射频消融诱导的肿瘤生长受 miR-21 抑制在鼠模型肝内结直肠癌中的抑制作用
Radiofrequency Ablation-Induced Tumor Growth Is Suppressed by MicroRNA-21 Inhibition in Murine Models of Intrahepatic Colorectal Carcinoma.
机构信息
Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel; Department of Radiology, University Hospital, LMU Munich, Munich, Germany.
Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel; Department of Radiology, the Laboratory for Minimally Invasive Tumor Therapies, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts; Department of Radiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
出版信息
J Vasc Interv Radiol. 2023 Oct;34(10):1785-1793.e2. doi: 10.1016/j.jvir.2023.06.019. Epub 2023 Jun 20.
PURPOSE
To investigate the role of microRNA-21 (miR21) in radiofrequency (RF) ablation-induced tumor growth and whether miR21 inhibition suppresses tumorigenesis.
MATERIAL AND METHODS
Standardized liver RF ablation was applied to 35 C57/BL6 mice. miR21 and target proteins pSTAT3, PDCD4, and PTEN were assayed 3 hours, 24 hours, and 3 days after 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 RF ablation or sham ablation was performed 24 hours later. Metastases were quantified and tumor microvascular density (MVD) and cellular proliferation were assessed at 14 or 21 days after the procedures, respectively.
RESULTS
RF ablation significantly increased miR21 levels in plasma and hepatic tissue at 3 and 24 hours as well as target proteins at 3 days after ablation (P < .05, all comparisons). RF ablation nearly doubled tumor growth (CT26, 2.0 SD ± 1.0 fold change [fc]; MC38, 1.9 SD ± 0.9 fc) and increased MVD (CT26, 1.9 SD ± 1.0 fc; MC38, 1.5 ± 0.5 fc) and cellular proliferation (CT26, 1.7 SD ± 0.7 fc; MC38, 1.4 SD ± 0.5 fc) compared with sham ablation (P < .05, all comparisons). RF ablation-induced tumor growth was suppressed when Antago-miR21 was administered (CT26, 1.0 SD ± 0.7 fc; MC38, 0.9 SD ± 0.4 fc) (P < .01, both comparisons). Likewise, Antago-miR21 decreased MVD (CT26, 1.0 SD ± 0.3 fc; MC38, 1.0 SD ± 0.2 fc) and cellular proliferation (CT26, 0.9 SD ± 0.3 fc; MC38, 0.8 SD ± 0.3 fc) compared with baseline (P < .05, all comparisons).
CONCLUSIONS
RF ablation upregulates protumorigenic miR21, which subsequently influences downstream 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 after hepatic thermal ablation.
目的
研究微小 RNA-21（miR21）在射频（RF）消融诱导的肿瘤生长中的作用，以及 miR21 抑制是否抑制肿瘤发生。
材料与方法
对 35 只 C57/BL6 小鼠进行标准化肝 RF 消融。消融后 3 小时、24 小时和 3 天检测 miR21 及靶蛋白 pSTAT3、PDCD4 和 PTEN。接下来，53 只 Balb/c 和 44 只 C57BL/6 小鼠分别接受 Antago-miR21 或对照 Antago-nc 治疗，然后经脾内注射 10000 个 CT26 或 MC38 结直肠肿瘤细胞。24 小时后进行肝 RF 消融或假消融。分别在术后 14 天和 21 天评估转移情况，测量肿瘤微血管密度（MVD）和细胞增殖情况。
结果
RF 消融后 3 小时和 24 小时，血浆和肝组织中 miR21 水平以及 3 天后靶蛋白水平均显著升高（P <.05，所有比较）。RF 消融使肿瘤生长增加近一倍（CT26，2.0 标准差±1.0 倍变化[fc]；MC38，1.9 标准差±0.9 fc），MVD（CT26，1.9 标准差±1.0 fc；MC38，1.5±0.5 fc）和细胞增殖（CT26，1.7 标准差±0.7 fc；MC38，1.4 标准差±0.5 fc）均显著增加（P <.05，所有比较）。与假消融相比，给予 Antago-miR21 可抑制 RF 消融诱导的肿瘤生长（CT26，1.0 标准差±0.7 fc；MC38，0.9 标准差±0.4 fc）（P <.01，两者比较）。同样，与基线相比，Antago-miR21 降低了 MVD（CT26，1.0 标准差±0.3 fc；MC38，1.0 标准差±0.2 fc）和细胞增殖（CT26，0.9 标准差±0.3 fc；MC38，0.8 标准差±0.3 fc）（P <.05，所有比较）。
结论
RF 消融上调促肿瘤发生的 miR21，随后影响下游促进肿瘤的蛋白途径。这种效应可能通过 miR21 的特异性抑制得到抑制，使这种 microRNA 成为肝热消融后肿瘤发生的关键和可靶向驱动因素。
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