Hepatocellular carcinoma (HCC) is an aggressive disease that occurs predominantly in men. Estrogen elicits protective effects against HCC development. Elucidation of the estrogen-regulated biological processes that suppress HCC could lead to improved prevention and treatment strategies. Here, we performed transcriptomic analyses on mouse and human liver cancer and identified LCAT as the most highly estrogen-upregulated gene and a biomarker of favorable prognosis. LCAT upregulation inhibited HCC in vitro and in vivo and mediated estrogen-induced suppression of HCC in an ESR1-dependent manner. LCAT facilitated high-density lipoprotein cholesterol (HDL-C) production and uptake via the LDLR and SCARB1 pathways. Consistently, high HDL-C levels corresponded to a favorable prognosis in HCC patients. The enhanced HDL-C absorption induced by LCAT impaired SREBP2 maturation, which ultimately suppressed cholesterol biosynthesis and dampened HCC cell proliferation. HDL-C alone inhibited HCC growth comparably to the cholesterol-lowering drug lovastatin, and SREBF2 overexpression abolished the inhibitory activity of LCAT. Clinical observations and cross-analyses of multiple databases confirmed the correlation of elevated LCAT and HDL-C levels to reduced cholesterol synthesis and improved HCC patient prognosis. Furthermore, LCAT deficiency mimicked whereas LCAT overexpression abrogated the tumor growth promoting effects of ovariectomy in HCC-bearing female mice. Most importantly, HDL-C and LCAT delayed the development of subcutaneous tumors in nude mice, and HDL-C synergized with lenvatinib to eradicate orthotopic liver tumors. Collectively, this study reveals that estrogen upregulates LCAT to maintain cholesterol homeostasis and dampen hepatocarcinogenesis. LCAT and HDL-C represent potential prognostic and therapeutic biomarkers for targeting cholesterol homeostasis as a strategy for treating HCC.

中文翻译：

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雌激素诱导 LCAT 维持胆固醇稳态并抑制肝细胞癌的发展

肝细胞癌（HCC）是一种侵袭性疾病，主要发生在男性中。雌激素对 HCC 的发展具有保护作用。阐明抑制 HCC 的雌激素调节生物过程可能会改善预防和治疗策略。在这里，我们对小鼠和人类肝癌进行了转录组分析，并确定 LCAT 是雌激素上调程度最高的基因和良好预后的生物标志物。 LCAT 上调可在体外和体内抑制 HCC，并以 ESR1 依赖性方式介导雌激素诱导的 HCC 抑制。 LCAT 通过 LDLR 和 SCARB1 途径促进高密度脂蛋白胆固醇 (HDL-C) 的产生和吸收。一致地，高 HDL-C 水平与 HCC 患者的良好预后相对应。 LCAT 诱导的 HDL-C 吸收增强会损害 SREBP2 的成熟，最终抑制胆固醇生物合成并抑制 HCC 细胞增殖。 HDL-C 单独抑制 HCC 生长的效果与降胆固醇药物洛伐他汀相当，并且 SREBF2 过表达消除了 LCAT 的抑制活性。多个数据库的临床观察和交叉分析证实了 LCAT 和 HDL-C 水平升高与胆固醇合成减少和 HCC 患者预后改善的相关性。此外，LCAT 缺乏模仿了 HCC 雌性小鼠中卵巢切除术的肿瘤生长促进作用，而 LCAT 过度表达则消除了这种作用。最重要的是，HDL-C和LCAT延缓了裸鼠皮下肿瘤的发展，并且HDL-C与乐伐替尼协同作用以根除原位肝脏肿瘤。总的来说，这项研究表明雌激素上调 LCAT 以维持胆固醇稳态并抑制肝癌发生。 LCAT 和 HDL-C 代表了以胆固醇稳态为治疗 HCC 策略的潜在预后和治疗生物标志物。