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Prostaglandin E2 promotes the cell growth and invasive ability of hepatocellular carcinoma cells by upregulating c-Myc expression via EP4 receptor and the PKA signaling pathway

SHUKAI XIA, JUAN MA, XIAOMING BAI, HAI ZHANG, SHANYU CHENG, MIN ZHANG, LI ZHANG, MINGZHAN DU, YIPIN WANG, HAI LI, RONG RONG, FENG SHI (+2 others)
2014 Oncology Reports  
Hepatocellular carcinoma (HCC) represents a major health problem worldwide. Prostaglandin E 2 (PGE 2 ), the predominant product of cyclooxygenase-2, has been implicated in hepatocarcinogenesis. However, the underlying molecular mechanisms remain to be further elucidated. c-myc, a cellular proto-oncogene, is activated or overexpressed in many types of human cancer, including HCC. The present study was designed to investigate the internal relationship and molecular mechanisms between PGE 2 and
more » ... etween PGE 2 and c-Myc in HCC, and to define its role in HCC cell growth and invasion. Our results showed that PGE 2 significantly upregulated c-Myc expression at both the mRNA and protein levels, and knockdown of c-Myc blocked PGE 2 -induced HCC cell growth and invasive ability in human HCC Huh-7 cells. The effect of PGE 2 on c-Myc expression was mainly through the EP4 receptor, and EP4 receptor-mediated c-Myc protein upregulation largely depended on de novo biosynthesis of c-Myc mRNA and its protein. EP4 receptor signaling activated G S / AC and increased the intracellular cAMP level in Huh-7 cells. The adenylate cyclase (AC) activator forskolin mimicked the effects of the EP4 receptor agonist on c-Myc expression, while the AC inhibitor SQ22536 reduced EP4 receptor-mediated c-Myc upregulation. These data confirm the involvement of the G S /AC/cAMP pathway in EP4 receptor-mediated c-Myc upregulation. Moreover, the phosphorylation levels of CREB protein were markedly elevated by EP4 receptor signaling, and by using specific inhibitor and siRNA interference, we demonstrated that PKA/CREB was also involved in the EP4 receptor-mediated c-Myc upregulation. In summary, the present study revealed that PGE 2 significantly upregulates c-Myc expression at both mRNA and protein levels through the EP4R/G S /AC/cAMP/PKA/CREB signaling pathway, thus promoting cell growth and invasion in HCC cells. Targeting of the PGE 2 /EP4R/c-Myc pathway may be a new therapeutic strategy to prevent and cure human HCC.
doi:10.3892/or.2014.3393 pmid:25109834 fatcat:jaii324ssvabhbytdmnug7pt64