磷脂酶Cβ1上调表达与肝细胞肝癌增殖和预后相关
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摘要
目的探讨磷脂酶Cβ1(PLCβ1)表达是否与肝细胞肝癌(HCC)患者临床病例参数及预后相关。方法采用组织芯片(TMA)技术和免疫组织化学法检测141例HCC患者肿瘤及癌旁组织PLCβ1表达,分析PLCβ1表达与临床病理特征相关性;集落形成与细胞凋亡实验检测PLCβ1对HCC细胞增殖的影响;Kaplan-Meier法和Cox回归模型多因素分析HCC预后。结果 PLCβ1在肿瘤组织中表达明显高于癌旁组织,并与肿瘤分期密切相关。Kaplan-Meier生存分析表明PLCβ1高表达HCC患者生存率低于低表达患者。Cox多因素分析结果显示PLCβ1高表达是HCC患者预后的独立影响因素。PLCβ1在HCC细胞中过表达,促进HCC细胞增殖并抑制其凋亡。进一步研究发现,细胞外调节蛋白激酶(ERK)信号通路激活可能参与PLCβ1介导的HCC细胞生长。结论 PLCβ1促进HCC进展,可作为HCC预后的独立影响因素,有望成为理想的治疗靶点。
Objective To investigate the correlation between the expression of phospholipase Cβ1(PLCβ1) and the clinical relevant parameters and prognosis in patients with hepatocellular carcinoma(HCC). Methods By using tissue microarray technique and immunohistochemical method, the expressions of PLCβ1 in tumor and pericancerous tissues were tested in 141 HCC patients. The relationship between the expressions of PLCβ1 and the clinical and pathological characteristics was analyzed. Colony formation assay and apoptosis experiments were used to check the effect of PLCβ1 on proliferation of HCC cells. KaplanMeier analysis and Cox multivariate regression model analysis were adopted to analyze the prognosis of HCC patients. Results The expression level of PLCβ1 in tumor tissues was obviously higher than that in pericancerous tissues, which was closely related to the tumor staging. Kaplan-Meier survival analysis indicated that the survival rate in HCC patients with high expression level of PLCβ1 was lower than that in HCC patients with low expression level of PLCβ1. Cox multivariate regression analysis revealed that high expression of PLCβ1 was an independent prognostic factor for HCC patients. Over expression of PLCβ1 in HCC cells could promote the proliferation of HCC cell and inhibit its apoptosis. Further investigation showed that activation of extracellular regulated protein kinase signaling pathway might be involved in PLC β1-mediated HCC cell growth. Conclusion PLCβ1 can promote the progression of HCC, and the expression level of PLCβ1 can be regarded as an independent prognostic factor for HCC, and it is expected that PLCβ1 may become an ideal therapeutic target.
Objective To investigate the correlation between the expression of phospholipase Cβ1(PLCβ1) and the clinical relevant parameters and prognosis in patients with hepatocellular carcinoma(HCC). Methods By using tissue microarray technique and immunohistochemical method, the expressions of PLCβ1 in tumor and pericancerous tissues were tested in 141 HCC patients. The relationship between the expressions of PLCβ1 and the clinical and pathological characteristics was analyzed. Colony formation assay and apoptosis experiments were used to check the effect of PLCβ1 on proliferation of HCC cells. KaplanMeier analysis and Cox multivariate regression model analysis were adopted to analyze the prognosis of HCC patients. Results The expression level of PLCβ1 in tumor tissues was obviously higher than that in pericancerous tissues, which was closely related to the tumor staging. Kaplan-Meier survival analysis indicated that the survival rate in HCC patients with high expression level of PLCβ1 was lower than that in HCC patients with low expression level of PLCβ1. Cox multivariate regression analysis revealed that high expression of PLCβ1 was an independent prognostic factor for HCC patients. Over expression of PLCβ1 in HCC cells could promote the proliferation of HCC cell and inhibit its apoptosis. Further investigation showed that activation of extracellular regulated protein kinase signaling pathway might be involved in PLC β1-mediated HCC cell growth. Conclusion PLCβ1 can promote the progression of HCC, and the expression level of PLCβ1 can be regarded as an independent prognostic factor for HCC, and it is expected that PLCβ1 may become an ideal therapeutic target.
