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.

Hepatocellular carcinoma (HCC): beyond sorafenib—chemotherapy

“…Interestingly, recent data have revealed that estrogen exerts protective effects against HCC through IL-6 restriction, STAT3 inactivation and tumor associated macrophage inhibition (63), which may explain the lack of efficacy of hormonal therapy in advanced HCC. Currently, hormonal therapy is not recommended for advanced HCC.…”

Stat3 is a candidate epigenetic biomarker of perinatal Bisphenol A exposure associated with murine hepatic tumors with implications for human health

“…Increased production of the cytokine IL-6 initiates downstream STAT3 signaling. 18,22 STAT3 signaling is a key event in inflammation-driven liver carcinogenesis. 18 In fact, the classical sexual dimorphism in HCC incidence is thought to be due to the anti-inflammatory influence of endogenous estrogen via suppression of IL-6 production in an ERa-dependent manner.…”

“…We chose translationally-relevant candidate genes with functional links to hepatocellular carcinoma (HCC) for analysis based on expression changes reported in the literature in both rodent and human liver tumors. Three candidate genes were chosen: estrogen receptor a (Esr1/ESR1) [13][14][15][16] ; interleukin 6 signal transducer (Il6st/IL6ST), [17][18][19][20] also known as gp130; and signal transducer and activator of transcription 3 (Stat3/STAT3). 18,21 These candidate genes are functionally linked.…”

Untitled

“…Several immunological factors such as P2RY2, TNF-α, SNAI1 and IL-6, can regulate the expression of TGF-β through ITGAV 15 , DCN 16 , TGFB1 10 and IL17A 17 respectively. Similarly, over expression of mutated variant of ER1 (ERαδ5) have been seen in the peri-tumoral cirrhotic tissue of HCC patients, which correlated with increased proliferation rates in HCC cases 18 . Due to their vital role in immune responses, it interacts with numerous immunological proteins such as TGF-β, AFP, ALDH1A1, DJ-1 and TLRs through their interacting partners SMAD 19 , FOXA1 20,21 , BRCA1 22 , AR 23 and CHUK 24 respectively.…”