Abstract
Microsomal prostaglandin E synthase-1 (mPGES-1) is a key enzyme that couples with cyclooxygenase-2 (COX-2) for the production of PGE2. Although COX-2 is known to mediate the growth and progression of several human cancers including hepatocellular carcinoma (HCC), the role of mPGES-1 in hepatocarcinogenesis is not well established. This study provides novel evidence for a key role of mPGES-1 in HCC growth and progression. Forced overexpression of mPGES-1 in two HCC cell lines (Hep3B and Huh7) increased tumor cell growth, clonogenic formation, migration and invasion, whereas knockdown of mPGES-1 inhibited these parameters, in vitro. In a mouse tumor xenograft model, mPGES-1-overexpressed cells formed palpable tumors at earlier time points and developed larger tumors when compared with the control (P<0.01); in contrast, mPGES-1 knockdown delayed tumor development and reduced tumor size (P<0.01). Mechanistically, mPGES-1-induced HCC cell proliferation, invasion and migration involve PGE2 production and activation of early growth response 1 (EGR1) and β-catenin. Specifically, mPGES-1-derived PGE2 induces the formation of EGR1-β-catenin complex, which interacts with T-cell factor 4/lymphoid enhancer factor 1 transcription factors and activates the expression of β-catenin downstream genes. Our findings depict a novel crosstalk between mPGES-1/PGE2 and EGR1/β-catenin signaling that is critical for hepatocarcinogenesis.
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Abbreviations
- COX-2:
-
cyclooxygenase-2
- GSK-3β:
-
glycogen synthase kinase 3 beta
- HCC:
-
hepatocellular carcinoma
- LEF:
-
lymphoid enhancer factor
- mPGES-1:
-
microsomal prostaglandin E synthase-1
- PGE2:
-
prostaglandin E2
- SUMO:
-
small ubiquitin-like modifier
- TCF:
-
T-cell factor
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Acknowledgements
This work is supported by the National Institutes of Health grants CA106280, CA102325, CA134568 and DK077776 (to TW) and CA137729 (to CH).
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Lu, D., Han, C. & Wu, T. Microsomal prostaglandin E synthase-1 promotes hepatocarcinogenesis through activation of a novel EGR1/β-catenin signaling axis. Oncogene 31, 842–857 (2012). https://doi.org/10.1038/onc.2011.287
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DOI: https://doi.org/10.1038/onc.2011.287
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