引文
[1]王燕,王茂强,段峰.索拉非尼治疗中晚期肝癌预后因素分析[J].介入放射学杂志,2017,26:258-262.
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[13]Bavelloni A,Poli A,Fiume R,et al.PLCβ1 regulates the expression of mi R-210 during mithramycin-mediated erythroid differentiation in K562 cells[J].Oncotarget,2014,5:4222-4231.
[14]Bavelloni A,Dmitrienko GI,Goodfellow VJ,et al.PLCβ1a and PLCβ1b selective regulation and cyclin D3 modulation reduced by kinamycin F during k562 cell differentiation[J].J Cell Physiol,2015,230:587-594.
[15]Ho KK,Mann DJ.Nuclear signalling through phospholipase C and phosphatidyl 4,5‐bisphosphat e[J].Signal Transd,2006,6:92-100.
[16]Fiume R,Huang X,Ramazzotti G,et al.Phospholipase C beta1(PLCβ1)in acute myeloid leukemia(AML):a novel potential therapeutic target[J].Ital J Anat Embryol,2014,119:88.
[17]Molinari C,Medri L,Follo MY,et al.PI-PLCβ1 gene copy number alterations in breast cancer[J].Oncol Rep,2012,27:403-408.
[18]Drabsch Y,ten Dijke P.TGF-βsignalling and its role in cancer progression and metastasis[J].Cancer Metastasis Rev,2012,31:553-568.
[19]Yin XX,Ye HL,Zhang G,et al.Targeting IP3-dependent calcium signaling enhances sorafenib lethality for hepatoma via ER stress related apoptosis[J].FASEB J,2015,29(1 Suppl):945-947.
[20]Philip F,Sahu S,Caso G,et al.Role of phospholipase C-βin RNA interference[J].Adv Biol Regul,2013,53:319-330.
[21]Follo MY,Faenza I,Piazzi M,et al.Nuclear PI-PLCβ1:an appraisal on targets and pathology[J].Adv Biol Regul,2014,54:2-11.
[22]Ishida S,Matsu-Ura T,Fukami K,et al.Phospholipase C-β1andβ4 contribute to non-genetic cell-to-cell variability in histamine-induced calcium signals in He La cells[J].Plo S One,2014,9:e86410.
[23]Weber RG,Pietsch T,von Schweinitz D,et al.Characterization of genomic alterations in hepatoblastomas:a role for gains on chromosomes 8q and 20 as predictors of poor outcome[J].Am J Pathol,2000,157:571-578.
[24]Albeck JG,Mills GB,Brugge JS.Frequency-modulated pulses of ERK activity transmit quantitative proliferation signals[J].Mol cell,2013,49:249-261.
[25]Xu A,Suh PG,Marmy-Conus N,et al.Phosphorylation of nuclear phospholipase Cβ1 by extracellular signal-regulated kinase mediates the mitogenic action of insulin-like growth factorⅠ[J].Mol Cell Biol,2001,21:2981-2990.
[26]Herrero A,Pinto A,Colon-Bolea P,et al.Small molecule inhibition of ERK dimerization prevents tumorigenesis by RASERK pathway oncogenes[J].Cancer Cell,2015,28:170-182.
[2]Forner A,Gilabert M,Bruix J,et al.Heterogeneity of intermediate-stage HCC necessitates personalized management including surgery[J].Nat Rev Clin Oncol,2015,12:10.
[3]Kanwal F,El-Serag HB,Ross D.Surveillance for hepatocellular carcinoma:can we focus on the mission?[J].Clin Gastroenterol Hepatol,2015,13:805-807.
[4]Zucman-Rossi J,Villanueva A,Nault JC,et al.The genetic landscape and biomarkers of hepatocellular carcinoma[J].Gastroenterology,2015,149:1226-1239.
[5]Martelli AM,Fiume R,Faenza I,et al.Nuclear phosphoinositide specific phospholipase C(PI-PLC)-β1:a central intermediary in nuclear lipid-dependent signal transduction[J].Histol Histopathol,2005,20:1251-1260.
[6]Spyridakis S,Leondaritis G,Nakos G,et al.A specific phospholipase C activity regulates phosphatidylinositol levels in lung surfactant of patients with acute respiratory distress syndrome[J].Am J Respir Cell Mol Biol,2010,42:357-362.
