缺氧诱导因子-1α参与癌细胞迁移和侵袭的作用机理

The molecular mechanisms of hypoxia inducible factor(HIF)-1α in the migration and invasion of cancer cells

在实体瘤中,无论是良性肿瘤,还是恶性肿瘤,低氧都是一种普遍现象,并且绝大多数肿瘤中存在低氧微环境。低氧与肿瘤的恶性进展、放射与化疗的耐受性和不良的预后有着密切的联系。缺氧诱导因子1(hypoxia inducible factor-1,HIF-1)广泛存在于大多数肿瘤组织中,并且HIF-1是一种存在于低氧条件下的转录因子。它是由氧调控表达的HIF-1α亚基与组成型表达的HIF-1β亚基组成的异二聚体。在常氧环境下,通过激活泛素蛋白酶体及氧依赖性降解区域的脯氨酸羟化而使HIF-1α迅速降解,半衰期约为5 min,而在低氧状态下,HIF-1α与β亚基二聚化并稳定存在。二聚化的HIF-1能够促进癌细胞的增殖、迁移以及侵袭。因此,HIF-1α有可能成为抑制癌细胞生长迁移与侵袭的靶点,这将为化疗及高压氧治疗提供新的思路。综述近年国内外抗氧化环境下HIF-1基因所主导的与癌细胞迁移和侵袭及其抑制相关的分子机理的研究,以便通过在抗炎、抗氧化条件下的增氧作用机理改进化疗效果。

In a solid tumor, whether benign or malignant, hypoxia is a very common phenomenon, which affects the radiation and chemotherapies. Hypoxia-inducible factor （HIF）-1 as a transcription factor has been found in the majority of tumor tissues. HIF-1 is a heterodimer made of the subunit HIF-1α regulated by oxygen and the HIF-1β subunit with constitutive expression. Under normoxic environment, through the activation of the ubiquitin - oxygen- dependent degradation domain （ODDD）, the HIF-1α is rapidly degraded through proline hydroxylation in the proteasome pathway, the half-life of HIF-1α is about 5 min. Under hypoxic conditions, HIF-1α can be stabilized by functional dimerization together with β subunit, which accelerates cell proliferation, migration and invasion in different kinds of cancers, thus HIF-1α is becoming one of the important inhibition targets for chemotherapies. This article reviews recent development of HIF-1 gene＇s molecular action mechanism that are related to cancer cell migration and invasion as well as the inhibition target for chemotherapy and to improve the medication through hyperbaric oxygen together with the antioxidation and anti-inflammation.