EXPRESSION OF ANNEXIN Ⅰ IN TUMORIGENESIS OF ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Objective: To detect the expression of annexin I in esophageal squamous cell carcinoma and precursor lesions, and evaluate its effect on the tumorigenesis. Methods: The immunohistochemistry S-P method was used to determine the expression of annexin I in 135 cases of esophageal squamous cell carcinoma, in which precursor lesions were found in some cases, and in the corresponding normal controls. Results: Of 135 cases, 35 (25.9%) were strongly positive, 60 (44.4%) were weakly positive and 40 (29.6%) negative, while in the corresponding normal controls, 129 (95.6%) were strongly positive, 6 (6.4%) weakly positive. The expression of annexin I was decreased in esophageal squamous cell carcinoma (P<0.0001), and the degree and rate of the decrease did not show correlation with age, gender, differentiation, and lymph node metastasis (P<0.05). The expression of annexin I was also decreased in the lesions of dysplasia and carcinomain situ, with 2 (4.3%) strongly positive, 17 (37.0%) weakly positive and 27(58.7%) negative (P<0.0001). Conclusion: Annexin I may be useful in early detection of esophageal squamous cell carcinoma and in evaluation of predisposition for the risk of cancerization of precursor lesions. Foundation item: This work was supported by the National Natural Science Foundation of China (No.30271460). Biography: LU Ning (1955-), associate professor, Cancer Institute (Hospital), Peking Union Medical College, Chinese Academy of Medical Sciences, majors in pathology of cancer. E-mail: ninglv@hotmail.com     

食管鳞状细胞癌淋巴结转移与血清蛋白指纹图谱的相关性研究

目的 分析食管鳞状细胞癌(ESCC)患者血清蛋白表达谱的改变;比较有无淋巴结转移(LM)的患者血清蛋白指纹图谱,筛选与LM相关的蛋白峰.方法 术前收集64例ESCC患者和60名性别、年龄相匹配的健康成年人的血清.采用弱阳离子交换型(WCX-2)蛋白芯片为检查介质,经SELDI-TOF-MS测定蛋白指纹图谱.行有癌和无癌的对照研究;ESCC患者组内分别按性别、年龄、肿瘤位置、肿瘤大小、浸润程度和有无LM分别进行对照,得到蛋白指纹图谱并用Biomarker Wizard软件分析比较.结果 在质量/电荷(m/z)0～50000范围内,ESCC与健康成年人血清检测出120个蛋白峰,其中31个蛋白峰差异有统计学意义(P<0.05);不同浸润程度分组对比,T1与T3、T4比较有1个m/z是4174的差异蛋白峰(P<0.05);有无LM组间,3个蛋白峰差异有统计学意义(P<0.05),m/z分别为3970、4174、和4277.其中m/z为4174的蛋白峰是浸润组和LM组所共有的;年龄、性别、肿瘤位置、肿瘤大小分组未发现差异蛋白峰.结论 ESCC患者组和健康成年人组比较,血清蛋白有显著差异;ESCC浸润程度的不同和有无LM血清蛋白指纹存在一定差异,但远较ESCC与健康成年人之间差异小;浸润程度严重和LM在血清蛋白指纹中存在着一定的共性.     

微小 RNA 与食管鳞状细胞癌

微小 RNA（miRNA）可通过细胞信号转导、上皮间质转化、血管生成等调控机制影响食管鳞状细胞癌细胞的增殖、凋亡、侵袭和转移。特定的血清 miRNA 可作为食管鳞状细胞癌诊断、预后的新型肿瘤标志物。近来研究表明 miRNA 可提高食管鳞状细胞癌放疗敏感性甚至逆转多药耐药,具有极大的临床价值。     

A case of esophageal squamous cell carcinoma metastatic to the breast

Metastasis to the breast from extramammary malignancies is rare. There are especially few reports of metastasis from esophageal cancer. We report the pathological and autopsy findings of a 44-year-old man with advanced esophageal cancer and a left breast tumor. Squamous cell carcinoma invading the mammary glands was demonstrated histologically. Immunostains for ER, PgR, and ErbB-2 were negative. At autopsy, metastatic lesions were found in lung, liver, diaphragm, peritoneum, spine, and mediastinal lymph nodes, with no evidence of metastasis to the skin. While metastatic breast tumors are rarely the initial sign of malignancy, it is important to distinguish a metastasis from primary breast cancer to avoid unnecessary conflicting treatments.     

