Wnt信号通路介导CIP2A沉默诱导肺癌细胞凋亡
摘要
目的探讨Wnt信号通路在沉默蛋白磷酸酶2A的癌性抑制因子(CIP2A)对肺癌细胞凋亡影响中的作用。方法以H1299细胞为探讨对象,用CIP2A shRNA慢病毒感染后,Realtime PCR和Western印迹检测沉默效果。以Western印迹检测沉默CIP2A后的肺癌细胞中β-catenin、c-myc蛋白表达水平。用Wnt信号通路激活剂处理沉默CIP2A后的肺癌细胞,噻唑蓝(MTT)法测定细胞增殖,流式细胞术检测细胞凋亡,Western印迹检测细胞中活化的含半胱氨酸的天冬氨酸蛋白水解酶(Cleaved Caspase)-3、Cleaved Caspase-9、β-catenin、c-myc蛋白水平。结论 CIP2A shRNA慢病毒感染显著降低肺癌细胞中CIP2A表达水平。沉默CIP2A后的肺癌细胞增殖活性显著降低,细胞凋亡率显著升高,细胞中Cleaved Caspase-3、Cleaved Caspase-9蛋白水平显著升高,β-catenin、c-myc蛋白水平显著降低(P<0.05)。Wnt信号通路激活剂可以逆转沉默CIP2A对肺癌细胞增殖抑制、凋亡促进作用,降低细胞中Cleaved Caspase-3、Cleaved Caspase-9蛋白水平,升高细胞中β-catenin、c-myc蛋白水平。结论 Wnt信号通路参与介导沉默CIP2A对肺癌细胞凋亡诱导作用。
引文
1 Xu P,Yao J,He J,et al.CIP2A down regulation enhances the sensitivity of pancreatic cancer cells to gemcitabine[J].Oncotarget,2016;7(12):14831-40.
2 Xiao X,He Z,Cao W,et al.Oridonin inhibits gefitinib-resistant lung cancer cells by suppressing EGFR/ERK/MMP-12 and CIP2A/Akt signaling pathways[J].Int J Oncol,2016;48(6):2608-18.
3 Mathiasen DP,Egebjerg C,Andersen SH,et al.Identification of a c-Jun N-terminal kinase-2-dependent signal amplification cascade that regulates c-Myc levels in ras transformation[J].Oncogene,2012;31(3):390-401.
4 Dong QZ,Wang Y,Dong XJ,et al.CIP2A is overexpressed in non-small cell lung cancer and correlates with poor prognosis[J].Ann Surg Oncol,2011;18(3):857-65.
5 Khanna A,B?ckelman C,Hemmes A,et al.MYC-dependent regulation and prognostic role of CIP2A in gastric cancer[J].J Natl Cancer Inst,2009;101(11):793-805.
6 Fang Y,Li Z,Wang X,et al.CIP2A is overexpressed in human ovarian cancer and regulates cell proliferation and apoptosis[J].Tumour Biol,2012;33(6):2299-306.
7 B?ckelman C,Koskensalo S,Hagstr?m J,et al.CIP2A overexpression is associated with c-Myc expression in colorectal cancer[J].Cancer Biol Ther,2012;13(5):289-95.
8 Vaarala MH,Marja-Riitta V,Ari R.CIP2A expression is increased in prostate cancer[J].J Exp Clin Cancer Res,2010;29(1):1-4.
9 Lucas CM,Harris RJ,Giannoudis A,et al.Cancerous inhibitor of PP2A (CIP2A) at diagnosis of chronic myeloid leukemia is a critical determinant of disease progression[J].Blood,2011;117(24):6660-8.
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12 Huang LP,Savoly D,Sidi AA,et al.CIP2A protein expression in high-grade,high-stage bladder cancer[J].Cancer Med,2012;1(1):76-81.
13 Choi YA,Koo JS,Park JS,et al.Estradiol enhances CIP2A expression by the activation of p70 S6 kinase[J].Endocr Relat Cancer,2014;21(2):189-202.
