头颈部鳞状细胞癌相关肿瘤标志物的研究进展

头颈部鳞状细胞癌(head and neck squamous cell carcinoma,HNSCC)是头颈部恶性肿瘤的主要病理类型,约占所有头颈部肿瘤的90%。而据我们临床所见,大约有70%~80%的患者就诊时已为局部晚期,其治疗效果欠佳,预后差。肿瘤标志物又叫做肿瘤标记物,是指特征性存在于恶性肿瘤细胞,或是由恶性肿瘤细胞异常而产生的物质,或是宿主对于肿瘤的刺激反应而产生的物质,并且能够反映肿瘤发生、发展,以及监测肿瘤对治疗反应的一类物质。作为近年来研究热点的肿瘤标志物,具有简便、经济、快速、无创的特点,更重要的是一些标志物在组织器官发生形态学变化之前就有表达。因此,肿瘤标志物的研究对头颈部鳞状细胞癌的早期诊断以及判断预后都具有十分重要的意义。本文综述近几年来发现的可能与头颈部鳞状细胞癌的发生发展或者预后相关的肿瘤标志物。     

NOB1在食管鳞状细胞癌中的表达及临床意义

目的研究NOB1基因在食管鳞状细胞癌（Esophageal squamous cell carcinoma,ESCC）中的表达及临床意义。方法利用免疫组织化学SP法检测59例ESCC及其相应（50例）的远端正常食管黏膜组织中NOB1的表达。结果 ESCC中NOB1的阳性率为71%,正常食管黏膜鳞状上皮中的阳性率为26%,两组比较,差异有统计学意义（P〈0.05）。NOB1的表达与ESCC的分化程度及淋巴结转移相关,与患者的性别,年龄以及肿瘤浸润深度无关。结论 NOB1在ESCC中表达升高,可能在ESCC发生发展过程中起重要作用。     

血常规在头颈部鳞状细胞癌早期诊断中的作用

目的:探究血常规指标在头颈部鳞状细胞癌早期诊断中的作用,从血液学的角度为头颈部鳞状细胞癌的早期诊断提供参考依据。方法:对181例头颈部良恶性肿瘤患者的血常规结果进行回顾性分析,比较头颈部鳞状细胞癌患者组(实验组)和头颈部良性肿瘤组(对照组)患者的血小板计数(PLT)、血小板比积(PCT)、血小板平均容积(MPV)、血小板分布宽度(PDW)、大血小板比率(P-LCR)、中性粒细胞计数(NEU)、淋巴细胞计数(LYM)、单核细胞计数(MONO)、嗜酸性粒细胞计数(EOS)、嗜碱性粒细胞计数(BASO)、血小板计数/淋巴细胞计数比值(PLR)以及中性粒细胞计数/淋巴细胞计数比值(NLR)共12个指标。结果:实验组和对照组的PLT、PCT、MPV、PDW、P-LCR以及BASO计数值比较均没有统计学差异(p0.05)。对照组NEU、MONO、EOS、PLR和NLR均低于实验组,而LYM计数值高于实验组,其差异均具有统计学意义(p0.05),ROC曲线显示NLR对于早期诊断的意义要优于PLR。结论:血小板相关指标在头颈部鳞状细胞癌早期诊断中无明显意义,白细胞亚型计数具有重要的提示作用,而NLR的诊断意义要高于PLR,或许可以联合其他鳞癌标志物进行早期诊断。     

乙醛脱氢酶1在喉鳞状细胞癌中的表达及临床病理意义

目的探讨乙醛脱氢酶1在喉鳞状细胞癌中的表达及临床病理意义。方法采用免疫组化Elivision法及原位杂交法对2007年6月-2009年1月间我院收治的86例喉鳞状细胞癌患者的癌组织及其正常喉组织进行ALDH1蛋白及mRNA检测,结合临床病理特征进行相关性分析和无病生存期分析。结果 ALDH1蛋白在喉正常组织中低表达,在喉鳞癌组织中不同程度表达,喉癌组织中ALDH1mRNA的表达和蛋白的表达基本一致。ALDH1蛋白的表达与患者年龄、喉癌的部位、浸润范围、临床分期无明显相关性(P0.05);有淋巴结转移患者ALDH1蛋白表达高于淋巴结阴性患者,具有统计学意义(P0.05);5年生存率ALDH1阳性患者明显低于ALDH1阴性患者(P0.05)。结论 ALDH1在喉鳞癌组织中的高表达与淋巴结转移有关,ALDH1阳性表达可作为喉鳞癌患者预后判断的指标。     

SRSF1和Survivin在口腔鳞状细胞癌中的表达及临床意义

目的:研究人丝氨酸/精氨酸富有剪接因子1(SRSF1)和凋亡抑制因子(Survivin)在口腔鳞状细胞癌(OSCC)组织和正常口腔黏膜(NOM)中的表达,探究两因子在OSCC中的相关性及其临床意义。方法:采用免疫组织化学SP法,检测两因子在60例OSCC组织、20例NOM组织中的表达,并结合组织学分级、淋巴结转移及临床分期等相关的信息进行相关性分析。结果:在NOM中SRSF1和Survivin低表达,在OSCC组织中均高表达,比例分别为68.3%和60%。SRSF1和Survivin与淋巴结转移、组织学分级以及临床分期之间存在统计学差异(P0.05);并且在OSCC组织中二者之间表达存在着显著正相关性,(r=0.541,P0.05)。结论:SRSF1和Survivin在OSCC中均高表达,与口腔鳞癌的发生、发展密切相关并具有协同作用。     

ERK_2在食管鳞状细胞癌组织中的表达及临床意义

目的研究ERK2在食管鳞状细胞癌组织中的表达及临床意义。方法应用免疫组化S-P法检测食管正常黏膜、癌旁组织及食管癌组织中ERK2表达状况。结果食管正常黏膜、癌旁组织及食管癌组织中ERK2表达率分别为20.0%(4/20)、45.7%(16/35)及86.2%(81/94),食管癌组织中ERK2表达率明显高于正常黏膜及癌旁组织组(P<0.05)。正常黏膜组和癌旁组织组ERK2表达率无明显差异(P>0.05),食管癌组织中ERK2表达与患者年龄、性别、肿瘤浸润深度、组织分化、淋巴结转移、临床分期及其它临床病理因素无关(P>0.05)。结论ERK2过表达在食管癌发生中起重要作用,单独检测ERK表达可能无助于判断患者的预后。     

影响口腔鳞状细胞癌患者预后的临床病理因素分析

目的：研究影响口腔鳞状细胞癌（Oral squamous cellcar cinoma,OSCC）术后患者预后的临床病理因素。方法：回顾性研究55例手术治疗的原发口腔鳞状细胞癌患者与预后相关的因素：年龄、性别、发病部位、颈部淋巴结转移情况、肿瘤细胞分化程度等。结果：平均发病年龄为57.35±12.02岁,牙龈鳞癌的复发转移率最高（45.5%）,舌部第二（44%）,颊部第三（37.5%）,唇癌预后最好（0.0%）。术前颈部淋巴结转移情况、肿瘤细胞分化程度与预后有关。肿瘤细胞的分化程度与术前淋巴结转移无显著相关性。术前有颈部淋巴结转移合并中低分化与预后差相关。结论：口腔鳞状细胞癌的预后与发病部位无显著相关性。肿瘤中低分化及术前有淋巴结转移者易出现术后复发转移。     

影响口腔鳞状细胞癌患者预后的临床病理因素分析

目的:研究影响口腔鳞状细胞癌(Oral squamous cellcar cinoma,OSCC)术后患者预后的临床病理因素。方法:回顾性研究55例手术治疗的原发口腔鳞状细胞癌患者与预后相关的因素:年龄、性别、发病部位、颈部淋巴结转移情况、肿瘤细胞分化程度等。结果:平均发病年龄为57.35±12.02岁,牙龈鳞癌的复发转移率最高(45.5%),舌部第二(44%),颊部第三(37.5%),唇癌预后最好(0.0%)。术前颈部淋巴结转移情况、肿瘤细胞分化程度与预后有关。肿瘤细胞的分化程度与术前淋巴结转移无显著相关性。术前有颈部淋巴结转移合并中低分化与预后差相关。结论:口腔鳞状细胞癌的预后与发病部位无显著相关性。肿瘤中低分化及术前有淋巴结转移者易出现术后复发转移。     

RHBDF1在ccRCC中的临床意义及其免疫浸润情况

[目的]探讨RNBDH1在肾透明细胞癌(ccRCC)中的临床意义及RHBDF1在ccRCC中免疫浸润的情况.[方法]从TCGA数据库下载ccRCC病人的mRNA表达及相关临床信息.然后提取出ccRCC病人的RHBDF1的单基因矩阵.评估了肿瘤与非肿瘤组织中的RHBDF1的差异表达.Kaplan-Meier生存分析RHB...     

HERG在鳞状细胞癌中的表达

目的:探讨HERG在鳞状细胞癌中的表达水平及其意义,对比其与正常骨与软组织中表达有何差别.方法:鳞状细胞癌患者组织标本来自于我科手术室,经免疫组化染色及PCR方法查看其HERG表达水平.结果:免疫组化染色与PCR结果显示,鳞状细胞癌中HERG的表达呈阳性,主要呈膜表达.结论:HERG在鳞状细胞癌中的表达水平呈阳性,且表达水平较高,它可能与肿瘤的发生发展有关.     

Serial studies of autologous antibody reactivity to squamous cell carcinoma of the head and neck

Summary In previous studies we evaluated the incidence and specificity of autologous antibody reactivity against squamous cell carcinoma of the head and neck (SCCHN). We were able to demonstrate that autologous antibody reactivity is present in native sera but was usually of too low a titer to allow further analysis. Dissociation of immune complexes by acidification and ultrafiltration of serum augmented autologous antibody reactivity in nine out of nine autologous systems tested. Native antibody and antibody derived from immune complexes produced by the host and reactive with autologous tumor cells may be directed against physiologically relevant antigens. Therefore, correlations of antibody titers with clinical course may provide insight into the nature of the host response to cancer. In the present analysis, serological studies of six patients with SCCHN were performed with serum samples obtained over many months. Results of serial serological assays were correlated to tumor progression and clinical course. Fluctuations in autologous antibody reactivity were noted over time. In four cases, rises in autologous antibody titers preceded the clinical diagnosis of recurrence by several months. Drops in autologous antibody reactivity were noted in two cases following surgery or radiation therapy. In two cases of long-term survivors, no correlation between antibody reactivity and clinical course was noted. Specificity analysis of the six autologous systems demonstrated reactivity against autologous and allogeneic SCCHN as well as melanoma cell lines. These sera did not react with glioma, neuroblastoma, renal cell, breast, bladder and colon carcinoma cell lines nor with fetal calf serum, pooled lymphocytes, red blood cells and platelets. Autologous serial serological studies may provide a means by which to evaluate the host/tumor relationship in patients with SCCHN.     

Hypoxia-related LncRNAs signature predicts prognosis and is associated with immune infiltration and progress of head and neck squamous cell carcinoma

BackgroundDisclosing prognostic information is necessary to enable good treatment selection and improve patient outcomes. Previous studies suggest that hypoxia is associated with an adverse prognosis in patients with HNSCC and that long non-coding RNAs (lncRNAs) show functions in hypoxia-associated cancer biology. Nevertheless, the understanding of lncRNAs in hypoxia related HNSCC progression remains confusing.MethodsData were downloaded from TCGA and GEO database. Bioinformatic tools including R packages GEOquery, limma, pheatmap, ggplot2, clusterProfiler, survivalROC and survcomp and LASSO cox analysis were utilized. Si-RNA transfection, CCK8 and real-time quantified PCR were used in functional study.ResultsGEO data (GSE182734) revealed that lncRNA regulation may be important in hypoxia related response of HNSCC cell lines. Further analysis in TCGA data identified 314 HRLs via coexpression analysis between differentially expressed lncRNAs and hypoxia-related mRNAs. 23 HRLs were selected to build the prognosis predicting model using lasso Cox regression analyses. Our model showed excellent performance in predicting survival outcomes among patients with HNSCC in both the training and validation sets. We also found that the risk scores were related to tumor stage and to tumor immune infiltration. Moreover, LINC01116 were selected as a functional study target. The knockdown of LINC01116 significantly inhibited the proliferation of HNSCC cells and effected the hypoxia induced immune and the NF-κB/AKT signaling.ConclusionsData analysis of large cohorts and functional experimental validation in our study suggest that hypoxia related lncRNAs play an important role in the progression of HNSCC, and its expression model can be used for prognostic prediction.     

