Gastrin inhibits a novel, pathological colon cancer signaling pathway involving EGR1, AE2, and P-ERK.
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.
Department of Pathology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China.
Ling-Jun
LJ
Song
Rui-Jun
RJ
Liu
Zhi
Z
Zeng
Seth L
SL
Alper
Heng-Jing
HJ
Cui
Yang
Y
Lu
Lin
L
Zheng
Zhao-Wen
ZW
Yan
Guo-Hui
GH
Fu
D027321:Anion Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017920:Antiporters / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000503:physiopathology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D005755:Gastrins / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000502:physiology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D064606:SLC4A Proteins
D027321:Anion Transport Proteins; D000970:Antineoplastic Agents; D017920:Antiporters; D019941:Cyclin-Dependent Kinase Inhibitor p16; D051766:Early Growth Response Protein 1; D005755:Gastrins; D012333:RNA, Messenger; D064606:SLC4A Proteins