14 Lee J,Hwang JW,Noh JW,et al.SAT0059 Inhibition of CIP2A facilitate C-MYC independent apoptosis of fibroblast-like synoviocytes in rheumatoid arthritis[J].Rheumatol Int,2013;33(9):2241-8.
15 Janghorban M,Farrell AS,Allen-Petersen BL,et al.Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer[J].Proc Natl Acad Sci USA,2014;111(25):9157-62.
16 Wang CY,Chao TT,Chang FY,et al.CIP2A mediates erlotinib-induced apoptosis in non-small cell lung cancer cells without EGFR mutation[J].Lung Cancer,2014;85(2):152-60.
17 Villapol S,Acarin L,Faiz M,et al.Survivin and heat shock protein 25/27 colocalize with cleaved caspase-3 in surviving reactive astrocytes following excitotoxicity to the immature brain[J].Neuroscience,2008;153(1):108-19.
18 Chen Y,Lin C,Yang L,et al.HMGB1 promotes HCC progression partly by downregulating p21 via ERK/c-Myc pathway and upregulating MMP-2[J].Tumor Biol,2016;37(4):4399-408.
19 Ai G,Dachineni R,Muley P,et al.Aspirin and salicylic acid decrease c-Myc expression in cancer cells:a potential role in chemoprevention[J].Tumor Biol,2016;37(2):1-12.
20 Zhang HF,Wu C,Alshareef A,et al.The PI3K/AKT/c-MYC axis promotes the acquisition of cancer stem-like features in esophageal squamous cell carcinoma[J].Stem Cells,2016;34(8):2040-51.
21 Calvisi DF,Conner EA,Ladu S,et al.Activation of the canonical Wnt/beta-catenin pathway confers growth advantages in c-Myc/E2F1 transgenic mouse model of liver cancer[J].J Hepatol,2005;42(6):842-9.
22 Fox HMA,Kerosuo L,Wartiovaara K.The function of c-kit,cip2a,and c-myc,in neural progenitor and glioblastoma cells[J].Int J Dev Neurosci,2008;26(8):891.
23 Balliu M,Cellai C,Lulli M,et al.HDAC1 controls CIP2A transcription in human colorectal cancer cells[J].Oncotarget,2016;7(18):25862-71.
24 Cristóbal I,Rojo F,Madozgúrpide J,et al.Cross talk between Wnt/β-Catenin and CIP2A/Plk1 signaling in prostate cancer:Promising therapeutic implications[J].Mol Cell Biol,2016;36(12):1734-9.
25 Gao F,Xu T,Wang X,et al.CIP2A mediates fibronectin-induced bladder cancer cell proliferation by stabilizing β-catenin[J].J Exp Clin Cancer Res,2017;36(1):70.
2 Xiao X,He Z,Cao W,et al.Oridonin inhibits gefitinib-resistant lung cancer cells by suppressing EGFR/ERK/MMP-12 and CIP2A/Akt signaling pathways[J].Int J Oncol,2016;48(6):2608-18.
3 Mathiasen DP,Egebjerg C,Andersen SH,et al.Identification of a c-Jun N-terminal kinase-2-dependent signal amplification cascade that regulates c-Myc levels in ras transformation[J].Oncogene,2012;31(3):390-401.
4 Dong QZ,Wang Y,Dong XJ,et al.CIP2A is overexpressed in non-small cell lung cancer and correlates with poor prognosis[J].Ann Surg Oncol,2011;18(3):857-65.
5 Khanna A,B?ckelman C,Hemmes A,et al.MYC-dependent regulation and prognostic role of CIP2A in gastric cancer[J].J Natl Cancer Inst,2009;101(11):793-805.
6 Fang Y,Li Z,Wang X,et al.CIP2A is overexpressed in human ovarian cancer and regulates cell proliferation and apoptosis[J].Tumour Biol,2012;33(6):2299-306.
7 B?ckelman C,Koskensalo S,Hagstr?m J,et al.CIP2A overexpression is associated with c-Myc expression in colorectal cancer[J].Cancer Biol Ther,2012;13(5):289-95.
