Tiam1蛋白在喉癌中的表达及其临床意义
|
摘要
目的检测T淋巴细胞侵袭转移诱导因子1(Tiam1)蛋白在喉癌组织中的表达,并探讨其表达水平与喉癌临床病理特征和预后之间的关系。方法采用免疫组织化学染色技术检测Tiam1蛋白在98例喉癌石蜡组织切片中的表达,并统计分析Tiam1蛋白表达水平与喉癌临床病理特征和预后之间的关系。结果 Tiam1蛋白的表达与喉癌的淋巴结转移(P<0.001)、临床分期(Ⅰ期、Ⅱ期/Ⅲ期、Ⅳ期)(P=0.027)、组织病理学分级(P=0.020)及复发(P=0.003)密切相关;Kaplan-Meier生存曲线分析结果显示Tiam1高表达组的5年无复发生存率(P=0.001)和5年总生存率(P<0.001)均明显低于Tiam1低表达组;而且通过Kaplan-Meier生存曲线分析Tiam1蛋白表达和淋巴结转移情况与头颈鳞癌患者预后之间的关系,发现Tiam1高表达并有淋巴结转移组的5年无复发生存率和5年总生存率明显低于其它(Tiam1低表达或无淋巴结转移)组(P均<0.001);多因素Cox比例风险回归模型进一步显示,淋巴结转移(P=0.001)及Tiam1表达水平(P=0.020)为喉癌的独立预后因素。结论 Tiam1在喉癌组织中表达显著升高,且其高表达与喉癌患者的淋巴结转移、复发及预后密切相关。Tiam1可能在喉癌的发生、发展中起重要作用,其表达水平对喉癌的复发及预后具有评估价值。
Objective To evaluate the expression of T-lymphoma invasion and metastasis 1(Tiam1) in tissue specimens of laryngeal carcinoma, and explore the correlation between Tiam1 expression and clinicopathological parameters as well as prognosis of laryngeal carcinoma.Methods Tiam1 expression in 98 primary laryngeal carcinoma tissue specimens was detected by immunohistochemistry. The correlations between Tiam1 expression and clinicopathological parameters as well as patients' survival were analyzed.Results Immunohistochemical staining revealed that Tiam1 was detected in all primary tumor samples. Moreover, Tiam1 overexpression was significantly correlated with lymph node metastasis(P<0.001), clinical stage(P=0.027), histological grade(P=0.020), and recurrence(P=0.003). Survival analysis demonstrated that high Tiam1 expression was significantly correlated with shorter disease-free survival(P=0.001) and overall survival(P<0.001). When combining the Tiam1 expression and lymph node status, Kaplan-Meier survival analysis showed that patients with Tiam1 overexpression/lymph node metastasis(+) had both shorter disease-free and overall survival than others(both P<0.001). Multivariate Cox proportional hazards model analysis confirmed that lymph node metastasis(P=0.001) and Tiam1 overexpression(P=0.020) were statistically significant, independent predictors of prognosis for patients with laryngeal carcinoma.Conclusions The Tiam1 protein is obviously over-expressed in laryngeal carcinoma, which is associated with lymph node metastasis, recurrence, and poor prognosis of this tumor. Tiam1 may contribute to laryngeal carcinoma progression, and represent as a novel prognostic indicator as well as potential therapeutic target for laryngeal carcinoma.
