Expression of AE1/p16 promoted degradation of AE2 in gastric cancer cells.
Human anion exchanger 1 and 2 (AE1 and AE2) mediate the exchange of Cl(-)/HCO3 (-) across the plasma membrane and regulate intracellular pH (pHi). AE1 is specifically expressed on the surface of erythrocytes, while AE2 is widely expressed in most tissues, and is particularly abundant in parietal cells. Previous studies showed that an interaction between AE1 and p16 is a key event in gastric cancer (GC) progression, but the importance of AE2 in GC is unclear.



The relationship among AE1, AE2 and p16 in GC cells was characterized by molecular and cellular experiments. AE2 expression and pHi were measured after knockdown or forced expression of AE1 or p16 in GC cells. The effect of AE2 on GC growth and the correlation of AE2 expression with differentiation and prognosis of GC were also evaluated. The effect of gastrin on AE2 expression and GC growth was investigated in cellular experiments and mouse xenograft models.



p16 binds to both AE1 and AE2 simultaneously. AE1 or p16 silencing elevated AE2 expression on the plasma membrane where it plays a role in pHi regulation and GC suppression. AE2 expression was decreased in GC tissue, and these decreased levels were correlated with poor differentiation and prognosis of GC. The low AE2 protein levels are due to rapid ubiquitin-mediated degradation that was facilitated in the presence of p16. Gastrin inhibited the growth of GC cells at least partially through up-regulation of AE2 expression.



AE1/p16 expression promoted AE2 degradation in GC cells. Gastrin is a potential candidate drug for targeted therapies for AE1- and p16-positive GC.
Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, No.280, South Chong-Qing Road, Shanghai, 200025, People's Republic of China.
Ting
T
Wang
Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, No.280, South Chong-Qing Road, Shanghai, 200025, People's Republic of China.
Hong-Jun
HJ
Fei
Department of Digestive Medicine, Ningbo No. 2 Hospital, Ningbo, 315010, People's Republic of China.
Ye
Y
Yang
Department of Pathophysiology, Harbin Medical University, Harbin, 150081, People's Republic of China.
Xiao-Shu
XS
Jiang
Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China.
Min
M
Yan
Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, No.280, South Chong-Qing Road, Shanghai, 200025, People's Republic of China.
Zhi
Z
Zeng
Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, No.280, South Chong-Qing Road, Shanghai, 200025, People's Republic of China.
Jun
J
Wu
Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, No.280, South Chong-Qing Road, Shanghai, 200025, People's Republic of China.
Ling-Jun
LJ
Song
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, People's Republic of China.
Hua
H
Tian
Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, No.280, South Chong-Qing Road, Shanghai, 200025, People's Republic of China. fuguhu@263.net.
Guo-Hui
GH
Fu
D000818:Animals; D001457:Anion Exchange Protein 1, Erythrocyte / Q000378:metabolism*; D045744:Cell Line, Tumor; D027963:Chloride-Bicarbonate Antiporters / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D005755:Gastrins / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D013274:Stomach Neoplasms / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D001457:Anion Exchange Protein 1, Erythrocyte; D027963:Chloride-Bicarbonate Antiporters; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005755:Gastrins
AE1; AE2; Gastric cancer; Gastrin; p16