School of Basic Medical Sciences, Nanchang University, Nanchang 330006, China.
Agricultural and Health Center, Jiangxi Center for Disease Control and Prevention, Nanchang 330006, China.
Acta Biochim Biophys Sin (Shanghai). 2020 Apr 20;52(4):421-429. doi: 10.1093/abbs/gmaa010.
Local hypoxia is a universal phenomenon in most solid tumors. The role of local hypoxia in the tumor microenvironment and cancer growth and metastasis has been well established. However, the effect of acute systemic hypoxia (exposing the whole body to 10% O2 environment) on cancer has not yet been investigated. In this study, we investigated the potential effects of acute systemic hypoxia itself and in combination with metformin on hepatocellular carcinoma (HCC) growth and metastasis in a mouse model of HCC. Acute systemic hypoxia significantly decreased tumor volume and weight in H22 tumor-bearing mice. Interestingly, the combined treatment of acute systemic hypoxia and metformin showed a more pronounced effect in reducing tumor volume and weight. Moreover, acute systemic hypoxia and metformin in combination had a potent inhibitory effect on tumor progression. More importantly, the expressions of hypoxia response genes including hypoxia-inducible factor-1 α, vascular endothelial growth factor, and matrix metalloproteinase 2 were significantly decreased in the tumor tissues with combination treatment. Our study demonstrated that acute systemic hypoxia repressed tumor progression of the HCC and potentiated the anti-tumor activities of metformin. This study supports that combination of systemic hypoxia and metformin treatment may represent a novel strategy for HCC.
局部缺氧是大多数实体瘤中普遍存在的现象。局部缺氧在肿瘤微环境以及癌症生长和转移中的作用已得到充分证实。然而，急性全身缺氧（将整个身体暴露在 10%氧气环境中）对癌症的影响尚未得到研究。在这项研究中，我们研究了急性全身缺氧本身以及与二甲双胍联合应用对肝癌（HCC）在 HCC 小鼠模型中生长和转移的潜在影响。急性全身缺氧可显著降低 H22 荷瘤小鼠的肿瘤体积和重量。有趣的是，急性全身缺氧与二甲双胍联合治疗在减轻肿瘤体积和重量方面表现出更显著的效果。此外，急性全身缺氧与二甲双胍联合应用对肿瘤进展具有强大的抑制作用。更重要的是，在联合治疗的肿瘤组织中，缺氧反应基因（包括缺氧诱导因子-1α、血管内皮生长因子和基质金属蛋白酶 2）的表达明显降低。我们的研究表明，急性全身缺氧抑制了 HCC 的肿瘤进展，并增强了二甲双胍的抗肿瘤活性。这项研究支持全身缺氧与二甲双胍联合治疗可能是 HCC 的一种新策略。
