Role of hypoxia-inducible factor – 1 alpha on the progression of cervical intraepithelial neoplasia and cervical cancer: a narrative review

Abstract

Cervical cancer represents a global public health problem, hence the importance of optimizing therapeutic options and expanding knowledge of prognostic markers. Clinical and experimental evidence shows that hypoxia-inducible factor (HIF) is a key inducer of aggressive phenotypes in cervical cancer: promoting angiogenesis, invasion, epithelial-mesenchymal transition (EMT), modulation of the immune microenvironment, and contributing to resistance to radiotherapy/chemotherapy in a possible synergistic effect with the human papilloma virus oncogenes. Hypoxic microenvironments that modulate the early activation of HIF pathways may be present in pre-invasive lesions and favor the acquisition of invasive phenotypes that precede invasion. This review highlights the mechanisms of HIF-1α in the progression of cervical intraepithelial neoplasia and cervical cancer. In this regard, HIF-1α is involved in the expression of genes related to angiogenesis, apoptosis and progression such as GLUT1, uPAR, BIRC5, EPO, EpoR, LIMD1, VHL, MET and pro-angiogenic genes (VEGF, PGF, PDGF-β, PAI-1, MMP-2, MMP-9, ANG-1, ANG-2, using pathways such as YAP/TA2. However, the balance between antitumor factors (miR-143) and protumor factors can define the progression of this neoplasia. In the future, the characterization of hypoxia signatures and the evaluation of HIF-1α pathway inhibitors are promising tools for optimizing outcomes in the treatment of cervical cancer, integrated with modern, high-precision radiation therapy techniques and predictive models based on imaging and artificial intelligence, which represent a key pillar of personalized oncology in cervical cancer, with the potential to improve tumor control and reduce toxicity; however, specific clinical trials are still needed to validate their impact on survival and safety.