The Role And Its Mechanism Of SENP2 Gene In The Pathogenesis Of Chronic Lymphocytic Leukemia

Objective: To study the relationship between SENP2 gene and the biological characteristics of patients with chronic lymphocytic leukemia(CLL)by detecting the expression of SENP2 gene in primary CLL cells;to study the effects of SENP2 gene on proliferation,chemotherapeutic sensitivity,invasion,chemokinesis,apoptosis and cell cycle of CLL cells;to study the effects of SENP2 gene on NOTCH1 signaling pathway,Wnt/?-catenin signaling pathway and NF-?B signaling pathway in CLL cells.Therefore,we will reveal the role and its mechanism of SENP2 gene in regulating of the growth of CLL cells.Methods: 1.The peripheral blood mononuclear cells of 44 patients with CLL were collected.The transcription and the protein expression level of SENP2 gene was detected by the q RT-PCR and Western Blot,respectively.2.CLL cell line which high expression or low expression SENP2 gene was constructed.The effects of SENP2 gene on proliferation,chemotherapeutic sensitivity,invasion,chemokinesis,apoptosis and cell cycle of CLL cells were detected by CCK8 assay,Transwell assay,Boyden chamber assay and flow cytometry,respectively.3.The level of gene transcription and protein expression related with NOTCH1,Wnt/?-catenin as well as NF-?B signaling pathway were detected by the q RT-PCR and Western Blot,respectively.Results: 1.The transcription level of SENP2 gene in the treat-naive group was significantly higher than that in the control group.Single factor analysis showed a positive correlation between the transcription level of SENP2 gene and the expression level of LDH.2.SENP2 gene overexpression:(1)the proliferation of CLL cells were inhibited;(2)the inhibitory effect on the proliferation of MEC2 cells caused by Ara-c and dexamethasone were more obvious after cultured 24h;(3)the invasion ability of MEC2 cells were decreased;(4)the chemotaxis of MEC2 cells induced by CXCL12 were inhibited;(5)apotosis and cell cycle of MEC2 cells were unaffected.SENP2 gene expression reduced:(1)the proliferation of CLL cells were promoted after cultured 24 h and turn into inhibition to the proliferation as time goes on;(2)the inhibitory effect on the proliferation of MEC2 cells caused by Ara-c were reduced after cultured 24h;(3)the invasion ability of MEC2 cells were increased;(4)the chemotaxis of MEC2 cells induced by CXCL12 were promoted;(5)apotosis and cell cycle of MEC2 cells were unaffected.3.There have no significant changes were observed in the transcription levels of NOTCH1,Hes1,?-catenin,WWOX and some other genes participating in NF-?B signaling pathway regardless of the transcription level of the SENP2 gene.The expression of NOTCH1,C-myc,?-catenin and P65,P50,IKK?,IKK? were increased after SENP2 overexpression and reduced after the decreasion of SENP2 expression.Conclusion: 1.The transcription level of the SENP2 gene in treat-naive CLL patients were significantly higher than that of healthy control.2.SENP2 has a negative effect on the proliferation,drug resistance and chemotaxis of CLL cells.3.SENP2 can negatively regulate NOTCH1,Wnt/?-catenin and NF-?B signaling pathway at protein level.The regulation mechanism of SENP2 on NOTCH1,Wnt/?-catenin and NF-?B signaling pathway may be related to the ability of SENP2 which could reverse the SUMO modification of protein molecules.