Hormonal Influences on Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) exhibits a pronounced sex disparity in incidence and progression, with men developing and succumbing to the disease more frequently than women. This difference has been linked to the actions of sex hormones—principally androgens and estrogens—on liver cells and the tumour microenvironment. Androgen signalling via the androgen receptor promotes hepatocyte proliferation, modulates viral oncogenesis in hepatitis B virus–associated HCC and cooperates with inflammatory cascades to drive tumour initiation. In contrast, oestrogens exert protective effects by tempering pro-inflammatory cytokine release, inhibiting alternative activation of tumour-associated macrophages and downregulating oncogenic transcription factors. Beyond direct receptor-mediated actions, the balance of circulating hormones influences metabolic pathways, immune cell recruitment and epigenetic regulation in the liver. Understanding these mechanisms has paved the way for hormone-modulating strategies in screening, chemoprevention and targeted therapy, with the aim of narrowing sex-based disparities and improving outcomes globally.

Research from Nature Portfolio

Recent studies have elucidated an inflammatory–metabolic axis in obesity-associated HCC. One investigation identified cell cycle-related kinase (CCRK) as an androgen-responsive oncogene that cooperates with obesity-induced inflammation to activate mTORC1 signalling. CCRK induction fosters a positive feedback loop involving STAT3 and androgen receptor co-occupancy of the CCRK promoter, thereby amplifying lipid accumulation, insulin resistance and tumour development. Genetic ablation of CCRK in male mice on a high-fat diet abrogated both metabolic dysfunction and hepatocarcinogenesis, underscoring CCRK as a nexus between endocrine cues and tumour metabolism.

In parallel, transgenic zebrafish models of HCC have revealed the opposing roles of sex hormones during early tumourigenesis. Male fish developed more aggressive and proliferative liver tumours, characterised by WNT/β-catenin activation and loss of cell adhesion, whereas females exhibited slower, more uniform lesions. Exogenous oestrogen administration suppressed cell proliferation and delayed tumour onset, while androgen supplementation accelerated growth. These findings establish zebrafish as a versatile platform for dissecting hormone-driven mechanisms in HCC.

Hormonal Influences on Hepatocellular Carcinoma publication trend

The graph below shows the total number of articles in hormonal influences on hepatocellular carcinoma across all publications each year (not limited to Nature Index journals).

Technical terms

Androgen receptor (AR): Nuclear receptor that mediates cellular responses to male sex hormones.

Estrogen receptor (ER): Nuclear receptor that mediates cellular responses to female sex hormones.

mTORC1: A protein complex (mechanistic target of rapamycin complex 1) that integrates nutrient and growth-factor signals to regulate cell growth and metabolism.

STAT3: Signal transducer and activator of transcription 3, a transcription factor activated by cytokines and growth factors, key in inflammatory signalling.

CCRK: Cell cycle-related kinase, an oncogenic kinase whose expression is driven by androgen receptor and inflammatory signals.

References

1. Role of Sex Hormones in the Development and Progression of Hepatitis B Virus‐Associated Hepatocellular Carcinoma. International Journal of Endocrinology (2015).
2. Estrogen Represses Hepatocellular Carcinoma (HCC) Growth via Inhibiting Alternative Activation of Tumor-associated Macrophages (TAMs)*. Journal of Biological Chemistry (2012).
3. Role of estrogen in hepatocellular carcinoma: is inflammation the key?. Journal of Translational Medicine (2014).
4. An inflammatory-CCRK circuitry drives mTORC1-dependent metabolic and immunosuppressive reprogramming in obesity-associated hepatocellular carcinoma. Nature Communications (2018).
5. Males develop faster and more severe hepatocellular carcinoma than females in krasV12 transgenic zebrafish. Scientific Reports (2017).
6. Distinct molecular etiologies of male and female hepatocellular carcinoma. BMC Cancer (2019).
7. Cytochrome P450 1A2 Metabolizes 17β-Estradiol to Suppress Hepatocellular Carcinoma. PLOS ONE (2016).