression and Lung Metastasis by Directly Binding to and Stabilizing IGF2BP1.

Basal-type muscle-invasive bladder cancer (BMIBC) is characterized by aggressive metastasis and poor prognosis but lacks molecularly defined therapeutic targets. Through integrative analyses of clinical cohorts and BBN-induced mouse models, we identified KRT14 as a core oncogenic driver that orchestrates the KRT14-IGF2BP1 signaling axis to promote BMIBC progression and lung metastasis. Mechanistically, residues K294 and E295 within the KH2 domain of IGF2BP1 specifically recognize conserved residues D226 and E227 within the nuclear export signal of KRT14. This direct interaction facilitates IGF2BP1-mediated cytoplasmic trafficking and auto-stabilization of its own mRNA, establishing a positive feedback loop that amplifies IGF2BP1-targeted pro-invasive gene expression. Functional disruption of this axis suppressed primary tumor progression and lung metastasis in BMIBC models. Collectively, our findings define the KRT14-IGF2BP1 axis as a previously unrecognized, potentially targetable vulnerability in BMIBC, whose inhibition may limit aggressive disease progression and inform future therapeutic strategies.