Mucin Phenotypic Expression in Early Signet Ring Cell Carcinoma of the Stomach: Its Relationship with the Clinicopathologic Factors

Gastric early-stage signet ring cell carcinoma (SIG) has been reported to have a lower rate of lymph node metastasis and a higher rate of favorable prognosis than other histological types. However, the development and progression mechanisms of early-stage SIG (early SIG) are controversial. This study examined the correlation between the mucin phenotype of early SIG and its clinicopathologic factors, particularly for the sake of less invasive surgery. Sixty-nine early SIGs were studied immunohistochemically with gastric mucin (M1 and MUC6) and intestinal mucin (MUC2). SIGs were classified into gastric (G), intestinal (I), gastrointestinal (GI), or unclassified (U) type. The intramucosal spreading patterns of SIG were investigated and then classified as either expansive or infiltrative. SIGs were classified into G-type (59.4%) and GI-type (40.6%). Neither the I- nor the U-type was observed. The GI-type expression correlated with the depth of tumor invasion in SIGs (P < 0.05). In contrast, there was no increase in GI-type expression in relation to tumor size. Intramucosal infiltrative growth correlated with intestinal metaplasia (IM) of background mucosa of SIGs (P < 0.01). There was no significant correlation between phenotypes and intramucosal spreading pattern. In conclusion, the GI-type expression of SIG is a clinically useful factor for predicting submucosal invasion. The findings of SIG surrounded with IM revealed the need to exercise great care in determining the surgical margin.     

Mucin core protein expression by colorectal mucinous carcinomas with or without mucus hyperplasia

Background In the categorization of colorectal mucinous carcinomas, much attention has been paid to the amount of extracellular mucin, but little to that of intracellular mucin. Perhaps this factor would be useful in further categorization.Methods We estimated the amount of intracellular mucin morphologically, and classified colorectal tumors (tubular adenomas, mucinous carcinomas, and nonmucinous carcinomas) into two categories each, those with and without intracellular mucus hyperplasia. From preliminary results, we chose a range of 50% or more for the ratio of intracellular mucus to the total area of tumor cells for our definition of such hyperplasia. Then, mucin expression in the different categories was examined immunochemically with antibodies to the mucin core proteins MUC1, MUC2, MUC5AC, and MUC6.Results MUC1 expression was found in none of the 40 adenomas, 8 (17%) of the 48 mucinous carcinomas (with little difference in those with and without mucus hyperplasia), and 4 (16%) of the 25 nonmucinous carcinomas. MUC2 was found in all mucinous carcinomas. MUC5AC was found in 18 (86%) of the 21 mucinous carcinomas with mucus hyperplasia and 18 (90%) of the 20 adenomas with mucus hyperplasia, but in only 9 (33%) of the 27 mucinous carcinomas without mucus hyperplasia, 5 (20%) of the 25 nonmucinous carcinomas, and 2 (10%) of the 20 adenomas without mucus hyperplasia.Conclusions Mucinous carcinomas with and without mucus hyperplasia may arise from adenomas with and without mucus hyperplasia, respectively. The amount of intracellular mucin may be a morphologic reflection of the origin of colorectal mucinous carcinomas.     

粘蛋白MUC1、MUC2、MUC4和MUC5AC在胰腺导管腺癌中的表达及意义

目的 研究胰腺导管腺癌(pancreatic ductal adenocarcinoma,PDA)组织中粘蛋白MUC1、MUC2、MUC4和MUC5AC的表达及其与临床病理参数间的关系.方法 应用SP免疫组织化学方法检测26例PDA、4例CP、16例正常胰腺组织、2例导管内乳头状黏液性肿瘤(IPMN)、4例实性假乳头状瘤(SPT)和1例浆液性囊性肿瘤(SCN)组织中MUC1、MUC2、MUC4、MUCSAC的表达.结果 正常胰腺和CP组织仅有MUC1表达,表达率均为100%;PDA中MUC1、MUC4和MUC5AC表达率分别为100%、88.5%(23/26)和76.9%(20/26);2例IPMN均见MUC2和MUC5AC表达;SPT和SCN中4种粘蛋白均无表达.MUC4和MUC5AC表达同PDA的临床病理参数之间无相关性(P＞0.05).结论 PDA时存在多种粘蛋白的表达,联合检测MUC1、MUC2、MUC4和MUC5AC的表达可能有助于对PDA的诊断和鉴别诊断.     