Latexin在食管鳞癌组织中的表达及其临床价值

目的 探讨Latexin（LXN）在食管鳞癌组织中的表达情况及临床价值。方法 采用组织芯片和免疫组织化学技术检测183例食管鳞癌组织中的LXN蛋白表达,并分析其表达情况与临床病理参数（肿瘤大小、T分期、N分期、分化程度和TNM分期）及预后间的关系。结果LXN在癌旁食管鳞状上皮中呈微弱表达,阳性表达率为100.0%,而在食管鳞癌组织中呈淡黄色或不表达,其阳性表达率为48.6%（89/183）,低于癌旁组织（P＜0.05）;LXN阳性表达与肿瘤大小、T分期、N分期、组织分化及TNM分期有关。单因素生存分析表明LXN阳性表达者的中位总生存期长于LXN阴性表达者（P=0.001）。结论LXN在食管鳞癌中表达下调,且与临床病理参数有关,在一定程度上反映了食管癌的不良预后。     

Livin和caspase-3在食管鳞癌组织中的表达及相关性分析

目的 探讨食管鳞癌组织中Livin与caspase-3的表达情况,以及两者与临床病理特征的关系。方法 采用免疫组织化学SP法检测36例食管鳞癌组织及20例癌旁正常食管组织中Livin和caspase-3蛋白的表达,分析其与食管鳞癌临床病理特征的关系。结果 食管鳞癌组织中Livin 的阳性表达率为69.4％,高于癌旁正常组织中的10.0％（P=0.000）;caspase 3在食管鳞癌组织中的阳性表达率为38.9％,低于癌旁正常组织中的80.0（P=0.003）。两者表达与组织分化程度、浆膜浸润和淋巴结转移有关,与性别、年龄无关。Livin与caspase-3的表达在食管鳞癌组织中呈负相关（r=-0.337,P=0.045）。结论Livin和caspase-3在食管鳞癌的发生、发展过程中起重要作用。     

应用cDNA芯片分析与食管鳞癌相关的基因表达

目的：应用cDNA芯片技术研究食管鳞癌的异常基因表达,并对这些基因的功能进行初步分析。方法：选择382个肿瘤相关基因克隆,制备成cDNA芯片,提取食管鳞癌组织以及相应正常食管组织RNA,反转录后标记为cDNA探针,与自行制备的cDNA芯片杂交,经扫描及分析后筛选出两种组织中差异表达基因。结果：发现差异表达基因75个,表达上调基因44个,下调基因31个,包括癌基因、抑癌基因、细胞周期相关蛋白、粘附因子、基质金属蛋白酶、信号传导因子、生长因子及其受体、与细胞代谢相关的酶等。结论：食管鳞癌的发生发展涉及多基因改变,cDNA芯片技术是疾病基因筛选的有效方法。     

A comparative analysis of clinicopathological factors and survival between esophageal basaloid squamous cell carcinoma and conventional esophageal squamous cell carcinoma

IntroductionRecently, the number of diagnosed esophageal basaloid squamous cell carcinoma (EBSCC) has gradually increased. However, available data on EBSCC are limited to date.MethodsA total of 165 EBSCC (Cohort 1) and 515 conventional esophageal squamous cell carcinoma (ESCC) (Cohort 2) were retrospectively analyzed.ResultsIn Cohort 1, 70 cases only had invasive EBSCC component (42.4%, defined as Group 1), 73 cases had concomitant invasive ESCC component (44.2%, Group 2), and 22 had concomitant invasive poor-differentiated component (13.3%, Group 3). Lymph node metastasis rates of Group 3, Group 2 and Group 1 were ranked from high to low (P = 0.044). There were higher patient age (P = 0.047), smaller tumor size (P = 0.009), more nerve invasion (P < 0.001), and lower pTNM stage (P < 0.001) in EBSCC (Cohort 1), compared with ESCC (Cohort 2). In Cohort 1 and Cohort 2, pTNM stage was an independent prognostic factor for both DFS and OS. No significant survival difference was found between EBSCC (Cohort 1) and ESCC (Cohort 2) in pIA-B stage, pIIA-B stage, pIIIA-B stage and pIVA-B stage (P > 0.05).ConclusionOur analysis of the largest EBSCC series from a single institution to date with conventional ESCC demonstrated that EBSCC carried a similar prognosis with ESCC in pIA-B stage, pIIA-B stage, pIIIA-B stage and pIVA-B stage. And pure EBSCC, didn't have poorer survival than mixed EBSCC with concomitant ESCC or other components. Our findings may be valuable in the better understanding of EBSCC's biological behaviors, and the related molecular mechanism is needed to be explored in the future.     