Objective To evaluate the expression of T-lymphoma invasion and metastasis 1(Tiam1) in tissue specimens of laryngeal carcinoma, and explore the correlation between Tiam1 expression and clinicopathological parameters as well as prognosis of laryngeal carcinoma.Methods Tiam1 expression in 98 primary laryngeal carcinoma tissue specimens was detected by immunohistochemistry. The correlations between Tiam1 expression and clinicopathological parameters as well as patients' survival were analyzed.Results Immunohistochemical staining revealed that Tiam1 was detected in all primary tumor samples. Moreover, Tiam1 overexpression was significantly correlated with lymph node metastasis(P<0.001), clinical stage(P=0.027), histological grade(P=0.020), and recurrence(P=0.003). Survival analysis demonstrated that high Tiam1 expression was significantly correlated with shorter disease-free survival(P=0.001) and overall survival(P<0.001). When combining the Tiam1 expression and lymph node status, Kaplan-Meier survival analysis showed that patients with Tiam1 overexpression/lymph node metastasis(+) had both shorter disease-free and overall survival than others(both P<0.001). Multivariate Cox proportional hazards model analysis confirmed that lymph node metastasis(P=0.001) and Tiam1 overexpression(P=0.020) were statistically significant, independent predictors of prognosis for patients with laryngeal carcinoma.Conclusions The Tiam1 protein is obviously over-expressed in laryngeal carcinoma, which is associated with lymph node metastasis, recurrence, and poor prognosis of this tumor. Tiam1 may contribute to laryngeal carcinoma progression, and represent as a novel prognostic indicator as well as potential therapeutic target for laryngeal carcinoma.
引文
[1] Zhao L, Liu Y, Sun X, et al. Overexpression of T lymphoma invasion and metastasis 1 predict renal cell carcinoma metastasis and overall patient survival[J]. J Cancer Res Clin Oncol, 2011, 137(3):393-398.
[2] Torre LA, Bray F, Siegel RL , et al. Global cancer statistics, 2012[J]. CA Cancer J Clin, 2015, 65(2):87-108.
[3] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015[J]. CA Cancer J Clin, 2015, 65(1):5-29.
[4] Meng XY, Liu J, Lv F, et al. Study on the correlation between extracellular matrix protein-1 and the growth, metastasis and angiogenesis of laryngeal carcinoma[J]. Asian Pac J Cancer Prev, 2015, 16(6):2313-2316.
[5] 周芨,邓世山,刘海. USP7在喉癌组织中的表达及其临床意义[J]. 中国耳鼻咽喉颅底外科杂志, 2015, 21(1):27-30. Zhou J, Deng SS, Liu H. Expression of USP7 in human laryngeal carcinoma and its significance[J]. Chin J Otorhinolaryngol Skull Base Surg,2015,21(1):27-30.
[6] Habets GG, Scholtes EH, Zuydgeest D, et al. Identification of an invasion-inducing gene, Tiam-1, that encodes a protein with homology to GDP-GTP exchangers for Rho-like proteins[J]. Cell, 1994, 77(4):537-549.
[7] Boissier P, Huynh-Do U. The guanine nucleotide exchange factor Tiam1: a Janus-faced molecule in cellular signaling[J]. Cell Signal, 2014, 26(3):483-491.
[8] Minard ME, Kim LS, Price JE, et al. The role of the guanine nucleotide exchange factor Tiam1 in cellular migration, invasion, adhesion and tumor progression[J]. Breast Cancer Res Treat, 2004, 84(1):21-32.
[9] Yang H, Cai YC, Cao Y, et al. The prognostic value of Tiam1 protein expression in head and neck squamous cell carcinoma: a retrospective study[J]. Chin J Cancer, 2015, 34(12):614-621.
[10] Ding Y, Chen B, Huang J, et al. Overexpression of Tiam1 is associated with malignant phenotypes of nasopharyngeal carcinoma[J]. Oncol Rep, 2014, 32(2):607-618.
[11] Liu N, Jiang N, Guo R, et al. MiR-451 inhibits cell growth and invasion by targeting MIF and is associated with survival in nasopharyngeal carcinoma[J]. Mol Cancer, 2013, 12(1):123.
[12] Qi Y, Huang B, Yu L, et al. Prognostic value of Tiam1 and Rac1 overexpression in nasopharyngeal carcinoma[J]. ORL J Otorhinolaryngol Relat Spec, 2009, 71(3):163-171.
[13] Liu N, Tang LL, Sun Y, et al. MiR-29c suppresses invasion and metastasis bytargeting TIAM1 in nasopharyngeal carcinoma[J]. Cancer Lett, 2013, 329(2):181-188.
[14] Lin L, You J, Qian Y, et al. The prognostic value of T-lymphoma invasion and metastasis 1 (TIAM1) expression in oral squamous cell carcinoma[J]. J Biochem Mol Toxicol, 2017, 31(4): Epub 2016Nov9.
