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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

  • Authors:
    • Shukai Xia
    • Juan Ma
    • Xiaoming Bai
    • Hai Zhang
    • Shanyu  Cheng
    • Min Zhang
    • Li Zhang
    • Mingzhan Du
    • Yipin  Wang
    • Hai Li
    • Rong Rong
    • Feng Shi
    • Qinyi Yang
    • Jing Leng

  • View Affiliations

  • Published online on: August 7, 2014     https://doi.org/10.3892/or.2014.3393
  • Pages: 1521-1530
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Abstract

Hepatocellular carcinoma (HCC) represents a major health problem worldwide. Prostaglandin E2 (PGE2), 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 PGE2 and c-Myc in HCC, and to define its role in HCC cell growth and invasion. Our results showed that PGE2 significantly upregulated c-Myc expression at both the mRNA and protein levels, and knockdown of c-Myc blocked PGE2-induced HCC cell growth and invasive ability in human HCC Huh-7 cells. The effect of PGE2 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 GS/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 GS/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 PGE2 significantly upregulates c-Myc expression at both mRNA and protein levels through the EP4R/GS/AC/cAMP/PKA/CREB signaling pathway, thus promoting cell growth and invasion in HCC cells. Targeting of the PGE2/EP4R/c-Myc pathway may be a new therapeutic strategy to prevent and cure human HCC.
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October 2014
Volume 32 Issue 4

Print ISSN: 1021-335X
Online ISSN:1791-2431

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  • Source Normalized Impact per Paper (SNIP): 0.786
  • SCImago Journal Rank (SJR): 0.812
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Spandidos Publications style
Xia S, Ma J, Bai X, Zhang H, Cheng S, Zhang M, Zhang L, Du M, Wang Y, Li H, Li H, et al: 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. Oncol Rep 32: 1521-1530, 2014
APA
Xia, S., Ma, J., Bai, X., Zhang, H., Cheng, S., Zhang, M. ... Leng, J. (2014). 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. Oncology Reports, 32, 1521-1530. https://doi.org/10.3892/or.2014.3393
MLA
Xia, S., Ma, J., Bai, X., Zhang, H., Cheng, S., Zhang, M., Zhang, L., Du, M., Wang, Y., Li, H., Rong, R., Shi, F., Yang, Q., Leng, J."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". Oncology Reports 32.4 (2014): 1521-1530.
Chicago
Xia, S., Ma, J., Bai, X., Zhang, H., Cheng, S., Zhang, M., Zhang, L., Du, M., Wang, Y., Li, H., Rong, R., Shi, F., Yang, Q., Leng, J."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". Oncology Reports 32, no. 4 (2014): 1521-1530. https://doi.org/10.3892/or.2014.3393