Serotonin-induced miR-221/222 contribute to the activation of hepatic stellate cells

In the diseased liver, hepatic stellate cells (HSCs) transdifferentiate into “activated” myofibroblasts that then drive fibrogenesis by promoting the net deposition of extracellular matrix. This regulatory function requires stimulation of the 5-hydroxytryptamine 2B receptor (5-HT2B) on HSCs by serotonin (5-HT), which activates extracellular regulated protein kinases and the transcription factor JunD. However, the regulation mechanisms of 5-HT on microRNAs in the activation of HSCs need a thorough study. In this study, our data show that the expression of miR-221/222 increases with the stimulation of 5-HT and is correlated with the expression levels of alpha 1 type I collagen and α-smooth muscle actin in HSCs. Silencing against 5-HT2B attenuates miR-221/222 expression. Stimulation of stellate cells with 5-HT significantly upregulated miR-221/222 expression, while knockdown of JunD or treatment with the ERK inhibitor PD98059 significantly reduced miR-221/222 expression. miR-221 and miR-222 are potential targets in the quest for a cure for human liver fibrosis.

[1]  E. Lam,et al.  Targeting amphiregulin (AREG) derived from senescent stromal cells diminishes cancer resistance and averts programmed cell death 1 ligand (PD‐L1)‐mediated immunosuppression , 2019, Aging cell.

[2]  D. Richter,et al.  Attenuated palmitoylation of serotonin receptor 5-HT1A affects receptor function and contributes to depression-like behaviors , 2019, Nature Communications.

[3]  S. Ghanem,et al.  Circulating microRNA-301 as a promising diagnostic biomarker of hepatitis C virus-related hepatocellular carcinoma , 2019, Molecular Biology Reports.

[4]  K. Zibara,et al.  The AP-1 transcriptional complex: Local switch or remote command? , 2019, Biochimica et biophysica acta. Reviews on cancer.

[5]  S. Chakrapani,et al.  Molecular mechanism of setron-mediated inhibition of full-length 5-HT3A receptor , 2019, Nature Communications.

[6]  T. Masaki,et al.  Serum microRNA-125a-5p as a potential biomarker of HCV-associated hepatocellular carcinoma. , 2019, Oncology letters.

[7]  Ji-Fu Wei,et al.  METTL3 promote tumor proliferation of bladder cancer by accelerating pri-miR221/222 maturation in m6A-dependent manner , 2019, Molecular cancer.

[8]  Yushui Ma,et al.  Dual Regulatory Mechanisms of Expression and Mutation Involving Metabolism-Related Genes FDFT1 and UQCR5 during CLM , 2019, Molecular therapy oncolytics.

[9]  B. Sveinbjørnsson,et al.  The Novel Oncolytic Compound LTX-401 Induces Antitumor Immune Responses in Experimental Hepatocellular Carcinoma , 2019, Molecular therapy oncolytics.

[10]  Z. Pan,et al.  Upregulated exosomal miR-221/222 promotes cervical cancer via repressing methyl-CpG-binding domain protein 2. , 2019, European review for medical and pharmacological sciences.

[11]  Lilya V. Matyunina,et al.  Essential role of JunD in cell proliferation is mediated via MYC signaling in prostate cancer cells. , 2019, Cancer letters.

[12]  Hongwei Liang,et al.  Injured liver-released miRNA-122 elicits acute pulmonary inflammation via activating alveolar macrophage TLR7 signaling pathway , 2019, Proceedings of the National Academy of Sciences.

[13]  F. Deng,et al.  Protein kinase Ds promote tumor angiogenesis through mast cell recruitment and expression of angiogenic factors in prostate cancer microenvironment , 2019, Journal of Experimental & Clinical Cancer Research.

[14]  Lei Chen,et al.  miR-221/222-Mediated Inhibition of Autophagy Promotes Dexamethasone Resistance in Multiple Myeloma. , 2019, Molecular therapy : the journal of the American Society of Gene Therapy.

[15]  Jiah Shin Chin,et al.  Scaffold-Mediated Sustained, Non-viral Delivery of miR-219/miR-338 Promotes CNS Remyelination. , 2019, Molecular therapy : the journal of the American Society of Gene Therapy.

[16]  Hansi Liang,et al.  A novel circular RNA, circFAT1(e2), inhibits gastric cancer progression by targeting miR-548g in the cytoplasm and interacting with YBX1 in the nucleus. , 2019, Cancer letters.

