12-Lipoxygenase inhibition induced apoptosis in human gastric cancer cells

Arachidonic acid release from membrane phospholipids is essential for tumour cell proliferation. Lipoxygenases constitute a pathway for arachidonate metabolism. The present study investigated the expression of 12-lipoxygenase and its effect on cell proliferation as well as survival in two human gastric cancer cell lines (AGS and MKN-28). RT-PCR and western blots, respectively, showed 12-LOX mRNA and protein expression in both AGS and MKN-28 cell lines. Treatment with a 12-LOX inhibitor, baicalein, significantly inhibited cancer cell proliferation, but a metabolite of 12-LOX activity, 12 hydroxyeicosatetraenoic acid (12-HETE) reversed baicalein-induced growth inhibition. Furthermore, the blockade of the 12-LOX pathway through a 12-LOX inhibitor and antisense induced apoptosis of gastric cancer cell lines. The biochemical characteristics of apoptosis were p53-independent combined with a decrease in bcl-2 expression. Caspase-7 was proteolytically activated and responsible for the apoptosis execution.     

宫颈癌中S-100蛋白阳性的树突状细胞的表达及意义

目的研究子宫颈正常上皮组织、慢性炎症组织、子宫颈上皮内瘤变（cervical intraepithelial neoplasia，CIN）组织及子宫颈癌组织中树突状细胞（dendritic cells，DC）的浸润程度、分布变化，以及它们之间的关系，以探讨肿瘤局部免疫功能状态。方法应用免疫组化S-P法检测15例正常子宫颈上皮、15例慢性炎症组织、30例CIN组织及40例宫颈癌组织中的DC的浸润程度和形态分布特征。结果子宫颈癌组中DC高度浸润13例，低度浸润27例；CIN组中高度浸润24例，低度浸润组6例；慢性炎症组中高度浸润11例，低度浸润4例：正常对照组中高度浸润10例，低度浸润5例。CIN组的DC高度浸润率高于宫颈癌组和正常对照组，相比差异有统计学意义（P〈0．05），CIN组与炎症组DC高度浸润率相比差异无统计学意义（P〉0．05）。宫颈癌组DC高度浸润率小于正常对照组和炎症组，差异有统计学意义（P〈0．05）。结论DC在子宫颈癌的发生、发展中起着重要的作用，检测其浸润程度可反映肿瘤局部的免疫状态，为宫颈癌预后的判断和生物治疗提供实验依据。     

Detection of proliferative cells in dysplasia, carcinoma in situ, and invasive carcinoma of the uterine cervix by monoclonal antibody against DNA polymerase alpha

The distribution of DNA polymerase alpha-positive cells in neoplasia of the uterine cervix and in normal cervical epithelium was studied using a monoclonal antibody against DNA polymerase alpha. The positive cells were found only in the parabasal layer of normal cervical epithelium and only in the nonkeratinized areas of the cancer nests of invasive keratinizing carcinoma. Most cells in cancer nests of an invasive nonkeratinizing carcinoma were found to be DNA polymerase alpha-positive. In cases of mild or moderate dysplasia DNA polymerase alpha-positive cells were found only in the lower half of the epithelium. DNA polymerase alpha-positive cells in severe dysplasia to carcinoma in situ were distributed throughout the full thickness of the epithelium. The percentages of DNA polymerase alpha-positive cells in mild or moderate dysplasia, severe dysplasia to carcinoma in situ, and invasive carcinoma were 32.2%, 45.7%, and 53.7%, respectively. The authors previously developed immunohistochemical methods for detecting DNA polymerase alpha by monoclonal antibody that allowed the proliferative activity of cells in normal and neoplastic tissues to be estimated.     