[15] Song B, Wang LF, Fan XH, et al. Expression of T-lymphoma invasion and metastasis factor on the occurrence of oral squamous cell carcinoma[J]. J Biol Regul Homeost Agents, 2017, 31(2):289-295.
[16] Hsueh C, Lin JD, Yang CF, et al. Prognostic significance of Tiam1 expression in papillary thyroid carcinoma[J]. Virchows Arch, 2011, 459(6):587-593.
[17] Liu H, Wang X, Shi G, et al. Tiam1 siRNA enhanced the sensitivity of sorafenib on esophageal squamous cell carcinoma in vivo[J]. Tumour Biol, 2014, 35(8):8249-8258.
[18] Engers R, Mueller M, Walter A, et al. Prognostic relevance of Tiam1 protein expression in prostate carcinomas[J]. Br J Cancer, 2006, 95(8):1081-1086.
[19] Du X, Wang S, Lu J, et al. Clinical value of Tiam1-Rac1 signaling in primary gallbladder carcinoma[J]. Med Oncol, 2012, 29(3):1873-1878.
[20] Vaughan L, Tan CT, Chapman A, et al. HUWE1 ubiquitylates and degrades the RAC activator TIAM1 promoting cell-cell adhesion disassembly, migration, and invasion[J]. Cell Rep, 2015, 10(1):88-102.
[21] Huang J, Ye X, Guan J, et al. Tiam1 is associated with hepatocellular carcinoma metastasis[J]. Int J Cancer, 2013, 132(1):90-100.
[22] Yang W, Lv S, Liu X, et al. Up-regulation of Tiam1 and Rac1 correlates with poor prognosis in hepatocellular carcinoma[J]. Jpn J Clin Oncol, 2010, 40(11):1053-1059.
[23] Wang B, Li W, Liu H, et al. miR-29b suppresses tumor growth and metastasis in colorectal cancer via downregulating Tiam1 expression and inhibiting epithelial-mesenchymal transition[J]. Cell Death Dis, 2014, 17(5):e1335.
[24] Wang YL, Li DS, Wang Y, et al. Lymph node ratio for postoperative staging of laryngeal squamous cell carcinoma with lymph node metastasis[J]. PLoS One, 2014, 9(1):e87037.
[25] 夏良平, 曾宗渊, 魏茂文, 等. 影响喉癌生存率的单因素和多因素分析[J]. 中国肿瘤, 2002, 11(11):655-657. Xia LP, Zeng ZY, Wei MW, et al. The univariate and multivariate analysis of the factors affecting the survival rate of laryngeal carcinoma[J]. China Cancer,2002,11(11):655-657.
[2] Torre LA, Bray F, Siegel RL , et al. Global cancer statistics, 2012[J]. CA Cancer J Clin, 2015, 65(2):87-108.
[3] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015[J]. CA Cancer J Clin, 2015, 65(1):5-29.
[4] Meng XY, Liu J, Lv F, et al. Study on the correlation between extracellular matrix protein-1 and the growth, metastasis and angiogenesis of laryngeal carcinoma[J]. Asian Pac J Cancer Prev, 2015, 16(6):2313-2316.
[5] 周芨,邓世山,刘海. USP7在喉癌组织中的表达及其临床意义[J]. 中国耳鼻咽喉颅底外科杂志, 2015, 21(1):27-30. Zhou J, Deng SS, Liu H. Expression of USP7 in human laryngeal carcinoma and its significance[J]. Chin J Otorhinolaryngol Skull Base Surg,2015,21(1):27-30.
[6] Habets GG, Scholtes EH, Zuydgeest D, et al. Identification of an invasion-inducing gene, Tiam-1, that encodes a protein with homology to GDP-GTP exchangers for Rho-like proteins[J]. Cell, 1994, 77(4):537-549.
[7] Boissier P, Huynh-Do U. The guanine nucleotide exchange factor Tiam1: a Janus-faced molecule in cellular signaling[J]. Cell Signal, 2014, 26(3):483-491.
[8] Minard ME, Kim LS, Price JE, et al. The role of the guanine nucleotide exchange factor Tiam1 in cellular migration, invasion, adhesion and tumor progression[J]. Breast Cancer Res Treat, 2004, 84(1):21-32.