[17]  Jun Li,et al.  Exosome-mediated secretion of LOXL4 promotes hepatocellular carcinoma cell invasion and metastasis , 2019, Molecular Cancer.

[18]  Y. Soda,et al.  Extremely Low Organ Toxicity and Strong Antitumor Activity of miR-34-Regulated Oncolytic Coxsackievirus B3 , 2019, Molecular therapy oncolytics.

[19]  Yiguo Jiang,et al.  Circular RNA 100146 functions as an oncogene through direct binding to miR-361-3p and miR-615-5p in non-small cell lung cancer , 2019, Molecular Cancer.

[20]  Yue Yu,et al.  miR-190 enhances endocrine therapy sensitivity by regulating SOX9 expression in breast cancer , 2019, Journal of experimental & clinical cancer research : CR.

[21]  M. Selzer,et al.  Promoting Axon Regeneration in Adult CNS by Targeting Liver Kinase B1. , 2019, Molecular therapy : the journal of the American Society of Gene Therapy.

[22]  R. Dutta,et al.  A Neutralizing Aptamer to TGFBR2 and miR-145 Antagonism Rescue Cigarette Smoke- and TGF-β-Mediated CFTR Expression , 2018, Molecular therapy : the journal of the American Society of Gene Therapy.

[23]  Keqiu Jiang,et al.  Multipotent mesenchymal stromal cells play critical roles in hepatocellular carcinoma initiation, progression and therapy , 2018, Molecular Cancer.

[24]  Keqiu Jiang,et al.  Multipotent mesenchymal stromal cells play critical roles in hepatocellular carcinoma initiation, progression and therapy , 2018, Molecular Cancer.

[25]  M. Kay,et al.  miR-122 removal in the liver activates imprinted microRNAs and enables more effective microRNA-mediated gene repression , 2018, Nature Communications.

[26]  A. Kutikhin,et al.  Dynamic matrisome: ECM remodeling factors licensing cancer progression and metastasis. , 2018, Biochimica et biophysica acta. Reviews on cancer.

[27]  Wei Zhang,et al.  miR-30 Family Reduction Maintains Self-Renewal and Promotes Tumorigenesis in NSCLC-Initiating Cells by Targeting Oncogene TM4SF1. , 2018, Molecular therapy : the journal of the American Society of Gene Therapy.

[28]  R. Mahato,et al.  Therapeutic Potential of OMe-PS-miR-29b1 for Treating Liver Fibrosis. , 2018, Molecular therapy : the journal of the American Society of Gene Therapy.

[29]  Ying Jiang,et al.  Targeting Endothelial Erk1/2-Akt Axis as a Regeneration Strategy to Bypass Fibrosis during Chronic Liver Injury in Mice. , 2018, Molecular therapy : the journal of the American Society of Gene Therapy.

[30]  Hanyu Ma,et al.  Upregulation of lncRNA ADAMTS9-AS2 Promotes Salivary Adenoid Cystic Carcinoma Metastasis via PI3K/Akt and MEK/Erk Signaling. , 2018, Molecular therapy : the journal of the American Society of Gene Therapy.

[31]  G. Pesole,et al.  EphB2 stem-related and EphA2 progression-related miRNA-based networks in progressive stages of CRC evolution: clinical significance and potential miRNA drivers , 2018, Molecular Cancer.

[32]  W. Chen,et al.  CircSLC3A2 functions as an oncogenic factor in hepatocellular carcinoma by sponging miR-490-3p and regulating PPM1F expression , 2018, Molecular Cancer.

[33]  Tianxin Lin,et al.  Invasion-related circular RNA circFNDC3B inhibits bladder cancer progression through the miR-1178-3p/G3BP2/SRC/FAK axis , 2018, Molecular Cancer.

[34]  W. Zhai,et al.  Sunitinib-suppressed miR-452-5p facilitates renal cancer cell invasion and metastasis through modulating SMAD4/SMAD7 signals , 2018, Molecular Cancer.

[35]  M. Bennett,et al.  Disease-relevant transcriptional signatures identified in individual smooth muscle cells from healthy mouse vessels , 2018, Nature Communications.

[36]  Yushui Ma,et al.  Downregulation of miR-223 and miR-19a induces differentiation and promotes recruitment of osteoclast cells in giant-cell tumor of the bone via the Runx2/TWIST-RANK/RANKL pathway. , 2018, Biochemical and biophysical research communications.