VEGF-C在宫颈鳞癌组织中的表达及临床意义

目的检测血管内皮生长因子C（VEGF-C）在正常宫颈、宫颈上皮内瘤变（CIN）及宫颈鳞癌组织中的表达,探讨VEGF-C与宫颈癌发生发展、淋巴结转移的关系。方法采用免疫组织化学S-P法,检测22例正常宫颈上皮、63例CIN、45例宫颈鳞癌组织中VEGF-C的表达。结果VEGF-C在正常宫颈黏膜上皮、CIN及宫颈鳞癌组织中的表达依次增高,三者之间相比,差异有统计学意义（P〈0．05）。伴有淋巴结转移的宫颈癌组织中VEGF-C的表达明显高于无淋巴结转移病例（P〈0．01）。VEGF-C在低分化鳞癌组织中的表达明显高于中高分化鳞癌组织（P〈0．05）,但与临床分期无关。结论VEGF-C蛋白表达与宫颈鳞癌发生发展及淋巴转移有关。     

Extent of treatment of early carcinoma of the uterine cervix--local treatment of 198 stage I patients

The extent of treatment of early carcinoma of the uterine cervix is still controversial. 198 patients with Stage I carcinoma of the uterine cervix who received local treatment for the primary tumor are summarized, 107 with early invasive carcinoma and 91 with invasive cancer. Microscopic examination showed that 62.2% of the patients had lesions less than 1 cm in diameter. In 82.8% of the patients, the invasion was confined to the cervical ring by pathological examination. The accuracy of multiple biopsies was 79.3%. Of 198 patients, 124 received intracavitary radiotherapy only, 73 hysterectomy and 1 cone resection of the uterine cervix. All of them were followed for 5 years or more. The 5-year survival rate was 98% and none of them died of cancer. The author considers that the extent of treatment of early invasive carcinoma can be localized. For localized invasive carcinoma (stage Ib) with lesion less than 1 cm and extent of invasion less than half of the uterine cervix ring as confirmed by biopsy, the treatment of regional lymph nodes can be omitted. Multiple biopsies may replace diagnostic cone resection in most instances.     

CD_(44v6)及C-myc在宫颈鳞癌中的表达及意义

目的探讨CD44v6及C-myc在宫颈鳞癌发生、发展中的作用和意义以及二者之间的关系。方法选取30例正常宫颈组织和60例宫颈鳞癌组织应用组织芯片和免疫组化技术分别检测CD44v6及C-myc蛋白的表达情况。结果CD44v6在Ⅰ￣Ⅱ期宫颈鳞癌中的表达与病理分级、累及颈管肌层深度、淋巴结转移相关,而与年龄、临床分期无关。C-myc的表达与临床分期、累及颈管肌层深度、淋巴结转移相关,而与年龄、病理分级无关。结论CD44v6及C-myc在宫颈鳞癌中的表达可作为预后指标;二者有协同作用,共同检测有助于预测宫颈癌的侵袭、转移、预后。     

Constitutive expression of 8-lipoxygenase in papillomas and clastogenic effects of lipoxygenase-derived arachidonic acid metabolites in keratinocytes

The expression pattern, enzymatic activity, and products of 8-lipoxygenase (LOX) were analyzed in normal and neoplastic skin of NMRI mice. While barely detectable in normal epidermis, 8-LOX was transiently induced by 12-O-tetradecanoylphorbol-13-acetate and constitutively expressed in papillomas but not carcinomas obtained by the initiation-promotion protocol of mouse skin carcinogenesis. The product profile and chirality of both the native and the recombinant protein produced the S enantiomers of 8-hydroxy-5Z,9E,11Z,14Z-eicosatetraenoic acid (8-HETE) and 9-hydroxy-10E,12Z-octadecadienoic acid (9-HODE) as the main arachidonic acid- and linoleic acid-derived metabolites. As compared with normal epidermis, papillomas exhibited 25- and 4-fold elevated levels of 8-HETE and 9-HODE, respectively. However, the varying S to R ratios of 8-HETE and the predominance of 9(R)-HODE indicated that in addition to 8(S)-LOX, other enzymes yet to be defined may be involved in 8-HETE and 9-HODE production. The massive accumulation of both 8-HETE and 12-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (12-HETE) point to a critical role of these LOX pathways in epidermal tumor development, in particular in the papilloma stage. Here we showed that 8- and 12-hydroperoxyeicosatetraenoic acids and 8- and 12-HETE induce chromosomal alterations in cycling primary basal keratinocytes.     

