HIF-1α/VEGF信号通路对口腔癌生物学行为影响及诊疗意义

Signaling pathway of HIF-1α/VEGF regulates biological behavior of oral squamous cell carcinoma as therapeutic targets and predictive biomarkers

口腔鳞状细胞癌是一种特殊的以局部侵袭和颈淋巴结转移为特点的上皮性恶性肿瘤,晚期常有较大范围的缺血甚至坏死,使肿瘤组织同时酸性化和缺氧。缺氧导致缺氧诱导因子(hypoxia inducible factor,HIF)的高表达,它是肿瘤危害性和危险性的决定因素之一。HIF-1是细胞缺氧应答的关键调控因子,在缺氧环境下,羟基化被抑制,HIF-1的α、β亚基结合成异二聚体,形成稳定HIF-1-DNA,HIF-1α被激活。活化的HIF-1是包括血管内皮生成因子(vascular endothelial growth factor,VEGF)及其受体VEGFR在内的很多基因的转录调控因子,调控它们的转录活性。VEGF在肿瘤中表达,既是血管通透因子,也是肿瘤血管和淋巴管生成的关键调控因子。HIF-1α/VEGF信号通路调控着肿瘤血管生成以及细胞增殖、代谢、抗凋亡和移行的生理通路。已有研究表明,缺氧在口腔癌进展(增殖和转移)、药物抵抗和预后方面起主要作用,本文阐述了HIF-1α/VEGF信号通路的基本生理特征,分析了HIF-1α、VEGF在口腔癌中的表达效应及与其相关分子的作用,并评价了它们作为治疗靶点和预后判断生物标记的可行性和临床意义。

Oral squamous cell carcinoma （OSCC） is a special locally aggressive malignant epithelial tumor with lymph node metastasis to the neck that presents large areas of tumoral necrosis with ischemia, in which the levels of acidity and hypoxia are very high. Hypoxia is a critical and decisive factor for malignancy and appears to be controlled mainly by hypoxia inducible factor （HIF）. HIF-1 is the key regulator of cellular response to hypoxia. In hypoxic conditions, hydroxyl- ation does not occur, and HIF-1 DNA-binding complex is ot heterodimer of α and β subunits. Then HIF-1α is activated and the stabilized HIF-1α induces transcriptional activity. HIF-1 is recognized as an important protein that regulates the transcription of several genes related to angiogenesis, including vascular endothelial growth factor （VEGF） and VEGF re- ceptor. VEGF is an angiogenic cytokine expressed by tumors. VEGF is also known as a vascular permeability factor, being considered a key regulator in tumor-induced angiogenesis and lymphangiogenesis. Signaling pathway of HIF- 1α/VEGF regulates several important biologic pathways, including cell proliferation, angiogenesis, cell metabolism, anti-apoptosis and migration. In the present study, hypoxia plays a major role in tumor progression （proliferation and metastasis）, therapy resistance and for prognosis of 0SCC. The goal of this article is to describe basic biological features of HIF/VEGF signaling pathway, analyze the effects of their expression in OSCC and its relationship with other molecules and to assess the possibil- ity of their manipulation as therapeutic targets and predictive biomarkers.