Department of Hepatobiliary Surgery, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China.
Int J Hyperthermia. 2022;39(1):888-896. doi: 10.1080/02656736.2022.2093995.
Angiogenesis occurs during tumor progression of hepatocellular carcinoma (HCC) after insufficient radiofrequency ablation (RFA). Arsenic trioxide (ATO) shows promising therapeutic potential in advanced HCC. Whether ATO regulates angiogenesis and can be used to prevent tumor progression in HCC after insufficient RFA is still unknown.
Insufficient RFA was simulated using a water bath. MTT assay and tube formation assay were used to evaluate the effects of ATO on viability and proangiogenic abilities of SMMC7721 and HepG2 cells after insufficient RFA . The molecular changes with the treatment of ATO were evaluated through Western blot. An ectopic nude mice model was used to evaluate the effect of ATO on the tumor of SMMC7721 cells after insufficient RFA.
In this study, HepG2 and SMMC7721 cells after insufficient RFA (named HepG2-H and SMMC7721-H, respectively) showed higher proliferation than the untreated cells and promoted tube formation of endothelial cells in a paracrine manner. ATO eliminated the difference in proliferation between untreated and RFA-treated cells and suppressed angiogenesis induced by HCC cells after insufficient RFA through the Ang-1 (angiopoietin-1)/Ang-2 (angiopoietin-2)/Tie2 pathway. Hif-1α overexpression abolished the inhibitory effect of ATO on angiogenesis in HCC after insufficient RFA. ATO inhibited tumor growth and angiogenesis in HCC after insufficient RFA.
Our results demonstrate that ATO blocks the paracrine signaling of Ang-1 and Ang-2 by inhibiting p-Akt/Hif-1α and further suppresses the angiogenesis of HCC after insufficient RFA.
在射频消融（RFA）不足的肝细胞癌（HCC）肿瘤进展过程中会发生血管生成。三氧化二砷（ATO）在晚期 HCC 中显示出有希望的治疗潜力。ATO 是否调节血管生成以及能否用于预防 RFA 不足后 HCC 的肿瘤进展尚不清楚。
使用水浴模拟 RFA 不足。MTT 测定和管形成测定用于评估 ATO 对 SMMC7721 和 HepG2 细胞在 RFA 不足后的活力和促血管生成能力的影响。通过 Western blot 评估 ATO 治疗的分子变化。建立异位裸鼠模型，用于评估 ATO 对 RFA 不足后 SMMC7721 细胞肿瘤的影响。
在这项研究中，RFA 不足后的 HepG2 和 SMMC7721 细胞（分别命名为 HepG2-H 和 SMMC7721-H）比未处理的细胞具有更高的增殖能力，并以旁分泌方式促进内皮细胞的管形成。ATO 消除了未处理和 RFA 处理的细胞之间增殖的差异，并通过 Ang-1（血管生成素-1）/Ang-2（血管生成素-2）/Tie2 通路抑制 HCC 细胞不足 RFA 后诱导的血管生成。Hif-1α 过表达消除了 ATO 对不足 RFA 后 HCC 血管生成的抑制作用。ATO 抑制了不足 RFA 后 HCC 的肿瘤生长和血管生成。
我们的结果表明，ATO 通过抑制 p-Akt/Hif-1α 阻断 Ang-1 和 Ang-2 的旁分泌信号，进一步抑制不足 RFA 后 HCC 的血管生成。
