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Gastric precancerous lesions (GPL) are a special histopathological stage before the occurrence of gastric cancer. Effective treatment of GPL is the key to preventing its progression to gastric cancer. GPL has a high level of inflammation in gastric mucosa, and a large number of inflammatory cells, inflammatory factors and inflammatory mediators are metabolized at a high level, which increases oxygen consumption and leads to the formation of a hypoxia microenvironment in gastric mucosa at the GPL stage, which is conducive to the initiation of mitochondrial autophagy and glucose metabolism reprogramming. As a conserved biological process, mitochondrial autophagy exists in various tissues and cells of the body. It can form autophagosome to wrap mitochondria with damaged functions and bind with lysosomes to digest and reuse target mitochondria. Appropriate autophagy level can prevent excessive proliferation of GPL heterotype cells and inhibit the progress of GPL. However, mitochondrial autophagy activity is inhibited during the course of GPL, and the activity of glycometabolic reprogramming into glycolysis is increased during GPL. Glycolysis is a way of energy metabolism in the hypoxia state of cells, which can accelerate the energy supply of cells and the proliferation of abnormal cells, and thus accelerate the deterioration of GPL. Some evidences suggest that there may be a mutually restricting relationship between mitochondrial autophagy and glycolysis reprogramming. The inhibition of autophagy in GPL can increase glycolysis activity on the one hand, while the increase of autophagy inhibits glycolysis activity on the other hand. At present, the specific relationship and mechanism of autophagy and glycolysis are not clear, however, the complex pathological environment of GPL gastric mucosa composed of hypoxia, bacterial infection, inflammation, oxidative stress, activation disorder of signal molecules and other factors may be the key to the low autophagy level and high glycolysis activity. Hypoxia-inducible factor 1α (HIF-1α), which is involved in hypoxia adaptation, is stably expressed in gastric mucosa at the GPL stage and acts as a switch to initiate autophagy and glycolysis. However, HIF-1α seems to be more involved in the regulation of glycolysis in the pathological process of GPL. The cause of this change may be related to the above-mentioned pathological factors. H. pylori infection, activation of phosphoinositide 3-kinase (PI3K)/protein kinase (AKT)/mammalian target of rapamycin (mTOR) pathway and other factors inhibit autophagy. However, the continuous accumulation of reactive oxygen species (ROS) after autophagy inhibition and the aggravation of inflammation caused by H. pylori infection can promote a series of signal interactions and synergies among nuclear factor kappa-B (NF-Κb), signal transducer and activator of transcription 3 (STAT3) and PI3K/AKT/mTOR signaling pathways, and thus indirectly affect HIF-1α to promote glycolysis or directly improve glycolysis level. HIF-1α may be more involved in the activation of glycolysis due to the regulation of GPL pathological microenvironment and its upstream complex signals, thus unable to fully activate BNIP-3 mediated hypoxia-initiated autophagy, leading to the down-regulation or inhibition of autophagy level, and the inhibition of autophagy indirectly promotes the improvement of glycolysis level, forming a vicious cycle, and ultimately leading to the deterioration of GPL. This article reviewed the research progress of hypoxia-induced mitochondrial autophagy and glucose metabolism reprogramming in gastric precancerous lesions. |
