2. Academic Validation
  3. DAGLβ is the principal synthesizing enzyme of 2-AG and promotes aggressive intrahepatic cholangiocarcinoma via AP-1/DAGLβ/miR4516 feedforward circuitry

DAGLβ is the principal synthesizing enzyme of 2-AG and promotes aggressive intrahepatic cholangiocarcinoma via AP-1/DAGLβ/miR4516 feedforward circuitry

  • Am J Physiol Gastrointest Liver Physiol. 2023 Jun 27. doi: 10.1152/ajpgi.00243.2022.
Mingjian Ma 1,  Guangyan Zeng 1 2,  Bingyan Tan 3,  Guangyin Zhao 4,  Qiao Su 4,  Wenhui Zhang 5,  Yan Song 5,  Jiahua Liang 1,  Borui Xu 1,  Zicheng Wang 1,  Jiancong Chen 1,  Mengjun Hou 3,  Chuntao Yang 6,  Jingping Yun 7 8,  Yuhua Huang 7 8,  Yansong Lin 7 8,  Demeng Chen 9,  Yuyan Han 10,  Sharon DeMorrow 11 12,  Lijian Liang 1,  Jiaming Lai 1,  Li Huang 1
Affiliations

Affiliations

  • 1 Department of Pancreatobiliary Surgery, Center of Hepatopancreatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 2 Department of Gastrointestinal Surgery, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
  • 3 Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, China.
  • 4 Laboratory Animal Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 5 Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 6 Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Key Laboratory of Protein Modification and Degradation, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, China.
  • 7 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 8 Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 9 Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 10 School of Biological Sciences, University of Northern Colorado, Greeley, CO, United States.
  • 11 Central Texas Veterans Health Care System, Temple, TX, United States.
  • 12 Division of Pharmacology and Toxicology, College of Pharmacy; Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, TX, United States.
PMID: 37366545 DOI: 10.1152/ajpgi.00243.2022
Abstract

The endocannabinoid system (ECS) is dysregulated in various liver diseases. Previously we had shown that the major endocannabinoid 2-arachidonoyl glycerol (2-AG) promoted tumorigenesis of intrahepatic cholangiocarcinoma (ICC). However, biosynthesis regulation and clinical significance of 2-AG remain elusive. In present study we quantified 2-AG by gas chromatography/mass spectrometry (GC/MS) and showed that 2-AG was enriched in ICC patients' samples as well as in thioacetamide-induced orthotopic rat ICC model. Moreover, we found that diacylglycerol Lipase beta (DAGLβ) was the principal synthesizing Enzyme of 2-AG which significantly upregulated in ICC. DAGLβ promoted tumorigenesis and metastasis of ICC in vitro and in vivo, and positively correlated with clinical stage and poor survival in ICC patients. Functional studies showed that AP-1 (heterodimers of c-Jun and FRA1) directly binded to the promoter and regulated transcription of DAGLβ, which can be enhanced by lipopolysaccharide (LPS). miR-4516 was identified as the tumor-suppressing miRNA of ICC which can be significantly suppressed by LPS, 2-AG or ectopic DAGLβ overexpression. FRA1 and STAT3 were targets of miR-4516 and overexpression of miRNA-4516 significantly suppressed expression of FRA1, SATA3 and DAGLβ. Expression of miRNA-4516 was negatively correlated with FRA1, SATA3 and DAGLβ in ICC patients' samples. Our findings identify DAGLβ as the principal synthesizing Enzyme of 2-AG in ICC. DAGLβ promotes oncogenesis and metastasis of ICC and is transcriptionally regulated by a novel AP-1/DAGLβ/miR4516 feedforward circuitry.

Keywords

AP-1; DAGLβ; Endocannabinoid; Intrahepatic cholangiocarcinoma; miRNA-4516.

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