Abstract
Aims: 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 NFĸ-B inhibitor to clarify the relationship between PARG, PARP and NF-ĸB. 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-ĸB (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. Conclusion: PARG knockdown, concomitant with inhibition of PARP, suppressed the metastatic potency of colon carcinoma cells by activation of PI3K/Akt signaling pathway.
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