المؤلفون: Gang Wang, Jia-Hui Gao, Min Zhang, Xiao-Hua Yu, Da-Wei Zhang, Zhen-Wang Zhao, Xiang-Jun Wan, Chao-Ke Tang, Jin Zou, Li Zhou

المصدر: Journal of Cardiovascular Pharmacology. 77:217-227

مصطلحات موضوعية: Male, 0301 basic medicine, Mice, Knockout, ApoE, THP-1 Cells, Anti-Inflammatory Agents, 030204 cardiovascular system & hematology, Pharmacology, Proinflammatory cytokine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Animals, Humans, Kaempferols, Interleukin 6, ATP Binding Cassette Transporter, Subfamily G, Member 1, Foam cell, biology, Chemistry, Macrophages, Atherosclerosis, Plaque, Atherosclerotic, Up-Regulation, Disease Models, Animal, Cholesterol, HEK293 Cells, 030104 developmental biology, ABCG1, ABCA1, biology.protein, lipids (amino acids, peptides, and proteins), Tumor necrosis factor alpha, Astragalin, Efflux, Inflammation Mediators, Cardiology and Cardiovascular Medicine, ATP Binding Cassette Transporter 1, Foam Cells

الوصف: Lipid metabolism disorder and inflammatory response are considered to be the major causes of atherosclerogenesis. Astragalin, the most important functional component of flavonoid obtained from persimmon leaves, has the hypolipidemic effects. However, it is unknown, how astragalin protects against atherosclerosis. The aim of this study was to observe the effects of astragalin on cholesterol efflux and inflammatory response and to explore the underlying mechanisms. Our results showed that astragalin upregulated the expression of ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1), promoted cholesterol efflux, and suppressed foam cell formation. Inhibition of the PPARγ/LXRα pathway abrogated the promotive effects of astragalin on both transporter expression and cholesterol efflux. In addition, treatment of astragalin markedly decreased the secretion of inflammatory factors, including interleukin 6, monocyte chemotactic protein 1, tumor necrosis factor α, and interleukin 1β. Mechanistically, astragalin upregulated ABCA1 and ABCG1 expression, which in turn reduced TLR4 surface levels and inhibited NF-κB nuclear translocation. Consistently, astragalin reduced atherosclerotic plaque area in apoE-/- mice. Taken together, these findings suggest that astragalin protects against atherosclerosis by promoting ABCA1- and ABCG1-mediated cholesterol efflux and inhibiting proinflammatory mediator release.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b362e362b1362b161e7b57abbb298116Test
https://doi.org/10.1097/fjc.0000000000000944Test

المؤلفون: Guangcheng Qin, Zhaoyang Fei, Jie Liang, Jiang Wang, Xue Zhou, Lixue Chen, Jiying Zhou, Dunke Zhang

المصدر: NeuroReport. 32:144-156

مصطلحات موضوعية: 0301 basic medicine, Mitochondrial DNA, NF-E2-Related Factor 2, Migraine Disorders, Blotting, Western, NF-E2-Related Factor 1, Pharmacology, DNA, Mitochondrial, Trigeminal Nuclei, 03 medical and health sciences, 0302 clinical medicine, SRT1720, Chronic Migraine, Sirtuin 1, Downregulation and upregulation, medicine, Animals, Nociception assay, NRF1, Neurons, business.industry, General Neuroscience, medicine.disease, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Pathophysiology, Mitochondria, Rats, Up-Regulation, 030104 developmental biology, Migraine, business, hormones, hormone substitutes, and hormone antagonists, 030217 neurology & neurosurgery, Transcription Factors

