Gastrin inhibits a novel, pathological colon cancer signaling pathway involving EGR1, AE2, and P-ERK

Abstract

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.

Trastuzumab Inhibits Growth of HER2-Negative Gastric Cancer Cells Through Gastrin-Initialized CCKBR Signaling

“…Increasing evidence supports the view that gastrin prevents rather than promotes GC and colon cancer progression. For example, our previous work demonstrated that gastrin/CCKBR inhibits growth of GC and colon cancer cells after long-term treatment with gastrin in vitro and in vivo [15][16][17][18][19][20][21]30]. These contradictory results suggest that gastrin has variable effects on different cancer types and at different pathological stages.…”

“…Studies have demonstrated that effects of gastrin on GC cells are mediated by CCKBR [16,17]. To understand the underlying mechanism(s) involved in the synergistic role(s) of gastrin and trastuzumab, CCKBR levels were measured by Western Blot after treatment of SGC7901 and NCI-N87 cells.…”

“…The effect of gastrin on cancer is controversial. Papers have reported that gastrin plays a role in GC progression [12][13][14]; however, recent studies indicated that gastrin inhibits the growth of CCKBR-expressing cancers in vitro and in vivo [15][16][17][18][19][20]. We previously found that gastrin-sensitive GC cells express a large amount of cytoplasmic AE1 and p16 [21].…”

Pinopodes, leukemia inhibitory factor, integrin-β3, and mucin-1 expression in the peri-implantation endometrium of women with unexplained recurrent pregnancy loss

“…Five random fields of view were taken for every slide. Staining was quantitatively analyzed using the Axioplan 2 Imaging Analysis System (Zeiss) with KS400 version 3.0, and the results were expressed as the percentage of positively stained tissue area, where <10% expression was considered ''loss'' (À), and >10% expression was designated (þ) (23). The final value was expressed as the ratio of positive-staining cell area to entire cell area.…”

Ion channels and transporters in metastasis

“…In human hepatocellular carcinoma AE2 is overexpressed [123] and its inhibition induces apoptosis [124,125]. Induction of AE2 also contributes to colonic carcinogenesis through the activation of the extracellular signal-regulated kinase (ERK) pathway which can be blocked by AE2-targeted small interfering RNA (siRNA) or gastrin treatment [126]. In gastric cancer cells, however, AE2, downregulation of AE2 can be correlated with carcinogenesis which can be blocked by gastrin [127].…”