The HIF-1α as a Potent Inducer of the Hallmarks 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.

The hypoxia-inducible factor-1α in stemness and resistance to chemotherapy in gastric cancer: Future directions for therapeutic targeting

“…Upregulation of HIF-1α stimulates angiogenesis, Warburg effect, epithelial-mesenchymal transition, growth factor signaling, replicative immortality, tumor-promoting inflammation, and stemness in gastric cancer. Furthermore, apoptosis in response to anticancer therapy and immune attack is attenuated under the influence of HIF-1α, limiting the efficacy of chemotherapeutics, molecularly targeted agents, and immunotherapy in gastric cancer ( Pei et al, 2021 ; Ucaryilmaz Metin and Ozcan, 2022 ). Understanding the molecular mechanisms by which HIF-1α induces stemness and chemoresistance is essential to prevent tumor progression and chemoresistance in gastric cancer.…”

Construction of a hypoxia-immune-related prognostic panel based on integrated single-cell and bulk RNA sequencing analyses in gastric cancer

“…Hypoxia is involved in GC cell proliferation, migration and invasion through activation and upregulation of NHE1 ( 30 ). Hypoxia influences the expression of a variety of genes (including HIF-1α and von Hippel Lindau protein (pVHL)), resulting in the progression of cancer ( 31 , 32 ).…”

Cancer-associated fibroblasts: protagonists of the tumor microenvironment in gastric cancer

“…Hypoxic environments further enhance angiogenesis by upregulating proangiogenic factors and inflammatory mediators or growth factor signaling pathways ( Ucaryilmaz Metin and Ozcan, 2022b ). Park et al suggested that hypoxic CAFs promote some of the gastric cancer cell lines’ migratory and invasion capabilities by downregulating COL4A2 expression ( Park et al, 2023 ).…”