title: RNA interference of PARG could inhibit the metastatic potency of colon carcinoma cells via PI3-kinase/Akt pathway.
abstract: OBJECTIVE
  To investigate the role and mechanism of PARG inhibition of metastatic behavior in colonic carcinoma cells.
  
  
  METHODS
  We examined the effects of PARG protein knockdown by RNA interference on invasion, migration and matrix adhesion of colon carcinoma cell lines in vitro and using a murine in vivo model of liver metastasis. Metastasis related genes were detected using mRNA and protein levels. Moreover, LY294002, an Akt phosphorylation inhibitor, was used to determine whether the suppression of metastatic behavior of colon carcinoma cells was mediated by Akt phosphorylation that was confirmed by EMSA. Pyrrolidine dithiocarbamate (PDTC) was used as a selective NFκ-B inhibitor to clarify the relationship between PARG, PARP and NF-κB.
  
  
  RESULTS
  PARG protein was undetectable following specific shRNA transfection; mRNA and protein levels of PARP were significantly decreased. PARG-shRNA cells showed high levels of phosphorylated Akt with decreased expression of NF-κB (both total & nuclear), MMP2 and MMP9. However, no additional changes were noted following inhibition of PI3K/Akt pathway by LY294002 in the PARG-shRNA cells; these cells displayed reduced number of liver metastases when characterized in the murine in vivo model.
  
  
  CONCLUSIONS
  PARG knockdown, concomitant with inhibition of PARP, suppressed the metastatic potency of colon carcinoma cells by activation of PI3K/Akt signaling pathway.
authors.affiliation: Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, China.
authors.forename: Qiaozhuan
authors.initials: Q
authors.lastname: Li
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Ya-Lan
authors.initials: YL
authors.lastname: Wang
authors.forename: Nilufer Jasmine Selimah
authors.initials: NJ
authors.lastname: Fauzee
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.forename: Juan
authors.initials: J
authors.lastname: Pan
authors.forename: Lian
authors.initials: L
authors.lastname: Yang
authors.forename: Alexander
authors.initials: A
authors.lastname: Lazar
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement; D002867:Chromones / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006026:Glycoside Hydrolases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000556:secondary; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013859:Thiocarbamates / Q000494:pharmacology; D014162:Transfection
chemical_list: D002867:Chromones; D006026:Glycoside Hydrolases; D020778:Matrix Metalloproteinase 2; D009025:Morpholines; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D051057:Proto-Oncogene Proteins c-akt; D011759:Pyrrolidines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013859:Thiocarbamates; C549075:LY 290042; C020972:pyrrolidine dithiocarbamic acid; C022407:poly ADP-ribose glycohydrolase; C522361:MMP2 protein, human