[9] Yang H, Cai YC, Cao Y, et al. The prognostic value of Tiam1 protein expression in head and neck squamous cell carcinoma: a retrospective study[J]. Chin J Cancer, 2015, 34(12):614-621.
[10] Ding Y, Chen B, Huang J, et al. Overexpression of Tiam1 is associated with malignant phenotypes of nasopharyngeal carcinoma[J]. Oncol Rep, 2014, 32(2):607-618.
[11] Liu N, Jiang N, Guo R, et al. MiR-451 inhibits cell growth and invasion by targeting MIF and is associated with survival in nasopharyngeal carcinoma[J]. Mol Cancer, 2013, 12(1):123.
[12] Qi Y, Huang B, Yu L, et al. Prognostic value of Tiam1 and Rac1 overexpression in nasopharyngeal carcinoma[J]. ORL J Otorhinolaryngol Relat Spec, 2009, 71(3):163-171.
[13] Liu N, Tang LL, Sun Y, et al. MiR-29c suppresses invasion and metastasis bytargeting TIAM1 in nasopharyngeal carcinoma[J]. Cancer Lett, 2013, 329(2):181-188.
[14] Lin L, You J, Qian Y, et al. The prognostic value of T-lymphoma invasion and metastasis 1 (TIAM1) expression in oral squamous cell carcinoma[J]. J Biochem Mol Toxicol, 2017, 31(4): Epub 2016Nov9.
[15] Song B, Wang LF, Fan XH, et al. Expression of T-lymphoma invasion and metastasis factor on the occurrence of oral squamous cell carcinoma[J]. J Biol Regul Homeost Agents, 2017, 31(2):289-295.
[16] Hsueh C, Lin JD, Yang CF, et al. Prognostic significance of Tiam1 expression in papillary thyroid carcinoma[J]. Virchows Arch, 2011, 459(6):587-593.
[17] Liu H, Wang X, Shi G, et al. Tiam1 siRNA enhanced the sensitivity of sorafenib on esophageal squamous cell carcinoma in vivo[J]. Tumour Biol, 2014, 35(8):8249-8258.
[18] Engers R, Mueller M, Walter A, et al. Prognostic relevance of Tiam1 protein expression in prostate carcinomas[J]. Br J Cancer, 2006, 95(8):1081-1086.
[19] Du X, Wang S, Lu J, et al. Clinical value of Tiam1-Rac1 signaling in primary gallbladder carcinoma[J]. Med Oncol, 2012, 29(3):1873-1878.
[20] Vaughan L, Tan CT, Chapman A, et al. HUWE1 ubiquitylates and degrades the RAC activator TIAM1 promoting cell-cell adhesion disassembly, migration, and invasion[J]. Cell Rep, 2015, 10(1):88-102.
[21] Huang J, Ye X, Guan J, et al. Tiam1 is associated with hepatocellular carcinoma metastasis[J]. Int J Cancer, 2013, 132(1):90-100.
[22] Yang W, Lv S, Liu X, et al. Up-regulation of Tiam1 and Rac1 correlates with poor prognosis in hepatocellular carcinoma[J]. Jpn J Clin Oncol, 2010, 40(11):1053-1059.
[23] Wang B, Li W, Liu H, et al. miR-29b suppresses tumor growth and metastasis in colorectal cancer via downregulating Tiam1 expression and inhibiting epithelial-mesenchymal transition[J]. Cell Death Dis, 2014, 17(5):e1335.
[24] Wang YL, Li DS, Wang Y, et al. Lymph node ratio for postoperative staging of laryngeal squamous cell carcinoma with lymph node metastasis[J]. PLoS One, 2014, 9(1):e87037.
[25] 夏良平, 曾宗渊, 魏茂文, 等. 影响喉癌生存率的单因素和多因素分析[J]. 中国肿瘤, 2002, 11(11):655-657. Xia LP, Zeng ZY, Wei MW, et al. The univariate and multivariate analysis of the factors affecting the survival rate of laryngeal carcinoma[J]. China Cancer,2002,11(11):655-657.