Kidney-specific HIF-1α-dependent ARL10/miR-1271-5p overexpression in clear cell renal cell carcinoma

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is primarily driven by chromosome 3p loss and inactivation of the von Hippel-Lindau (VHL) gene, which is frequently accompanied by chromosome 5q gain. However, the oncogenic contribution of 5q remains unclear. This study examines how 5q gain affects the expression of microRNAs implicated in ccRCC. METHODS: Bioinformatic analyses were conducted to evaluate miRNAs associated with 5q gain and 3p loss. RT-qPCR validation was performed in tumour tissues and patient plasma. Mechanistic investigations integrated open-source ChIP-seq datasets and luciferase reporter assays. RESULTS: miR-1271-5p overexpression was significantly associated with both 5q gain and 3p loss and strongly correlated with its host gene, ARL10. RT-qPCR confirmed elevated levels of miR-1271-5p and ARL10 in ccRCC tumours and increased circulating miR-1271-5p in patient plasma. Mechanistically, these upregulations resulted from VHL loss and subsequent HIFα stabilisation. ChIP-seq datasets and luciferase assays demonstrated that HIF-1α, but not HIF-2α, directly binds within the intragenic region of ARL10. Importantly, this regulatory mechanism was specific to kidney cells. CONCLUSIONS: Coordinated upregulation of miR-1271-5p and ARL10 reflects key genomic events in ccRCC and is driven by kidney-specific HIF-1a activity. Our findings suggest their promise for early detection and disease monitoring.