胃癌组织中HuR表达与临床病理及生存状况的关系
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摘要
目的研究RNA结合蛋白HuR在胃癌组织中的表达及其临床意义。方法选择铜川矿务局中心医院2010年8月至2012年3月收治的胃癌根治术患者的73份胃癌组织标本作为胃癌组,选择在同一时期内接受胃切除术的21例正常胃组织作为对照组。通过免疫组织化学技术检测胃组织福尔马林固定标本的表达情况,分别用细胞质和核染色评估HuR表达。比较正常胃组织和胃癌组织中HuR表达的差异。探讨HuR的表达与临床病理特征之间的关系,并比较不同HuR表达患者的生存率差异。通过COX模型确定胃癌根治术后预后的影响因素。结果在胃癌组织细胞中,癌细胞核中HuR的表达在53个样本中表达率很高(72. 6%;得分2,n=33;得分3,n=20)。癌细胞中的细胞质表达在20个样本中表达较高(27. 4%;得分2,n=13;得分3,n=7)。与正常胃组织相比,胃癌细胞核和细胞质HuR的表达显著增高(Z=5. 269、8. 475,P <0. 01)。在癌细胞核中,未观察到HuR表达与临床病理学特征有明显相关(P>0. 05);而在癌细胞质中,观察到HuR表达与TNM分期、淋巴结转移和肿瘤大小明显相关(P <0. 05)。在细胞质中,HuR阴性表达患者的中位生存期(54个月)比HuR阳性表达患者(29个月)更长(P <0. 01)。在细胞核中,HuR阴性表达患者的中位生存期(52个月)比HuR阳性表达患者(44个月)长(P=0. 016)。应用多元Cox回归模型分析独立预后因素,结果表明细胞质HuR蛋白表达、肿瘤大小、淋巴结转移和TNM分期是影响患者生存的独立预后因素(P=0. 046、0. 041、0. 035和0. 012)。结论细胞质HuR表达与胃癌患者的恶性侵袭性和预后显著相关,可作为胃癌根治术后转移的预测指标。
Objective To investigate the expression of RNA binding protein HuR in gastric carcinoma and to analyze their clinical significance. Methods A total of 73 gastric cancer tissue samples of patients who underwent gastric surgery in Tongchuan mining bureau central hospital from August 2010 to March 2012 were included in this observational study. Meanwhile,21 patients with normal gastric tissues,who underwent gastrectomy during the same period,were included as control group. All expressions were examined by immunohistochemical techniques,and HuR expression was evaluated with cytoplasmic and nuclear staining respectively. The difference of HuR expression between normal gastric tissue and gastric cancer was compared. The relationship between HuR expression and clinicopathological features was explored in patients with gastric cancer. The difference in HuR expression between these two groups was compared. The relationship between expression of HuR and clinicopathological features was also explored in gastric cancer patients. Survival rates of HuR expression were compared by logarithmic rank test. Furthermore,the prognostic factors of radical gastrectomy for gastric cancer were determined by COX model. Results In gastric cancer group,the expression rate of HuR in cancer cells was high in 53 specimens( 72. 6%; score 2,n = 33; score 3,n = 20). The expression rate of cytoplasm in cancer cells was high in 20 specimens( 27. 4%; score 2,n = 13; score 3,n = 7). Compared with normal gastric tissues,the expressions of HuR in nucleus and cytoplasm of gastric cancer cells were significantly increased( Z = 5. 269,8. 475,P < 0. 001).No correlation between HuR expression and clinicopathological features was observed in the nucleus of cancer cells( P > 0. 05),while HuR expression was significantly correlated with TNM stage,lymph node metastasis and tumor size in the cytoplasm of cancer cells( P < 0. 05). In cytoplasm,the median survival time of HuR-negative patients( median survival time was 54 months) was longer than that of HuR-positive patients( median survival time was 29 months)( P < 0. 001). Similarly,in the nucleus,the median survival time of HuR negative expression( median survival time was 52 months) was longer than that of HuR positive expression( median survival time was 44 months)( P = 0. 016).Multivariate cox regression model analysis showed the results that cytoplasmic HuR protein expression,tumor size,lymph node metastasis and TNM stage were independent prognostic factors affecting survival( P = 0. 046,0. 041,0. 035 and 0. 012). Conclusion Cytoplasmic HuR expression was significantly associated with malignant aggressiveness and prognosis of gastric carcinoma patient,which was useful as a predictive marker of metastasis for patients with gastric cancer after radical gastrectomy.