[37]  B. Xiang,et al.  LncRNA CDKN2B-AS1 promotes tumor growth and metastasis of human hepatocellular carcinoma by targeting let-7c-5p/NAP1L1 axis. , 2018, Cancer letters.

[38]  Jun Yu,et al.  Dietary cholesterol promotes steatohepatitis related hepatocellular carcinoma through dysregulated metabolism and calcium signaling , 2018, Nature Communications.

[39]  E. Lam,et al.  Targeting SPINK1 in the damaged tumour microenvironment alleviates therapeutic resistance , 2018, Nature Communications.

[40]  Yushui Ma,et al.  MicroRNA-302a/d inhibits the self-renewal capability and cell cycle entry of liver cancer stem cells by targeting the E2F7/AKT axis , 2018, Journal of experimental & clinical cancer research : CR.

[41]  Xin Tong,et al.  Circular RNA hsa_circ_0008305 (circPTK2) inhibits TGF-β-induced epithelial-mesenchymal transition and metastasis by controlling TIF1γ in non-small cell lung cancer , 2018, Molecular Cancer.

[42]  Yushui Ma,et al.  Proteogenomic characterization and comprehensive integrative genomic analysis of human colorectal cancer liver metastasis , 2018, Molecular Cancer.

[43]  P. Khaw,et al.  Development of Targeted siRNA Nanocomplexes to Prevent Fibrosis in Experimental Glaucoma Filtration Surgery , 2018, Molecular therapy : the journal of the American Society of Gene Therapy.

[44]  Yanyan Song,et al.  S100B suppression alters polarization of infiltrating myeloid-derived cells in gliomas and inhibits tumor growth , 2018, Cancer letters.

[45]  M. Caputo,et al.  miR-210 Enhances the Therapeutic Potential of Bone-Marrow-Derived Circulating Proangiogenic Cells in the Setting of Limb Ischemia. , 2018, Molecular therapy : the journal of the American Society of Gene Therapy.

[46]  Yushui Ma,et al.  Tumor suppressive microRNA-124a inhibits stemness and enhances gefitinib sensitivity of non-small cell lung cancer cells by targeting ubiquitin-specific protease 14. , 2018, Cancer letters.

[47]  M. Hashizume,et al.  Basement membrane destruction by pancreatic stellate cells leads to local invasion in pancreatic ductal adenocarcinoma. , 2018, Cancer letters.

[48]  John D. Chan,et al.  Coalescing beneficial host and deleterious antiparasitic actions as an antischistosomal strategy , 2018, eLife.

[49]  Yushui Ma,et al.  DRR1 promotes glioblastoma cell invasion and epithelial-mesenchymal transition via regulating AKT activation. , 2018, Cancer letters.

[50]  E. Lam,et al.  The senescence-associated secretory phenotype is potentiated by feedforward regulatory mechanisms involving Zscan4 and TAK1 , 2018, Nature Communications.

[51]  Yue Yu,et al.  miR-190 suppresses breast cancer metastasis by regulation of TGF-β-induced epithelial–mesenchymal transition , 2018, Molecular Cancer.

[52]  Shanshan Liu,et al.  The critical roles of activated stellate cells-mediated paracrine signaling, metabolism and onco-immunology in pancreatic ductal adenocarcinoma , 2018, Molecular Cancer.

[53]  Aniruddh Agrawal,et al.  Regulation of insulin resistance and type II diabetes by hepatitis C virus infection: A driver function of circulating miRNAs , 2018, Journal of cellular and molecular medicine.

[54]  S. Alahari,et al.  Nischarin regulates focal adhesion and Invadopodia formation in breast cancer cells , 2018, Molecular Cancer.

[55]  M. Kennedy,et al.  Adenovirus-Mediated Delivery of Decoy Hyper Binding Sites Targeting Oncogenic HMGA1 Reduces Pancreatic and Liver Cancer Cell Viability , 2018, Molecular therapy oncolytics.

[56]  E. Barnes.  Unravelling the fate of functional PD1+ T cells in chronic viral hepatitis , 2018, The Journal of clinical investigation.

[57]  S. Milstein,et al.  Advanced siRNA Designs Further Improve In Vivo Performance of GalNAc-siRNA Conjugates , 2018, Molecular therapy : the journal of the American Society of Gene Therapy.

[58]  Y. Liu,et al.  Development of GPC3-Specific Chimeric Antigen Receptor-Engineered Natural Killer Cells for the Treatment of Hepatocellular Carcinoma. , 2017, Molecular therapy : the journal of the American Society of Gene Therapy.

