Gastrin inhibits a novel, pathological colon cancer signaling pathway involving EGR1, AE2, and P-ERK
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Human anion exchanger 2 (AE2) is a plasma membrane protein that regulates intracellular pH and cell volume. AE2 contributes to transepithelial transport of chloride and bicarbonate in normal colon and other epithelial tissues. We now report that AE2 overexpression in colon cancer cells is correlated with expression of the nuclear proliferation marker, Ki67. Survival analysis of 24 patients with colon cancer in early stage or 33 patients with tubular adenocarcinoma demonstrated that expression of AE2 is correlated with poor prognosis. Cellular and molecular experiments indicated that AE2 expression promoted proliferation of colon cancer cells. In addition, we found that transcription factor EGR1 underlies AE2 upregulation and the AE2 sequester p16INK4a (P16) in the cytoplasm of colon cancer cells. Cytoplasmic P16 enhanced ERK phosphorylation and promoted proliferation of colon cancer cells. Gastrin inhibited proliferation of colon cancer cells by suppressing expression of EGR1 and AE2 and by blocking ERK phosphorylation. Taken together, our data describe a novel EGR1/AE2/P16/P-ERK signaling pathway in colon carcinogenesis, with implications for pathologic prognosis and for novel therapeutic approaches.
KeywordsAnion exchanger 2 Tumor suppressor P16 ERK Gastrin
The authors thank China Zhenjiang First People’s Hospital for providing the 202 paraffin-embedded colon cancer specimens. pcDNA3.0-EGR1 construct were kindly provided by Ian de Belle (Laval University, Canada). This work was supported in part by the National Natural Science Foundation of China (NO30570697; NO30770960), National High Technology Research and Development Program of China (863 Program; NO2008AA02Z120), Shanghai Natural Science Foundation (NO11ZR1419700).
Conflict of interest
The authors declare no conflict of interest.
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