Liu Yujin, Gao Feng, Song Weixiang
Department of Interventional Radiology, Yueyang Hospital of Integrated Traditional Chinese & Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Department of Interventional Radiology, Yueyang Hospital of Integrated Traditional Chinese & Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Biomed Pharmacother. 2017 Apr;88:342-348. doi: 10.1016/j.biopha.2017.01.052. Epub 2017 Jan 21.
Hypoxia has been suggested to induce chemoresistance in tumor cells. In this study, we aimed to test the hypothesis that hypoxia-inducible factor-1alpha (HIF-1α)/periostin axis might promote arsenic trioxide resistance in hepatocellular carcinoma (HCC) cells under hypoxia. HCC cells were exposed to hypoxia and measured for periostin expression. Loss-of-function studies were done to assess the role of periostin in arsenic trioxide resistance. In vivo xenograft mouse studies were performed to determine the effect of periostin silencing on HCC susceptibility to arsenic trioxide. It was found that periostin expression was significantly increased in SMMC7721 and Hep3B HCC cells after hypoxic treatment. Depletion of HIF-1α blocked the upregulation of periostin induced by hypoxia. HCC cells under hypoxia displayed more resistant to arsenic trioxide than those under normoxia. Interestingly, downregulation of periostin re-sensitized hypoxic SMMC7721 and Hep3B cells to arsenic trioxide, which was accompanied by increased apoptosis. Luciferase reporter assay revealed that periostin overexpression enhanced HIF-1α-dependent transcriptional activity and induced the expression of vascular endothelial growth factor, Mcl-1, and Bcl-xL in SMMC7721 cells. Administration of arsenic trioxide resulted in a significant inhibition of SMMC7721 tumor growth. Notably, downregulation of periostin significantly enhanced the anticancer effect of arsenic trioxide against SMMC7721 tumors and reduced the percentage of Ki-67-positive proliferating cells. Taken together, periostin contributes to arsenic trioxide resistance in HCC under hypoxic microenvironment, which is likely associated with promotion of HIF-1α-dependent activation of survival genes. Targeting periostin may represent a promising strategy to improve arsenic trioxide-based anticancer therapy against HCC.
缺氧被认为可诱导肿瘤细胞产生化学抗性。在本研究中，我们旨在验证以下假设：缺氧诱导因子-1α（HIF-1α）/骨膜蛋白轴可能在缺氧条件下促进肝癌（HCC）细胞对三氧化二砷产生抗性。将HCC细胞暴露于缺氧环境中，并检测骨膜蛋白的表达。通过功能缺失研究来评估骨膜蛋白在三氧化二砷抗性中的作用。进行体内异种移植小鼠研究，以确定骨膜蛋白沉默对HCC对三氧化二砷敏感性的影响。结果发现，缺氧处理后，SMMC7721和Hep3B HCC细胞中的骨膜蛋白表达显著增加。HIF-1α的缺失阻断了缺氧诱导的骨膜蛋白上调。与常氧条件下的细胞相比，缺氧条件下的HCC细胞对三氧化二砷表现出更强的抗性。有趣的是，骨膜蛋白的下调使缺氧的SMMC7721和Hep3B细胞对三氧化二砷重新敏感，同时伴随着细胞凋亡增加。荧光素酶报告基因检测显示，骨膜蛋白的过表达增强了HIF-1α依赖性转录活性，并诱导了SMMC7721细胞中血管内皮生长因子、Mcl-1和Bcl-xL的表达。给予三氧化二砷可显著抑制SMMC7721肿瘤的生长。值得注意的是，骨膜蛋白的下调显著增强了三氧化二砷对SMMC7721肿瘤的抗癌作用，并降低了Ki-67阳性增殖细胞的百分比。综上所述，在缺氧微环境下，骨膜蛋白有助于HCC对三氧化二砷产生抗性，这可能与促进HIF-1α依赖性存活基因的激活有关。靶向骨膜蛋白可能是一种有前景的策略，可改善基于三氧化二砷的HCC抗癌治疗。
