Hypoxia-induced exosomal LNCOC1 orchestrates bladder cancer progression via the YBX1/PIK3CA axis and serves as a potential liquid biopsy biomarker

Bladder cancer (BCa) is a prevalent genitourinary malignancy characterized by limited specific diagnostic and therapeutic options. Although hypoxia is known to drive tumor progression via exosome-mediated communication, the specific oncogenic roles of hypoxia-induced exosomal long non-coding RNAs (lncRNAs) remain poorly elucidated. Here, we profiled exosomes from normoxic and hypoxic BCa cells using high-throughput sequencing, identifying LNCOC1 as a significantly upregulated lncRNA under hypoxic conditions. Mechanistically, hypoxia-inducible factor 1α (HIF1A) directly binds to the LNCOC1 promoter to drive its transcription and subsequent exosomal encapsulation. Upon transfer to recipient cells, exosomal LNCOC1 promotes BCa cell proliferation, migration, and invasion. It acts as a nuclear scaffold, directly recruiting the transcription factor YBX1 to the PIK3CA promoter, thereby upregulating PIK3CA expression and hyperactivating the PI3K/AKT signaling pathway. Clinically, elevated LNCOC1 levels in tumor tissues and circulating plasma exosomes from 96 BCa patients positively correlated with advanced tumor grade, metastasis, and poor prognosis. Furthermore, circulating exosomal LNCOC1 demonstrated moderate diagnostic efficacy in distinguishing BCa patients from healthy controls (AUC = 0.789) and metastatic from non-metastatic cases (AUC = 0.765). Collectively, these findings elucidate a novel HIF1A/LNCOC1/YBX1/PIK3CA regulatory axis, highlighting circulating exosomal LNCOC1 as a preliminary candidate biomarker for BCa diagnosis that warrants further validation in independent cohorts.