Expressions and clinical significances of Eag1 and VEGF in colorectal cancer tissues

doi:10.3760/cma.j.issn.1673422X.2018.02.005

Abstract

Abstract: 目的研究Eag1和血管内皮生长因子（VEGF）在结直肠癌中的表达，探讨Eag1和VEGF表达与结直肠癌临床病理特征的关系，探讨二者表达之间的相关性以及二者的临床意义。方法收集2015年1月至2016年12月湖南省人民医院结直肠癌组织标本73例、结直肠腺瘤组织标本25例、正常结直肠黏膜组织10例。采用免疫组织化学和实时荧光定量PCR（RTqPCR）检测73例结直肠癌组织、25例结直肠腺瘤和10例正常结直肠黏膜中Eag1、VEGF蛋白和mRNA的表达水平，分析其与结直肠癌临床病理之间的关系。结果免疫组织化学结果表明，Eag1蛋白在结直肠癌组中的阳性率为86.30%（63/73），显著高于结直肠腺瘤组的20.00%（5/25）和正常结直肠黏膜组的10.00%（1/10），差异均具有统计学意义（χ2=38.539，P＜0.001； χ2=24.874，P＜0.001）；VEGF蛋白在结直肠癌组中的阳性率为89.04%（65/73），显著高于结直肠腺瘤组的56.00%（14/25）和正常结直肠黏膜组的30.00%（3/10），差异均具有统计学意义（χ2=10.980，P＜0.001； χ2=16.911，P＜0.001）。Eag1与VEGF在结直肠癌组织和结直肠腺瘤组织中的表达均呈显著正相关（c=0.580，P=0.010；c=0.669，P＜0.001）。RTqPCR检测结果表明Eag1和VEGF的mRNA在结直肠癌组中相对表达量分别为4.50±0.34、3.14±0.44，在结肠腺瘤组相对表达量分别为1.42±0.22、1.61±0.15，在正常结直肠黏膜组中的相对表达量为1.00±0.16、1.00±0.53，差异具有统计学意义（F=15.546，P=0.014；F=5.363，P=0.025），二者在结直肠癌组的相对表达量约为正常结直肠黏膜中表达量的4.50倍（t=31.851，P=0.003）和3.14倍（t=6.870，P=0.014）。Eag1、VEGF mRNA在结直肠癌中的表达水平与结直肠癌的分化程度（F=840.725，P＜0.001；F=102.950，P＜0.001）、浸润深度（t=4.754，P＜0.001；t=8.557，P＜0.001）、Duke分期（F=179.902，P＜0.001；F=55.911，P＜0.001）和淋巴结转移（t=20.337，P＜0.001；t=25.218，P＜0.001）显著相关，与患者年龄（t=0.196，P=0.845；t=0.534，P=0.595）、性别（t=0.409，P=0.684；t=1.078，P=0.285）无明显相关性。结论Eag1、VEGF在结直肠癌组织中高表达且二者呈正相关，与结直肠癌的分化程度、浸润深度、Duke分期及淋巴结转移密切相关，二者在结直肠癌的发生和发展进程中起重要作用，有望为结直肠癌的早期诊断、治疗和预后提供有利的研究方向。【关键词】结直肠肿瘤；血管内皮生长因子类； Eag1 Expressions and clinical significances of Eag1 and VEGF in colorectal cancer tissuesJiang Runmei*, Tian Zhi, Liao Jiangtao, Zeng Juanli. *Third Department of Gastroenterology, Affiliated Hunan Provincial People′s Hospital of Nanhua University, Changsha 410000, China Corresponding author: Liao Jiangtao, Email: jt99399@163.com【Abstract】ObjectiveTo study the expressions of Eag1 and vascular endothelial growth factor (VEGF) in colorectal cancer, and to explore the relationships between Eag1 and VEGF expressions and clinicopathologic features of colorectal cancer. The correlation between Eag1 and VEGF and their clinical significance in colorectal cancer were explored. MethodsA total of 73 cases of colorectal cancer tissues, 25 cases of colorectal adenoma and 10 cases of normal colorectal mucosa from January 2015 to December 2016 in Hunan Provincial People′s Hospital were collected. The expressions of Eag1, VEGF protein and mRNA in 73 cases of colorectal cancer tissues, 25 cases of colorectal adenoma and 10 cases of normal colorectal mucosa were detected by immunohistochemistry and realtime fluorescence quantitative polymerase chain reaction (RTqPCR). The relationships between the two factors and the clinical pathological features of patients with colorectal cancer were analyzed. ResultsImmunohistochemistry showed that the positive rate of Eag1 in colorectal cancer group was 86.30% (63/73), which was significantly higher than that in colorectal adenoma group (20.00%, 5/25) and normal colorectal mucosa group (10.00%, 1/10), with significant differences (χ2=38.539, P＜0.001; χ2=24.874, P＜0.001). The positive rate of VEGF in colorectal cancer group was 89.04% (65/73), which was significantly higher than that in colorectal adenoma group (56.00%, 14/25) and normal colorectal mucosa group (30.00%, 3/10), with significant differences (χ2=10.980, P＜0.001; χ2=16.911, P＜0.001). There was a significant positive correlation between Eag1 and VEGF in colorectal cancer and colorectal adenoma tissues (c=0.580, P=0.010; c=0.669, P＜0.001). The results of RTqPCR showed that the expressions of Eag1 and VEGF mRNA in colorectal cancer group, colorectal adenoma group and normal colorectal mucosa group were 4.50±0.34, 3.14±0.44; 1.42±0.22, 1.61±0.15 and 1.00±0.16, 1.00±0.53, respectively, and the differences were statistically significant (F=15.546, P=0.014; F=5.363, P=0.025). The relative expression levels of Eag1 and VEGF mRNA in colorectal cancer group was about 4.50 times (t=31.851, P=0.003) and 3.14 times (t=6.870, P=0.014) than those in normal colorectal mucosa group. The mRNA expression levels of Eag1 and VEGF in colorectal cancer were correlated with degree of differentiation (F=840.725, P＜0.001; F=102.950, P＜0.001), depth of invasion (t=4.754, P＜0.001; t=8.557, P＜0.001), Duke staging (F=179.902, P＜0.001; F=55.911, P＜0.001) and lymph node metastasis (t=20.337, P＜0.001; t=25.218, P＜0.001). But they were not related to age (t=0.196, P=0.845; t=0.534, P=0.595) and sex (t=0.409, P=0.684; t=1.078, P=0.285). ConclusionEag1 and VEGF are highly expressed in colorectal cancer tissues with positive correlation, and are closely related to the degree of differentiation, depth of invasion, Duke staging and lymph node metastasis of colorectal cancer. Both of them play important roles in the occurrence and development of colorectal cancer, which is expected to provide favorable research directions to the early diagnosis, treatment and prognosis of colorectal cancer.【Key words】

