胃癌组织中miR-320a和CYLD的表达及与临床病理特征及预后的关系
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摘要
目的研究miR-320a和头帕肿瘤综合征蛋白(CYLD)在胃癌患者中的表达及其与临床病理特征及预后的关系。方法选取2013年3月—2014年11月在我院行肿瘤切除术的460例胃癌患者作为研究对象,分别收集患者肿瘤组织及癌旁非肿瘤胃粘膜组织,采用荧光定量PCR检测miR-320a和CYLD mRNA表达水平,采用免疫组织化学染色法检测CYLD蛋白表达,分析miR-320a和CYLD表达水平及其与临床病理特征及预后的关系。结果 miR-320a和CYLD mRNA在肿瘤组织中的相对表达量为(0. 37±0. 09)、(0. 91±0. 23),在癌旁非肿瘤组织中的相对表达量为(0. 86±0. 15),(1. 56±0. 42),miR-320a和CYLD mRNA在肿瘤组织中的相对表达量与非肿瘤组织比较,差异具有统计学意义(t=60. 078,29. 113,P <0. 001); CYLD蛋白在肿瘤组织中的阳性表达率43. 48%与癌旁非肿瘤组织73. 91%比较,差异具有统计学意义(χ2=86. 624,P=0. 003); miR-320a表达水平与患者肿瘤直径和淋巴结转移有关(χ2=25. 859,13. 742,P <0. 05); YLD表达水平与患者TNM分期和肿瘤分化程度有关(χ2=37. 725,59. 323,P <0. 05)。miR-320a低表达患者中位生存期(20. 36±0. 56)(95%CI:19. 252～21. 462)与miR-320a高表达患者中位生存期(28. 29个月95%CI:27. 158～29. 412个月)比较,差异具有统计学意义(χ2=87. 967,P <0. 001); CYLD阴性表达患者中位生存期(17. 70个月95%CI:16. 599～18. 796个月)与CYLD阳性表达患者中位生存期(26. 74个月95%CI:25. 474～27. 997个月)比较,差异具有统计学意义(χ2=109. 887,P <0. 001); miR-320a和CYLD共表达患者中位生存期(29. 01个月95%CI:26. 831～28. 946个月)与非共表达患者中位生存期(17. 13个月95%CI:17. 214～19. 568个月)比较,差异具有统计学意义(χ2=117. 680,P <0. 001)。肿瘤组织miR-320a与CYLD mRNA表达水平呈正相关(r=0. 607,P <0. 001); miR-320a低表达、CYLD阴性表达、TNM分期、淋巴结转移及肿瘤分化程度是影响胃癌患者预后的独立危险因素(HR=1. 939、2. 180、1. 561、1. 719、1. 608,95%CI:1. 141～3. 295,1. 252～3. 796,1. 014～2. 403,1. 115～2. 650,1. 097～2. 357,P <0. 05)。结论 miR-320a和CYLD在胃癌患者肿瘤组织中表达量明显降低,与疾病发生发展及不良预后有关,是潜在的胃癌诊断及治疗新靶点。
Objective The aim of this study was to investigate the expression of miR-320 a and cephalospermoma syndrome protein( CYLD) in patients with gastric cancer and its relationship with clinicopathological characteristics and prognosis. Methods A total of 460 patients with gastric cancer underwent tumor resection in our hospital from March 2013 to November 2014 were enrolled.Tumor tissues,non-tumor gastric mucosa tissues and normal tissues were collected. The expression of miR-320 a and CYLD at levels of mRNA and protein were detected by Real-Time PCR,immunohistochemistry and Western blotting. The relationship between the expression of miR-320 a and CYLD,and the clinicopathological features & prognosis of gastric cancer patients was analyzed. Results The relative expression of miR-320 a and CYLD at the mRNA level in tumor tissues was( 0. 37 ± 0. 09),( 0. 91 ± 0. 23),and the relative expression in non-tumor tissues was( 0. 86 ± 0. 15),( 1. 56 ± 0. 42),respectively. The relative expression of miR-320 a and CYLD mRNA in tumor tissues was significantly different from non-tumor tissues( t = 60. 078,29. 113,P = 0. 000),the positive expression rate of CYLD protein in tumor tissues was 43. 48% when compared to 73. 91% in non-tumor tissues. The difference was statistically significant( χ2= 86. 624,P = 0. 003). The expression level of miR-320 a was significantly associated with the diameter of the tumor and lymph node metastasis( χ2= 25. 859 and 13. 742,P < 0. 05). The expression of CYLD was also significantly associated with the TNM stage and degree of tumor differentiation( χ2= 37. 725 and 59. 323,P < 0. 05). The median survival of patients with low miR-320 a expression( 20. 36 months,95% CI: 19. 252 ～ 21. 462 months) and those with high miR-320 a expression( 28. 29 months,95% CI: 27. 158 ～ 29. 412 months) were statistically significant( χ2= 87. 967,P < 0. 001). The median survival of patients with CYLD negative expression( 17. 70 months,95% CI: 16. 599 ～ 18. 796 months) and those with CYLD positive expression( 26. 74 months,95% CI: 25. 474 ～ 27. 997 months) were statistically significant( χ2= 109. 887,P < 0. 001); The median survival of patients with the co-expressed miR-320 a and CYLD was( 29. 01 months,95% CI: 26. 831 ～ 28. 946 months) and those with the non-co-expressed miR-320 a and CYLD( 17. 13 months,95% CI: 17. 214 ～ 19. 568 months) were statistically significant( χ2= 117. 680,P <0. 001). There showed a positive correlation between the expression of miR-320 a and CYLD at mRNA level( r = 0. 