Role of estrogen in hepatocellular carcinoma: is inflammation the key?

Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and accounts for the third-leading cause of cancer-related deaths. Over the past decades, advances have been made in the field of surgery, but effective treatment of HCC is lacking. Due to a marked male predominance in morbidity and mortality in HCC patients, it has long been considered that sex hormones play a role in HCC development. Recently estrogen has been proven to exert protective effects against HCC through IL-6 restrictions, STAT3 inactivation and tumour-associated macrophage inhibition. While IL-6-dependent STAT3 activation is considered a key event in inflammation-induced liver cancer, the anti-inflammation effect of estrogen is well documented. The roles of the estrogen receptor and aromatase and interactions between microRNAs and estrogen in HCC have been investigated. In this review, we present a novel model to elucidate the mechanism of estrogen-mediated inhibition of HCC development through an anti-inflammation effect and provide new insights into the roles of estrogen in liver disease.

Figure 1

Four types of ER-α variants in the liver. Alternative splicing events generate several different isoforms of ER-α. In the liver, all types of ER-α have been reported and play a role in HCC. These variants are mainly AF-1- or HBD-depleted. ERα-36 has an additional 27-amino-acid sequence at its COOH terminus.

Figure 2

Estrogen inhibits HCC development through its anti-inflammatory effects. Estrogen exerts its protective effects through different pathways in KCs and hepatocytes. Ligand-bound ER-β inhibits M2 phenotype polarization in the ANA-1 cell line, and this procedure occurs mainly in TAMs, and not in KCs. Several miRNAs promote HCC by inhibiting ER-α. FOXA1/2 assists a ligand-bound ER-α to locate and bind to the ERE, and STAT3 plays a central role in these axes. Necrosis caused by liver injury defines the inflammatory microenvironment in the liver and eventually leads to HCC.