Hepatic circadian and differentiation factors control liver susceptibility for fatty liver disease and tumorigenesis.
Hepatic circadian and differentiation factors control liver susceptibility for fatty liver disease and tumorigenesis.
复制标题
DOI：
10.1096/fj.202101398r
复制
发表时间：
2022-09
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
肝细胞癌（HCC）是癌症死亡的主要原因，也是临床上最常见的原发性肝脏恶性肿瘤。除了肝移植外，晚期HCC的治疗选择有限，但改进的肿瘤分层可以为新的治疗选择打开大门。之前，我们证明了昼夜节律调节因子Aryl碳氢化合物样受体样1 （Aryl hydrocarbon Like Receptor Like 1，或Bmal1）和肝脏富集核因子4α (HNF4α)在健康肝脏中稳定共表达，但在HCC背景下不相容。HNF4α的昼夜节律表达错误——无论是通过异构体转换还是表达缺失——都会导致HCC的风险增加，而BMAL1在HNF4α阳性的HCC中获得功能导致细胞凋亡和肿瘤消退。我们假设HNF4α和BMAL1的转录程序在肝脏疾病和HCC中具有拮抗作用。在这里，我们通过建立小鼠模型，诱导肝脏HNF4α和BMAL1表达丧失来研究这种拮抗作用。结果表明，HNF4α和BMAL1的同时缺失在癌变诱导的肝损伤和肝疾病“STAM”模型中对脂肪肝和HCC具有保护作用。此外，我们的研究结果表明，在缺乏HNF4α的情况下靶向Bmal1表达可抑制HCC的生长和进展。具体来说，用REV-ERB激动剂SR9009在hnf4 α-缺陷、Bmal1阳性的HCC中抑制Bmal1，以REV-ERB依赖的方式损害肿瘤细胞的增殖和迁移，而对健康肝细胞没有影响。总之，我们的研究结果表明，基于HNF4α和BMAL1表达的HCC分层可能为HCC的性质和潜在的靶向治疗提供了新的视角。
Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths, and the most common primary liver malignancy to present in the clinic. With the exception of liver transplant, treatment options for advanced HCC are limited, but improved tumor stratification could open the door to new treatment options. Previously, we demonstrated that the circadian regulator Aryl Hydrocarbon-Like Receptor Like 1 (ARNTL, or Bmal1) and the liver-enriched nuclear factor 4 alpha (HNF4α) are robustly co-expressed in healthy liver but incompatible in the context of HCC. Faulty circadian expression of HNF4α– either by isoform switching, or loss of expression- results in an increased risk for HCC, while BMAL1 gain-of-function in HNF4α-positive HCC results in apoptosis and tumor regression. We hypothesize that the transcriptional programs of HNF4α and BMAL1 are antagonistic in liver disease and HCC. Here, we study this antagonism by generating a mouse model with inducible loss of hepatic HNF4α and BMAL1 expression. The results reveal that simultaneous loss of HNF4α and BMAL1 is protective against fatty liver and HCC in carcinogen-induced liver injury and in the “STAM” model of liver disease. Furthermore, our results suggest that targeting Bmal1 expression in the absence of HNF4α inhibits HCC growth and progression. Specifically, pharmacological suppression of Bmal1 in HNF4α-deficient, BMAL1-positive HCC with REV-ERB agonist SR9009 impairs tumor cell proliferation and migration in a REV-ERB-dependent manner, while having no effect on healthy hepatocytes. Collectively, our results suggest that stratification of HCC based on HNF4α and BMAL1 expression may provide a new perspective on HCC properties and potential targeted therapeutics.