Key words: Colorectal neoplasms, Vascular endothelial growth factors, Eag1

JIANG Run-Mei, TIAN Zhi, LIAO Jiang-Tao, ZENG Juan-Li. Expressions and clinical significances of Eag1 and VEGF in colorectal cancer tissues[J]. Journal of International Oncology, 2018, 45(2): 80-86.

References

［1］ Kondratskyi A, Kondratska K, Skryma R, et al. Ion channels in the regulation of apoptosis［J］. Biochim Biophys Acta, 2015, 1848(10 Pt B): 25322546. DOI: 10.1016/j.bbamem.2014.10.030. ［2］ Pardo LA, Stühmer W. The roles of K(+) channels in cancer［J］. Nat Rev Cancer, 2014, 14(1): 3948. DOI: 10.1038/nrc3635. ［3］ Haitin Y, Carlson AE, Zagotta WN. The structural mechanism of KCNHchannel regulation by the eag domain［J］. Nature, 2013, 501(7467): 444448. DOI: 10.1038/nature12487. ［4］ RodríguezRasgado JA, AcuaMacías I, Camacho J. Eag1 channels as potential cancer biomarkers［J］. Sensors (Basel), 2012, 12(5): 59865895. DOI: 10.3390/s120505986. ［5］林爽, 李力, 易萍, 等. 宫颈癌中Eag1钾离子通道的表达以及缺氧对其的调控作用［J］. 重庆医学, 2010, 39(8): 899901. DOI: 10.3969/j.issn.16718348.2010.08.002. ［6］ Rapisarda A, Melillo G. Role of the VEGF/VEGFR axis in cancer biology and therapy［J］. Adv Cancer Res, 2012, 114: 237267. DOI: 10.1016/B9780123865038.000065. ［7］ Wu X, Chen Z, Zeng W, et al. Silencing of Eag1 gene inhibits osteosarcoma proliferation and migration by targeting STAT3VEGF pathway［J］. Biomed Res Int, 2015, 2015: 617316. DOI: 10.1155/2015/617316. ［8］ PerrotApplanat M, Di Benedetto M. Autocrine functions of VEGF in breast tumor cells: adhesion, survival, migration and invasion［J］. Cell Adh Migr, 2012, 6(6): 547553. DOI: 10.4161/cam.23332. ［9］ Hao XP, Willis JE, Pretlow TG, et al. Loss of fragile histidine triad expression in colorectal carcinomas and premalignant lesions［J］. Cancer Res, 2000, 60(1): 1821. ［10］姜艳芳, 魏志, 孙自勤. 中国青年大肠癌发病趋势分析［J］. 胃肠病学和肝病学杂志, 2016, 25(9): 982987. DOI: 10.3969/j.issn.10065709.2016.09.006. ［11］珠珠, 黄鉴, 李文亮, 等. 1628例大肠癌临床发病特点及发病趋势分析［J］. 昆明医科大学学报, 2013, (10): 8487. DOI: 10.3969/j.issn.10034706.2013.10.021. ［12］ RestrepoAngulo I, SánchezTorres C, Camacho J. Human EAG1 potassium channels in the epithelialtomesenchymal transition in lung cancer cells［J］. Anticancer Res, 2011, 31(4): 12651270. ［13］ Pardo LA, Stühmer W. Eag1: an emerging oncological target［J］. Cancer Res, 2008, 68(6): 16111613. DOI: 10.1158/00085472.CAN075710. ［14］ Agarwal JR, Griesinger F, Stühmer W, et al. The potassium channel Ether à gogo is a novel prognostic factor with functional relevance in acute myeloid leukemia［J］. Mol Cancer, 2010, 9: 18. DOI: 10.1186/14764598918. ［15］刘邦, 刘钧, 蹇顺海, 等. Eag1钾离子通道、HIF1α以及VEGF在子宫颈癌中的表达及其临床意义［J］. 川北医学院学报, 2014, 29(1): 5762. DOI: 10.3969/j.issn.10053697.2014.01.12. ［16］魏学明, 顾国利, 任力, 等. 