Radiofrequency ablation induced tumor growth is suppressed by microRNA21 inhibition in murine models of intrahepatic colorectal carcinoma.

PURPOSE: To investigate the role of microRNA21 (miR21) in RFA (radiofrequency ablation)-induced tumor growth, and whether miR21 inhibition suppresses tumorigenesis.

MATERIAL AND METHODS: Standardized liver RFA was applied to 35 C57/BL6 mice. miR21 and target proteins pSTAT3 (phosphorylated signal transducer/activator of transcription 3), PDCD4 (programmed cell death protein 4), and PTEN (phosphatase and tensin homolog) were assayed 3hr, 24hr, and 3d post-ablation. Next, 53 Balb/c and 44 C57BL/6 mice received Antago-miR21 or scrambled Antago-nc control followed by intrasplenic injection of 10,000 CT26 or MC38 colorectal tumor cells, respectively. Hepatic RFA or sham ablation was performed 24hr later. Metastasis were quantified and tumor microvascular density (MVD) and cellular proliferation assessed at 14d or 21d post procedures, respectively.

RESULTS: RFA significantly increased miR21 in plasma and hepatic tissue at 3 and 24hr, as well as target proteins at 3d post ablation (p<0.05, all comparisons). RFA nearly doubled tumor growth (CT26: 2.0±1.0; MC38: 1.9±0.9 fold change [fc]) and increased MVD (CT26: 1.9±1.0; MC38: 1.5±0.5 fc), and cellular proliferation (CT26: 1.7±0.7; MC38: 1.4±0.5 fc) compared to sham ablation (p<0.05, all comparisons). RFA-induced tumor growth was suppressed when Antago-miR21 was administered (CT26: 1.0±0.7; MC38: 0.9±0.4 fc) (p<0.01, both comparisons). Likewise, Antago-miR21 decreased MVD (CT26: 1.0±0.3; MC38: 1.0±0.2 fc) and cellular proliferation (CT26: 0.9±0.3; MC38: 0.8±0.3 fc) to baseline (p<0.05, all comparisons).

CONCLUSION: RFA upregulates pro-tumorigenic miR21 which subsequently influences down-stream tumor-promoting protein pathways. This effect can potentially be suppressed by specific inhibition of miR21 rendering this microRNA a pivotal and targetable driver of tumorigenesis post hepatic thermal ablation.