Objective To investigate the expression of RNA binding protein HuR in gastric carcinoma and to analyze their clinical significance. Methods A total of 73 gastric cancer tissue samples of patients who underwent gastric surgery in Tongchuan mining bureau central hospital from August 2010 to March 2012 were included in this observational study. Meanwhile,21 patients with normal gastric tissues,who underwent gastrectomy during the same period,were included as control group. All expressions were examined by immunohistochemical techniques,and HuR expression was evaluated with cytoplasmic and nuclear staining respectively. The difference of HuR expression between normal gastric tissue and gastric cancer was compared. The relationship between HuR expression and clinicopathological features was explored in patients with gastric cancer. The difference in HuR expression between these two groups was compared. The relationship between expression of HuR and clinicopathological features was also explored in gastric cancer patients. Survival rates of HuR expression were compared by logarithmic rank test. Furthermore,the prognostic factors of radical gastrectomy for gastric cancer were determined by COX model. Results In gastric cancer group,the expression rate of HuR in cancer cells was high in 53 specimens( 72. 6%; score 2,n = 33; score 3,n = 20). The expression rate of cytoplasm in cancer cells was high in 20 specimens( 27. 4%; score 2,n = 13; score 3,n = 7). Compared with normal gastric tissues,the expressions of HuR in nucleus and cytoplasm of gastric cancer cells were significantly increased( Z = 5. 269,8. 475,P < 0. 001).No correlation between HuR expression and clinicopathological features was observed in the nucleus of cancer cells( P > 0. 05),while HuR expression was significantly correlated with TNM stage,lymph node metastasis and tumor size in the cytoplasm of cancer cells( P < 0. 05). In cytoplasm,the median survival time of HuR-negative patients( median survival time was 54 months) was longer than that of HuR-positive patients( median survival time was 29 months)( P < 0. 001). Similarly,in the nucleus,the median survival time of HuR negative expression( median survival time was 52 months) was longer than that of HuR positive expression( median survival time was 44 months)( P = 0. 016).Multivariate cox regression model analysis showed the results that cytoplasmic HuR protein expression,tumor size,lymph node metastasis and TNM stage were independent prognostic factors affecting survival( P = 0. 046,0. 041,0. 035 and 0. 012). Conclusion Cytoplasmic HuR expression was significantly associated with malignant aggressiveness and prognosis of gastric carcinoma patient,which was useful as a predictive marker of metastasis for patients with gastric cancer after radical gastrectomy.
引文
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[5]Badawi A,Biyanee A,Nasrullah U,et al.Inhibition of IRES-dependent translation of caspase-2 by HuR confers chemotherapeutic drug resistance in colon carcinoma cells[J].Oncotarget,2018,9(26):18367-18385.doi:10.18632/oncotarget.24840.
[6]Eberhardt W,Badawi A,Biyanee A,et al.Cytoskeleton-dependent transport as a potential target for interfering with post-transcriptional HuRmRNA regulons[J].Front Pharmacol,2016,7:251.doi:10.3389/fphar.2016.00251.
[7]Davidson B,Holth A,Hellesylt E,et al.HUR mRNA expression in ovarian high-grade serous carcinoma effusions is associated with poor survival[J].Hum Pathol,2016,48:95-101.doi:10.1016/j.humpath.2015.09.027.
[8]罗年安,屈亚琦,张洪科,等.HuR和PDGFC在乳腺癌组织中的表达及相关性分析[J].现代生物医学进展,2014,14(26):5011-5013.doi:10.13241/j.cnki.pmb.2014.26.003.
[9]Zarei M,Lal S,Parker SJ,et al.Posttranscriptional upregulation of IDH1by HuR establishes a powerful survival phenotype in pancreatic cancer cells[J].Cancer Res,2017,77(16):4460-4471.doi:10.1158/0008-5472.CAN-17-0015.
[10]Lal A,Mazan-Mamczarz K,Kawai T,et al.Concurrent versus individual binding of HuR and AUF1 to common labile target mRNAs[J].Embo J,2014,23(15):3092-3102.doi:10.1038/sj.emboj.7600305.
