Ozcan Gulnihal
Department of Medical Pharmacology, School of Medicine, Koç University, Istanbul, Turkiye.
Koç University Research Center for Translational Medicine, Istanbul, Turkiye.
Front Cell Dev Biol. 2023 Feb 8;11:1082057. doi: 10.3389/fcell.2023.1082057. eCollection 2023.
Hypoxia-inducible factor-1α (HIF-1α) is a crucial mediator of intra-tumoral heterogeneity, tumor progression, and unresponsiveness to therapy in tumors with hypoxia. Gastric tumors, one of the most aggressive tumors in the clinic, are highly enriched in hypoxic niches, and the degree of hypoxia is strongly correlated with poor survival in gastric cancer patients. Stemness and chemoresistance in gastric cancer are the two root causes of poor patient outcomes. Based on the pivotal role of HIF-1α in stemness and chemoresistance in gastric cancer, the interest in identifying critical molecular targets and strategies for surpassing the action of HIF-1α is expanding. Despite that, the understanding of HIF-1α induced signaling in gastric cancer is far from complete, and the development of efficacious HIF-1α inhibitors bears various challenges. Hence, here we review the molecular mechanisms by which HIF-1α signaling stimulates stemness and chemoresistance in gastric cancer, with the clinical efforts and challenges to translate anti-HIF-1α strategies into the clinic.
缺氧诱导因子-1α（HIF-1α）是肿瘤内异质性、肿瘤进展以及缺氧肿瘤对治疗无反应的关键介质。胃癌是临床上侵袭性最强的肿瘤之一，其缺氧微环境高度富集，缺氧程度与胃癌患者的不良生存率密切相关。胃癌中的干性和化疗耐药性是导致患者预后不良的两个根本原因。基于HIF-1α在胃癌干性和化疗耐药性中的关键作用，识别关键分子靶点以及超越HIF-1α作用的策略的研究兴趣正在不断扩大。尽管如此，对HIF-1α在胃癌中诱导的信号传导的理解仍远未完善，开发有效的HIF-1α抑制剂面临各种挑战。因此，在此我们综述HIF-1α信号传导刺激胃癌干性和化疗耐药性的分子机制，以及将抗HIF-1α策略转化为临床应用所做的临床努力和面临的挑战。
