Department of Pathology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea.
Department of Radiology, Yonsei University College of Medicine, Seoul, Korea.
Exp Mol Med. 2021 Jun;53(6):1055-1067. doi: 10.1038/s12276-021-00639-2. Epub 2021 Jun 18.
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 alpha（ERα，由 ESR1 编码）的表达已被证明与多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 例 HCC 患者中 ERα 的表达及其与临床病理特征的关系。在 339 例 HCC 中，9.4%（32/339）表达 ERα，与更好的总生存期（OS；风险比[HR] = 0.11，p = 0.009，95%置信区间[CI] = 0.016-0.82）和无病生存期（DFS，HR = 0.4，p = 0.013，95%CI = 0.18-0.85）相关。ERα 的表达也与更有利的预后特征相关，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 进展中的作用机制，我们进行了整合转录组数据分析，结果表明，在 ESR1 表达的 HCC 中，Yes 相关蛋白（YAP）通路显著受到抑制。通过进行细胞培养实验，我们验证了 ERα 的表达增强了 YAP 的磷酸化，从而抑制了其核易位，进而抑制了下游信号通路和癌细胞的生长。总之，我们认为 ERα 的表达是 HCC 预后更有利的指标，这种作用是通过 YAP 信号失活介导的。我们的研究结果为 ERα 和 YAP 信号在 HCC 中的临床和病理生物学意义提供了新的见解。