الوصف: Although the mechanism of chronic migraine is still unclear, more and more studies have shown that mitochondrial dysfunction plays a possible role in migraine pathophysiology. Silent information regulator 1 (SIRT1) plays a vital role in mitochondrial dysfunction in many diseases. However, there is no research on the role of SIRT1 in mitochondrial dysfunction of chronic migraine. The aim of this study was to explore the role of SIRT1 in mitochondrial dysfunction in chronic migraine. A rat model was established through repeated dural infusions of inflammatory soup for 7 days to simulate chronic migraine attacks. Cutaneous hyperalgesia caused by the repeated infusions of inflammatory soup was detected using the von Frey test. Then, we detected SIRT1 expression in the trigeminal nucleus caudalis. To explore the effect of SIRT1 on mitochondrial dysfunction in chronic migraine rats, we examined whether SRT1720, an activator of SIRT1, altered mitochondrial dysfunction in chronic migraine rats. Repeated infusions of inflammatory soup resulted in cutaneous hyperalgesia accompanied by downregulation of SIRT1. SRT1720 significantly alleviated the cutaneous hyperalgesia induced by repeated infusions of inflammatory soup. Furthermore, activation of SIRT1 markedly increased the expression of peroxisome proliferator-activated receptor gamma-coactivator 1-alpha, transcription factor A, nuclear respiratory factor 1 and nuclear respiratory factor 2 mitochondrial DNA and increased the ATP content and mitochondrial membrane potential. Our results indicate that SIRT1 may have an effect on mitochondrial dysfunction in chronic migraine rats. Activation of SIRT1 has a protective effect on mitochondrial function in chronic migraine rats.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::141792d7a4b224f6531321e1191f2f04Test
https://doi.org/10.1097/wnr.0000000000001569Test

المؤلفون: Circe McDonald, Jeffrey J. Wallin, Anh Hoa Nguyen, Diana Y. Chen, Edward Gane, Priyanka Arora, Kumar Visvanathan, Hyung Joon Kim, Young-Suk Lim, Susanna K. Tan, Anuj Gaggar, Yoon Jun Kim, Stuart K. Roberts

المصدر: Hepatology. 74:1737-1749

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Agonist, medicine.medical_specialty, Sustained Virologic Response, Nausea, medicine.drug_class, medicine.disease_cause, Placebo, Antiviral Agents, Dizziness, Gastroenterology, 03 medical and health sciences, Hepatitis B, Chronic, 0302 clinical medicine, Pharmacokinetics, Internal medicine, medicine, Clinical endpoint, Humans, Adverse effect, Hepatitis B virus, Dose-Response Relationship, Drug, Hepatology, Interleukin-12 Subunit p40, business.industry, Headache, Middle Aged, Interleukin 1 Receptor Antagonist Protein, Pyrimidines, 030104 developmental biology, Toll-Like Receptor 8, Pharmacodynamics, Female, 030211 gastroenterology & hepatology, medicine.symptom, Hexanols, business

الوصف: Background and aims In patients with chronic hepatitis B (CHB) infection, activation of toll-like receptor 8 may induce antiviral immunity and drive functional cure. Selgantolimod, a toll-like receptor 8 agonist, was evaluated in patients with CHB who were virally suppressed on oral antiviral treatment or viremic and not on oral antiviral treatment. Approach and results In this phase 1b study, patients were randomized 4:1 to receive either selgantolimod or placebo once weekly. Virally suppressed patients received either 1.5 mg (for 2 weeks) or 3 mg (for 2 weeks or 4 weeks). Viremic patients received 3 mg for 2 weeks. The primary endpoint was safety, as assessed by adverse events (AEs), laboratory abnormalities, and vital sign examination. Pharmacokinetic and pharmacodynamic parameters were assessed by plasma analysis. A total of 38 patients (28 virally suppressed, 10 viremic) were enrolled from six sites in Australia, New Zealand, and South Korea. Twenty patients (53%) experienced an AE and 32 (84%) had laboratory abnormalities, all of which were mild or moderate in severity. The most common AEs were headache (32%), nausea (24%), and dizziness (13%). With a half-life of 5 hours, no accumulation of selgantolimod was observed with multiple dosing. Selgantolimod induced transient dose-dependent increases in serum cytokines, including IL-12p40 and IL-1RA, which are important for the expansion and activity of multiple T- cell subsets and innate immunity. Conclusion Selgantolimod was safe and well-tolerated in virally suppressed and viremic patients with CHB and elicited cytokine responses consistent with target engagement. Further studies with longer durations of selgantolimod treatment are required to evaluate efficacy.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3eaee717e84933eb95f6de3ac41a3f49Test
https://doi.org/10.1002/hep.31795Test

المؤلفون: Yingying Xu, Wei Liu, Xiongjun Wang, Leping Yang, Li Gao, Hua Yu, Jun He, Yan Zhou, Xuyang Hou, Yawei Zhang, Shuya Feng

