右美托咪定通过激活肝星状细胞促进肝癌进展
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右美托咪定通过激活肝星状细胞促进肝癌进展
翻译：任文鑫 编辑：冯玉蓉 审校：曹莹
右美托咪啶(DEX)是临床上广泛使用的一种麻醉剂，据报道它在多发性实体瘤的发展过程中表现出矛盾的作用。在这项研究中，我们试图探索DEX调节肝细胞癌（HCC）进展并导致肝纤维化的的机制。我们测定了DEX对肝纤维化小鼠原位肝癌模型肿瘤进展的影响。采用小鼠肝癌细胞(H22)与原代活化的肝星状细胞(AHSCs)共培养体系和异种皮下移植模型，研究DEX对肝癌进展的影响。我们发现，在临床前肝纤维化小鼠模型中，DEX治疗显著缩短了小鼠的中位生存期，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，而在HCC细胞中几乎检测不到。在共培养体系和共移植小鼠模型中，DEX均能显著增强AHSCs对肝癌恶性行为的影响，但单独使用DEX对肝癌的恶性程度无明显影响。机制上，DEX通过激活STAT3诱导AHSCs分泌IL-6，促进肝癌进展。我们的研究结果表明，DEX的临床应用可能会对伴有肝纤维化的HCC患者产生不良副作用。
原始文献来源：Peng Chen, Xiaojun Luo, Guanqi Dai,et al.Dexmedetomidine promotes the progression of hepatocellular carcinoma through hepatic stellate cell activation. Experimental & Molecular Medicine (2020) 52:1062–1074.
Dexmedetomidine promotes the progression of hepatocellular carcinoma through hepatic stellate cell activation
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.
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