乏氧诱导因子-1α在口腔鳞状细胞癌颈淋巴转移中的作用
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摘要
目的:探讨乏氧诱导因子-1α(hypoxia-inducible factor 1α,HIF-1α)蛋白表达在口腔鳞状细胞癌颈淋巴转移中的作用及其在判断预后方面的意义。方法:1993年6月至2010年5月在北京大学口腔医院住院并接受手术治疗的原发口腔鳞状细胞癌患者125例纳入本次研究,收集所有患者的临床病理学资料,制作组织病理切片,应用免疫组织化学方法检测HIF-1α蛋白的表达情况,根据表达情况分为高表达组和低表达组,主要评估指标为颈淋巴转移率和癌相关生存率(disease-specific survival,DSS)。颈淋巴转移率与各项临床病理学参数的关系比较采用秩和检验,组间及组内癌相关生存率的差异性比较采用Kaplan-Meier分析,并应用COX多因素生存分析对DSS的独立预测因子进行统计分析。所有统计学分析均采用SPSS 17.0软件包完成。结果:随访截止日期为2013年6月1日,生存患者的中位随访时间为73个月,有75例HIF-1α高表达,48例HIF-1α低表达,2例无法评估。秩和检验分析发现,HIF-1α高表达组淋巴转移率显著高于HIF-1α低表达组(58.7%vs.37.5%,P=0.027)。Kaplan-Meier生存分析发现,HIF-1α低表达组患者无病生存率显著高于高表达组(60.4%vs.36.0%,P=0.009),癌相关生存率显著高于高表达组(70.8%vs.46.7%,P=0.005)。多因素生存分析表明,HIF-1α表达(HR=2.164,95%CI:1.150~4.074,P=0.017)和T分期(HR=1.387,95%CI:1.066~1.804,P=0.015)均是判断口腔鳞状细胞癌患者预后的独立预测因子。结论:HIF-1α蛋白表达是预测口腔鳞状细胞癌预后的独立因子,且与颈淋巴转移显著相关,能够作为口腔鳞状细胞癌潜在的分子诊断标志物和靶向治疗靶点。
Objective: To explore the association between hypoxia-inducible factor 1α( HIF-1α) expression and lymph node metastasis in oral squamous cell carcinoma( OSCC). Methods: Tumor specimens from 125 patients with histologically-proven,surgically-treated OSCC were examined by immunohistochemical staining for expression of HIF-1α. The patients were divided into two groups by the expression of HIF-1α,high expression of HIF-1α group( H-group) and low expression of HIF-1α group( Lgroup). The main assessment parameters were lymph node metastasis rate and disease-specific survival( DSS). The lymph node metastasis rate and clinicopathologic features were compared using Mann-Whitney test. The Kaplan-Meier curve was generated for each group and compared using the log-rank test.Cox proportional hazard models were utilized for multivariate analyses of HIF-1α expression and other baseline factors with DSS. All calculations and analyses were performed using the SPSS 17. 0 software package. Results: The protein expression levels of HIF-1α were up-regulated in OSCC and two patients were unable to evaluate. There were 48 patients in L-group and 75 patients in H-group. Lymph node metastasis rate was 37. 5%( 18/48) for L-group and 58. 7%( 44/75) for H-group( P = 0. 027). Expression of HIF-1α was significantly correlated with lymph node metastasis. The patients of L-group had a significantly better DSS than the patients of H-group( 70. 8% vs. 46. 7%,P = 0. 005),while the patients of L-group had a significantly better disease-free survival( DFS) than the patients of H-group( 60. 4%vs. 36. 0%,P = 0. 009) by Kaplan-Meier method. A multivariate survival analysis also showed that HIF-1α expression( HR = 2. 164,95% CI: 1. 150-4. 074,P = 0. 017) and T-stage( HR = 1. 387,95% CI:1. 066-1. 804,P = 0. 015) both were the independent factors associated with prognosis. Conclusion:HIF-1α expression is significantly correlated with lymph node metastasis in OSCC. HIF-1α expression is an independent predictive factor for prognosis of OSCC patients,and may serve as a potential biomarker for molecular diagnosis and targeted therapy in future.
