Expression of anion exchanger 1 sequestrates p16 in the cytoplasm in gastric and colonic adenocarcinoma.
p16(INK4A) (p16) binds to cyclin-dependent kinase 4/6 and negatively regulates cell growth. Recent studies have led to an understanding of additional biologic functions for p16; however, the detailed mechanisms involved are still elusive. In this article, we show an unexpected expression of anion exchanger 1 (AE1) in the cytoplasm in poorly and moderately differentiated gastric and colonic adenocarcinoma cells and in its interaction with p16, thereby sequestrating the protein in the cytoplasm. Genetic alterations of p16 and AE1 were not detectable. Forced expression of AE1 in these cells sequestrated more p16 in the cytoplasm, whereas small interfering RNA-mediated silencing of AE1 in the cells induced the release of p16 from the cytoplasm to the nucleus, leading to cell death and growth inhibition of tumor cells. By analyzing tissue samples obtained from patients with gastric and colonic cancers, we found that 83.33% of gastric cancers and 56.52% of colonic cancers coexpressed AE1 and p16 in the cytoplasm. We conclude that AE1 plays a crucial role in the pathogenesis of gastric and colonic adenocarcinoma and that p16 dysfunction is a novel pathway of carcinogenesis.
Shen
Wei-Wei
WW
Department of Pathology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China.
Wu
Jun
J
Cai
Li
L
Liu
Bing-Ya
BY
Gao
Yan
Y
Chen
Guo-Qiang
GQ
Fu
Guo-Hui
GH
D000230:Adenocarcinoma / Q000378:metabolism*; D001457:Anion Exchange Protein 1, Erythrocyte / Q000096:biosynthesis*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D021381:Protein Transport; D034741:RNA, Small Interfering; D013274:Stomach Neoplasms / Q000378:metabolism*
D001457:Anion Exchange Protein 1, Erythrocyte; D019941:Cyclin-Dependent Kinase Inhibitor p16; D034741:RNA, Small Interfering