miR-132-3p promotes heat stimulation-induced esophageal squamous cell carcinoma tumorigenesis by targeting KCNK2

Epidemiological evidence supports that consumption of high-temperature food and beverages is an important risk factor for esophageal squamous cell carcinoma (ESCC); however, the underlying mechanism still remains unclear. Here, we established a series of animal models and found that drinking 65°C water can promote esophageal tumor progression from preneoplastic lesions to ESCC. RNA sequencing data showed that miR-132-3p was highly expressed in the heat stimulation group compared with controls. Further study verified that miR-132-3p were upregulated in human premalignant lesion tissues of the esophagus, ESCC tissues, and cells. Overexpression of miR-132-3p could promote ESCC cell proliferation and colony formation, whereas knockdown of miR-132-3p could inhibit ESCC progression in vitro and in vivo. Importantly, dual-luciferase reporter assays showed that miR-132-3p could bind with the 3′-untranslated region of KCNK2 and inhibit KCNK2 gene expression. Knockdown or overexpression of KCNK2 could promote or suppress ESCC progression in vitro. These data suggest that heat stimulation can promote ESCC progression and miR-132-3p mediated this process by directly targeting KCNK2.     

Proteoglycans and their functions in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is a highly malignant disease that has a poor prognosis. Its high lethality is mainly due to the lack of symptoms at early stages, which culminates in diagnosis at a late stage when the tumor has already metastasized. Unfortunately, the common cancer biomarkers have low sensitivity and specificity in esophageal cancer. Therefore, a better understanding of the molecular mechanisms underlying ESCC progression is needed to identify novel diagnostic markers and therapeutic targets for intervention. The invasion of cancer cells into the surrounding tissue is a crucial step for metastasis. During metastasis, tumor cells can interact with extracellular components and secrete proteolytic enzymes to remodel the surrounding tumor microenvironment. Proteoglycans are one of the major components of extracellular matrix. They are involved in multiple processes of cancer cell invasion and metastasis by interacting with soluble bioactive molecules, surrounding matrix, cell surface receptors, and enzymes. Apart from having diverse functions in tumor cells and their surrounding microenvironment, proteoglycans also have diagnostic and prognostic significance in cancer patients. However, the functional significance and underlying mechanisms of proteoglycans in ESCC are not well understood. This review summarizes the proteoglycans that have been studied in ESCC in order to provide a comprehensive view of the role of proteoglycans in the progression of this cancer type. A long term goal would be to exploit these molecules to provide new strategies for therapeutic intervention.     

食管鳞状细胞癌的肿瘤血管生成机制

血管内皮生长因子、缺氧诱导因子、白细胞介素、血管生成素样蛋白、整合素和上皮间质转化在食管鳞状细胞癌血管生成中为癌细胞的生长、侵袭和转移提供了营养支持和有利环境.对食管鳞状细胞癌血管生成机制的研究将为其抗血管靶向治疗提供更多思路和潜在靶点.     

食管鳞癌中斯钙素-1的表达及其临床意义

目的 探讨斯钙素-1（STC-1）在食管鳞癌（ESCC）中的表达及其临床意义。方法 收集85 例ESCC患者的手术标本,免疫组化法检测癌组织及其癌旁组织中STC-1 蛋白的表达水平,并分析其与患者的临床病理特征及无进展生存期（PFS）的关系。结果 83.5％（71／85）的癌组织中STC-1蛋白表达评分高于对应的癌旁组织;癌组织中STC-1蛋白的高、中表达率为65.9%（56/85）,而癌旁组织中仅为7.1％（6／85）,差异有统计学意义（P＜0.001）。STC-1 蛋白表达与临床分期（P=0.015） 及淋巴结转移（P=0.022） 相关。STC-1蛋白高、中表达组平均PFS为17.5个月（95％CI： 15.669～19.259个月）,低于STC-1 蛋白低、未表达组的21.1个月（95％CI： 19.128～23.079个月）,差异具有统计学意义（P=0.006）。Cox 风险比例模型显示,STC-1蛋白表达是影响PFS 的独立预后因素。结论 STC-1 蛋白表达在ESCC发生发展中起重要作用,有可能成为ESCC 预后的分子标记物。     

Resveratrol-induced apoptosis is enhanced by inhibition of autophagy in esophageal squamous cell carcinoma

