The expression of estrogen receptor alpha (ERα, encoded by ESR1) has been shown to be associated with the prognostic outcomes of patients in various cancers; however, its prognostic and mechanistic significance in hepatocellular carcinoma (HCC) remain unclear. Here, we evaluated the expression of ERα and its association with clinicopathological features in 339 HCC patients. ERα was expressed in 9.4% (32/339) of HCCs and was related to better overall survival (OS; hazard ratio [HR] = 0.11, p = 0.009, 95% C.I. = 0.016–0.82) and disease-free survival (DFS, HR = 0.4, p = 0.013, 95% C.I. = 0.18–0.85). ERα expression was also associated with features related to more favorable prognosis, such as older age, lower serum alpha-fetoprotein level, and less microvascular invasion (p < 0.05). In addition, to obtain mechanistic insights into the role of ERα in HCC progression, we performed integrative transcriptome data analyses, which revealed that yes-associated protein (YAP) pathway was significantly suppressed in ESR1-expressing HCCs. By performing cell culture experiments, we validated that ERα expression enhanced YAP phosphorylation, attenuating its nuclear translocation, which in turn suppressed the downstream signaling pathways and cancer cell growth. In conclusion, we suggest that ERα expression is an indicator of more favorable prognosis in HCC and that this effect is mediated by inactivation of YAP signaling. Our results provide new clinical and pathobiological insights into ERα and YAP signaling in HCC.

雌激素受体α（ERα，由ESR1编码）的表达已被证明与各种癌症患者的预后结果相关；然而，其在肝细胞癌（HCC）中的预后和机制意义仍不清楚。在这里，我们评估了 339 名 HCC 患者中 ERα 的表达及其与临床病理学特征的关联。ERα 在 9.4% (32/339) 的 HCC 中表达，并与更好的总生存期（OS；风险比 [HR] = 0.11，p  = 0.009，95% CI = 0.016-0.82）和无病生存期（DFS）相关, HR = 0.4, p = 0.013, 95% CI = 0.18–0.85)。ERα表达也与预后较好的特征相关，如年龄较大、血清甲胎蛋白水平较低和微血管侵犯较少（p  < 0.05）。此外，为了深入了解 ERα 在 HCC 进展中的作用，我们进行了综合转录组数据分析，结果表明，yes 相关蛋白 (YAP) 通路在ESR1中受到显着抑制-表达HCC。通过进行细胞培养实验，我们验证了 ERα 表达增强了 YAP 磷酸化，减弱了其核转位，进而抑制了下游信号通路和癌细胞生长。总之，我们认为 ERα 表达是 HCC 预后更佳的指标，并且这种效应是由 YAP 信号传导的失活介导的。我们的结果为 HCC 中的 ERα 和 YAP 信号传导提供了新的临床和病理生物学见解。