大肠癌EGFR、HER2、VEGF表达特点及其对分子靶向治疗的指导意义［J］. 世界华人消化杂志, 2009, 17(18): 18361841. DOI: 10.3969/j.issn.10093079.2009.18.007. ［17］ AcuaMacías I, Vera E, VázquezSánchez AY, et al. Differential regulation of human Eag1 channel expression by serum and epidermal growth factor in lung and breast cancer cells［J］. Onco Targets Ther, 2015, 8: 29592965. DOI: 10.2147/OTT.S85504. ［18］ Ding XW, Yan JJ, An P, et al. Aberrant expression of ether à gogo potassium channel in colorectal cancer patients and cell lines［J］. World J Gastroenterol, 2007, 13(8): 12571261. ［19］ Ousingsawat J, Spitzner M, Puntheeranurak S, et al. Expression of voltagegated potassium channels in human and mouse colonic carcinoma［J］. Clin Cancer Res, 2007, 13(3): 824831. DOI: 10.1158/10780432.CCR061940. ［20］ Ding XW, Luo HS, Jin X, et al. Aberrant expression of Eag1 potassium channels in gastric cancer patients and cell lines［J］. Med Oncol, 2007, 24(3): 345350. ［21］ ChávezLópez MG, ZúigaGarcía V, PérezCarreón JI, et al. Eag1 channels as potential earlystage biomarkers of hepatocellular carcinoma［J］. Biologics, 2016, 10: 139148. DOI: 10.2147/BTT.S87402. ［22］ IzumiNakaseko H, Nakamura Y, Cao X, et al. Possibility as an anticancer drug of astemizole: evaluation of arrhythmogenicity by the chronic atrioventricular block canine model［J］. J Pharmacol Sci, 2016, 131(2): 150153. DOI: 10.1016/j.jphs.2016.04.024. ［23］ Menéndez ST, Villaronga MA, Rodrigo JP, et al. Frequent aberrant expression of the human ether à gogo (hEAG1) potassium channel in head and neck cancer: pathobiological mechanisms and clinical implications［J］. J Mol Med (Berl), 2012, 90(10): 11731184. DOI: 10.1007/s0010901208930. ［24］ Ding XW, Wang XG, Luo HS, et al. Expression and prognostic roles of Eag1 in resected esophageal squamous cell carcinomas［J］. Dig Dis Sci, 2008, 53(8): 20392044. DOI: 10.1007/s1062000701167. ［25］ Wu J, Zhong D, Wei Y, et al. Potassium channel ether à gogo1 is aberrantly expressed in human liposarcoma and promotes tumorigenesis［J］. Biomed Res Int, 2014, 2014: 345678. DOI: 10.1155/2014/345678. ［26］ Rapisarda A, Melillo G. Role of the VEGF/VEGFR axis in cancer biology and therapy［J］. Adv Cancer Res, 2012, 114: 237267. DOI: 10.1016/B9780123865038.000065. ［27］吴进, 刘庆军, 曾文容, 等. 沉默Ether à gogo 1基因调控VEGF/PI3K/AKT抑制骨肉瘤增殖和血管生成的研究［J］. 肿瘤预防与治疗, 2016, 29(4): 193198. DOI: 10.3969/j.issn.16740904.2016.04.001. ［28］ Ousingsawat J, Spitzner M, Puntheeranurak S, et al. Expression of voltagegated potassium channels in human and mouse colonic carcinoma［J］. Clin Cancer Res, 2007, 13(3): 824831. ［29］刘长兵, 吴继锋. 胃癌中TGFβ1、HIF1α、VEGF的表达及临床意义［J］. 临床与实验病理学杂志, 2013, 29(7): 733736. DOI: 10.13315/j.cnki.cjcep.2013.07.027.

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