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AU-rich element-binding proteins in colorectal cancer

World Journal of Gastrointestinal Oncology 2019年第2期11卷 71-90页

作者： Noémie Legrand Dan A Dixon Cyril Sobolewski Department of Microbiology Faculty of Medicine University of Geneva Department of Molecular Biosciences University of Kansas Lawrence Kansasand University of Kansas Cancer Center Department of Cell Physiology and Metabolism Faculty of MedicineUniversity of Geneva

Trans-acting factors controlling mRNA fate are critical for the post-transcriptional regulation of inflammation-related genes, as well as for oncogene and tumor suppressor expression in human cancers. Among them, a group of RNA-binding proteins called "Adenylate-Uridylate-rich elements binding proteins"(AUBPs)control mRNA stability or translation through their binding to AU-rich elements enriched in the 3'UTRs of inflammation-and cancer-associated mRNA transcripts. AUBPs play a central role in the recruitment of target mRNAs into small cytoplasmic foci called Processing-bodies and stress granules(also known as P-body/SG). Alterations in the expression and activities of AUBPs and Pbody/SG assembly have been observed to occur with colorectal cancer(CRC)progression, indicating the significant role AUBP-dependent post-transcriptional regulation plays in controlling gene expression during CRC tumorigenesis.Accordingly, these alterations contribute to the pathological expression of many early-response genes involved in prostaglandin biosynthesis and inflammation,along with key oncogenic pathways. In this review, we summarize the current role of these proteins in CRC development. CRC remains a major cause of cancer mortality worldwide and, therefore, targeting these AUBPs to restore efficient post-transcriptional regulation of gene expression may represent an appealing therapeutic strategy.

关键词： Colorectal cancer Adenylate-Uridylate-rich element-binding proteins Oncogenes Tumor suppressors Post-transcriptional regulation

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Hypolipidemic effect of SIPI-7623,a derivative of an extract from oriental wormwood,through farnesoid X receptor antagonism

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Chinese Journal of Natural Medicines 2018年第8期16卷 572-579页

作者： DENG Yi-Fang HUANG Xiao-Ling SU Mei YU Peng-Xia ZHANG Zhen LIU Quan-Hai WANG Guo-Ping LIU Min-Yu Department of Pharmacology Shanghai Institute of Pharmaceutical Industry Jiangsu Carephar Pharmaceutical Co. Ltd.

Farnesoid X receptor(FXR) is a member of the nuclear receptor superfamily of ligand-activated transcription factors.As a metabolic regulator,FXR plays key roles in bile acid and cholesterol metabolism and lipid and glucose homeostasis.Therefore,FXR is a potential drug target for several metabolic syndromes,especially those related to lipidemia disorders.In the present study,we identified small molecule SIPI-7623,a derivative of an extract from Oriental wormwood(Artemisia capillaris),and found that it specifically upregulated the expression of cholesterol-7-alpha-hydroxylase(CYP7 A1),downregulated the expression of sterol-regulatory element-binding protein 1 c(SREBP-1 c) in the liver,and inhibited the expression of ileal bile acid binding-protein(IBABP) in the ileum of rats.We found that inhibition of FXR by SIPI-7623 decreased the level of cholesterol and triglyceride.SIPI-7623 reduced the levels of cholesterol and triglyceride in in vitro Hep G2 cell models,ameliorated diet-induced atherosclerosis,and decreased the serum lipid content on rats and rabbits model of atherosclerosis in vivo.Furthermore,SIPI-7623 decreased the extent of atherosclerotic lesions.Our resutls demonstrated that antagonism of the FXR pathway can be employed as a therapeutic strategy to treat metabolic diseases such as hyperlipidemia and atherosclerosis.In conclusion,SIPI-7623 could be a promising lead compound for development of drugs to treat hyperlipidemia and atherosclerosis.

