Upregulation of P2Y2 nucleotide receptor in human hepatocellular carcinoma cells.
Objective To examine if hypoxia inducible factor-1α (HIF-1α) can induce the upregulation of the purinergic receptor P2Y2 (P2Y2) and thereby promote the viability of human hepatocellular carcinoma (HCC) cells under hypoxic conditions. Methods Archival HCC tumour specimens and corresponding non-cancerous tissues were examined immunohistochemically for P2Y2 protein. A series of in vitro experiments were undertaken using HCC cell lines to determine the effect of hypoxia on HIF-1α and P2Y2 levels, the effect of HIF-1α upregulation on P2Y2 levels, and the effect of P2Y2 upregulation on cell viability under hypoxic conditions. Results Human HCC specimens were positive for P2Y2. Hypoxia and upregulated HIF-1α both upregulated the P2Y2 levels in HCC cell lines. P2Y2 upregulation using plasmid transfection resulted in enhanced cell viability under hypoxia. Treatment of HepG2 cells with the selective P2Y2 antagonist MRS2312 downregulated P2Y2 and reduced cell viability in five HCC cell lines. P2Y2 knockdown reduced HepG2 cell viability under hypoxia. Conclusions These present results suggest that HCC cells upregulate P2Y2 levels during hypoxia, which in turn promotes their growth. P2Y2 could be a potential therapeutic target for treating HCC.
1 Asan Institute for Life Sciences, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Eunyoung
E
Tak
1 Asan Institute for Life Sciences, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Dae Young
DY
Jun
2 Department of Surgery, Division of Liver Transplantation and Hepatobiliary Surgery, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Seok-Hwan
SH
Kim
2 Department of Surgery, Division of Liver Transplantation and Hepatobiliary Surgery, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Gil-Chun
GC
Park
1 Asan Institute for Life Sciences, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Jooyoung
J
Lee
2 Department of Surgery, Division of Liver Transplantation and Hepatobiliary Surgery, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Shin
S
Hwang
2 Department of Surgery, Division of Liver Transplantation and Hepatobiliary Surgery, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Gi-Won
GW
Song
2 Department of Surgery, Division of Liver Transplantation and Hepatobiliary Surgery, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Sung-Gyu
SG
Lee
D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D060787:Neoplasm Grading; D010100:Oxygen / Q000494:pharmacology; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D058473:Receptors, Purinergic P2Y2 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D058473:Receptors, Purinergic P2Y2; D010100:Oxygen
MRS2312; Purinergic receptor P2Y2; hepatocellular carcinoma; hypoxia inducible factor-1α