The anti-cancer activity of resveratrol in human esophageal squamous cell carcinoma (ESCC) was investigated focusing on the role of autophagy and its effects on apoptotic cell death. We demonstrated that resveratrol inhibits ESCC cell growth in a dose-dependent manner by inducing cell cycle arrest at the sub-G1 phase and resulting in subsequent apoptosis. Mechanistically, resveratrol-induced autophagy in the ESCC cells is AMPK/mTOR pathway independent. Since both pharmacological and genetic inhibition of autophagy enhanced the resveratrol-induced cytotoxicity to the ESCC cells, this provided a novel strategy in potentiating the anti-cancer effects of resveratrol and other chemotherapeutic reagents in ESCC cancer treatment.     

lncRNA在食管鳞癌转移中的作用及机制

食管鳞状细胞癌(ESCC)具有高度侵袭性和转移性,早期易发生转移,预后差,是世界范围内常见的癌症之一。长链非编码RNA(long non-coding RNA,lncRNA)作为转录调控因子,可以调控多种基因组过程和细胞过程,如细胞增殖、迁移和侵袭等。lncRNA也被证明参与调节与肿瘤转移相关的信号通路。已有大量研究试图揭示lncRNA在食管癌发生和转移中的重要作用。本文着重强调lncRNA在表观遗传学、基因表达水平以及作为竞争性内源性RNA途径的作用,综述lncRNA在ESCC转移中的研究进展,对于ESCC患者的预后监测和靶向治疗具有重要意义。     

食管鳞癌肿瘤微环境相关研究进展

食管鳞癌是我国食管癌的主要类型，危害严重。近年来，许多研究发现，其发生、发展与所在的肿瘤微环境密切相关。食管鳞癌细胞所在的肿瘤微环境可通过调控免疫微环境、释放细胞因子、改变血管生成等多种途径促进食管鳞癌细胞生长、侵袭和转移，并造成免疫逃逸。本综述从白介素-6（interleukin-6，IL-6）、程序性死亡［蛋白］-1（programmed death-1，PD-1）/程序性死亡［蛋白］配体-1（programmed death ligand-1，PD-L1）、转化生长因子-β（transforming growth factor-β，TGF-β）、乏氧诱导因子-1（hypoxia inducible factor-1，HIF-1）及血管内皮细胞生长因子（vascular endothelial growth factor，VEGF）等影响食管鳞癌肿瘤微环境的重要通路方面，阐述肿瘤微环境与食管鳞癌预后的关系及相关机制，并介绍相关靶向治疗的研究进展，旨在为食管鳞癌的防治研究提供参考。     

Signatures within esophageal microbiota with progression of esophageal squamous cell carcinoma

ObjectiveEsophageal squamous cell carcinoma (ESCC) is one of the dominant malignances worldwide, but currently there is less focus on the microbiota with ESCC and its precancerous lesions.MethodsPaired esophageal biopsy and swab specimens were obtained from 236 participants in Linzhou, China. Data from 16S ribosomal RNA gene sequencing were processed using quantitative insights into microbial ecology (QIIME2) and R Studio to evaluate differences. The Wilcoxon rank sum test and Kruskal-Wallis rank sum test were used to compare diversity and characteristic genera by specimens and participant groups. Ordinal logistic regression model was used to build microbiol prediction model.ResultsMicrobial diversity was similar between biopsy and swab specimens, including operational taxonomic unit (OTU) numbers and Shannon index. There were variations and similarities of esophageal microbiota among different pathological characteristics of ESCC. Top 10 relative abundance genera in all groups include Streptococcus, Prevotella, Veillonella, Actinobacillus, Haemophilus, Neisseria, Alloprevotella, Rothia, Gemella and Porphyromonas. Genus Streptococcus, Haemophilus, Neisseria and Porphyromonas showed significantly difference in disease groups when compared to normal control, whereas Streptococcus showed an increasing tendency with the progression of ESCC and others showed a decreasing tendency. About models based on all combinations of characteristic genera, only taken Streptococcus and Neisseria into model, the prediction performance was the ideal one, of which the area under the curve (AUC) was 0.738. ConclusionsEsophageal biopsy and swab specimens could yield similar microbial characterization. The combination of Streptococcus and Neisseria has the potential to predict the progression of ESCC, which is needed to confirm by large-scale, prospective cohort studies.     

