The P2Y2 nucleotide receptor mediates the proliferation and migration of human hepatocellular carcinoma cells induced by ATP.
ATP is an abundant biochemical component of the tumor microenvironment and a physiologic ligand for the P2Y2 nucleotide receptor (P2Y2R). In this study, we investigated the effect of ATP on the cellular behavior of human hepatocellular carcinoma (HCC) cells and the role of P2Y2R in ATP action and aimed to find a new therapeutic target against HCC. The experiments were performed in native isolated human HCC cells, normal hepatocytes, human HCC cell lines, and nude mice. We found that the mRNA and protein expression levels of P2Y2R in native human HCC cells and the human HCC cell lines HepG2 and BEL-7404 were enhanced markedly compared with human normal hepatocytes and the normal hepatocyte line LO2, respectively. ATP induced intracellular Ca(2+) increases in HCC cells and promoted the proliferation and migration of HCC cells and the growth of HCC in nude mice. The P2Y receptor antagonist suramin, P2Y2R-specific shRNA, the store-operated calcium channel inhibitors 2-aminoethoxydiphenyl borate (2-APB) and 1-(β-3-(4-methoxy-phenyl) propoxyl-4-methoxyphenethyl)1H-imidazole-hydrochloride (SKF96365), and stromal interaction molecule (STIM1)-specific shRNA inhibited the action of ATP on HCC cells. In conclusion, P2Y2R mediated the action of ATP on the cellular behavior of HCC cells through store-operated calcium channel-mediated Ca(2+) signaling, and targeting P2Y2R may be a promising therapeutic strategy against human HCC.
From the Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, Zunyi 563003, China, the Digestive Disease Institute of Guizhou Province, Zunyi 563003, China.
Rui
R
Xie
From the Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, Zunyi 563003, China, the Digestive Disease Institute of Guizhou Province, Zunyi 563003, China, the Research Center of Medicine and Biology, Zunyi Medical College, Zunyi 563003, China, and.
Jingyu
J
Xu
From the Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, Zunyi 563003, China, the Digestive Disease Institute of Guizhou Province, Zunyi 563003, China, the Research Center of Medicine and Biology, Zunyi Medical College, Zunyi 563003, China, and.
Guorong
G
Wen
From the Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, Zunyi 563003, China, the Digestive Disease Institute of Guizhou Province, Zunyi 563003, China, the Research Center of Medicine and Biology, Zunyi Medical College, Zunyi 563003, China, and.
Hai
H
Jin
From the Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, Zunyi 563003, China, the Digestive Disease Institute of Guizhou Province, Zunyi 563003, China.
Xuemei
X
Liu
From the Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, Zunyi 563003, China, the Digestive Disease Institute of Guizhou Province, Zunyi 563003, China.
Yuan
Y
Yang
From the Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, Zunyi 563003, China, the Digestive Disease Institute of Guizhou Province, Zunyi 563003, China.
Bei
B
Ji
From the Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, Zunyi 563003, China, the Digestive Disease Institute of Guizhou Province, Zunyi 563003, China.
Yixia
Y
Jiang
the Key Laboratory of Combined Multiorgan Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
Penghong
P
Song
From the Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, Zunyi 563003, China, the Digestive Disease Institute of Guizhou Province, Zunyi 563003, China, h2dong@ucsd.edu.
Hui
H
Dong
From the Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, Zunyi 563003, China, the Digestive Disease Institute of Guizhou Province, Zunyi 563003, China, the Research Center of Medicine and Biology, Zunyi Medical College, Zunyi 563003, China, and tuobiguang@aliyun.com.
Biguang
B
Tuo
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000328:Adult; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D058473:Receptors, Purinergic P2Y2 / Q000235:genetics / Q000378:metabolism*
D015220:Calcium Channels; D058473:Receptors, Purinergic P2Y2; D000255:Adenosine Triphosphate; D002118:Calcium
ATP; Calcium Channel; Calcium Signaling; Cell Proliferation; Hepatocellular Carcinoma; P2Y2 Receptor; Purinergic Receptor; Store-operated Calcium Channel; Tumor Microenvironment