Abstract
Phosphorylation of PTEN at residues Ser380/Thr382/383 leads to loss of phosphatase activity and tumor suppressor function. Here, we found that phosphorylation of PTEN at residues Ser380/Thr382/383 was increased with gastric carcinogenesis, and more importantly, Helicobacter pylori was a trigger of this modification in chronic non-atrophic gastritis. H. pylori could phosphorylate and inactivate PTEN in vivo and in vitro, resulting in survival of gastric epithelial cells. Furthermore, stable expression of dominant-negative mutant PTEN or inhibition of Akt prevented the enhanced survival induced by H. pylori. These results indicate that PTEN phosphorylation at residues Ser380/Thr382/383 is a novel mechanism of PTEN inactivation in gastric carcinogenesis, and H. pylori triggers this modification, resulting in activation of the PI3K/Akt pathway and promotion of cell survival.
Highlights
Gastric cancer is the fourth most common cancer worldwide, the third leading cause of cancer-related death in males and the fifth among females [1]
We demonstrated that aberrant phosphorylation of Phosphatase and tensin homolog (PTEN) at residue Ser380 was an early event that could contribute to gastric carcinogenesis [21]
Weak to strong phosphorylated PTEN was observed in 57.5%, 87.5%, 82.5%, and 75.0% of chronic non-atrophic gastritis, intestinal metaplasia, dysplasia, and gastric cancer, respectively, indicating that phosphorylated PTEN was significantly increased in intestinal metaplasia, and dysplasia compared to chronic non-atrophic gastritis (Figure 2A)
Summary
Gastric cancer is the fourth most common cancer worldwide, the third leading cause of cancer-related death in males and the fifth among females [1]. The incidence and mortality of gastric cancer have declined, it is still one of the most significant health burdens in the world [1, 2]. Treatment with chemotherapy has limited effects and usually serves as palliative care to relieve patient symptoms and increase survival time [1]. Surgical resection remains the only curative means to improve survival. As the underlying mechanisms responsible for the development and progression of gastric cancer are still poorly understood, further investigation is needed to develop novel preventative strategies. It is known that Helicobacter pylori infection induces chronic non-atrophic gastritis which can progress to intestinal metaplasia, dysplasia and gastric cancer [3]. Epidemiologic, animal and clinical studies have confirmed this critical role of H. pylori, which has been classified as a class I carcinogen for gastric cancer by the International Agency for Research of Cancer [4]
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