上调HuR基因对食管鳞癌细胞Kyse450放射敏感性的影响

目的 研究HuR基因上调对于食管鳞癌细胞Kyse450放射敏感性的影响。方法 慢病毒上调Kyse450细胞HuR基因,同时选取X射线6Gy照射剂量作为干预条件。采用Western blot和qPCR技术分别检测Kyse450转染后的蛋白和RNA表达情况;CCK8试剂盒检测细胞的增殖速率;克隆形成试验检测细胞克隆形成能力;伤口愈合试验和Transwell试验检测细胞迁移能力的改变。结果 CCK8试验显示HuR基因上调后细胞的增殖能力增强,放射后这种增强趋势更加明显;平板克隆试验显示随着放射剂量的增加,两组细胞的克隆形成率都随之降低,但是过表达组的克隆形成数多于对照组;伤口愈合试验以及Transwell试验表明过表达组的伤口愈合速率和迁移能力高于对照组,放射治疗后这种差异更显著;Western blot显示放射治疗后24h过表达组细胞内MMP9、MMP2水平高于对照组。结论 HuR上调会增强食管鳞癌细胞增殖、克隆、迁移能力,降低其放射敏感性。     

食管鳞癌中CAV-1基因的表达及甲基化状态

背景与目的：作为重要的表观遗传学现象之一,DNA甲基化对基因表达发挥着重要的调控功能。研究表明肿瘤细胞基因组正常DNA甲基化模式异常改变所导致的肿瘤相关基因功能异常可能参与肿瘤发生与发展。本研究通过检测食管鳞状细胞癌(esophageal squamous cell carcinomas,ESCC)组织中质膜微囊蛋白-1(caveolin-1,CAV-1)基因的表达及甲基化状态,探讨CAV-1基因在食管鳞癌发生及发展中的作用。方法：分别应用甲基化特异性PCR(MSP)、RT-PCR法、免疫组织化学SP法检测食管癌及相应癌旁正常黏膜组织标本中CAV-1基因甲基化状态、mRNA及蛋白表达情况。结果：CAV-1 mRNA在食管癌和癌旁正常组织中的表达量分别为0.86±0.56和0.40±0.36,食管癌组织中CAV-1 mRNA表达量明显高于癌旁正常组织,2者差异有统计学意义(P<0.05)。CAV-1 mRNA表达与患者的淋巴结转移及肿瘤组织学分级有关(P<0.05);食管鳞癌组织中,CAV-1蛋白表达阳性率为66.7%(34/51);显著高于正常食管黏膜组织(15.7%,8/51)(P<0.01)。CAV-1蛋白表达与患者的淋巴结转移有关(P<0.05),而与肿瘤的临床分期和分化程度无关(P>0.05)。51例食管癌组织中1例发生了基因启动子区甲基化,甲基化率为2.0%(1/51);而相应癌旁正常黏膜组织中未发现有该基因的甲基化现象。食管癌组织中该基因的甲基化率与相应癌旁正常组织相比,差异无统计学意义(P>0.05)。结论：CAV-1基因在食管鳞癌组织中mRNA及蛋白表达均明显高于癌旁正常黏膜组织,该基因的高表达对于肿瘤的发生及淋巴结的转移起到了一定的促进作用;癌及癌旁组织中该基因的表达异常均与该基因的甲基化状态无关。     

食管鳞癌新辅助放化疗后复发风险分层分析

目的 探讨胸段食管鳞癌新辅助放化疗联合手术治疗后的复发风险模式,并分析术后病理分期与复发风险之间的关系。方法 回顾分析2002-2015年郑州大学附属肿瘤医院及中山大学肿瘤防治中心收治的174例局部晚期胸段食管鳞癌患者的病历资料。全组患者均采用术前同期放化疗联合手术治疗,化疗采用以铂类为基础的化疗方案,放疗剂量为40.0~50.4 Gy,常规分割。采用Kaplan-Meier法计算生存率,Logrank检验差异,Cox模型多因素分析。结果 中位随访时间为53.9个月,新辅助放化疗后病理完全缓解率为44.8%,其中59例(33.9%)患者复发。术后病理分期为0/Ⅰ、Ⅱ、Ⅲ期患者复发率分别为22.2%、38.7%、68.2%(P=0.000),疗后5年无复发生存率分别为74.7%、61.4%、20.9%(P=0.000)。20.5%的0/Ⅰ期或Ⅱ期患者的复发时间在术后3年以上,而Ⅲ期患者的复发时间均在2年以内。多因素分析结果显示年龄、临床分期、化疗方案、放化疗相关病理反应是影响无复发生存的因素(P=0.027、0.047、0.010、0.005)。结论 胸段食管鳞癌新辅助放化疗后的病理分期与复发风险密切相关,临床医生可根据不同的病理分期制定个体化的随访监测策略。