宫颈癌组织和外周血HIF-1a、PDGF、VEGF和Ang-2表达与MVD的关系
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摘要
目的 探讨宫颈癌患者组织和外周血中低氧诱导因子-1α(HIF-1α)、血小板衍生生长因子(PDGF)、血管内皮生长因子(VEGF)、血管生成素-2(Ang-2)水平变化以及与微血管密度(MVD)的关系。方法 选取2013年11月至2017年10月期间在我院接受治疗的宫颈癌124例和良性宫颈病变患者61例,收集其术前外周血和术后病理标本。采用免疫组化染色和ELISA法检测两组患者组织和外周血HIF-1a、PDGF、VEGF和Ang-2的表达以及与MVD关系。采用受试者工作特征曲线(ROC)分析MVD的诊断效力。结果 宫颈癌患者组织中HIF-1a、PDGF、VEGF和Ang-2高表达率分别为78.23%、71.77%、79.84%、73.39%,外周血中的表达水平分别为(544.82±119.36)ng/ml、(748.19±315.24)pg/ml、(1189.45±313.62)pg/ml、(539.65±218.57)pg/ml,均高于宫颈良性病变患者(P<0.05)。HIF-1α、PDGF、VEGF、Ang-2蛋白高表达者MVD值分别为43.09±9.35、42.49±8.27、38.56±9.54、44.63±9.09,明显高于低表达者(P<0.05)。ROC曲线结果显示,MVD预测宫颈癌的敏感度为77.3%,特异度为60.0%,最佳截断值为20.58。MVD>21宫颈癌患者中血清HIF-1α、PDGF、VEGF、Ang-2水平分别为(723.11±252.74)ng/ml、(997.28±376.12)pg/ml、(1349.23±353.87)pg/ml、(735.65±226.78)pg/ml,均高于MVD≤21宫颈癌患者的(156.24±199.38)ng/ml、(423.25±284.69)ng/ml、(841.21±298.46)ng/ml和(330.01±194.77)ng/ml,差异有统计学意义(P<0.05)。结论 宫颈癌组织和外周血中HIF-1α、PDGF、VEGF、Ang-2水平可作为预测其侵袭和转移的参考指标。
Objective To investigate the changes of hypoxia inducible factor-1 α(HIF-1α), platelet-derived growth factor(PDGF), vascular endothelial growth factor(VEGF), angiopoietin-2(Ang-2) levels in tissues and peripheral blood of patients with cervical cancer and their relationship with microvessel density(MVD). Methods One hundred and twenty-four cases of cervical cancer and 61 cases of benign cervical lesions treated in our hospital from November 2013 to October 2017 were selected to collect preoperative peripheral blood and postoperative pathological specimens. Immunohistochemical staining and ELISA were used to detect the expression of HIF-1 a, PDGF, VEGF and Ang-2 in tissues and peripheral blood and their relationship with MVD. The diagnostic efficacy of MVD was analyzed by ROC. Results The high expression rates of HIF-1 a, PDGF, VEGF and Ang-2 in cervical cancer tissues were 78.23%, 71.77%, 79.84% and 73.39%,The expression levels of HIF-1 a, PDGF, VEGF and Ang-2 in peripheral blood were(544.82±119.36) ng/ml,(748.19±315.24) pg/ml,(1189.45±313.62) pg/ml,(539.65±218.57) pg/ml, respectively, which were higher than those in benign cervical lesions(P< 0.05). MVD values of HIF-1α, PDGF, VEGF and Ang-2 protein overexpression were 43.09±9.35, 42.49±8.27, 38.56±9.54 and 44.63±9.09, respectively, which were significantly higher than those of low expression(P< 0.05). ROC curve showed that the sensitivity, specificity and cut-off value of MVD in predicting cervical cancer were 77.3%, 60.0% and 20.58 respectively. Serum levels of HIF-1α, PDGF, VEGF and Ang-2 in patients with MVD> 21 cervical cancer were(723.11±252.74) ng/ml,(997.28±376.12) pg/ml,(1349.23±353.87) pg/ml,(735.65±226.78) pg/ml, which were higher than those in patients with MVD≤21(156.24±199.38) ng/ml,(423.25±284.69) ng/ml,(841.21±298.46) ng/ml and(330.01±194.77) ng/ml, with significant difference(P< 0.05). Conclusion The levels of HIF-1α, PDGF, vascular endothelial growth factor and Ang-2 in cervical cancer tissues and peripheral blood can be used as reference indicators for predicting its invasion and metastasis.