Objective: To explore the association between hypoxia-inducible factor 1α( HIF-1α) expression and lymph node metastasis in oral squamous cell carcinoma( OSCC). Methods: Tumor specimens from 125 patients with histologically-proven,surgically-treated OSCC were examined by immunohistochemical staining for expression of HIF-1α. The patients were divided into two groups by the expression of HIF-1α,high expression of HIF-1α group( H-group) and low expression of HIF-1α group( Lgroup). The main assessment parameters were lymph node metastasis rate and disease-specific survival( DSS). The lymph node metastasis rate and clinicopathologic features were compared using Mann-Whitney test. The Kaplan-Meier curve was generated for each group and compared using the log-rank test.Cox proportional hazard models were utilized for multivariate analyses of HIF-1α expression and other baseline factors with DSS. All calculations and analyses were performed using the SPSS 17. 0 software package. Results: The protein expression levels of HIF-1α were up-regulated in OSCC and two patients were unable to evaluate. There were 48 patients in L-group and 75 patients in H-group. Lymph node metastasis rate was 37. 5%( 18/48) for L-group and 58. 7%( 44/75) for H-group( P = 0. 027). Expression of HIF-1α was significantly correlated with lymph node metastasis. The patients of L-group had a significantly better DSS than the patients of H-group( 70. 8% vs. 46. 7%,P = 0. 005),while the patients of L-group had a significantly better disease-free survival( DFS) than the patients of H-group( 60. 4%vs. 36. 0%,P = 0. 009) by Kaplan-Meier method. A multivariate survival analysis also showed that HIF-1α expression( HR = 2. 164,95% CI: 1. 150-4. 074,P = 0. 017) and T-stage( HR = 1. 387,95% CI:1. 066-1. 804,P = 0. 015) both were the independent factors associated with prognosis. Conclusion:HIF-1α expression is significantly correlated with lymph node metastasis in OSCC. HIF-1α expression is an independent predictive factor for prognosis of OSCC patients,and may serve as a potential biomarker for molecular diagnosis and targeted therapy in future.
引文
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[23]Zheng Y,Ni Y,Huang X,et al.Overexpression of HIF-1alpha indicates a poor prognosis in tongue carcinoma and may be associated with tumour metastasis[J].Oncol Lett,2013,5(4):1285-1289.
[24]刘文曙,尚建伟,高岩,等.口腔鳞状细胞癌组织乏氧状况的初步研究[J].中华口腔医学杂志,2009,44(5):282-285.
[25]董兰兰,袁响林.乏氧诱导因子促进肿瘤侵袭转移的研究进展[J].中国肿瘤生物治疗杂志,2006(5):390-392.
[26]Shemirani B,Crowe D L.Hypoxic induction of HIF-1alpha and VEGF expression in head and neck squamous cell carcinoma lines is mediated by stress activated protein kinases[J].Oral Oncol,2002,38(3):251-257.
[27]Aga M,Kondo S,Wakisaka N,et al.Siah-1 is associated with expression of hypoxia-inducible factor-1alpha in oral squamous cell carcinoma[J].Auris Nasus Larynx,2017,44(2):213-219.
[28]杨大江,郝晓鸣,梁新华.口腔鳞状细胞癌组织中HIF-1α,VEGF-C的表达及与淋巴管生成的关系[J].口腔医学研究,2014(2):159-162.
[29]Liang X,Yang D,Hu J,et al.Hypoxia inducible factor-alpha expression correlates with vascular endothelial growth factor-C expression and lymphangiogenesis/angiogenesis in oral squamous cell carcinoma[J].Anticancer Res,2008,28(3A):1659-1666.
[30]Feng Z,Li JN,Li CZ,et al.Elective neck dissection versus observation in the management of early tongue carcinoma with clinically node-negative neck:A retrospective study of 229 cases[J].J Craniomaxillofac Surg,2014,42(6):806-810.
[31]Ghattass K,Assah R,El-Sabban M,et al.Targeting hypoxia for sensitization of tumors to radio-and chemotherapy[J].Curr Cancer Drug Targets,2013,13(6):670-685.
[32]Lin SC,Liao WL,Lee JC,et al.Hypoxia-regulated gene network in drug resistance and cancer progression[J].Exp Biol Med(Maywood),2014,239(7):779-792.
[2]Brockstein B,Haraf DJ,Rademaker AW,et al.Patterns of failure,prognostic factors and survival in locoregionally advanced head and neck cancer treated with concomitant chemoradiotherapy:a 9-year,337-patient,multi-institutional experience[J].Ann Oncol,2004,15(8):1179-1186.
[3]Warnakulasuriya S.Global epidemiology of oral and oropharyngeal cancer[J].Oral Oncol,2009,45(4-5):309-316.
[4]孟宪瑞,刘进忠.口腔癌的早期诊断[J].国际口腔医学杂志,2008,35(3):329-331.
[5]Haddad R,O’Neill A,Rabinowits G,et al.Induction chemotherapy followed by concurrent chemoradiotherapy(sequential chemoradiotherapy)versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer(PARADIGM):a randomised phase 3 trial[J].Lancet Oncol,2013,14(3):257-264.
[6]Leemans CR,Braakhuis BJ,Brakenhoff RH.The molecular biology of head and neck cancer[J].Nat Rev Cancer,2011,11(1):9-22.
[7]van den Broek GB,Wildeman M,Rasch CR,et al.Molecular markers predict outcome in squamous cell carcinoma of the head and neck after concomitant cisplatin-based chemoradiation[J].Int J Cancer,2009,124(11):2643-2650.
[8]冯芝恩,张萍,王丽珍,等.cyclin D1蛋白表达预测头颈鳞癌预后[J].中国口腔颌面外科杂志,2012,10(4):277-281.