关键词： Farnesoid X receptor antagonist Hypolipidemic Bile acid enterohepatic circulation Cholesterol-7-alpha-hydroxylase Sterol-regulatory element-binding protein 1c

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Mori Cortex extract ameliorates nonalcoholic fatty liver disease( NAFLD) and insulin resistance in high-fat-diet/streptozotocininduced type 2 diabetes in rats

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Chinese Journal of Natural Medicines 2018年第6期16卷 411-417页

作者： MA Li-Li YUAN Yan-Yan ZHAO Ming ZHOU Xin-Rong Tashina Jehangir WANG Fu-Yan XI Yang BU Shi-Zhong Runliang Diabetes Laboratory Diabetes Research Center School of Medicine Ningbo University

Nonalcoholic fatty liver disease(NAFLD) and type 2 Diabetes Mellitus(T2 DM) are highly prevalent diseases and are closely associated, with NAFLD being present in the majority of T2 DM patients. In Asian traditional medicine, Mori Cortex is widely used for the treatment of diabetes and hyperlipidemia. However, whether it has a therapeutic effect on T2 DM associated with NAFLD is still unknown. The present study showed that the oral treatment with Mori Cortex extract(MCE; 10 g·kg-1·d-1) lowered the blood lipid levels and reversed insulin resistance(IR) in high fat-diet/streptozotocin-induced type 2 diabetes in rats. The expression levels of sterol receptor element-binding protein-1 c(SREBP-1 c) and carbohydrate-responsive element binding protein(Ch REBP), which are involved in steatosis in NAFLD rats, were measured in the liver samples. MCE decreased the protein and m RNA expression levels of SREBP-1 c and Ch REBP. In conclusion, down-regulation of SREBP-1 c and Ch REBP might contribute to the protective effect of MCE on hepatic injury and IR in the rats with T2 DM associated with NAFLD.

关键词： Mori Cortex extract Type 2 diabetes Non-alcoholic fatty liver Sterol receptor element-binding protein-It Carbohy-drate-responsive element binding protein

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Novel diagnosis and therapy for hepatoma targeting HBV-related carcinogenesis through alternative splicing of FIR (PUF60)/FIRΔexon2

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Hepatoma Research 2018年第9期4卷 142-158页

作者： Kazuyuki Matsushita Tyuji Hoshino Department of Laboratory Medicine&Division of Clinical Genetics and Proteomics Chiba University HospitalChiba260-8677Japan Department of Physical Chemistry Chiba UniversityChiba 260-8670Japan

Aim: Disturbed alternative splicing of far upstream element-binding protein-interacting repressor (FIR) was found to be unable to repress c-Myc transcription and so it might be important for suppressing tumor development. FIR is a splicing variant of poly (U)-binding-splicing factor (PUF60), and forms complex with other splicing factors. FIR/PUF60 is a splicing factor of U2 small nuclear ribonucleoprotein auxiliary factor family, Thus FIR/PUF60 is a multifunctional protein. The expression of exon2-lacking splicing variant of FIR, FIRΔexon2, is elevated in many cancer tissues and promotes tumor development by disabling FIR-repression to sustain c-Myc activation. FIRΔexon2, as a dominant negative of FIR, opposed apoptosis in cancer cells. FIR/FIRΔexon2 interacts with degron pocket of F-box and W (Typ) D (Asp) repeat domain-containing 7 and inhibits proteolysis of substrates proteins. Recently, FIR/PUF60 was identified as a versatile regulator of transcriptional and post-transcriptional steps in expression of hepatitis B virus (HBV) pregenomic RNA (pgRNA) expression. Methods: Small molecular chemical compounds against FIR and FIRΔexon2 were screened among 2,3275 chemicals by natural product depository array (RIKEN, Wako, Saitama, Japan). Results: Nine chemicals against FIR and four chemicals against FIRΔexon2 were identified as candidates of interacting chemicals. Interestingly, BK697 contains WD -like structure. Among them, BK697 against FIRΔexon2 inhibited hepatoma cell growth. Conclusion: Therefore, FIR (PUF60)/FIRΔexon2 is multifunctional and applicable for clinical use for HBV suppression and hepatoma treatment. Together, one clue to the development of hepatome diagnosis and therapies directed against FIR/FIRΔexon2/PUF60 with small molecular weight chemicals that inhibit HBV cccDNA replication.

关键词： Hepatocellular carcinoma hepatitis B virus covalently closed circular DNA far upstream element-binding protein-interacting repressor poly (U)-binding-splicing factor F-box and W (Typ) D (Asp) repeat domain-containing 7 natural product depository array U2A

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