Change of telomerase activity in peripheral blood of patients with head and neck squamous cell carcinoma pre and post curative treatment

BackgroundThere is no clinically applicable tumor marker for head and neck cancers. Telomerase is detected in approximately 90% of all malignant tumors, it may predict poor or favorable outcomes, thus being both a highly attractive biomarker and a target for the development of molecular-based cancer diagnostics, prognostics, and therapeuticsAimPrimary aim was to detect a change of telomerase activity before and after curative treatment.Materials and MethodsPatients with biopsy proven head and neck squamous cell carcinoma, stage I-IVB treated with a curative intent, performance status 0–2 and malignancy at one primary site were included in the study. Telomerase levels were tested in tissue biopsy. Plasma telomerase levels were tested at baseline, 5 days and at 3 months after treatment using ELISA.ResultsRaised plasma telomerase activity was seen in all the patients with cancer at baseline. The mean plasma telomerase level at baseline was 861.4522 ng/ml, at 5 days after completion of curative treatment was 928.92 ng/ml and at 3 months of follow up was 898.87 ng/ml. The mean tissue biopsy telomerase level was 19768.53 ng/mg. There was a significant increase in baseline telomerase levels in cancer patients compared to normals (volunteers) (t = −3.52, p = 0.001).There was a significant increase in plasma levels of telomerase at 3 months compared to baseline values (z = −1.98, p = 0.04). The increase in telomerase level did not correlate with the response of the treatment.ConclusionIn patients with head and neck squamous cell carcinomas treated with a curative intent, the change in levels of telomerase correlates neither with the disease status nor with prognostic factors.     

DNA methylation biomarkers for head and neck squamous cell carcinoma

DNA methylation plays an important role in the etiology and pathogenesis of head and neck squamous cell carcinoma (HNSCC). The current study aimed to identify aberrantly methylated-differentially expressed genes (DEGs) by a comprehensive bioinformatics analysis. In addition, we screened for DEGs affected by DNA methylation modification and further investigated their prognostic values for HNSCC. We included microarray data of DNA methylation (GSE25093 and GSE33202) and gene expression (GSE23036 and GSE58911) from Gene Expression Omnibus. Aberrantly methylated-DEGs were analyzed with R software. The Cancer Genome Atlas (TCGA) RNA sequencing and DNA methylation (Illumina HumanMethylation450) databases were utilized for validation. In total, 27 aberrantly methylated genes accompanied by altered expression were identified. After confirmation by The Cancer Genome Atlas (TCGA) database, 2 hypermethylated-low-expression genes (FAM135B and ZNF610) and 2 hypomethylated-high-expression genes (HOXA9 and DCC) were identified. A receiver operating characteristic (ROC) curve confirmed the diagnostic value of these four methylated genes for HNSCC. Multivariate Cox proportional hazards analysis showed that FAM135B methylation was a favorable independent prognostic biomarker for overall survival of HNSCC patients.     

Immunotherapy for head and neck cancer

Head and neck cancer represents a challenging disease. Despite recent treatment advances, which have improved functional outcomes, the long-term survival of head and neck cancer patients has remained unchanged for the past 25 years. One of the goals of adjuvant cancer therapy is to eradicate local regional microscopic and micrometastatic disease with minimal toxicity to surrounding normal cells. In this respect, antigen-specific immunotherapy is an attractive therapeutic approach. With the advances in molecular genetics and fundamental immunology, antigen-specific immunotherapy is being actively explored using DNA, bacterial vector, viral vector, peptide, protein, dendritic cell, and tumor-cell based vaccines. Early phase clinical trials have demonstrated the safety and feasibility of these novel therapies and the emphasis is now shifting towards the development of strategies, which can increase the potency of these vaccines. As the field of immunotherapy matures and as our understanding of the complex interaction between tumor and host develops, we get closer to realizing the potential of immunotherapy as an adjunctive method to control head and neck cancer and improve long-term survival in this patient population.     

