Journal of Molecular Medicine

, Volume 90, Issue 6, pp 707–718

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

  • Ling-Jun Song
  • Rui-Jun Liu
  • Zhi Zeng
  • Seth L. Alper
  • Heng-Jing Cui
  • Yang Lu
  • Lin Zheng
  • Zhao-Wen Yan
  • Guo-Hui Fu
Original Article

DOI: 10.1007/s00109-011-0851-2

Cite this article as:
Song, LJ., Liu, RJ., Zeng, Z. et al. J Mol Med (2012) 90: 707. doi:10.1007/s00109-011-0851-2

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.

Keywords

Anion exchanger 2Tumor suppressor P16ERKGastrin

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Ling-Jun Song
    • 1
  • Rui-Jun Liu
    • 1
  • Zhi Zeng
    • 1
  • Seth L. Alper
    • 2
  • Heng-Jing Cui
    • 3
  • Yang Lu
    • 3
  • Lin Zheng
    • 1
  • Zhao-Wen Yan
    • 1
  • Guo-Hui Fu
    • 1
    • 4
  1. 1.Department of Pathology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institutes of Medical SciencesShanghai Jiao Tong University School of MedicineShanghaiPeople’s Republic of China
  2. 2.Renal Division and Molecular and Vascular Medicine Unit, Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonUSA
  3. 3.Department of PharmacyShanghai Jiao Tong University School of MedicineShanghaiPeople’s Republic of China
  4. 4.Department of PathologyShanghai Jiao Tong University, School of MedicineShanghaiPeople’s Republic of China