[11]Badawi A,Hehlgans S,Pfeilschifter J,et al.Silencing of the mRNA-binding protein HuR increases the sensitivity of colorectal cancer cells to ionizing radiation through upregulation of caspase-2[J].Cancer Lett,2017,393:103-112.doi:10.1016/j.canlet.2017.02.010.
[12]Li DS,Ainiwaer JL,Sheyhiding I,et al.Identification of key long noncoding RNAs as competing endogenous RNAs for miRNA-mRNA in lung adenocarcinoma[J].Eur Rev Med Pharmacol Sci,2016,20(11):2285-2295.
[13]楚慧丽,关雅萍.RNA结合蛋白HuR在肿瘤耐药及药物敏感性中的作用[J].中国肿瘤生物治疗杂志,2014,21(6):707-711.doi:10.3872/j.issn.1007-385X.2014.06.020.
[14]Ahuja D,Goyal A,Ray PS.Interplay between RNA-binding protein HuR and microRNA-125b regulates p53 mRNA translation in response to genotoxic stress[J].Rna Biol,2016,13(11):1152-1165.doi:10.1080/15476286.2016.1229734.
[15]Gauchotte G,Hergalant S,Vigouroux C,et al.Cytoplasmic overexpression of RNA-binding protein HuR is a marker of poor prognosis in meningioma,and HuR knockdown decreases meningioma cell growth and resistance to hypoxia[J].J Pathol,2018,242(4):421-434.doi:10.1002/path.4916.
[16]Astakhova AA,Chistyakov DV,Sergeeva MG,et al.Regulation of the ARE-binding proteins,TTP(tristetraprolin)and HuR(human antigen R),in inflammatory response in astrocytes[J].Neurochem Int,2018,118:82-90.doi:10.1016/j.neuint.2018.04.014.
[17]Ronkainen H,Vaarala MH,Hirvikoski P,et al.HuR expression is a marker of poor prognosis in renal cell carcinoma[J].Tumor Biol,2011,32(3):481-487.doi:10.1007/s13277-010-0141-6.
[18]Al-Haidari A,Algaber A,Madhi R,et al.MiR-155-5p controls colon cancer cell migration via post-transcriptional regulation of Human Antigen R(HuR)[J].Cancer Lett,2018,421:145-151.doi:10.1016/j.canlet.2018.02.026.
[19]Muralidharan R,Babu A,Amreddy N,et al.Folate receptor-targeted nanoparticle delivery of HuR-RNAi suppresses lung cancer cell proliferation and migration[J].J Nanobiotechnol,2016,14(1):47.doi:10.1186/s12951-016-0201-1.
[20]Cha J,Kim H,Cha I.Cytoplasmic HuR expression:Correlation with cellular inhibitors of apoptosis protein-2 expression and clinicopathologic factors in oral squamous cell carcinoma cells[J].Head Neck,2014,36(8):1168-1175.doi:10.1002/hed.23431.
[21]耿申,吴婷,穆先敏,等.细胞间黏附分子-1在ARDS小鼠肺微血管内皮细胞内的表达变化[J].医学研究生学报,2016,29(4):342-347.
[2]Chen S,Li T,Zhao Q,et al.Using circular RNA hsa_circ_0000190 as a new biomarker in the diagnosis of gastric cancer[J].Clin Chim Acta,2017,466:167-171.doi:10.1016/j.cca.2017.01.025.
[3]Guo J,Jing L,Chang S,et al.Inhibiting cytoplasmic accumulation of HuR synergizes genotoxic agents in urothelial carcinoma of the bladder[J].Oncotarget,2016,7(29):45249-45262.doi:10.18632/oncotarget.9932.
[4]Trojanowicz B,Sekulla C,Dralle H,et al.Expression of ARE-binding proteins AUF1 and HuR in follicular adenoma and carcinoma of thyroid gland[J].Neoplasma,2016,63(3):371-377.doi:10.4149/305_150819N450.
[5]Badawi A,Biyanee A,Nasrullah U,et al.Inhibition of IRES-dependent translation of caspase-2 by HuR confers chemotherapeutic drug resistance in colon carcinoma cells[J].Oncotarget,2018,9(26):18367-18385.doi:10.18632/oncotarget.24840.
