Abstract
Kremen2 (Krm2) plays an important role in embryonic development, bone formation, and tumorigenesis as a crucial regulator of classical Wnt/β-catenin signaling pathway. However, the role of Krm2 in gastric cancer is not clear. The aim of this study was to explore the regulatory role of Krm2 in the tumorigenesis and metastasis of gastric cancer. It was demonstrated that, compared to para-cancerous tissues, Krm2 was significantly up-regulated in gastric cancer tissues and was positively correlated with the pathological grade of gastric cancer patients. Given that Krm2 is abundantly expressed in most tested gastric cancer cell lines, Krm2 knockdown cell models were established and further used to construct mice xenograft model. After knocking down Krm2, both the cell survival in vitro and tumorigenesis in vivo of gastric cancer cells were inhibited. At the same time, knockdown of Krm2 induced apoptosis, cell cycle arrest at G2/M phase and repression of migration in gastric cancer cells in vitro. Mechanistically, we found that knockdown of Krm2 suppressed PI3K/Akt pathway. Therefore, we revealed the novel role and the molecular mechanism of Krm2 in promoting the tumorigenesis and metastasis in gastric cancer. Krm2 can be a potent candidate for designing of targeted therapy.
Highlights
Gastric cancer (GC) is the third leading cause of cancer-related death in the world [1], and about 50% gastric cancer occurs in China
During the 43 tested proteins, caspase 3, caspase 8, CD40L, p21, p27, p53, and TNF-a were significantly upregulated after knockdown of Kremen2 (Figure 5D). These results suggested that the inhibited cell proliferation by Krm2 knockdown may be related to regulation of apoptosis and cell cycle arrest, so we tested the changes of proteins in PI3K/Akt pathway
After Krm2 knockdown, expression levels of p-Akt, Akt, E2F1, PI3K, and cyclin D1 sharply decreased in SGC-7901 cells
Summary
Gastric cancer (GC) is the third leading cause of cancer-related death in the world [1], and about 50% gastric cancer occurs in China. Since the disease is asymptomatic in its early stages, more than half of patients are diagnosed in the advanced stage of tumor, for whom resection is no longer possible. Chemotherapy is another major method for treating gastric cancer. For patients with advanced gastric cancer, traditional cytotoxic chemotherapy only results in a median survival of 9–11 months [2], and the 5-year survival rate of metastatic gastric cancer is less than 10%. Molecular targeted therapy has brought new hope to the therapy of gastric cancer. It is necessary to deepen the understanding of the molecular mechanism of gastric carcinogenesis and identify potential drug-targets for GC targeted therapy
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