Abstract
Gastric cancer is one of the most common causes of cancer-related death worldwide. Helicobacter pylori infection plays an important role in the development and progression of gastric cancer. The expression of astrocyte-elevated gene-1 (AEG-1) is increased in gastric cancer tissues, thereby contributing to the inflammatory response. We investigated whether and how AEG-1 regulated proinflammatory signaling in gastric cancer cells. We used human gastric cancer cell lines and athymic nude mice to investigate the role of AEG-1 in the regulation of the TLR4/nuclear factor-κB (NF-κB) signaling pathway and cancer invasion and compared the expression of AEG-1 and related proteins in 93 patients with gastric cancer by immunohistochemistry. In human gastric cancer cells, both AEG-1 and TLR4 could be induced by lipopolysaccharide (LPS) stimulation. AEG-1 was upregulated via LPS-TLR4 signaling and in turn promoted nuclear translocation of the NF-κB p65 subunit. At the same time, AEG-1 overexpression decreased the levels of suppressor of cytokine signaling (SOCS) protein SOCS-1, a negative regulator of the TLR4 pathway. Furthermore, nude mice engrafted with AEG-1/TLR4-expressing cells demonstrated larger tumor volumes than control animals. In patients with gastric cancer, the expression of AEG-1 correlated with that of TLR4, SOCS-1, and NF-κB and was higher in tumors compared with noncancerous adjacent tissues. Overall survival in patients with gastric cancer with simultaneous expression of AEG-1 and TLR4 was poor. Our results demonstrate that AEG-1 can promote gastric cancer progression by a positive feedback TLR4/NF-κB signaling-related mechanism, thus providing new mechanistic explanation for the role of inflammation in cancer progression.
Highlights
Gastric cancer remains the fourth most common cancer and the second leading cause of cancer-related death in the world [1]
We explored the role of astrocyte-elevated gene-1 (AEG-1) in the regulation of TLR4/nuclear factor-kB (NF-kB) signaling in gastric cancer
For all the 4 patients examined, protein and mRNA expression of both AEG-1 and TLR4 was higher in gastric tumors than in the adjacent noncancerous gastric tissues from the same patient (Fig. 1A–C)
Summary
Gastric cancer remains the fourth most common cancer and the second leading cause of cancer-related death in the world [1]. Dietary changes, and reduction in chronic Helicobacter pylori infection have resulted in a substantial decrease of stomach cancer rates in most parts of the world [2, 3]. China alone accounts for nearly 42% of all gastric cancer cases worldwide [4]. AEG-1, known as metadherin (MTDH) or LYRIC, is induced in primary human fetal astrocytes infected with HIV-1 or treated with recombinant HIV-1 envelope glycoprotein (gp120) or tumor necrosis factor-a AEG-1 is markedly overexpressed in many tumors such as breast cancer, hepatocellular carcinoma, and neuroblastoma [7,8,9].
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