Intratumoral but not circulating estradiol predicts postoperative survival in men with hepatocellular carcinoma

Sex disparity in HCC indicates vital estrogen signaling roles. The clinical significance of intratumoral and circulating estradiol (E2) remains unclear in male HCC. This study explored their correlations with clinicopathological features, postoperative survival and tumor growth.

Paired tumor and adjacent liver tissues and preoperative serum were collected from 120 male HCC patients; serum from 120 healthy men served as controls. E2 levels were measured by iodine-125 radioimmunoassay, and estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) expression was assessed by immunohistochemistry. Survival was analyzed using Kaplan-Meier and Cox regression, with sensitivity analyses based on cohort median, 12-month time-dependent ROC-derived cutoffs, and continuous-variable Cox models. HepG2 cells were treated with E2 and evaluated by CCK-8, colony formation, RT-qPCR, and western blotting. Mouse xenograft models were established with HepG2 cells pretreated with or without E2.

Intratumoral E2 was significantly lower in HCC than in adjacent tissues, while serum E2 was higher in HCC patients than in healthy controls (both P < 0.001). ERα and ERβ expression was reduced in tumor tissues (both P < 0.01). Low intratumoral E2, but not serum E2, was associated with larger tumor size and poorer postoperative survival (HR = 1.722, 95% CI 1.145-2.592, P = 0.009). E2 inhibited HepG2 proliferation and reduced PCNA expression in vitro, whereas xenografts established from E2-pretreated HepG2 cells showed reduced growth.

Lower intratumoral E2 levels were associated with larger tumor size and poorer postoperative survival in men with HCC. These findings support further evaluation of intratumoral E2 as a potential prognostic biomarker.