Survivin、COX-2和VEGF在胃癌中的表达及其与预后的意义

目的研究生存素(Survivin)、环氧合酶-2(COX-2)和血管内皮生长因子(VEGF)在胃癌组织中的表达,探讨它们表达的关系及其与胃癌预后的关系。方法选取淮南东方医院集团总医院1992~2002年10年间行根治性手术治疗,临床、病理和随访资料齐全的胃癌患者65例,应用免疫组化S-P技术,检测Survivin、COX-2和VEGF在胃癌组织中表达。结果早期胃癌的5年生存率为95.2%(20/21),中期胃癌的5年生存率为63.6%(7/11)。中期胃癌组Survivin阳性表达高于早期胃癌组(73.6%vs 66.7%,P<0.05),其VEGF阳性表达和微血管密度(MVD)平均值高于早期胃癌组(P<0.05)。Survivin和COX-2在慢性萎缩性胃炎中的表达明显低于不典型增生者(P<0.05),在癌组织中的表达明显高于非癌组织(P<0.05)。胃癌组中的VEGF阳性表达率和MVD平均值均明显高于非癌组,且与胃癌浸润深度有关(P<0.05)。胃癌中Survivin、VEGF阳性表达的MVD值显著高于Survivin、VEGF阴性表达者(P<0.05);Survivin、COX-2、VEGF及MVD值与胃癌淋巴结转移、血管浸润均密切相关(P<0.05);Survivin、COX-2阳性表达及VEGF阳性表达者5年生存率明显低于阴性或低表达者(P<0.05)。多因素分析显示,淋巴结转移、浸润深度、Survivin表达、VEGF表达均为胃癌独立的预后因素。结论Survivin、COX-2、VEGF与胃癌的生长和浸润转移关系密切,可以作为反映胃癌生物学行为和判断预后的有效指标。     

胃癌组织中COX-2、MMP-9的表达及临床意义

目的探讨COX-2和MMP-9在人胃癌组织中的表达及临床意义。方法应用免疫组化SABC法检测45例人胃癌组织中COX-2、MMP-9的表达,并以30例正常胃黏膜组织作为对照。对COX-2、MMP-9的表达采用平均光密度测定,并对临床相关资料进行统计学分析。结果胃癌组织中COX-2、MMP-9的平均光密度值(OD)为19.85±7.34,18.81±7.56,显著高于正常胃黏膜组织的表达(12.49±4.87,11.46±4.82,P<0.01)。癌组织中COX-2、MMP-9的表达与患者性别、年龄及肿瘤的部位、组织类型、分化程度无相关性,而与肿瘤直径、TNM分期、淋巴转移、远处转移相关(P<0.05);同时经相关分析发现,在胃癌组织中,COX-2与MMP-9表达有显著相关性(r=0.437,P=0.001)。结论COX-2可能诱导MMP-9的表达而促进肿瘤的侵袭转移。     

抑癌基因P15在胃癌中的表达及其临床意义

采用ＳＰ免疫组化法测定了８０例胃癌及２６例胃良性病变患者胃组织石蜡标本的Ｐ＾１５基因蛋白表达情况,结合临床病理指标（肿瘤大小、生长方式、组织分化、浸润深度、转移及ＰＴＮＭ分期）进行分析。结果在胃癌组织中Ｐ＾１５阳性表达率为４３．８％,胃良性病变为６９．２％;Ｐ＾１５表达与肿瘤大小、生长方式、组织分化、浸润深度,转移及ＰＴＮＭ分期无关。认为Ｐ＾１５在胃癌发生中起重要调控作用,与临床病理因素无关。     

Enhanced Cell Surface Expression of Matrix Metalloproteinases and Their Inhibitors, and Tumor-Induced Host Response in Progression of Human Gastric Carcinoma

The cell surface and/or intracellular expression of the matrix metalloproteinases (MMP -2, 7, and -9 and MT1-MMP) and their inhibitors (TIMP-2 and -4) were investigated in tumor and tumor-infiltrating lymphocytes (TIL) in gastric carcinoma (n = 15) from the primary locus, metastatic gastric carcinoma (n = 20) from malignant ascites, and benign gastric mucosa (n = 20) for the control. The quantitative analysis was based on the percentage of positive cells by flow cytometry. The results clearly showed increased cell surface expression of MMP-2, -7, and -9, MT1-MMP, and TIMP-2 and -4 in both tumor cells and TIL during the development of invasion and/or metastasis of gastric carcinoma. There were equilateral correlations with cancer progression and frequency of cell surface expression of MMPs and their inhibitors, TIMPs, suggesting not only the aggressive nature of particularly metastatic gastric carcinoma, but also the presence of MMPs complexed with TIMPs on tumor cells and TIL. The enhanced cell surface expression of MMPs and TIMPs on TIL within metastatic carcinoma nests showed the result of a host response induced by tumors. These suggest that the increased cell surface expression of MMPs and TIMPs, and tumor-induced host response play a key role in gastric cancer invasion and/or metastasis.     