Incidence trends in invasive uterine cervix cancer and carcinoma in situ in Incheon, South Korea

Introduction: This study examined trends of invasive and carcinoma in situ(CIS) in terms of the incidence and mortality of uterine cervix cancer in Incheon over a twelve year period. Methods: Uterine cervical cancer data were retrieved from the Incheon Cancer Registry(ICR) and Korea Central Cancer Registry(KCCR) from 1997 to 2008. The time trend in age-standardized incidence rates (ASR) of invasive uterine cervix cancer and CIS were calculated and compared with the nation-wide cancer registry data for each year. Mortality/incidence (M/I) ratios according to age and the incidence of pathological subtype in Incheon each year were also examined, along with an international comparison. Results: A total of 3,096 cases of invasive cervical cancer and 2,079 cases of carcinoma in situ were analyzed from 1997 to 2008. The time trend incidence of the total ASR in uterine cervical cancer decreased from 25.7 in 1997 to 13.4 in 2008, but incidence of CIS increased from 7.6 to 15.8 in same period. In invasive cancers, the age-specific incidence rates were highest in those in their sixties and patients in their forties showed highest incidence of CIS. The mortality rate in ICR was 3.7 from 1998 to 2002. Compared to the other countries which have high risk factors for cervix cancer, the peak incidence zone was different in Incheon. Conclusion: The ICR showed a decrease in the incidence of invasive cervical cancer that was similar to the nation-wide data. An early increase zone is a characteristic pattern in the age specific incidence curve. Early screening and a vaccination program should be activated for prevention of young age cervical cancer.     

Global DNA Methylation in Precancerous and Cancerous Lesions of the Uterine Cervix

Introduction: Persistent human papillomavirus (HPV) infection is the primary causal agent in the developmentof the uterine cervix carcinoma. Nevertheless, only a minority of high-risk HPV-associated lesions progressto cervical cancer, suggesting involvement of other molecular alterations. Among putative changes, aberrantmethylation might be a crucial event. Design: Paraffin-embedded samples of benign lesions, cervical intraepithelialneoplasia (CIN) and invasive squamous cell carcinomas (SCC) were analyzed for DNA 5-methylcytosine contentby immunohistochemistry with anti-5-methylcytosine antibodies and by high-performance liquid capillaryelectrophoresis (HPCE). Results: No significant difference of DNA 5-methylcytosine content was observed betweennormal tissues, benign lesions, low-grade lesions and high-grade lesions (p=0.6). In contrast, DNAs extractedfrom invasive SCC were hypomethylated when compared with normal and preneoplastic lesions (p=0.0004). Anassociation between global DNA hypomethylation and the SCC stage was confirmed by HPCE. Conclusions: Thetransition from CIN lesions to invasive carcinoma seems to be closely linked to global DNA hypomethylation,which could be a useful marker of invasive uterine cervical lesions.     