Objective To investigate the changes of hypoxia inducible factor-1 α(HIF-1α), platelet-derived growth factor(PDGF), vascular endothelial growth factor(VEGF), angiopoietin-2(Ang-2) levels in tissues and peripheral blood of patients with cervical cancer and their relationship with microvessel density(MVD). Methods One hundred and twenty-four cases of cervical cancer and 61 cases of benign cervical lesions treated in our hospital from November 2013 to October 2017 were selected to collect preoperative peripheral blood and postoperative pathological specimens. Immunohistochemical staining and ELISA were used to detect the expression of HIF-1 a, PDGF, VEGF and Ang-2 in tissues and peripheral blood and their relationship with MVD. The diagnostic efficacy of MVD was analyzed by ROC. Results The high expression rates of HIF-1 a, PDGF, VEGF and Ang-2 in cervical cancer tissues were 78.23%, 71.77%, 79.84% and 73.39%,The expression levels of HIF-1 a, PDGF, VEGF and Ang-2 in peripheral blood were(544.82±119.36) ng/ml,(748.19±315.24) pg/ml,(1189.45±313.62) pg/ml,(539.65±218.57) pg/ml, respectively, which were higher than those in benign cervical lesions(P< 0.05). MVD values of HIF-1α, PDGF, VEGF and Ang-2 protein overexpression were 43.09±9.35, 42.49±8.27, 38.56±9.54 and 44.63±9.09, respectively, which were significantly higher than those of low expression(P< 0.05). ROC curve showed that the sensitivity, specificity and cut-off value of MVD in predicting cervical cancer were 77.3%, 60.0% and 20.58 respectively. Serum levels of HIF-1α, PDGF, VEGF and Ang-2 in patients with MVD> 21 cervical cancer were(723.11±252.74) ng/ml,(997.28±376.12) pg/ml,(1349.23±353.87) pg/ml,(735.65±226.78) pg/ml, which were higher than those in patients with MVD≤21(156.24±199.38) ng/ml,(423.25±284.69) ng/ml,(841.21±298.46) ng/ml and(330.01±194.77) ng/ml, with significant difference(P< 0.05). Conclusion The levels of HIF-1α, PDGF, vascular endothelial growth factor and Ang-2 in cervical cancer tissues and peripheral blood can be used as reference indicators for predicting its invasion and metastasis.
引文
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[18] Biel NM,Siemannr DW.Targeting the angiopoietin-2/tie-2 axis in conjunction with VEGF signal interference[J].Cancer Lett,2016,380(2):525-533.
[2] Miller JW,Hanson V,Johnson GD,et al.From cancer screening to treatment:service delivery and referral in the national breast and cervical cancer early detection program [J].Cancer,2014,120(16):2549-2556.
[3] Pan XF,Zhao,Sun J,et al.Acceptability and correlates of primary and secondary prevention of cervical cancer amo ng medical students in southwest China:Implications for cancer education[J/OL].PLoS One,2014[2018-10-05].http://www.docin.com/p-1404713231.html.
[4] Macedo F,Ladeira K,Filho AL,et al.Gastric cancer and angiogenesis:Is VEGF a useful biomarker to assess progression and remission?[J].J Gastric Cancer,2017,17(1):1-10.
[5] Felix AS,Lenz P,Pfeiffer RM,et al.Relationships between mammographic density,tissue microvessel density,and breast biopsy diagnosis [J].Breast Cancer Res,2016,18(1):88.
[6] Scholz A,Harter PN,Cremer S,et al.Endothelial cell derived angiopoietin-2 is a therapeutic target in treatment naive and bevacizumab resistant glioblastoma [J].EMBO Mol Med,2016,8(1):39-57.
[7] Balamurugan K.HIF-1 at the crossroads of hypoxia,inflammation,and cancer [J].Int J Cancer,2016,138(5):1058-1066.
[8] Weidner N.Intratumor microvessel density as a prognostic factor in cancer[J].Am J Pathol,1995,147(1):9-19.
[9] Ndejjo R,Mukama T,Musabyimana A,et al.Uptake of cervical cancer screening and associated factors among women in rural Uganda:A cross sectional study [J/OL].PLoS One,2016[2018-10-05].https://www.ncbi.nlm.nih.gov/pubmed/26894270.
[10] Cantelmo AR,Pircher A,Kalucka J,et al.Vessel pruning or healing:endothelial metabolism as a novel target?[J].Expert Opin Ther Targets,2017,21(3):239-247.
[11] Toth RK,Warfel NA.Strange bedfellows:nuclear factor,erythroid 2-like 2 (Nrf2) and hypoxia-inducible factor 1 (HIF-1) in tumor hypoxia [J].Antioxidants (Basel),2017,6(2):27.
[12] Palazon A,Tyrakis PA,Macias D,et al.An HIF-1α/VEGF-A axis in cytotoxic T cells regulates tumor progression [J].Cancer Cell,2017,32(5):669-683.
[13] 李朦,张岩,那飞,等.RUNX3和VEGF在宫颈癌组织中的表达及相关性[J].现代肿瘤医学,2018,26(15):2430-2434.
[14] Moench R,Grimmig T,Kannen V,et al.Exclusive inhibition of PI3K/Akt/mTOR signaling is not sufficient to prevent PDGF-mediated effects on glycolysis and proliferation in colorectal cancer [J].Oncotarget,2016,7(42):68749-68767.
[15] Hacker UT,Espinosa LE,Consalvo N,et al.Evaluation of angiopoietin-2 as a biomarker in gastric cancer:results from the randomised phase III AVAGAST trial[J].Br J Cancer,2016,114(8):855-862.
[16] Eisermann K,Fraizer G.The androgen receptor and VEGF:Mechanisms of androgen-regulated angiogenesis in prostate cancer[J].Cancers (Basel),2017,9(4):32.
[17] Lee SH,Goldfinger LE.RLIP76 regulates HIF-1 activity,VEGF expression and secretion in tumor cells,and secretome transactivation of endothelial cells[J].FASEB J,2014,28(9):4158-168.
[18] Biel NM,Siemannr DW.Targeting the angiopoietin-2/tie-2 axis in conjunction with VEGF signal interference[J].Cancer Lett,2016,380(2):525-533.