المصدر: Hepatology. 74:1952-1970

مصطلحات موضوعية: 0301 basic medicine, Carcinoma, Hepatocellular, Epigenesis, Genetic, Proto-Oncogene Proteins c-myc, Mice, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, Gene expression, Tumor Microenvironment, medicine, Animals, Humans, Epigenetics, beta Catenin, Mice, Knockout, Hepatology, biology, Liver Neoplasms, Nuclear Proteins, Cancer, Proto-Oncogene Proteins c-met, Hypoxia-Inducible Factor 1, alpha Subunit, medicine.disease, 030104 developmental biology, Histone, HIF1A, Acetylation, PFKP, Disease Progression, biology.protein, Cancer research, Tumor Hypoxia, 030211 gastroenterology & hepatology, Liver cancer, Glycolysis

الوصف: BACKGROUND AND AIMS Proteins that recognize epigenetic modifications function as mediators to interpret epigenetic codes. Hypoxia response and metabolic rewiring are two major events during cancer progression. However, whether and how the epigenetic regulator integrates hypoxia response and metabolism together remain open for study. APPROACH AND RESULTS We data mined the clinical association of 33 histone lysine acetylation reader proteins with liver cancer and found that ALL1-fused gene from chromosome 9 (AF9) is up-regulated in cancer and correlates with tumor stage and poor prognosis. Conditional deletion of Af9 in mouse liver resulted in decreased tumor formation induced by c-MET proto-oncogene/β-catenin. Loss of AF9 heavily impaired cell proliferation and completely blocked solid tumor formation. We further discovered that AF9 formed a positive feedback circuit with hypoxia-inducible factor 1 alpha (HIF1α) and also stabilized MYC proto-oncogene (cMyc). Mechanically, AF9 interacted with HIF1α and targeted HIF1A promoter whereas AF9 recognized cMyc acetylation at K148, protected cMyc phosphorylation at S62, and then stabilized cMyc, which, in turn, up-regulates phosphofructokinase, platelet expression. Otherwise, knockout of Af9 in mouse hepatocytes increased the infiltration of CD8+ T cells, which is linked to the down-regulation of lactate dehydrogenase A. CONCLUSIONS AF9 is up-regulated to promote gene expression of hypoxia tolerance and glycolysis by simultaneously forming a complex with HIF1α and recognizing acetylated cMyc. Our results establish the oncogenic role of AF9 in human liver cancer, which could be a potential target for designing drugs against liver cancer.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cc03c6c0825ea15e1ecf4e6e70f82eb9Test
https://doi.org/10.1002/hep.31870Test

المؤلفون: Sébastien Soubeyrand, Thomas A. Lagace, Paulina Lau, Kaitlyn Beehler, Majid Nikpay, Ruth McPherson, AnhThu Dang

المصدر: Arteriosclerosis, Thrombosis, and Vascular Biology. 41:2252-2262

مصطلحات موضوعية: 0301 basic medicine, Messenger RNA, Chemistry, Transfection, Molecular biology, Bone morphogenetic protein 1, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, LDL receptor, Allele, Signal transduction, Cardiology and Cardiovascular Medicine, Receptor, Lipoprotein

الوصف: Objective: Leveraging microRNA-Seq data and the 1000 Genomes imputed genotypes, we identified rs174561 as a strong microRNA quantitative trait loci for circulating microRNA-1908-5p with higher miR-1908-5p and reduced LDL (low-density lipoprotein)-cholesterol, fasting glucose and A1c concentrations in carriers of the rs-174561-C allele. Here, we have investigated the molecular mechanism(s) linking miR-1908-5p to LDL-C concentrations. Approach and Results: Transfection experiments demonstrate that the presence of the C allele significantly increases miR-1908-5p abundance relative to the T allele. LDLR mRNA and low-density lipoprotein receptor (LDLR) total protein were unchanged in response to differential miR-1908-5p expression. However, the ratio of the cleaved to full-length form of LDLR decreased with miR-1908-5p mimic and increased with miR-1908-5p inhibitor treatment. BMP1 (bone morphogenetic protein 1) is a protease responsible for LDLR cleavage, and we show that miR-1908-5p mimic reduces BMP1 mRNA. Using a reporter array, we identified the TGF-β (transforming growth factor-beta) signaling pathway activity to be reduced by miR-1908-5p mimic treatment, and this was associated with reduced TGFB1 expression. TGF-β signaling increases BMP1, and we further demonstrate that the effect of miR-1908-5p on LDLR cleavage is abolished by exogenous TGF-β treatment. Conclusions: These findings uncover a mechanism whereby miR-1908-5p reduces TGFB1 abundance resulting in lower expression of BMP1 , ultimately leading to reduced LDLR cleavage. Cleavage of the mature LDLR is known to reduce cell surface affinity for LDL, thereby linking miR-1908-5p to lower circulating LDL-cholesterol levels.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::e0880e08a6b6c9734c049781723537deTest
https://doi.org/10.1161/atvbaha.121.316473Test

