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Hepatic circadian and differentiation factors control liver susceptibility for fatty liver disease and tumorigenesis.
Fekry, Baharan; Ribas-Latre, Aleix; Drunen, Rachel Van; Santos, Rafael Bravo; Shivshankar, Samay; Dai, Yulin; Zhao, Zhongming; Yoo, Seung-Hee; Chen, Zheng; Sun, Kai; Sladek, Frances M; Younes, Mamoun; Eckel-Mahan, Kristin.
Afiliación
  • Fekry B; Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA.
  • Ribas-Latre A; Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA.
  • Drunen RV; Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA.
  • Santos RB; Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA.
  • Shivshankar S; Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA.
  • Dai Y; Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center, Houston, Texas, USA.
  • Zhao Z; Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center, Houston, Texas, USA.
  • Yoo SH; Human Genetics Center, School of Public Health, The University of Texas Health Science Center, Houston, Texas, USA.
  • Chen Z; Department of Biochemistry and Molecular Biology, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA.
  • Sun K; Department of Biochemistry and Molecular Biology, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA.
  • Sladek FM; Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA.
  • Younes M; Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA.
  • Eckel-Mahan K; Department of Molecular, Cell and Systems Biology, University of California, Riverside, California, USA.
FASEB J ; 36(9): e22482, 2022 09.
Article en En | MEDLINE | ID: mdl-35947136
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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Carcinoma Hepatocelular / Neoplasias Hepáticas Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: FASEB J Asunto de la revista: BIOLOGIA / FISIOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Carcinoma Hepatocelular / Neoplasias Hepáticas Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: FASEB J Asunto de la revista: BIOLOGIA / FISIOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos