The HIF-1α as a Potent Inducer of the Hallmarks in Gastric Cancer

SIMPLE SUMMARY: Gastric cancer is one of the most aggressive tumors in the clinic that is resistant to chemotherapy. Gastric tumors are rich in hypoxic niches, and high expression of hypoxia-inducible factor-1α is associated with poor prognosis. Therefore, strategies that target hypoxia-inducible factor-1α signaling may be highly effective in gastric cancer treatment. However, the precise mechanisms by which hypoxia-inducible factor-1α induces tumor hallmarks in gastric cancer are yet unrevealed. Here, we review the role of hypoxia-inducible factor-1α as a potent inducer of the cancer hallmarks in gastric cancer to provide a broad perspective and reveal missing links investigating which may offer new strategies to target hypoxia-inducible factor-1α signaling in gastric cancer. ABSTRACT: Hypoxia is the principal architect of the topographic heterogeneity in tumors. Hypoxia-inducible factor-1α (HIF-1α) reinforces all hallmarks of cancer and donates cancer cells with more aggressive characteristics at hypoxic niches. HIF-1α potently induces sustained growth factor signaling, angiogenesis, epithelial–mesenchymal transition, and replicative immortality. Hypoxia leads to the selection of cancer cells that evade growth suppressors or apoptotic triggers and deregulates cellular energetics. HIF-1α is also associated with genetic instability, tumor-promoting inflammation, and escape from immunity. Therefore, HIF-1α may be an important therapeutic target in cancer. Despite that, the drug market lacks safe and efficacious anti-HIF-1α molecules, raising the quest for fully unveiling the complex interactome of HIF-1α in cancer to discover more effective strategies. The knowledge gap is even wider in gastric cancer, where the number of studies on hypoxia is relatively low compared to other well-dissected cancers. A comprehensive review of the molecular mechanisms by which HIF-1α induces gastric cancer hallmarks could provide a broad perspective to the investigators and reveal missing links to explore in future studies. Thus, here we review the impact of HIF-1α on the cancer hallmarks with a specific focus on gastric cancer.