Abstract
The aberrant activation of Wnt signaling has been implicated in a variety of human cancers, including gastric cancer. Given the current hypothesis that cancer arises from cancer stem cells (CSCs), targeting the critical signaling pathways that support CSC self-renewal appears to be a useful approach for cancer therapy. Cell cycle and apoptosis regulator 1 (CCAR1) is a transcriptional coactivator which has been shown to be a component of Wnt/β-catenin signaling, and which plays an important role in transcriptional regulation by β-catenin. However, the function and clinical significance of CCAR1 in gastric cancer have not been elucidated. Here, we show that elevated CCAR1 nuclear expression correlates with the occurrence of gastric cancer. In addition, RNAi-mediated CCAR1 reduction not only suppressed the cell growth and increased apoptosis in AGS and MKN28 cells, but also reduced the migration and invasion ability of these cells. Furthermore, an in vivo xenograft assay revealed that the expression level of CCAR1 was critical for tumorigenesis. Our data demonstrates that CCAR1 contributes to carcinogenesis in gastric cancer and is required for the survival of gastric cancer cells. Moreover, CCAR1 may serve as a diagnostic marker and a potential therapeutic target.
Highlights
Gastric cancer is the fourth most common cancer and the second most common cause of cancer death after lung cancer, because of the poor prognosis of patients [1,2]
Gastric carcinogenesis can be viewed as a multi-step process involving Helicobacter pylori (H. pylori) infection, genetic alterations, and other risk factors that cause cells to progressively transform into cancer [4]
Many reports support the concept that tumors contain a small subset of cells, the “cancer stem cells (CSCs)”, which exhibit a self-renewal capacity and which are responsible for tumor maintenance and metastasis
Summary
Gastric cancer is the fourth most common cancer and the second most common cause of cancer death after lung cancer, because of the poor prognosis of patients [1,2]. It is very likely that, due to the accumulation of mutations, H. pylori infection, epigenetic changes, and genetic alteration, dysregulation of the signaling pathways that control these Lgr5+ stem cells will give rise to gastric cancer. Mutations in the Apc gene were found in approximately 85% of colorectal cancer cases [15], and activating β-catenin mutations that affect its phosphorylation by Gsk3β, have been identified in 50% of colon cancers that have wild-type Apc. Considering that the stomach and intestine share the same origin during development, and their adult stem cells express the same specific marker (Lgr5), it is likely that the Wnt signaling pathway has similar impacts on the development of gastric cancer and the development of colorectal cancer. The results of this study may provide us with a potentially valuable therapeutic target for treating gastric cancer patients
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