Expression of MUC2 in gastric carcinomas and background mucosae

BACKGROUND AND AIM: Gastric carcinomas contain elements of both intestinal and diffuse types. Such heterogeneous components may distort the evaluation of the role of the mucin MUC2 in gastric carcinoma. The role of MUC2 expression in background mucosa is not yet clarified. METHODS: We analyzed the expression of MUC2 in gastric mucosa and intestinal metaplasia adjacent to the tumoral area and carcinomas (n = 98) using immunohistochemistry. The immunoreactivity was quantified using an immunohistochemical scoring system. RESULTS: In the intestinal metaplasia adjacent to the tumoral area, MUC2 was detected in 76 (97.4%) of 78 intestinal metaplasia, and MUC2 expression was inversely associated with the depth of wall penetration (P = 0.026) and tumor stage (P = 0.021). Although the expression rate of MUC2 antigens was higher in intestinal-type adenocarcinoma than in diffuse-type adenocarcinoma, a significant correlation with pathologic staging of the TNM system (pTNM staging) and MUC2 expression could not be found in each subtype of gastric carcinomas. CONCLUSION: The expression of MUC2 in intestinal metaplasia was higher in tumors of earlier stages. These findings suggest that increased MUC2 expression in intestinal metaplasia in the neighborhood of the carcinomas may play an important role in gastric carcinomas. Further investigations regarding the role of MUC2 expression in gastric carcinoma and background mucosae are necessary.     

人宫颈癌基因在胃癌中的表达及其意义

目的 探讨人宫颈癌基因(human cervical cancer oncogene,HCCR)在人胃癌组织和胃癌细胞株中的表达及其与临床病理特征的关系,初步评价HCCR在胃癌发生中的作用及其意义,为寻找胃癌新的诊断标志物另辟新径.方法 采用Western blot方法检测SGC-7901、BGC-823胃癌细胞系中HCCR蛋白表达;采用免疫组化法检测30例胃癌患者的癌组织和10例癌旁正常组织中HCCR蛋白表达.结果 HCCR蛋白在两种不同分化程度的胃癌细胞株中均有阳性表达;胃癌组织中HCCR阳性表达率为73.3%(22/30),其表达位于细胞的胞膜和胞质,10例癌旁正常组织均为阴性表达,两者差异具有统计学意义(P＜0.01).HCCR的表达与胃癌患者的年龄、性别、浸润深度、组织分型、肿瘤分化程度及有无淋巴结转移均无显著相关性(P＞0.05).结论 HCCR与胃癌的发生密切相关,可能是反映早期胃癌发生的重要生物学指标之一.     

Ag－NOR计数在判断大肠癌预后中的价值

应用胶质银染技术对５６例根治性手术切除的大肠癌标本进行了定量观察。结果发现，Ａｇ－ＮＯＲ计数与患者的存活时间呈负相关（ｒ＝－０．７７Ｐ＜０．００１）。Ａｇ－ＮＯＲ＜４个／核，５年累积生存率是８０％，Ａｇ－ＮＯＲ４～６个／核为１５％，＞６／核为零。对数秩时序检验Ｐ＜０．００１。恶性程度低的肿瘤其颗粒分布以中央型为主，似恶性程度越高颗粒分布越弥散。大肠癌细胞核Ａｇ－ＮＯＲ计数与ＤＮＡ含量有一定相关性。多因素生存分析显示Ａｇ－ＮＯＲ计数是大肠癌一个重要预后指标。     

环氧合酶-2在胃癌中的表达及预后意义

目的:研究环氧合酶-2(COC-2)在胃癌、不典型增生及慢性萎缩性胃炎中的表达情况,探讨COX-2表达的预后意义。方法经手术病理证实的早、中期胃癌281例,进行预后随访调查。232例进行免疫组织化学染色。检则COX-2在胃癌及非癌组织中的表达情况,分析其与预后的关系。结果:早期胃癌的5年生存率为93.4％,中期胃癌的5年生存率为59.0％。COX-2在慢性萎缩性胃炎中的表达明显低于不典型增生者(P<0.01),在癌组织中的表达明显高于非癌组织(P<0.05～0.01);COX-2与胃癌淋巴结转移、血管浸润均密切相关(P<0.01);COX-2阳性表达者5年生存率明显低于阴性者(P<0.01)。结论:COX-2在胃癌组织呈过度表达状态,与胃癌的生长和浸润转移关系密切,可以作为反映胃癌生物学行为和判断预后的有效指标。     

Determination of High Mobility Group A1 (HMGA1) Expression in Hepatocellular Carcinoma: A Potential Prognostic Marker

Our objective was to investigate the expression of HMGA1 mRNA and protein in hepatocellular carcinoma (HCC) and the correlation between its expression and clinical pathological characteristics and prognosis. HMGA1 expression was determined at both the mRNA level and the protein level in 30 HCC tissues and their corresponding paracancer liver tissues (PCLTs) and 2 normal liver tissues by RT-PCR and IHC. Follow-up study was done on the 30 patients involved in this research. HMGA1 mRNA was detected in nine cases of HCC tissues and two PCLTs, for a positivity rate of 30% and 6.7%, respectively (P < 0.05), whereas no HMGA1 mRNA expression was found in normal liver tisssues. Clinicopathological analysis revealed that HMGA1 mRNA expression was significantly correlated with Edmondson's grade (P < 0.05). HMGA1 protein was detected in four HCC tissues by IHC and located mainly in the nuclei; no positive staining was found in PCLTs. Follow-up study showed that HMGA1 mRNA-positive patients had a higher risk of recurrence/metastasis and a shorter survival than negative cases (P < 0.05). Our findings indicate that HMGA1 may be involved in the carcinogenesis and invasiveness of HCC and the determination of HMGA1 can be of great value in predicting the prognosis of patients with HCC. This work was supported in part by National Key Technologies R&D Program Grant 2001BA703B04 and National Basic Research Program Grant 2004CB720303, Ministry of Science and Technology, People's Republic of China.     

红霉素抑制A549细胞中鼻病毒14介导的白介素8和MUC5AC的分泌

目的 探讨红霉素是否对鼻病毒14(RV14)介导的细胞因子产生和气道黏液高分泌有抑制作用.方法 EM预处理肺泡Ⅱ型上皮细胞A549 3h后,用RV14刺激细胞,然后采用酶联免疫吸附试验法检测细胞培养上清中细胞因子白介素8和细胞裂解液中黏液蛋白MUC5AC的浓度,并用Western blot检测磷酸化p44/42MAPK信号分子变化情况.结果 红霉索明显抑制RV14介导的白介素8和MUC5AC的产生和分泌,并且对RV14介导的p44/42MAPK的激活也有抑制作用.结论 红霉素可有效抑制RV14介导的细胞因子和黏液蛋白的产生和分泌,并且这种抑制作用可能是通过阻断p44/42MAPK信号分子的激活来实现的.     

白介素13诱导支气管哮喘气道黏液高泌的分子机制

白介素13(interleukin-13,IL-13)是一种主要由活化的Th2细胞分泌的多效能细胞因子,可刺激B细胞的增殖和IgE的合成.气道杯状细胞增生所致的黏液是哮喘的主要症状之一,黏液高分泌是肺功能第1秒用力呼气量下降加速的独立危险因素,可能成为重症哮喘的主要死因.Th2型细胞因子IL-4、IL-5、IL-9和IL-13在肺部的表达与哮喘的病理生理有密切联系,其中,IL-13被认为是目前最重要的细胞因子,它可能引起气道炎症、黏液过度分泌、杯状细胞增生和黏蛋白(MUC)基因MUC5AC高表达等多种改变.近来发现其引起黏液高分泌的作用机制成为目前研究的热点.本文针对其作用的具体分子机制作一综述.     

表皮生长因子协同上调不分型流感嗜血杆菌诱导的MUC5AC表达及其信号通路

目的 探索表皮生长因子(EGF)协同上调不分型流感嗜血杆菌(NTHi)诱导MUC5AC黏液素基因表达的细胞分子机制.方法 荧光定量PCR及Luciferase分析EGF协同上调NTHi诱导的MUCSAC表达.Western印迹法检测EGF及NTHi对P38有丝分裂原活化蛋白激酶(P38MAPK)、细胞外信号调节激酶(ERK)、P21激活激酶(PAK)4磷酸化的协同作用.采用P38MAPK或EGF特异性抑制剂,共转染P38MAPK、ERK显性失活质粒及PAK4 siRNA,判断对EGF协同上调NTHi诱导MUC5AC表达的影响,并研究PAK4显性失活质粒对EGF及NTHi所致的P38MAPK及ERK协同激活的影响.结果 在HM3、HeLa和HMEEC-1细胞mRNA及转录水平上,EGF协同上调NTHi诱导的MUC5AC基因表达.EGF及NTHi对P38MAPK、ERK、PAK4磷酸化有协同作用;P38MAPK、ERK特异性抑制剂或共转染P38MAPK、ERK显性失活质粒、PAK4siRNA,可显著抑制EGF对NTHi诱导的MUC5AC表达的协同作用,PAK4显性失活质粒抑制EGF和NTHi诱导的P38MAPK和ERK磷酸化的协同作用.结论 EGF通过PAK4依赖的P38MAPK及ERK细胞信号通路协同上调NTHi诱导的MUCSAC黏液素基因表达.     