المؤلفون: Swayam Prakash Srivastava, Qiongying Hu, Haijie Liu, Shaolan Li, Gaosong Wu, Daisuke Koya, Rongfen Gao, Munehiro Kitada, Keizo Kanasaki, Jinpeng Li

المصدر: Hypertension. 76:1935-1944

مصطلحات موضوعية: 0301 basic medicine, medicine.medical_specialty, Epithelial-Mesenchymal Transition, Kidney, Cell Line, Diabetes Mellitus, Experimental, Kidney Tubules, Proximal, 03 medical and health sciences, 0302 clinical medicine, Fibrosis, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Animals, Humans, Endothelium, Receptor, Fibroblast Growth Factor, Type 1, Receptor, Mice, Knockout, business.industry, Myocardium, Fibroblast growth factor receptor 1, Thymosin, Epithelial Cells, medicine.disease, Epithelium, Mice, Inbred C57BL, stomatognathic diseases, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, 030220 oncology & carcinogenesis, business, Oligopeptides, Transforming growth factor

الوصف: Endothelial-to-mesenchymal transition (EndMT) has been shown to contribute to organ fibrogenesis. We have reported that N-acetyl-seryl-aspartyl- lysyl-proline (AcSDKP) restored levels of diabetes mellitus-suppressed FGFR1 (fibroblast growth factor receptor 1), the endothelial receptor essential for combating EndMT. However, the molecular regulation and biological/pathological significance of the AcSDKP-FGFR1 relationship has not been elucidated yet. Here, we demonstrated that endothelial FGFR1 deficiency led to AcSDKP-resistant EndMT and severe fibrosis associated with EndMT-stimulated fibrogenic programming in neighboring cells. Diabetes mellitus induced severe kidney fibrosis in endothelial FGFR1-deficient mice ( FGFR1 fl/fl ; VE-cadherin-Cre: FGFR1 EKO ) but not in control mice (FGFR1 fl/fl ); AcSDKP completely or partially suppressed kidney fibrosis in control or FGFR1 EKO mice. Severe fibrosis was also induced in hearts of diabetic FGFR1 EKO mice; however, AcSDKP had no effect on heart fibrosis in FGFR1 EKO mice. AcSDKP also had no effect on EndMT in either kidney or heart but partially suppressed epithelial-to-mesenchymal transition in kidneys of diabetic FGFR1 EKO mice. The medium from FGFR1-deficient endothelial cells stimulated TGFβ (transforming growth factor β)/Smad-dependent epithelial-to-mesenchymal transition in cultured human proximal tubule epithelial cell line, AcSDKP inhibited such epithelial-to-mesenchymal transition. These data demonstrated that endothelial FGFR1 is essential as an antifibrotic core molecule as the target of AcSDKP.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b4babe41780ff1702428aec2859d3871Test
https://doi.org/10.1161/hypertensionaha.120.15587Test

المؤلفون: Carmine Nicoletti, Emanuele Arrabito, Rhian M. Touyz, Antonio Filippini, Massimo Volpe, Carmine Savoia, Allegra Battistoni, Luca Madaro, Rosa Parente, Ulrike Muscha Steckelings

المصدر: Savoia, C, Arrabito, E, Parente, R, Nicoletti, C, Madaro, L, Battistoni, A, Filippini, A, Steckelings, U M, Touyz, R M & Volpe, M 2020, ' Mas Receptor Activation Contributes to the Improvement of Nitric Oxide Bioavailability and Vascular Remodeling During Chronic AT1R (Angiotensin Type-1 Receptor) Blockade in Experimental Hypertension ', Hypertension, vol. 76, no. 6, pp. 1753-1761 . https://doi.org/10.1161/HYPERTENSIONAHA.120.15527Test

