Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, 510315, Guangzhou, China.
Department of Pathophysiology, School of Medicine, Jinan University, 510632, Guangzhou, China.
Exp Mol Med. 2020 Jul;52(7):1062-1074. doi: 10.1038/s12276-020-0461-6. Epub 2020 Jul 6.
Dexmedetomidine (DEX) is an anesthetic that is widely used in the clinic, and it has been reported to exhibit paradoxical effects in the progression of multiple solid tumors. In this study, we sought to explore the mechanism by which DEX regulates hepatocellular carcinoma (HCC) progression underlying liver fibrosis. We determined the effects of DEX on tumor progression in an orthotopic HCC mouse model of fibrotic liver. A coculture system and a subcutaneous xenograft model involving coimplantation of mouse hepatoma cells (H22) and primary activated hepatic stellate cells (aHSCs) were used to study the effects of DEX on HCC progression. We found that in the preclinical mouse model of liver fibrosis, DEX treatment significantly shortened median survival time and promoted tumor growth, intrahepatic metastasis and pulmonary metastasis. The DEX receptor (ADRA2A) was mainly expressed in aHSCs but was barely detected in HCC cells. DEX dramatically reinforced HCC malignant behaviors in the presence of aHSCs in both the coculture system and the coimplantation mouse model, but DEX alone exerted no significant effects on the malignancy of HCC. Mechanistically, DEX induced IL-6 secretion from aHSCs and promoted HCC progression via STAT3 activation. Our findings provide evidence that the clinical application of DEX may cause undesirable side effects in HCC patients with liver fibrosis.
右美托咪定（DEX）是一种临床上广泛使用的麻醉剂，据报道其在多种实体瘤的进展中表现出矛盾的作用。在本研究中，我们试图探讨 DEX 调节肝纤维化背景下肝细胞癌（HCC）进展的机制。我们确定了 DEX 对纤维性肝原位 HCC 小鼠模型中肿瘤进展的影响。使用共培养系统和涉及小鼠肝癌细胞（H22）和原代激活的肝星状细胞（aHSCs）共植入的皮下异种移植模型来研究 DEX 对 HCC 进展的影响。我们发现，在肝纤维化的临床前小鼠模型中，DEX 治疗显著缩短了中位生存时间并促进了肿瘤生长、肝内转移和肺转移。DEX 受体（ADRA2A）主要在 aHSCs 中表达，但在 HCC 细胞中几乎检测不到。DEX 在共培养系统和共植入小鼠模型中均在 aHSCs 的存在下显著增强了 HCC 的恶性行为，但 DEX 单独对 HCC 的恶性程度没有显著影响。在机制上，DEX 诱导 aHSCs 分泌 IL-6，并通过 STAT3 激活促进 HCC 进展。我们的研究结果提供了证据，表明在患有肝纤维化的 HCC 患者中，DEX 的临床应用可能会产生不良的副作用。
