title: Mannose-mediated inhibitory effects of PA-MSHA on invasion and metastasis of hepatocellular carcinoma via EGFR/Akt/IκBβ/NF-κB pathway.
abstract: OBJECTIVE
  Elevation of high-mannose glycans is a common feature of malignant cells and has been suggested to be the basis for alternative cancer therapy for several years. Here we want to investigate the antitumour effect of pseudomonas aeruginosa-mannosesensitive haemagglutinin (PA-MSHA), a genetically engineered heat-inactivated PA strain with mannose-sensitive binding activity, on hepatocellular carcinoma (HCC).
  
  
  METHODS
  Tumourigenicity and metastatic potentials of HCC were studied after PA-MSHA treatment by utilizing the in vitro/in vivo model of HCC. Expression of apoptosis-associated proteins and epithelial-mesenchymal transition (EMT) related genes were evaluated, and possible signalling pathways involved were investigated.
  
  
  RESULTS
  PA-MSHA induced significant cell proliferation inhibition and cell cycle arrest of HCC through decreasing the levels of cyclins D1, cyclins E, CDK2, CDK4, proliferating cell nuclear antigen (PCNA), and increasing the level of p21 and p27. Moreover, PA-MSHA suppressed the invasion, migration and adhesion of HCC through inhibiting epithelial-mesenchymal transition (EMT). PA-MSHA also inhibited EGFR/Akt/IκBβ/NF-κB pathway and overexpression of NF-κB significantly abrogated PA-MSHA induced EMT inhibition. In addition, competitive inhibition of the mannose binding activity of PA-MSHA by D-mannose significantly blocked its effect on cell cycle arrest and EMT. PA-MSHA also abrogated lung metastasis of HCC and significantly inhibited tumour growth in the in vivo study.
  
  
  CONCLUSIONS
  Our study demonstrated the essential role of EGFR/Akt/IκBβ/NF-κB pathway in the inhibitory effect of PA-MSHA on invasion and metastasis of HCC through suppressing EMT, and revealed an attractive prospect of PA-MSHA as a novel candidate agent in the treatment of HCC.
authors: Department of general surgery, Qilu Hospital, Shandong University, Jinan, 250012, China.
authors: Tao
authors: T
authors: Li
authors: Zhao-Ru
authors: ZR
authors: Dong
authors: Zong-Yi
authors: ZY
authors: Guo
authors: Cheng-Hao
authors: CH
authors: Wang
authors: Xu-Ting
authors: XT
authors: Zhi
authors: Jian-Wei
authors: JW
authors: Zhou
authors: Deng-Ke
authors: DK
authors: Li
authors: Ze-Ting
authors: ZT
authors: Chen
authors: Zhi-Qiang
authors: ZQ
authors: Chen
authors: San-Yuan
authors: SY
authors: Hu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000556:secondary; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D036781:Fimbriae Proteins / Q000494:pharmacology*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008175:Lung Neoplasms / Q000201:enzymology / Q000517:prevention & control* / Q000556:secondary; D008297:Male; D008358:Mannose / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; C000603452:mannosesensitive haemagglutinin, Pseudomonas aeruginosa; D036781:Fimbriae Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; D008358:Mannose
keywords: Pseudomonas aeruginosa; cell cycle; epithelial-mesenchymal transition; hepatocellular carcinoma; mannose