مصطلحات موضوعية: 0301 basic medicine, Angiotensin receptor, Tetrazoles, Blood Pressure, 030204 cardiovascular system & hematology, Proto-Oncogene Mas, Receptors, G-Protein-Coupled, chemistry.chemical_compound, 0302 clinical medicine, Enos, Rats, Inbred SHR, angiotensins, oxidative stress, Receptor, Mesenteric arteries, Mice, Knockout, biology, Chemistry, Angiotensin II, resistance arteries, Imidazoles, Mesenteric Arteries, Vasodilation, medicine.anatomical_structure, Hypertension, Olmesartan, medicine.drug, medicine.medical_specialty, Nitric Oxide Synthase Type III, vascular remodeling, Vascular Remodeling, Nitric Oxide, Receptor, Angiotensin, Type 2, Receptor, Angiotensin, Type 1, Nitric oxide, 03 medical and health sciences, nitric oxide, Proto-Oncogene Proteins, Internal medicine, Renin–angiotensin system, Internal Medicine, medicine, Animals, angiotensin receptor blockers, angiotensin receptors, biology.organism_classification, Peptide Fragments, 030104 developmental biology, Endocrinology, Angiotensin II Type 1 Receptor Blockers

الوصف: Angiotensin (1–7) production increases during AT1R (angiotensin type-1 receptor) blockade. The contribution of Ang (1–7) (angiotensin [1–7]) and its receptor (MasR) to the favorable effect of angiotensin receptor blockers on remodeling and function of resistance arteries remains unclear. We sought to determine whether MasR contributes to the improvement of vascular structure and function during chronic AT1R blockade. Spontaneously hypertensive rats were treated with Ang (1–7) or olmesartan ± MasR antagonist A-779, or vehicle, for 14 days. Blood pressure was measured by tail cuff methodology. Mesenteric arteries were dissected and mounted on a pressurized micromyograph to evaluate media-to-lumen ratio (M/L) and endothelial function. Expression of MasR and eNOS (endothelial nitric oxide synthase) was evaluated by immunoblotting, plasma nitrate by colorimetric assay, and reactive oxygen species production by dihydroethidium staining. Independently of blood pressure, olmesartan significantly reduced M/L and improved NO bioavailability, A-779 prevented these effects. Likewise, Ang (1–7) significantly reduced M/L and NO bioavailability. MasR expression was significantly increased by Ang (1–7) as well as by olmesartan, and it was blunted in the presence of A-779. Both Ang (1–7) and olmesartan increased eNOS expression and plasma nitrite which were reduced by A-779. Superoxide generation was attenuated by olmesartan and Ang (1–7) and was blunted in the presence of A-779. These MasR-mediated actions were independent of AT2R activation since olmesartan and Ang (1–7) increased MasR expression and reduced M/L in Ang II (angiotensin II)–infused AT2R knockout mice, independently of blood pressure control. A-779 prevented these effects. Hence, MasR activation may contribute to the favorable effects of AT1R antagonism on NO bioavailability and microvascular remodeling, independently of AT2R activation and blood pressure control.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e3737c2d1c72b76340b2530c9e771c7fTest
https://doi.org/10.1161/hypertensionaha.120.15527Test

المؤلفون: Bożena Cybulska-Stopa, Piotr Rutkowski, Jacek Calik, Natasza Kempa-Kamińska, Anna M. Czarnecka, Barbara Ziółkowska, Marcin Ziętek, Jacek Mackiewicz, Łukasz Galus, Tomasz Zemełka, Tomasz Kubiatowski, Stanisław Kieszko, Karolina Piejko, Grażyna Kamińska-Winciorek, Rafał Suwiński

المصدر: Melanoma Research. 31:49-57

مصطلحات موضوعية: Male, 0301 basic medicine, Cancer Research, medicine.medical_specialty, Skin Neoplasms, Metastatic melanoma, Programmed Cell Death 1 Receptor, Dermatology, Pembrolizumab, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Programmed cell death 1, medicine, Humans, Adverse effect, Melanoma, Aged, Aged, 80 and over, biology, business.industry, medicine.disease, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Toxicity, Cohort, biology.protein, Female, Nivolumab, business

الوصف: Immunotherapy with anti-programmed cell death-1 (PD-1) agents is an effective treatment for metastatic melanoma. Octogenarians and nonagenarians represent a significant cohort of melanoma patients. This multicenter retrospective analysis enrolled 499 patients treated with nivolumab or pembrolizumab. Seventy-three patients were aged 80-100, 218 patients were aged 65-79, and 208 patients were

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::aa959b4946890b96cd6e5c7109265544Test
https://doi.org/10.1097/cmr.0000000000000705Test

المؤلفون: Hui Zhi Zhang, Chun Nian Wang, Yang Ke Hu, Sheng Dong Wu, Ding Zhang, Ke Wang, Jian Nan Sun, Guo Gao, Cai De Lu

