Down-regulation of miR-146b-5p by long noncoding RNA MALAT1 in hepatocellular carcinoma promotes cancer growth and metastasis

MicroRNAs play an important role in liver cancer genesis and progression. In this study, we identified down-regulation of miR-146b-5p associated with tumor growth, metastasis and poor survival in hepatocellular carcinoma (HCC) patients. miR-146b-5p could suppress proliferation, migration, and invasion and induced apoptosis in vitro and in vivo. Remarkably, TNF receptor associated factor 6 (TRAF6) was confirmed as a direct target of miR-146b-5p in HCC and miR-146b-5p exerted the tumor suppression roles through inhibiting the phosphorylation of Akt mediated by TRAF6. Furthermore, we identified long non-coding RNA MALAT1 as a molecular sponge of miR-146b-5p to down-regulate its expression in HCC. In general, our results indicate that miR-146b-5p inhibits tumor growth and metastasis of HCC by targeting TRAF6 mediated Akt phosphorylation.

[1]  Ning Wang,et al.  Cancer survival in China, 2003–2005: A population‐based study , 2015, International journal of cancer.

[2]  Xin Zheng,et al.  Prognostic significance of miR-218 in human hepatocellular carcinoma and its role in cell growth. , 2014, Oncology reports.

[3]  Zhi-xin Wang,et al.  miR-34a induces cellular senescence via modulation of telomerase activity in human hepatocellular carcinoma by targeting FoxM1/c-Myc pathway , 2015, Oncotarget.

[4]  Xin Zheng,et al.  SREBP-1 Has a Prognostic Role and Contributes to Invasion and Metastasis in Human Hepatocellular Carcinoma , 2014, International journal of molecular sciences.

[5]  Ping Wang,et al.  Knockdown of long non-coding RNA HOTAIR inhibits malignant biological behaviors of human glioma cells via modulation of miR-326 , 2015, Oncotarget.

[6]  Hai Hu,et al.  MicroRNA-146b-5p inhibits the growth of gallbladder carcinoma by targeting epidermal growth factor receptor. , 2015, Molecular medicine reports.

[7]  Xin Zheng,et al.  Recombinant Human Adenovirus-p53 Injection Induced Apoptosis in Hepatocellular Carcinoma Cell Lines Mediated by p53-Fbxw7 Pathway, Which Controls c-Myc and Cyclin E , 2013, PloS one.

[8]  S. Choi,et al.  NOVA1 inhibition by miR-146b-5p in the remnant tissue microenvironment defines occult residual disease after gastric cancer removal , 2015, Oncotarget.

[9]  A. Wen,et al.  miR-592/WSB1/HIF-1α axis inhibits glycolytic metabolism to decrease hepatocellular carcinoma growth , 2016, Oncotarget.

[10]  A. Sapino,et al.  In Situ Hybridization Analysis of miR-146b-5p and miR-21 in Thyroid Nodules: Diagnostic Implications , 2015, Endocrine pathology.

[11]  M. Pittet,et al.  MicroRNA-mediated control of macrophages and its implications for cancer. , 2013, Trends in immunology.

[12]  M. Esteller,et al.  lncRNAs and microRNAs with a role in cancer development. , 2016, Biochimica et biophysica acta.

[13]  Ya Cao,et al.  miR‐28‐5p‐IL‐34‐macrophage feedback loop modulates hepatocellular carcinoma metastasis , 2016, Hepatology.

[14]  Q. Ye,et al.  MicroRNA‐26a suppresses angiogenesis in human hepatocellular carcinoma by targeting hepatocyte growth factor‐cMet pathway , 2014, Hepatology.

[15]  S. Leeder,et al.  A population based study , 1993, The Medical journal of Australia.

[16]  A. Bowie,et al.  Poxviral Protein A52 Stimulates p38 Mitogen-activated Protein Kinase (MAPK) Activation by Causing Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) Self-association Leading to Transforming Growth Factor β-activated Kinase 1 (TAK1) Recruitment* , 2013, The Journal of Biological Chemistry.

[17]  A. Aboussekhra,et al.  MicroRNA-141 and MicroRNA-146b-5p Inhibit the Prometastatic Mesenchymal Characteristics through the RNA-binding Protein AUF1 Targeting the Transcription Factor ZEB1 and the Protein Kinase AKT* , 2014, The Journal of Biological Chemistry.

[18]  Jing Liu,et al.  miR-146b-5p inhibits glioma migration and invasion by targeting MMP16. , 2013, Cancer letters.

[19]  Xuhui Zhou,et al.  miR-146b-5p promotes invasion and metastasis contributing to chemoresistance in osteosarcoma by targeting zinc and ring finger 3. , 2016, Oncology reports.

[20]  Xin Zheng,et al.  Fbxw7 is an independent prognostic marker and induces apoptosis and growth arrest by regulating YAP abundance in hepatocellular carcinoma , 2014, Molecular Cancer.

[21]  D. Fan,et al.  Regulation of UHRF1 by miR‐146a/b modulates gastric cancer invasion and metastasis , 2013, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[22]  Xin Wang 王 欣,et al.  Inhibitory effects of miR-146b-5p on cell migration and invasion of pancreatic cancer by targeting MMP16 , 2011, Journal of Huazhong University of Science and Technology [Medical Sciences].

[23]  S. Sidhu,et al.  Papillary thyroid cancer-derived exosomes contain miRNA-146b and miRNA-222. , 2015, The Journal of surgical research.

[24]  A. Schetter,et al.  microRNA and inflammatory gene expression as prognostic marker for overall survival in esophageal squamous cell carcinoma , 2013, International journal of cancer.

[25]  Hongyang Wang,et al.  HBx Sensitizes Cells to Oxidative Stress-induced Apoptosis by Accelerating the Loss of Mcl-1 Protein via Caspase-3 Cascade , 2011, Molecular Cancer.

[26]  Xiang Yun Guo,et al.  Low expression of microRNA-146b-5p and microRNA-320d predicts poor outcome of large B-cell lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisone. , 2014, Human pathology.

[27]  Gang Pan,et al.  Expression Profile and Clinical Significance of MicroRNAs in Papillary Thyroid Carcinoma , 2014, Molecules.

[28]  E. Kimura,et al.  MicroRNA miR-146b-5p regulates signal transduction of TGF-β by repressing SMAD4 in thyroid cancer , 2012, Oncogene.

[29]  Chul-Seung Park,et al.  Cereblon negatively regulates TLR4 signaling through the attenuation of ubiquitination of TRAF6 , 2016, Cell Death and Disease.

[30]  E. Kimura,et al.  MiRNA-146b-5p upregulates migration and invasion of different Papillary Thyroid Carcinoma cells , 2016, BMC Cancer.

[31]  Yingying Liu,et al.  MiR-146b-5p overexpression attenuates stemness and radioresistance of glioma stem cells by targeting HuR/lincRNA-p21/β-catenin pathway , 2016, Oncotarget.

[32]  Hongliang Li,et al.  The ubiquitin E3 ligase TRAF6 exacerbates pathological cardiac hypertrophy via TAK1-dependent signalling , 2016, Nature Communications.

[33]  Zuozhang Yang,et al.  MicroRNAs in apoptosis, autophagy and necroptosis , 2015, Oncotarget.