Prediction of Prognosis in Gallbladder Carcinoma by Mucin and p53 Immunohistochemistry

Mucin core proteins are known to be present in various organs and are specifically expressed with carcinogenesis and closely associated with the prognoses of various malignant tumors in the digestive tract such as colorectal cancer. The present study evaluated correlations between mucin and p53 expression and prognosis of gallbladder cancer using surgically resected tissue specimens from 26 patients with gallbladder carcinoma surgically treated at our hospital. Immunohistochemical staining was performed using MUC1, MUC2, and p53 monoclonal antibody. The level of antigen expression in the lesion was classified into four stages: none(−), slight(+), moderate (++), and severe (+++). According to the UICC classification, histopathological grading, levels of T, N, and M factors, and tumor stages were compared with regard to the correlations with mucin and p53 expression. All cases were classified into two groups according to the results of mucin immunohistochemistry: group A (MUC1, ≥{++}; and MUC2, ≤+) and group B (MUC1, < ++; or MUC2, > +). Postoperative survival periods were compared between the two groups and p53-positive and -negative groups. Neither histological grading nor T factor correlated with mucin or p53 expression, respectively. Moreover, neither N factor nor M factor correlated with mucin or p53 expression. Furthermore, stage grouping did not correlate with mucin or p53 expression. However, when the correlation between the postoperative survival period and mucin expression was evaluated, the mean postoperative surgical period was significantly shorter in Group A than in Group B (1.02 years in Group A vs 2.92 years in Group B; P = 0.016). There was no relationship between postoperative survival period and p53 positivity. Mucin expression was independent of various tumor growth factors and clearly reflected the prognosis of gallbladder cancer. Because the relative malignancy of gallbladder cancer could be evaluated by examining the level of glycoprotein expression in tumor tissue, mucin could be a more important marker than p53 for predicting prognosis in gallbladder carcinoma using surgically resected tissue specimens.     

肝癌组织中ICAM-1的表达和意义

目的研究细胞间黏附分子-1(1CAM-1)在原发性肝癌中的临床意义.方法以免疫组化方法结合全自动图像分析观察40例肝细胞癌组织及其癌旁组织和28例肝硬化组织中ICAM-1的表达.结果40例肝细胞癌组织ICAM-1表达阳性率为80.0%(32/40)、癌旁组织为57.5%(23/40)、肝硬化为53.6%(15/28),阳性率与组织学分类相关.肝癌组织中ICAM-1含量明显高于癌旁及肝硬化组织(P＜0.05),转移组肝癌中ICAM-1的含量明显高于非转移组(P＜0.05),而癌旁及肝硬化组织中表达差异无显著性(P＞0.05).结论肝癌组织中高度表达ICAM-1,ICAM-1有可能作为判断肝硬化及肝癌发展程度及预后的指标之一.     

Prognostic value of circulating KL-6 in idiopathic pulmonary fibrosis

OBJECTIVE: Circulating levels of KL-6, a high MW glycoprotein (MUC1 mucin), are elevated in a majority of patients with a number of interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF). However, KL-6 levels vary from patient to patient. The aim of the present study was to determine whether the serum KL-6 level at the time of diagnosis predicts prognosis in IPF. METHODS: The relationship between clinical variables and prognosis in 27 patients with IPF were analysed retrospectively. The diagnosis was made by histological examination (n = 16) or on clinical findings including high-resolution CT scanning (n = 11). All patients were followed up for at least 3 years. Variables such as age, FVC%, PaO(2) at rest, initial LDH level, C-reactive protein and KL-6 were used for analysis. RESULTS: At the cut-off level determined by receiver operating characteristic curves, LDH and KL-6 showed a significant correlation with the patient's prognosis by univariate analysis. However, multivariate analysis revealed that only KL-6 was a predictor of prognosis. The patients were categorized by their serum KL-6 levels (as above or below the cut-off level of 1000 U/mL) and their survival estimated using the Kaplan-Meier method. The difference in median survival between the two groups was significant. The median survival of patients with low KL-6 was more than 36 months, whereas that of patients with high KL-6 was only 18 months. CONCLUSION: These results suggest that initial evaluation of serum KL-6 level can predict survival in patients with IPF.