Prostaglandin E2 and Receptors: Insight Into Tumorigenesis, Tumor Progression, and Treatment of Hepatocellular Carcinoma.

Qingfei Chu,Jun Guan,Haihong Zhu,Xinyu Gu,Chao Chen

doi:10.3389/fcell.2022.834859

Abstract

Hepatocellular carcinoma (HCC) is a common primary liver cancer with ∼750,000 annual incidence rates globally. PGE2, usually known as a pro-inflammatory cytokine, is over-expressed in various human malignancies including HCC. PGE2 binds to EP receptors in HCC cells to influence tumorigenesis or enhance tumor progression through multiple pathways such as EP1-PKC-MAPK, EP2-PKA-GSK3β, and EP4-PKA-CREB. In the progression of hepatocellular carcinoma, PGE2 can promote the proliferation and migration of liver cancer cells by affecting hepatocytes directly and the tumor microenvironment (TME) through ERK/COX-2/PGE2 signal pathway in hepatic stellate cells (HSC). For the treatment of hepatocellular carcinoma, there are drugs such as T7 peptide and EP1 antagonist ONO-8711 targeting Cox-2/PGE2 axis to inhibit tumor progression. In conclusion, PGE2 has been shown to be a traditional target with pleiotropic effects in tumorigenesis and progression of HCC that could be used to develop a new potential clinical impact. For the treatment study focusing on the COX-PGE2 axis, the exclusive usage of non-steroidal anti-inflammatory agents (NSAIDs) or COX-2-inhibitors may be replaced by a combination of selective EP antagonists and traditional anti-tumoral drugs to alleviate severe side effects and achieve better outcomes.

Highlights

Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers with an annual incidence rate of ~750,000, ranking as the fifth most common malignant tumor worldwide in men and seventh in women (Ferlay et al, 2010; Hepatocellular carcinoma, 2016)
As the Cox-2/prostaglandin E2 (PGE2) axis plays an important role in the progress of hepatocellular carcinoma, there are a number of experiments focusing on the treatment of HCC based on it
The combination uses of drugs based on COX-2/PGE2 axis and traditional antitumor drugs show great potentials to diminish tumor progression of HCC in vivo and vitro, indicating that it might be a possible strategy for treatment of advanced primary hepatocellular carcinoma

Summary

Introduction

Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers with an annual incidence rate of ~750,000, ranking as the fifth most common malignant tumor worldwide in men and seventh in women (Ferlay et al, 2010; Hepatocellular carcinoma, 2016). Activate mTOR signaling pathway promotes HCC cell invasion and migration forming a positive feedback circuit inhibiting the ubiquitination of FBP1 and increasing FBP1 protein expression, promoting liver cancer cell growth Induce proto-oncogene c-Myc hepatocyte protective effects accumulate immunosuppressive cell as Th17 cells, regulate T cells and myeloid-derived suppressor cells (MDSCs)

Results

Conclusion