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

Autor:	Ma M; Department of Pancreatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.; Center of Hepatopancreatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China., Zeng G; Department of Pancreatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.; Center of Hepatopancreatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.; Department of Gastrointestinal Surgery, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, People's Republic of China., Tan B; Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, People's Republic of China., Zhao G; Laboratory Animal Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China., Su Q; Laboratory Animal Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China., Zhang W; Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China., Song Y; Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China., Liang J; Department of Pancreatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.; Center of Hepatopancreatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China., Xu B; Department of Pancreatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.; Center of Hepatopancreatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China., Wang Z; Department of Pancreatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.; Center of Hepatopancreatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China., Chen J; Department of Pancreatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.; Center of Hepatopancreatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China., Hou M; Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, People's Republic of China., Yang C; Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Key Laboratory of Protein Modification and Degradation, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, People's Republic of China., Yun J; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.; Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China., Huang Y; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.; Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China., Lin Y; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.; Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China., Chen D; Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China., Han Y; School of Biological Sciences, University of Northern Colorado, Greeley, Colorado, United States., DeMorrow S; Research Division, Central Texas Veterans Health Care System, Temple, Texas, United States.; Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas, United States.; Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, Texas, United States., Liang L; Department of Pancreatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.; Center of Hepatopancreatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China., Lai J; Department of Pancreatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.; Center of Hepatopancreatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China., Huang L; Department of Pancreatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.; Center of Hepatopancreatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.
Jazyk:	angličtina
Zdroj:	American journal of physiology. Gastrointestinal and liver physiology [Am J Physiol Gastrointest Liver Physiol] 2023 Sep 01; Vol. 325 (3), pp. G213-G229. Date of Electronic Publication: 2023 Jun 27.
DOI:	10.1152/ajpgi.00243.2022
Abstrakt:	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 the present study, we quantified 2-AG by gas chromatography/mass spectrometry (GC/MS) and showed that 2-AG was enriched in patients with ICC samples as well as in thioacetamide-induced orthotopic rat ICC model. Moreover, we found that diacylglycerol lipase β (DAGLβ) was the principal synthesizing enzyme of 2-AG that 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 patients with ICC. Functional studies showed that activator protein-1 (AP-1; heterodimers of c-Jun and FRA1) directly bound 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 that 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 patients with ICC 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. NEW & NOTEWORTHY Dysregulated endocannabinoid system (ECS) had been confirmed in various liver diseases. However, regulation and function of 2-arachidonoyl glycerol (2-AG) and diacylglycerol lipase β (DAGLβ) in intrahepatic cholangiocarcinoma (ICC) remain to be elucidated. Here, we demonstrated that 2-AG was enriched in ICC, and DAGLβ was the principal synthesizing enzyme of 2-AG in ICC. DAGLβ promotes tumorigenesis and metastasis in ICC via a novel activator protein-1 (AP-1)/DAGLβ/miR4516 feedforward circuitry.
Databáze:	MEDLINE
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