Long non-coding RNA (lncRNA) XIST drives TGF-β-induced renal cancer progression via miR-141-3p/ZEB1 signaling

Long non-coding RNA (lncRNA) X inactive-specific transcript (XIST) is linked to tumor metastasis; however, research on its role in renal cancer (RC) is limited. This study investigated the function and underlying mechanism of XIST in RC.

After transforming growth factor beta (TGF-β) stimulation of 786-O and Caki-1 cells, morphological changes were assessed by microscopy, and XIST expression was quantified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). XIST-microRNA-141-3p (miR-141-3p) and miR-141-3p-zinc-finger E-box binding protein 1 (ZEB1) interactions were validated by dual-luciferase reporter assays. Cells were then transfected with small interfering (si)-XIST alone or combined with miR-141-3p inhibitor, followed by analyses of: (I) XIST and miR-141-3p expression; (II) cellular morphology; (III) proliferation [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay]; (IV) apoptosis (flow cytometry); (V) epithelial-mesenchymal transition (EMT) markers (N-cadherin, Vimentin, and Snail) and E-cadherin (western blot/immunofluorescence); and (VI) migration and invasion (Transwell assays). ZEB1-mediated rescue of miR-141-3p mimic effects was similarly examined.

TGF-β triggered EMT in RC cells and elevated XIST expression. XIST knockdown suppressed proliferation, EMT, migration, and invasion, while promoting apoptosis in TGF-β-stimulated cells. Mechanistically, XIST sponged miR-141-3p, and miR-141-3p inhibition partially rescued the phenotypic effects of XIST silencing. Additionally, ZEB1 was identified as a miR-141-3p target, and ZEB1 overexpression reversed the miR-141-3p mimic-mediated suppression of TGF-β-induced malignant behaviors.

These findings establish the XIST/miR-141-3p/ZEB1 axis as a regulator of TGF-β-driven proliferation and metastasis in RC in vitro.