607,P < 0. 001);miR-320 a at the low expression,CYLD at the negative expression,TNM staging,lymph node metastasis and degree of tumor differentiation were independent risk factors for the prognosis of gastric cancer( HR = 1. 939,2. 180,1. 561,1. 719,1. 608,95% CI: 1. 141 ～3. 295,1. 252 ～ 3. 796,1. 014 ～ 2. 403,1. 115 ～ 2. 650,1. 097 ～ 2. 357,respectively)( P < 0. 05). Conclusion The expressions of miR-320 a and CYLD in tumor tissues of patients with gastric cancer is significantly decreased,which is related to the occurrence and development of diseases,and poor prognosis. It is a potential target for diagnosis and treatment of gastric cancer.
Objective The aim of this study was to investigate the expression of miR-320 a and cephalospermoma syndrome protein( CYLD) in patients with gastric cancer and its relationship with clinicopathological characteristics and prognosis. Methods A total of 460 patients with gastric cancer underwent tumor resection in our hospital from March 2013 to November 2014 were enrolled.Tumor tissues,non-tumor gastric mucosa tissues and normal tissues were collected. The expression of miR-320 a and CYLD at levels of mRNA and protein were detected by Real-Time PCR,immunohistochemistry and Western blotting. The relationship between the expression of miR-320 a and CYLD,and the clinicopathological features & prognosis of gastric cancer patients was analyzed. Results The relative expression of miR-320 a and CYLD at the mRNA level in tumor tissues was( 0. 37 ± 0. 09),( 0. 91 ± 0. 23),and the relative expression in non-tumor tissues was( 0. 86 ± 0. 15),( 1. 56 ± 0. 42),respectively. The relative expression of miR-320 a and CYLD mRNA in tumor tissues was significantly different from non-tumor tissues( t = 60. 078,29. 113,P = 0. 000),the positive expression rate of CYLD protein in tumor tissues was 43. 48% when compared to 73. 91% in non-tumor tissues. The difference was statistically significant( χ2= 86. 624,P = 0. 003). The expression level of miR-320 a was significantly associated with the diameter of the tumor and lymph node metastasis( χ2= 25. 859 and 13. 742,P < 0. 05). The expression of CYLD was also significantly associated with the TNM stage and degree of tumor differentiation( χ2= 37. 725 and 59. 323,P < 0. 05). The median survival of patients with low miR-320 a expression( 20. 36 months,95% CI: 19. 252 ～ 21. 462 months) and those with high miR-320 a expression( 28. 29 months,95% CI: 27. 158 ～ 29. 412 months) were statistically significant( χ2= 87. 967,P < 0. 001). The median survival of patients with CYLD negative expression( 17. 70 months,95% CI: 16. 599 ～ 18. 796 months) and those with CYLD positive expression( 26. 74 months,95% CI: 25. 474 ～ 27. 997 months) were statistically significant( χ2= 109. 887,P < 0. 001); The median survival of patients with the co-expressed miR-320 a and CYLD was( 29. 01 months,95% CI: 26. 831 ～ 28. 946 months) and those with the non-co-expressed miR-320 a and CYLD( 17. 13 months,95% CI: 17. 214 ～ 19. 568 months) were statistically significant( χ2= 117. 680,P <0. 001). There showed a positive correlation between the expression of miR-320 a and CYLD at mRNA level( r = 0. 607,P < 0. 001);miR-320 a at the low expression,CYLD at the negative expression,TNM staging,lymph node metastasis and degree of tumor differentiation were independent risk factors for the prognosis of gastric cancer( HR = 1. 939,2. 180,1. 561,1. 719,1. 608,95% CI: 1. 141 ～3. 295,1. 252 ～ 3. 796,1. 014 ～ 2. 403,1. 115 ～ 2. 650,1. 097 ～ 2. 357,respectively)( P < 0. 05). Conclusion The expressions of miR-320 a and CYLD in tumor tissues of patients with gastric cancer is significantly decreased,which is related to the occurrence and development of diseases,and poor prognosis. It is a potential target for diagnosis and treatment of gastric cancer.