[6]Eberhardt W,Badawi A,Biyanee A,et al.Cytoskeleton-dependent transport as a potential target for interfering with post-transcriptional HuRmRNA regulons[J].Front Pharmacol,2016,7:251.doi:10.3389/fphar.2016.00251.
[7]Davidson B,Holth A,Hellesylt E,et al.HUR mRNA expression in ovarian high-grade serous carcinoma effusions is associated with poor survival[J].Hum Pathol,2016,48:95-101.doi:10.1016/j.humpath.2015.09.027.
[8]罗年安,屈亚琦,张洪科,等.HuR和PDGFC在乳腺癌组织中的表达及相关性分析[J].现代生物医学进展,2014,14(26):5011-5013.doi:10.13241/j.cnki.pmb.2014.26.003.
[9]Zarei M,Lal S,Parker SJ,et al.Posttranscriptional upregulation of IDH1by HuR establishes a powerful survival phenotype in pancreatic cancer cells[J].Cancer Res,2017,77(16):4460-4471.doi:10.1158/0008-5472.CAN-17-0015.
[10]Lal A,Mazan-Mamczarz K,Kawai T,et al.Concurrent versus individual binding of HuR and AUF1 to common labile target mRNAs[J].Embo J,2014,23(15):3092-3102.doi:10.1038/sj.emboj.7600305.
[11]Badawi A,Hehlgans S,Pfeilschifter J,et al.Silencing of the mRNA-binding protein HuR increases the sensitivity of colorectal cancer cells to ionizing radiation through upregulation of caspase-2[J].Cancer Lett,2017,393:103-112.doi:10.1016/j.canlet.2017.02.010.
[12]Li DS,Ainiwaer JL,Sheyhiding I,et al.Identification of key long noncoding RNAs as competing endogenous RNAs for miRNA-mRNA in lung adenocarcinoma[J].Eur Rev Med Pharmacol Sci,2016,20(11):2285-2295.
[13]楚慧丽,关雅萍.RNA结合蛋白HuR在肿瘤耐药及药物敏感性中的作用[J].中国肿瘤生物治疗杂志,2014,21(6):707-711.doi:10.3872/j.issn.1007-385X.2014.06.020.
[14]Ahuja D,Goyal A,Ray PS.Interplay between RNA-binding protein HuR and microRNA-125b regulates p53 mRNA translation in response to genotoxic stress[J].Rna Biol,2016,13(11):1152-1165.doi:10.1080/15476286.2016.1229734.
[15]Gauchotte G,Hergalant S,Vigouroux C,et al.Cytoplasmic overexpression of RNA-binding protein HuR is a marker of poor prognosis in meningioma,and HuR knockdown decreases meningioma cell growth and resistance to hypoxia[J].J Pathol,2018,242(4):421-434.doi:10.1002/path.4916.
[16]Astakhova AA,Chistyakov DV,Sergeeva MG,et al.Regulation of the ARE-binding proteins,TTP(tristetraprolin)and HuR(human antigen R),in inflammatory response in astrocytes[J].Neurochem Int,2018,118:82-90.doi:10.1016/j.neuint.2018.04.014.
[17]Ronkainen H,Vaarala MH,Hirvikoski P,et al.HuR expression is a marker of poor prognosis in renal cell carcinoma[J].Tumor Biol,2011,32(3):481-487.doi:10.1007/s13277-010-0141-6.
[18]Al-Haidari A,Algaber A,Madhi R,et al.MiR-155-5p controls colon cancer cell migration via post-transcriptional regulation of Human Antigen R(HuR)[J].Cancer Lett,2018,421:145-151.doi:10.1016/j.canlet.2018.02.026.
[19]Muralidharan R,Babu A,Amreddy N,et al.Folate receptor-targeted nanoparticle delivery of HuR-RNAi suppresses lung cancer cell proliferation and migration[J].J Nanobiotechnol,2016,14(1):47.doi:10.1186/s12951-016-0201-1.
[20]Cha J,Kim H,Cha I.Cytoplasmic HuR expression:Correlation with cellular inhibitors of apoptosis protein-2 expression and clinicopathologic factors in oral squamous cell carcinoma cells[J].Head Neck,2014,36(8):1168-1175.doi:10.1002/hed.23431.
[21]耿申,吴婷,穆先敏,等.细胞间黏附分子-1在ARDS小鼠肺微血管内皮细胞内的表达变化[J].医学研究生学报,2016,29(4):342-347.