المصدر: Hepatology. 74:1695-1697

مصطلحات موضوعية: Male, 0301 basic medicine, Cirrhosis, Programmed Cell Death 1 Receptor, Disease, Antibodies, Monoclonal, Humanized, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, Programmed cell death 1, medicine, Adjuvant therapy, Hepatectomy, Humans, Basal cell, Immune Checkpoint Inhibitors, Aged, Hepatology, biology, business.industry, Liver Neoplasms, Microsatellite instability, medicine.disease, 030104 developmental biology, Chemotherapy, Adjuvant, Carcinoma, Squamous Cell, biology.protein, Cancer research, Microsatellite Instability, 030211 gastroenterology & hepatology, Hepatic Cyst, Liver cancer, business

الوصف: Primary hepatic squamous cell carcinoma (SCC) is a rare, highly aggressive liver cancer that is associated with intrahepatic stone, liver cirrhosis, hepatic cyst, and Caroli's disease. At present, there are no settled therapy guidelines for primary hepatic SCC. Patients with successful surgical resection have a tumor-free survival of approximately 6 to 9 months.(1,2) Immune checkpoint inhibitors (ICIs) are a promising treatment for multiple tumor types, with significant efficacy and manageable toxicity.(3).

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::065b1cff41fe51d1974fd9cb17d268b3Test
https://doi.org/10.1002/hep.31737Test

المؤلفون: Chen Qu, Yuchuan Jiang, Binkui Li, Mingrong Cao, Wei Huang, Nan Yao, Lu He, Jun Fan, Shuang Peng, Kunpeng Hu, Guo Chen, Wen-Cai Ye, Dong Chen, Jian Hong, Jinying Li, Yunfei Yuan

المصدر: Hepatology. 74:458-473

مصطلحات موضوعية: 0301 basic medicine, Genetically modified mouse, Carcinoma, Hepatocellular, macromolecular substances, Biology, Metastasis, Mice, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, medicine, Animals, Humans, Myofibroblasts, Mice, Knockout, Musashi2, Gene knockdown, Hepatology, Cell growth, Kinase, Liver Neoplasms, RNA-Binding Proteins, medicine.disease, digestive system diseases, Disease Models, Animal, Collagen, type I, alpha 1, 030104 developmental biology, Liver, Gene Knockdown Techniques, Disease Progression, Cancer research, 030211 gastroenterology & hepatology, sense organs, Myofibroblast

الوصف: BACKGROUND AND AIMS Myofibroblasts play a pivotal role in the development and progression of HCC. Here, we aimed to explore the role and mechanism of myofibroblast Musashi RNA binding protein 2 (MSI2) in HCC progression. APPROACH AND RESULTS Myofibroblast infiltration and collagen deposition were detected and assessed in the tissues from 117 patients with HCC. Transgenic mice (Msi2ΔCol1a1 ) with floxed Msi2 allele and collagen type I alpha 1 chain (Col1a1)-ligand inducible Cre recombinases (CreER) were constructed to generate a myofibroblast-specific Msi2 knockout model. Mouse HCC cells were orthotopically transplanted into the Msi2ΔCol1a1 or the control mice (Msi2F/F ). We found that the deposition of collagen fibers, the main product of myofibroblasts, predicted a poor prognosis for HCC; meanwhile, we detected high MSI2 expression in the peritumoral infiltrated myofibroblasts. Conditional deletion of Msi2 in myofibroblasts significantly inhibited the growth of orthotopically implanted HCC, reduced both intrahepatic and lung metastasis, and prolonged the overall survival of tumor-bearing mice (P = 0.002). In vitro analysis demonstrated that myofibroblasts promoted cell proliferation, invasion, and epithelial-mesenchymal transformation of HCC cells, whereas Msi2 deletion in myofibroblasts reversed these effects. Mechanically, Msi2 knockout decreased myofibroblast-derived IL-6 and IL-11 secretion by inhibiting the extracellular signal-regulated kinase 1/2 pathway, and thus attenuated the cancer stem cell-promoting effect of myofibroblasts. Interestingly, we found that the simultaneous knockout of Msi2 in myofibroblasts and knockdown of Msi2 in HCC cells could not further attenuate the implanted HCC progression. CONCLUSIONS Myofibroblast-specific Msi2 knockout abrogated the tumor-promoting function of myofibroblasts and inhibited HCC progression in mouse models. Targeting myofibroblast MSI2 expression may therefore prove to be a therapeutic strategy for HCC treatment in the future.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8d3ec7cef152949ec9f9d9532be2ad8fTest
https://doi.org/10.1002/hep.31754Test