引文
1 Ferlay J,Soerjomataram I,Dikshit R,et al. Cancer incidence and mortality worldwide:sources,methods and major patterns in GLOBOCAN 2012[J]. Int J Cancer,2015,136(5):359-386.
2 左婷婷,郑荣寿,曾红梅,等.中国胃癌流行病学现状[J].中国肿瘤临床,2017,44(1):52-58.
3 Wang Y,Zeng J,Pan J,et al. MiR-320a inhibits gastric carcinoma by targeting activity in the Fox M1-P27KIP1axis[J]. Oncotarget,2016,7(20):29275-29286.
4 Hayashi M,Shinriki S,Jono H,et al. Reduced expression of CYLD is an independent prognostic factor in breast cancer and confers treatment resistance and migratory activity in vitro[J]. Cancer Research,2013,73(8 Suppl):3466-3466.
5 Ioana H,Simona G,Suciu BA,et al. Preliminary results regarding the new changes in the 7th AJCC/UICC staging system of gastric carcinomas[J]. Acta Medica Marisiensis,2011,59:165-168.
6 姜可伟.规范全球第二大致死率疾病的诊断-《胃癌诊断标准》解读[J].中国卫生标准管理,2010,1(4):26-28.
7 Hu J,Shan Z,Hu K,et al. miRNA-223 inhibits epithelial-mesenchymal transition in gastric carcinoma cells via Sp1[J]. Int J Oncol,2016,49(1):325-335.
8 Satelli A,Li S. Vimentin in cancer and its potential as a molecular target for cancer therapy[J]. Cell Mol Life Sci,2011,68(18):3033-3046.
9 Lv Q,Hu JX,Li YJ,et al. MiR-320a effectively suppresses lung adenocarcinoma cell proliferation and metastasis by regulating STAT3 signals[J]. Cancer Biol Ther,2017,18(3):142-151.
10 Sun L,Liu B,Lin Z,et al. MiR-320a acts as a prognostic factor and Inhibits metastasis of salivary adenoid cystic carcinoma by targeting ITGB3[J]. Molecular Cancer,2015,14(1):96-109.
11 Shang C,Zhang H,Guo Y,et al. MiR-320a down-regulation mediates bladder carcinoma invasion by targeting ITGB3[J]. Molecular Biology Reports,2014,41(4):2521-2527.
12 Ying Z,Yan Z,Sui Z,et al. USP14 de-ubiquitinates vimentin and miR-320a modulates USP14 and vimentin to contribute to malignancy in gastric cancer cells[J]. Oncotarget,2016,8(30):48725-48736.
13 Kinoshita H,Okabe H,Beppu T,et al. CYLD downregulation is correlated with tumor development in patients with hepatocellular carcinoma[J]. Mol Clin Oncol,2013,1(2):309-314.
14 姜维民,徐小永,李春民,等. CYLD在胰腺癌组织中的表达变化及意义[J].山东医药,2017,57(9):50-52.
15 Marval PMD,Lutfeali S,Jin JY,et al. CYLD Inhibits Tumorigenesis and metastasis by blocking JNK/AP1 signaling at multiple Levels[J]. Cancer Prevention Research,2011,4(6):851-859.