[9]Carmeliet P,Jain RK.Angiogenesis in cancer and other diseases[J].Nature,2000,407(6801):249-257.
[10]Wang N,Dong CR,Jiang R,et al.Overexpression of HIF-1alpha,metallothionein and SLUG is associated with high TNM stage and lymph node metastasis in papillary thyroid carcinoma[J].Int J Clin Exp Pathol,2014,7(1):322-330.
[11]Chen L,Shi Y,Yuan J,et al.HIF-1 alpha overexpression correlates with poor overall survival and disease-free survival in gastric cancer patients post-gastrectomy[J/OL].PLo S One,2014,9(3):e90678.
[12]Le QT,Machtay M.Acceler-dated fractionation:the end of the era of the large,“one size fits all”trial for locally advanced head and neck cancer[J].Int J Radiat Oncol Biol Phys,2014,89(1):7-9.
[13]van’t Veer LJ,Bernards R.Enabling personalized cancer medicine through analysis of gene-expression patterns[J].Nature,2008,452(7187):564-570.
[14]Feng Z,Guo W,Zhang C,et al.CCND1 as a predictive biomarker of neoadjuvant chemotherapy in patients with locally advanced head and neck squamous cell carcinoma[J/OL].PLo S One,2011,6(10):e26399.
[15]Greco O,Scott S.Tumor hypoxia and targeted gene therapy[J].Int Rev Cytol,2007(257):181-212.
[16]Kunz M,Ibrahim SM.Molecular responses to hypoxia in tumor cells[J].Mol Cancer,2003(2):23.
[17]宋樱,孙善珍,曲迅,等.乏氧对人舌鳞癌细胞系Tca8113体外黏附和侵袭能力的影响[J].实用口腔医学杂志,2009,25(6):828-832.
[18]Gilkes DM,Semenza GL.Role of hypoxia-inducible factors in breast cancer metastasis[J].Future Oncol,2013,9(11):1623-1636.
[19]Brennan PA,Mackenzie N,Quintero M.Hypoxia-inducible factor1alpha in oral cancer[J].J Oral Pathol Med,2005,34(7):385-389.
[20]Gong L,Zhang W,Zhou J,et al.Prognostic value of HIFs expression in head and neck cancer:a systematic review[J/OL].PLo S One,2013,8(9):e75094.
[21]Zhou J,Huang S,Wang L,et al.Clinical and prognostic significance of HIF-1alpha overexpression in oral squamous cell carcinoma:a meta-analysis[J].World J Surg Oncol,2017,15(1):104.
[22]Dunkel J,Vaittinen S,Grenman R,et al.Prognostic markers in stageⅠoral cavity squamous cell carcinoma[J].Laryngoscope,2013,123(10):2435-2441.
[23]Zheng Y,Ni Y,Huang X,et al.Overexpression of HIF-1alpha indicates a poor prognosis in tongue carcinoma and may be associated with tumour metastasis[J].Oncol Lett,2013,5(4):1285-1289.
[24]刘文曙,尚建伟,高岩,等.口腔鳞状细胞癌组织乏氧状况的初步研究[J].中华口腔医学杂志,2009,44(5):282-285.
[25]董兰兰,袁响林.乏氧诱导因子促进肿瘤侵袭转移的研究进展[J].中国肿瘤生物治疗杂志,2006(5):390-392.
[26]Shemirani B,Crowe D L.Hypoxic induction of HIF-1alpha and VEGF expression in head and neck squamous cell carcinoma lines is mediated by stress activated protein kinases[J].Oral Oncol,2002,38(3):251-257.
[27]Aga M,Kondo S,Wakisaka N,et al.Siah-1 is associated with expression of hypoxia-inducible factor-1alpha in oral squamous cell carcinoma[J].Auris Nasus Larynx,2017,44(2):213-219.
[28]杨大江,郝晓鸣,梁新华.口腔鳞状细胞癌组织中HIF-1α,VEGF-C的表达及与淋巴管生成的关系[J].口腔医学研究,2014(2):159-162.
[29]Liang X,Yang D,Hu J,et al.Hypoxia inducible factor-alpha expression correlates with vascular endothelial growth factor-C expression and lymphangiogenesis/angiogenesis in oral squamous cell carcinoma[J].Anticancer Res,2008,28(3A):1659-1666.
[30]Feng Z,Li JN,Li CZ,et al.Elective neck dissection versus observation in the management of early tongue carcinoma with clinically node-negative neck:A retrospective study of 229 cases[J].J Craniomaxillofac Surg,2014,42(6):806-810.
[31]Ghattass K,Assah R,El-Sabban M,et al.Targeting hypoxia for sensitization of tumors to radio-and chemotherapy[J].Curr Cancer Drug Targets,2013,13(6):670-685.
[32]Lin SC,Liao WL,Lee JC,et al.Hypoxia-regulated gene network in drug resistance and cancer progression[J].Exp Biol Med(Maywood),2014,239(7):779-792.