[7]Ngoh A,Mc Tague A,Wentzensen IM,et al.Severe infantile epileptic encephalopathy due to mutations in PLCβ1:expansion of the genotypic and phenotypic disease spectrum[J].Dev Med Child Neurol,2014,56:1124-1128.
[8]Lo Vasco VR,Cardinale G,Polonia P.Deletion of PLCB1 gene in schizophrenia‐affected patients[J].J Cell Mol Med,2012,16:844-851.
[9]Poduri A,Chopra SS,Neilan EG,et al.Homozygous PLCB1deletion associated with malignant migrating partial seizures in infancy[J].Epilepsia,2012,53:e146-e150.
[10]Cocco L,Finelli C,Mongiorgi S,et al.An increased expression of PI-PLCβ1 is associated with myeloid differentiation and a longer response to azacitidine in myelodysplastic syndromes[J].J Leukoc Biol,2015,98:769-780.
[11]Guo Y,Scarlata S.A loss in cellular protein partners promotesα-synuclein aggregation in cells resulting from oxidative stress[J].Biochemistry,2013,52:3913-3920.
[12]Poli A,Faenza I,Chiarini F,et al.K562 cell proliferation is modulated by PLCβ1 through a PKCα-mediated pathway[J].Cell Cycle,2013,12:1713-1721.
[13]Bavelloni A,Poli A,Fiume R,et al.PLCβ1 regulates the expression of mi R-210 during mithramycin-mediated erythroid differentiation in K562 cells[J].Oncotarget,2014,5:4222-4231.
[14]Bavelloni A,Dmitrienko GI,Goodfellow VJ,et al.PLCβ1a and PLCβ1b selective regulation and cyclin D3 modulation reduced by kinamycin F during k562 cell differentiation[J].J Cell Physiol,2015,230:587-594.
[15]Ho KK,Mann DJ.Nuclear signalling through phospholipase C and phosphatidyl 4,5‐bisphosphat e[J].Signal Transd,2006,6:92-100.
[16]Fiume R,Huang X,Ramazzotti G,et al.Phospholipase C beta1(PLCβ1)in acute myeloid leukemia(AML):a novel potential therapeutic target[J].Ital J Anat Embryol,2014,119:88.
[17]Molinari C,Medri L,Follo MY,et al.PI-PLCβ1 gene copy number alterations in breast cancer[J].Oncol Rep,2012,27:403-408.
[18]Drabsch Y,ten Dijke P.TGF-βsignalling and its role in cancer progression and metastasis[J].Cancer Metastasis Rev,2012,31:553-568.
[19]Yin XX,Ye HL,Zhang G,et al.Targeting IP3-dependent calcium signaling enhances sorafenib lethality for hepatoma via ER stress related apoptosis[J].FASEB J,2015,29(1 Suppl):945-947.
[20]Philip F,Sahu S,Caso G,et al.Role of phospholipase C-βin RNA interference[J].Adv Biol Regul,2013,53:319-330.
[21]Follo MY,Faenza I,Piazzi M,et al.Nuclear PI-PLCβ1:an appraisal on targets and pathology[J].Adv Biol Regul,2014,54:2-11.
[22]Ishida S,Matsu-Ura T,Fukami K,et al.Phospholipase C-β1andβ4 contribute to non-genetic cell-to-cell variability in histamine-induced calcium signals in He La cells[J].Plo S One,2014,9:e86410.
[23]Weber RG,Pietsch T,von Schweinitz D,et al.Characterization of genomic alterations in hepatoblastomas:a role for gains on chromosomes 8q and 20 as predictors of poor outcome[J].Am J Pathol,2000,157:571-578.
[24]Albeck JG,Mills GB,Brugge JS.Frequency-modulated pulses of ERK activity transmit quantitative proliferation signals[J].Mol cell,2013,49:249-261.
[25]Xu A,Suh PG,Marmy-Conus N,et al.Phosphorylation of nuclear phospholipase Cβ1 by extracellular signal-regulated kinase mediates the mitogenic action of insulin-like growth factorⅠ[J].Mol Cell Biol,2001,21:2981-2990.
[26]Herrero A,Pinto A,Colon-Bolea P,et al.Small molecule inhibition of ERK dimerization prevents tumorigenesis by RASERK pathway oncogenes[J].Cancer Cell,2015,28:170-182.