16 Li D,Jian W,Wei C,et al. Down-regulation of miR-181 b promotes apoptosis by targeting CYLD in thyroid papillary cancer[J]. Int J Clin Exp Pathol,2014,7(11):7672-7680.
17 Sun B,Li L,Ma W,et al. MiR-130b inhibits proliferation and induces apoptosis of gastric cancer cells via CYLD[J]. Tumour Biol,2016,37(6):7981-7987.
18 Yan YF,Gong FM,Wang BS,et al. MiR-425-5p promotes tumor progression via modulation of CYLD in gastric cancer[J]. Eur Rev Med Pharmacol Sci,2017,21(9):2130-2136.
2 左婷婷,郑荣寿,曾红梅,等.中国胃癌流行病学现状[J].中国肿瘤临床,2017,44(1):52-58.
3 Wang Y,Zeng J,Pan J,et al. MiR-320a inhibits gastric carcinoma by targeting activity in the Fox M1-P27KIP1axis[J]. Oncotarget,2016,7(20):29275-29286.
4 Hayashi M,Shinriki S,Jono H,et al. Reduced expression of CYLD is an independent prognostic factor in breast cancer and confers treatment resistance and migratory activity in vitro[J]. Cancer Research,2013,73(8 Suppl):3466-3466.
5 Ioana H,Simona G,Suciu BA,et al. Preliminary results regarding the new changes in the 7th AJCC/UICC staging system of gastric carcinomas[J]. Acta Medica Marisiensis,2011,59:165-168.
6 姜可伟.规范全球第二大致死率疾病的诊断-《胃癌诊断标准》解读[J].中国卫生标准管理,2010,1(4):26-28.
7 Hu J,Shan Z,Hu K,et al. miRNA-223 inhibits epithelial-mesenchymal transition in gastric carcinoma cells via Sp1[J]. Int J Oncol,2016,49(1):325-335.
8 Satelli A,Li S. Vimentin in cancer and its potential as a molecular target for cancer therapy[J]. Cell Mol Life Sci,2011,68(18):3033-3046.
9 Lv Q,Hu JX,Li YJ,et al. MiR-320a effectively suppresses lung adenocarcinoma cell proliferation and metastasis by regulating STAT3 signals[J]. Cancer Biol Ther,2017,18(3):142-151.
10 Sun L,Liu B,Lin Z,et al. MiR-320a acts as a prognostic factor and Inhibits metastasis of salivary adenoid cystic carcinoma by targeting ITGB3[J]. Molecular Cancer,2015,14(1):96-109.
11 Shang C,Zhang H,Guo Y,et al. MiR-320a down-regulation mediates bladder carcinoma invasion by targeting ITGB3[J]. Molecular Biology Reports,2014,41(4):2521-2527.
12 Ying Z,Yan Z,Sui Z,et al. USP14 de-ubiquitinates vimentin and miR-320a modulates USP14 and vimentin to contribute to malignancy in gastric cancer cells[J]. Oncotarget,2016,8(30):48725-48736.
13 Kinoshita H,Okabe H,Beppu T,et al. CYLD downregulation is correlated with tumor development in patients with hepatocellular carcinoma[J]. Mol Clin Oncol,2013,1(2):309-314.
14 姜维民,徐小永,李春民,等. CYLD在胰腺癌组织中的表达变化及意义[J].山东医药,2017,57(9):50-52.
15 Marval PMD,Lutfeali S,Jin JY,et al. CYLD Inhibits Tumorigenesis and metastasis by blocking JNK/AP1 signaling at multiple Levels[J]. Cancer Prevention Research,2011,4(6):851-859.
16 Li D,Jian W,Wei C,et al. Down-regulation of miR-181 b promotes apoptosis by targeting CYLD in thyroid papillary cancer[J]. Int J Clin Exp Pathol,2014,7(11):7672-7680.
17 Sun B,Li L,Ma W,et al. MiR-130b inhibits proliferation and induces apoptosis of gastric cancer cells via CYLD[J]. Tumour Biol,2016,37(6):7981-7987.
18 Yan YF,Gong FM,Wang BS,et al. MiR-425-5p promotes tumor progression via modulation of CYLD in gastric cancer[J]. Eur Rev Med Pharmacol Sci,2017,21(9):2130-2136.