title: miR-4443 Participates in the Malignancy of Breast Cancer.
abstract: OBJECTIVE
  Chemo-resistance is the leading cause of failure in cancer therapy, however, much remains to be understood about the intrinsic mechanisms. In the present study, we discovered the novel miR-4443 that regulated malignancy of breast cancer both in vitro and in vivo.
  
  
  METHODS
  We examined the expression of miR-4443 in MDA-MB-231/S and MDA-MB-231 Epirubicin-resistant cell lines with 76 breast cancer formalin-fixed paraffin-embedded tissues by real-time PCR. Also, we investigated the loss- and gain-functions of miR-4443 by MTT assay and flow cytometry. Furthermore, we detected miR-4443 mediated tissue inhibitor of metalloproteinase 2 expression in cells by TargetScan, RT-qPCR and western blot.
  
  
  RESULTS
  We identified the up-regulated expression of miR-4443 in Epi-resistant cell lines versus MDA-MB-231/S cell(Epi versus S) and in post-chemotherapy FFPE tissues, along with statistically differential expressions in PR(partial response) versus SD(stable disease)/PD(progressive disease) patients. Overexpression of miR-4443 increased the IC50 value of Epi for the target cells transfected, while inhibition of miR-4443 could restored sensitivity of the target cells to Epi. Besides, down-regulation of endogenous miR-4443 by miRNA-inhibitors significantly enhanced Epi-induced apoptosis while up-regulation of miR-4443 by miRNA-mimics lead to less Epi-induced apoptotic cells. Consequently, changes in TIMP2 mRNA and protein expression revealed that miR-4443 mimics suppressed expression of TIMP2 and induced migration in breast cancer cells. Furthermore, TIMP2 expression associated with better prognosis(HR = 0.721, 95%CI: 0.529-0.983).
  
  
  CONCLUSIONS
  We revealed that miR-4443 induced malignancy of breast cancer mainly in chemo-resistance aspect for the very first time, providing a novel biomarker in breast cancer diagnosis and therapy.
authors: The Fourth Clinical School of Nanjing Medical University, Nanjing, China.|Department of General Surgery, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, China.
authors: Xiu
authors: X
authors: Chen
authors: Center of Clinical Laboratory Science, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, China.
authors: Shan-Liang
authors: SL
authors: Zhong
authors: School of Public Health Nanjing Medical University, Nanjing, China.
authors: Peng
authors: P
authors: Lu
authors: Department of General Surgery, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, China.
authors: Dan-Dan
authors: DD
authors: Wang
authors: Department of General Surgery, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, China.
authors: Si-Ying
authors: SY
authors: Zhou
authors: Department of General Surgery, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, China.
authors: Su-Jin
authors: SJ
authors: Yang
authors: Department of General Surgery, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, China.
authors: Hong-Yu
authors: HY
authors: Shen
authors: Department of General Surgery, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, China.
authors: Lei
authors: L
authors: Zhang
authors: Center of Clinical Laboratory Science, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, China.
authors: Xiao-Hui
authors: XH
authors: Zhang
authors: Center of Clinical Laboratory Science, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, China.
authors: Jian-Hua
authors: JH
authors: Zhao
authors: Department of General Surgery, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, China.|Department of General Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors: Jin-Hai
authors: JH
authors: Tang
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D012189:Retrospective Studies; D016019:Survival Analysis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C000621659:MIRN-4443 microRNA, human; D035683:MicroRNAs; C560823:TIMP2 protein, human; D019716:Tissue Inhibitor of Metalloproteinase-2