Aldehyde dehydrogenase 1 is a putative marker for cancer stem cells in head and neck squamous cancer

Aldehyde dehydrogenase 1 (ALDH1) has been considered to be a marker for cancer stem cells. However, the role of ALDH1 in head and neck squamous cell carcinoma (HNSCC) has yet to be determined. In this study, we isolated ALDH1-positive cells from HNSCC patients and showed that these HNSCC-ALDH1⁺ cells displayed radioresistance and represented a reservoir for generating tumors. Based on microarray findings, the results of Western blotting and immunofluorescent assays further confirmed that ALDH1⁺-lineage cells showed evidence of having epithelial-mesenchymal transition (EMT) shifting and endogenously co-expressed Snail. Furthermore, the knockdown of Snail expression significantly decreased the expression of ALDH1, inhibited cancer stem-like properties, and blocked the tumorigenic abilities of CD44⁺CD24⁻ALDH1⁺ cells. Finally, in a xenotransplanted tumorigenicity study, we confirmed that the treatment effect of chemoradiotherapy for ALDH1⁺ could be improved by Snail siRNA. In summary, it is likely that ALDH1 is a specific marker for the cancer stem-like cells of HNSCC.     

Targeting the immune system: novel therapeutic approaches in squamous cell carcinoma of the head and neck

Despite advances in surgery, radiotherapy, and chemotherapy, the overall survival rates for patients with squamous cell carcinoma of the head and neck (SCCHN) have not changed over the last decades. Clearly, novel therapeutic strategies are needed for this cancer, which is highly immunosuppressive. Therefore, biologic therapies able to induce and/or up-regulate antitumor immune responses could represent a complementary approach to conventional treatments. Because patients with SCCHN are frequently immunocompromised due to the elimination or dysfunction of critical effector cells of the immune system, it might be necessary to restore these immune functions to allow for the generation of more effective antitumor host responses. Simultaneously, to prevent tumor escape, it might be necessary to alter attributes of the malignant cells. The present review summarizes recent advances in the field of immunotherapy of SCCHN, including techniques of nonspecific immune stimulation, the use of monoclonal antibodies, advances in adoptive immunotherapy and genetic engineering, as well as anticancer vaccines. These biologic therapies, alone or in combination with conventional treatment, are likely to develop into useful future treatment options for patients with SCCHN.     

Identification of potential core genes and pathways predicting pathogenesis in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is the most common subtype of head and neck cancer; however, its pathogenesis and potential therapeutic targets remain largely unknown. In the present study, we analyzed three gene expression profiles and screened differentially expressed genes (DEGs) between HNSCC and normal tissues. The DEGs were subjected to gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG), protein–protein interaction (PPI), and survival analyses, while the connectivity map (CMap) database was used to predict candidate small molecules that may reverse the biological state of HNSCC. Finally, we measured the expression of the most relevant core gene in vitro and examined the effect of the top predicted potential drug against the proliferation of HNSCC cell lines. Among the 208 DEGs and ten hub genes identified, CDK1 and CDC45 were associated with unfavorable HNSCC prognosis, and three potential small molecule drugs for treating HNSCC were identified. Increased CDK1 expression was confirmed in HNSCC cells, and menadione, the top predicted potential drug, exerted significant inhibitory effects against HNSCC cell proliferation and markedly reversed CDK1 expression. Together, the findings of the present study suggest that the ten hub genes and pathways identified may be closely related to HNSCC pathogenesis. In particular, CDK1 and CDC45 overexpression could be reliable biomarkers for predicting unfavorable prognosis in patients with HNSCC, while the new candidate small molecules identified by CMap analysis provide new avenues for the development of potential drugs to treat HNSCC.