Hif1a, short for hypoxia-inducible factor 1 subunit alpha, is a crucial transcription factor. It responds to low oxygen availability (hypoxia) and plays essential roles in multiple biological processes. Hif1a activates the transcription of genes involved in angiogenesis, cell survival, glucose metabolism, and invasion [3]. It is a key regulator in the hypoxia-related pathway, and its dysregulation is associated with various diseases, especially cancer [3,5]. Genetic models, such as gene knockout (KO) or conditional knockout (CKO) mouse models, are valuable for studying Hif1a's function.

In endothelial cell-specific Atg7 knockout (atg7 KO) mice, ablation of Atg7 upregulated Stat1, which bound to the Hif1a promoter and suppressed its expression. This led to impaired angiogenesis, delayed blood-flow reperfusion after femoral artery ligation, demonstrating that Hif1a is critical for ischemia-induced angiogenesis [2]. In pancreatic cancer, lncRNA HIF1A-AS1 promoted gemcitabine resistance by upregulating Hif1a expression, enhancing glycolysis. Hif1a also promoted HIF1A-AS1 transcription, forming a positive-feedback loop [4]. In colorectal cancer, USP51 and Hif1a formed a positive-feed-forward loop. USP51 deubiquitinated Hif1a, activating hypoxia-induced gene transcription, while Hif1a upregulated USP51 expression. This loop promoted cancer stemness and chemoresistance [1].

In conclusion, Hif1a is a master regulator in hypoxia-related biological processes. Studies using KO/CKO mouse models have revealed its significance in angiogenesis, especially in ischemic conditions. In cancer, Hif1a is involved in processes like drug resistance, stemness, and chemoresistance, highlighting its potential as a therapeutic target in cancer treatment.

References:

1. Mu, Mingchao, Zhang, Qin, Li, Jing, Sun, Xuejun, Yu, Junhui. 2023. USP51 facilitates colorectal cancer stemness and chemoresistance by forming a positive feed-forward loop with HIF1A. In Cell death and differentiation, 30, 2393-2407. doi:10.1038/s41418-023-01228-8. https://pubmed.ncbi.nlm.nih.gov/37816999/

2. Yao, Hongmin, Li, Jian, Liu, Zhixue, Mu, Jing, Xie, Zhonglin. 2022. Ablation of endothelial Atg7 inhibits ischemia-induced angiogenesis by upregulating Stat1 that suppresses Hif1a expression. In Autophagy, 19, 1491-1511. doi:10.1080/15548627.2022.2139920. https://pubmed.ncbi.nlm.nih.gov/36300763/

3. Semenza, Gregg L. . Targeting HIF-1 for cancer therapy. In Nature reviews. Cancer, 3, 721-32. doi:. https://pubmed.ncbi.nlm.nih.gov/13130303/

4. Xu, Fengyu, Huang, Mengqi, Chen, Qingyong, Wang, Chunyou, Zhao, Gang. 2021. LncRNA HIF1A-AS1 Promotes Gemcitabine Resistance of Pancreatic Cancer by Enhancing Glycolysis through Modulating the AKT/YB1/HIF1α Pathway. In Cancer research, 81, 5678-5691. doi:10.1158/0008-5472.CAN-21-0281. https://pubmed.ncbi.nlm.nih.gov/34593522/

5. Gladek, I, Ferdin, J, Horvat, S, Calin, G A, Kunej, T. 2017. HIF1A gene polymorphisms and human diseases: Graphical review of 97 association studies. In Genes, chromosomes & cancer, 56, 439-452. doi:10.1002/gcc.22449. https://pubmed.ncbi.nlm.nih.gov/28165644/