LINC00460 drives clear cell renal cell carcinoma progression via complement/coagulation and p53 pathways: a potential therapeutic target.
TL;DR
Findings establish LINC00460 as an oncogenic driver in ccRCC and a promising target for both diagnosis and precision therapy and identifies cinchonine and iproniazid as candidate therapeutic agents.
Abstract
This study demonstrates that the long noncoding RNA (lncRNA) LINC00460 is significantly overexpressed in clear cell renal cell carcinoma (ccRCC) and is strongly associated with adverse clinical outcomes. Analysis of data from The Cancer Genome Atlas (TCGA), validated by an independent cohort (GSE53757) and quantitative real-time polymerase chain reaction (qRT-PCR), shows that high LINC00460 expression has robust diagnostic value (area under the curve [AUC] = 0.818) and predicts shorter overall survival, highlighting its potential as a prognostic biomarker. Functional enrichment analyses indicate that LINC00460 is involved in key pathways, including complement and coagulation cascades, cytokine-cytokine receptor interactions, extracellular matrix remodeling, and p53 signaling. In vitro experiments confirm that silencing LINC00460 in ccRCC cell lines (Caki-2 and ACHN) markedly inhibits tumor cell proliferation, migration, and invasion while promoting apoptosis. Mechanistically, LINC00460 knockdown reduces levels of inflammatory factors (interleukin-6 [IL-6], tumor necrosis factor-alpha [TNF-α], and C-X-C motif chemokine ligand 8 [CXCL8]) and coagulation-related proteins (C3, SERPINA1, and PLAU), and activates the p53 pathway by upregulating p21 and BAX while downregulating Bcl-2. Genomic analysis reveals higher mutation rates of BAP1 and LRP2 in LINC00460-high tumors, and drug repurposing screening identifies cinchonine and iproniazid as candidate therapeutic agents. These findings establish LINC00460 as an oncogenic driver in ccRCC and a promising target for both diagnosis and precision therapy.