[59]  M. Vila,et al.  Selective α-Synuclein Knockdown in Monoamine Neurons by Intranasal Oligonucleotide Delivery: Potential Therapy for Parkinson's Disease. , 2017, Molecular therapy : the journal of the American Society of Gene Therapy.

[60]  Yongkang Luo,et al.  Effects of collagen peptides intake on skin ageing and platelet release in chronologically aged mice revealed by cytokine array analysis , 2017, Journal of cellular and molecular medicine.

[61]  A. Vaag,et al.  Escitalopram Ameliorates Hypercortisolemia and Insulin Resistance in Low Birth Weight Men With Limbic Brain Alterations , 2018, The Journal of clinical endocrinology and metabolism.

[62]  S. Gong,et al.  PKN2 in colon cancer cells inhibits M2 phenotype polarization of tumor-associated macrophages via regulating DUSP6-Erk1/2 pathway , 2018, Molecular Cancer.

[63]  A. Wells,et al.  Bi-directional exosome-driven intercommunication between the hepatic niche and cancer cells , 2017, Molecular Cancer.

[64]  Xiaoming Li,et al.  MEK inhibitor, PD98059, promotes breast cancer cell migration by inducing β-catenin nuclear accumulation. , 2017, Oncology reports.

[65]  N. Kato,et al.  Suppression of Oncolytic Adenovirus-Mediated Hepatotoxicity by Liver-Specific Inhibition of NF-κB , 2017, Molecular therapy oncolytics.

[66]  Yushui Ma,et al.  Reduced miR-105-1 levels are associated with poor survival of patients with non-small cell lung cancer , 2017, Oncology letters.

[67]  Yushui Ma,et al.  Reduced miR-125a levels associated with poor survival of patients with hepatocellular cancer , 2017, Oncology letters.

[68]  Newaz I. Ahmed,et al.  The atypical antipsychotic olanzapine causes weight gain by targeting serotonin receptor 2C. , 2017, The Journal of clinical investigation.

[69]  S. Ikeda,et al.  The biology of Hepatocellular carcinoma: implications for genomic and immune therapies , 2017, Molecular Cancer.

[70]  Yushui Ma,et al.  Up-regulated microRNA-299 corrected with poor prognosis of glioblastoma multiforme patients by targeting ELL2 , 2017, Japanese journal of clinical oncology.

[71]  B. Finck,et al.  ChREBP refines the hepatic response to fructose to protect the liver from injury. , 2017, The Journal of clinical investigation.

[72]  Roland Strauss,et al.  Serotonin modulates a depression-like state in Drosophila responsive to lithium treatment , 2017, Nature Communications.

[73]  N. Yang,et al.  miR-203 inhibits the expression of collagen-related genes and the proliferation of hepatic stellate cells through a SMAD3-dependent mechanism , 2017, Molecular medicine reports.

[74]  Thomas D. Schmittgen,et al.  miR-221 regulates CD44 in hepatocellular carcinoma through the PI3K-AKT-mTOR pathway. , 2017, Biochemical and biophysical research communications.

[75]  T. Miyashita,et al.  Extravasated platelet aggregation in the livers of rats with drug‑induced hepatic sinusoidal obstruction syndrome. , 2017, Molecular medicine reports.

[76]  D. Engblom,et al.  Prostaglandin-mediated inhibition of serotonin signaling controls the affective component of inflammatory pain , 2017, The Journal of clinical investigation.

[77]  Lixin Wei,et al.  Autophagy-deficient Kupffer cells promote tumorigenesis by enhancing mtROS-NF-κB-IL1α/β-dependent inflammation and fibrosis during the preneoplastic stage of hepatocarcinogenesis. , 2017, Cancer letters.

[78]  R. Mohney,et al.  Near-Complete Correction of Profound Metabolomic Impairments Corresponding to Functional Benefit in MPS IIIB Mice after IV rAAV9-hNAGLU Gene Delivery. , 2017, Molecular Therapy.

[79]  E. Dahl,et al.  ITIH5 mediates epigenetic reprogramming of breast cancer cells , 2017, Molecular Cancer.

[80]  Erel Levine,et al.  Serotonin-dependent kinetics of feeding bursts underlie a graded response to food availability in C. elegans , 2017, Nature Communications.

[81]  Mingqi Xie,et al.  A Synthetic-Biology-Inspired Therapeutic Strategy for Targeting and Treating Hepatogenous Diabetes. , 2017, Molecular therapy : the journal of the American Society of Gene Therapy.