8 Vaarala MH,Marja-Riitta V,Ari R.CIP2A expression is increased in prostate cancer[J].J Exp Clin Cancer Res,2010;29(1):1-4.
9 Lucas CM,Harris RJ,Giannoudis A,et al.Cancerous inhibitor of PP2A (CIP2A) at diagnosis of chronic myeloid leukemia is a critical determinant of disease progression[J].Blood,2011;117(24):6660-8.
10 Choi YA,Park JS,Park MY,et al.Increase in CIP2A expression is associated with doxorubicin resistance[J].Febs Lett,2011;585(5):755-60.
11 Jung HM,Patel RS,Phillips BL,et al.Tumor suppressor miR-375 regulates MYC expression via repression of CIP2A coding sequence through multiple miRNA-mRNA interactions[J].Mol Biol Cell,2013;24(11):1638-48.
12 Huang LP,Savoly D,Sidi AA,et al.CIP2A protein expression in high-grade,high-stage bladder cancer[J].Cancer Med,2012;1(1):76-81.
13 Choi YA,Koo JS,Park JS,et al.Estradiol enhances CIP2A expression by the activation of p70 S6 kinase[J].Endocr Relat Cancer,2014;21(2):189-202.
14 Lee J,Hwang JW,Noh JW,et al.SAT0059 Inhibition of CIP2A facilitate C-MYC independent apoptosis of fibroblast-like synoviocytes in rheumatoid arthritis[J].Rheumatol Int,2013;33(9):2241-8.
15 Janghorban M,Farrell AS,Allen-Petersen BL,et al.Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer[J].Proc Natl Acad Sci USA,2014;111(25):9157-62.
16 Wang CY,Chao TT,Chang FY,et al.CIP2A mediates erlotinib-induced apoptosis in non-small cell lung cancer cells without EGFR mutation[J].Lung Cancer,2014;85(2):152-60.
17 Villapol S,Acarin L,Faiz M,et al.Survivin and heat shock protein 25/27 colocalize with cleaved caspase-3 in surviving reactive astrocytes following excitotoxicity to the immature brain[J].Neuroscience,2008;153(1):108-19.
18 Chen Y,Lin C,Yang L,et al.HMGB1 promotes HCC progression partly by downregulating p21 via ERK/c-Myc pathway and upregulating MMP-2[J].Tumor Biol,2016;37(4):4399-408.
19 Ai G,Dachineni R,Muley P,et al.Aspirin and salicylic acid decrease c-Myc expression in cancer cells:a potential role in chemoprevention[J].Tumor Biol,2016;37(2):1-12.
20 Zhang HF,Wu C,Alshareef A,et al.The PI3K/AKT/c-MYC axis promotes the acquisition of cancer stem-like features in esophageal squamous cell carcinoma[J].Stem Cells,2016;34(8):2040-51.
21 Calvisi DF,Conner EA,Ladu S,et al.Activation of the canonical Wnt/beta-catenin pathway confers growth advantages in c-Myc/E2F1 transgenic mouse model of liver cancer[J].J Hepatol,2005;42(6):842-9.
22 Fox HMA,Kerosuo L,Wartiovaara K.The function of c-kit,cip2a,and c-myc,in neural progenitor and glioblastoma cells[J].Int J Dev Neurosci,2008;26(8):891.
23 Balliu M,Cellai C,Lulli M,et al.HDAC1 controls CIP2A transcription in human colorectal cancer cells[J].Oncotarget,2016;7(18):25862-71.
24 Cristóbal I,Rojo F,Madozgúrpide J,et al.Cross talk between Wnt/β-Catenin and CIP2A/Plk1 signaling in prostate cancer:Promising therapeutic implications[J].Mol Cell Biol,2016;36(12):1734-9.
25 Gao F,Xu T,Wang X,et al.CIP2A mediates fibronectin-induced bladder cancer cell proliferation by stabilizing β-catenin[J].J Exp Clin Cancer Res,2017;36(1):70.