YAP inactivation in estrogen receptor alpha-positive hepatocellular carcinoma with less aggressive behavior

Abstract

The expression of estrogen receptor alpha (ER alpha, 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 ER alpha and its association with clinicopathological features in 339 HCC patients. ER alpha 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). ER alpha 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 ER alpha 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 ER alpha 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 ER alpha 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 ER alpha and YAP signaling in HCC. Liver cancer: How estrogen receptors hinder tumor growth Estrogen receptor signaling can act as a brake preventing the progression of an often deadly form of liver cancer. Studies have shown that women are at a lower risk of developing and succumbing to hepatocellular carcinoma (HCC) than men, suggesting a potential role for sex hormones. Researchers in South Korea led by Hyun Goo Woo of the Ajou University School of Medicine, Suwon, and Young Nyun Park of Yonsei University College of Medicine, Seoul, have now shown that expression of the estrogen receptor alpha is a strong prognostic predictor for HCC. In a survey of patient tumor samples, they found that expression of this hormone receptor is associated with nearly a tenfold increased likelihood of survival. The researchers identified a mechanism by which estrogen receptor alpha signaling impedes cancerous growth, revealing potential new drug targets.