[82]  Hongguang Zhang,et al.  hucMSC Exosome-Derived GPX1 Is Required for the Recovery of Hepatic Oxidant Injury. , 2017, Molecular therapy : the journal of the American Society of Gene Therapy.

[83]  Yushui Ma,et al.  Association of microRNA-33a Molecular Signature with Non-Small Cell Lung Cancer Diagnosis and Prognosis after Chemotherapy , 2017, PloS one.

[84]  M. Eccles,et al.  MicroRNA expression patterns and signalling pathways in the development and progression of childhood solid tumours , 2017, Molecular Cancer.

[85]  H. Tsukamoto,et al.  A Proof-of-Concept for Epigenetic Therapy of Tissue Fibrosis: Inhibition of Liver Fibrosis Progression by 3-Deazaneplanocin A , 2017, Molecular therapy : the journal of the American Society of Gene Therapy.

[86]  Bicheng Chen,et al.  HOTAIR Epigenetically Modulates PTEN Expression via MicroRNA-29b: A Novel Mechanism in Regulation of Liver Fibrosis. , 2017, Molecular therapy : the journal of the American Society of Gene Therapy.

[87]  E. Jho,et al.  Hippo signaling interactions with Wnt/&bgr;-catenin and Notch signaling repress liver tumorigenesis , 2017, The Journal of clinical investigation.

[88]  F. Tacke,et al.  Isolation and Culture of Primary Murine Hepatic Stellate Cells. , 2017, Methods in molecular biology.

[89]  Qi Zhang,et al.  G protein-coupled estrogen receptor deficiency accelerates liver tumorigenesis by enhancing inflammation and fibrosis. , 2016, Cancer letters.

[90]  S. Banskota,et al.  Tryptophan hydroxylase 1 and 5-HT7 receptor preferentially expressed in triple-negative breast cancer promote cancer progression through autocrine serotonin signaling , 2016, Molecular Cancer.

[91]  F. Tacke,et al.  Role of chemokine pathways in hepatobiliary cancer. , 2016, Cancer letters.

[92]  U. Settmacher,et al.  Proteinase-activated receptor 2 (PAR2) in hepatic stellate cells – evidence for a role in hepatocellular carcinoma growth in vivo , 2016, Molecular Cancer.

[93]  J. Jia,et al.  Matrix metalloproteinase-1 induction by diethyldithiocarbamate is regulated via Akt and ERK/miR222/ETS-1 pathways in hepatic stellate cells , 2016, Bioscience reports.

[94]  Mengchao Wu,et al.  An Artificially Designed Interfering lncRNA Expressed by Oncolytic Adenovirus Competitively Consumes OncomiRs to Exert Antitumor Efficacy in Hepatocellular Carcinoma , 2016, Molecular Cancer Therapeutics.

[95]  Ting Liu,et al.  AZGP1 suppresses epithelial-to-mesenchymal transition and hepatic carcinogenesis by blocking TGFβ1-ERK2 pathways. , 2016, Cancer letters.

[96]  G. Giamas,et al.  LMTK3 escapes tumour suppressor miRNAs via sequestration of DDX5. , 2016, Cancer letters.

[97]  K. Migita,et al.  Circulating microRNA Profiles in Patients with Type-1 Autoimmune Hepatitis , 2015, PloS one.

[98]  B. Fingleton,et al.  Host and tumor derived MMP13 regulate extravasation and establishment of colorectal metastases in the liver , 2015, Molecular Cancer.

[99]  H. Dienes,et al.  Kinetics of miR-122 Expression in the Liver during Acute HCV Infection , 2013, PloS one.

[100]  G. Lauer,et al.  Up‐regulation of circulating miR‐20a is correlated with hepatitis C virus‐mediated liver disease progression , 2013, Hepatology.

[101]  K. Yoshizato,et al.  MicroRNA-221/222 upregulation indicates the activation of stellate cells and the progression of liver fibrosis , 2012, Gut.

[102]  M. Ebrahimkhani,et al.  Stimulating healthy tissue regeneration by targeting the 5-HT2B receptor in chronic liver disease , 2011, Nature Medicine.

[103]  Anton P. McCaffrey,et al.  Correlation between microRNA expression levels and clinical parameters associated with chronic hepatitis C viral infection in humans , 2010, Laboratory Investigation.

[104]  L. Bryan-Lluka,et al.  A role for serotonin (5-HT) in hepatic stellate cell function and liver fibrosis. , 2006, The American journal of pathology.