Abstract
The metastasis of tumor cells to distant organs is an ominous feature of gastric cancer. However, the molecular mechanisms underlying the invasion and metastasis of gastric cancer cells remain elusive. In this study, we found that the expression of ATG4A, an autophagy-regulating molecule, was significantly increased in gastric cancer tissues and was significantlycorrelated with the gastric cancer differentiation degree, tumor invasion and lymph node metastasis. ATG4A over-expression significantly promoted gastric cancer cell migration and invasion in vitro and metastasis in vivo, as well as promoted gastric cancer cell stem-like properties and the epithelial-mesenchymal transition (EMT) phenotype. By contrast, ATG4A knockdown inhibited the migration, invasion and metastasis of cancer cells, as well as the stem-like properties and EMT phenotype. Mechanistically, ATG4A promotes gastric cancer cell stem-like properties and the EMT phenotype through the activation of Notch signaling not via autophagy, and using the Notch signaling inhibitor DAPT attenuated the effects of ATG4A on gastric cancer cells. Taken together, these findings demonstrated that ATG4A promotes the metastasis of gastric cancer cells via the Notch signaling pathway, which is an autophagy-independent mechanism.
Highlights
Gastric cancer is one of the most common malignancies worldwide
The results indicated that ATG4A expression is increased in gastric cancer, especially in the tumor invasion front and in lymph node metastatic lesions [18]
We first demonstrated that both gastric cancer cells in the invasive frontier area and metastatic lymph nodes expressed high levels of ATG4A compared with primary cancer cells
Summary
Gastric cancer is one of the most common malignancies worldwide. There were more than 700,000 deaths due to gastric cancer in 2014, making this disease the third most common cause of cancer death globally [1, 2]. Despite the development and identification of novel anticancer agents and treatment methods over the past decades, almost 50% of gastric cancer patients eventually develop recurrent disease and distant metastasis after surgical treatment [3]. The distant metastasis of gastric cancers is the main cause of more than 90% of patient deaths [4]. The identification of molecules associated with gastric cancer invasion and metastasis would contribute to the understanding of the mechanisms involved in gastric cancer malignancy, leading to the development of novel biomarkers and therapeutic targets for gastric cancer
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