COX-2和NET-1基因蛋白在宫颈癌中表达的意义

目的研究环氧合酶-2(COX-2)和NET-1基因蛋白在宫颈癌中的表达及与宫颈癌生物学行为的关系。方法采用免疫组化SP法,检测COX-2和NET-1基因蛋白在50例宫颈鳞癌组织、36例宫颈上皮内瘤样病变(CINⅠ~Ⅲ级)及5例正常宫颈组织中的表达。结果COX-2表达在宫颈浸润癌中明显高于CINⅢ级和早期浸润癌(P<0.01),而在CINⅢ级与早期浸润癌中无显著差异(P>0.05);COX-2阳性表达在低、中分化癌中均显著高于高分化癌(P<0.01);在淋巴结转移组中显著高于无淋巴结转移组(P<0.01)。NET-1在CINⅢ级中表达显著高于CINⅠ级和CINⅡ级(P<0.01)。而CINⅢ级和宫颈癌比较无显著差异(P>0.05)。NET-1阳性表达在淋巴结转移组明显高于无淋巴结转移组(P<0.01)。宫颈癌中COX-2表达与NET-1表达呈正相关(P<0.01)。结论COX-2表达上调是宫颈癌演进中的常见的分子事件。可作为判断宫颈癌淋巴结转移的一个指标。NET-1的过表达可能是宫颈癌发生的早期分子事件,有可能成为宫颈癌早期诊断的组织标记。在宫颈癌中COX-2和NET-1基因蛋白之间有协同作用。     

S100A8和S100A9在子宫颈鳞癌组织中的表达

目的:探讨S100A8、S100A9在子宫颈鳞癌及正常宫颈组织中的表达及其意义。方法:采用半定量的RT-PCR技术和免疫组织化学的方法,从mRNA及蛋白水平检测32例子宫颈鳞癌和15例正常宫颈组织中S100A8、S100A9的表达,及与不同临床病理参数的关系。结果:子宫颈鳞癌组织中,S100A8、S100A9在mRNA及蛋白水平上均低表达(P<0.05),其中,低分化肿瘤的表达明显低于高、中分化肿瘤(P<0.05)。结论:S100A8、S100A9在子宫颈鳞癌组织中低表达,且可能与鳞状细胞的分化程度相关。提示S100A8、S100A9低表达可能与子宫颈鳞癌的发生发展有关系。     

整合素α6在宫颈癌中的表达及意义

目的：探讨整合素α6在宫颈癌中的表达及意义。方法：在20例宫颈浸润癌中整合素α6基因及其蛋白分别采用反转录聚合酶链反应（RT-PCR）、免疫组织化学（IHC）SP法进行检测。18例正常宫颈上皮、20例宫颈原位癌、55例宫颈浸润癌中（包括前20例宫颈浸润癌）,整合素α6蛋白的表达采用免疫组织化学SP法检测。结果：20例宫颈浸润癌中整合素α6mRNA和蛋白表达率无统计学差异（P〉0.05）。整合素α6在宫颈癌中的表达率明显低于正常宫颈组织（P〈0.001）,而宫颈浸润癌和宫颈原位癌组织之间无显著性差异（P〉0.05）。整合素α6表达与宫颈鳞癌临床分期、肿瘤大小、病理分级、宫颈浸润深度无相关（P〉0.05）,而与淋巴转移相关（P〈0.05）。结论：整合素α6可能通过改变宫颈癌细胞的粘附力而发挥促进宫颈癌发生发展及淋巴结转移的作用。     

Dysplasias of uterine cervix: epidemiological aspects: role of age at first coitus and use of oral contraceptives

Age at first coitus and use of oral contraceptives were studied in a highly homogeneous population (French Canadian) during a cytologic cervical cancer screening program. Both factors were known in 84,540 women without cervical lesions and in 2017 patients with mild and moderate dysplasia. Highly significant correlations were found between: early onset of sexual activity and occurrence of dysplasia; oral contraceptive use and occurrence of dysplasia; early age at first coitus and oral contraceptive use. When correlated for age at first coitus, there was a significant excess of dysplasias in oral contraceptive users. Dysplasia of the uterine cervix behaves epidemiologically like carcinoma in situ and invasive squamous carcinoma, that is, essentially as a venereal disease. It remains to be seen whether all dysplasias form one continuum or whether there are two morphologically similar but biologically distinct forms of dysplasia: one more frequent, regressing spontaneously, the other relatively rare, progressing to carcinoma in situ and invasive squamous carcinoma of the cervix.     

血小板型12-脂加氧酶与肿瘤

花生四烯酸通过脂加氧酶(lipoxygenase,LOX)途径代谢产生多种生物活性脂类,这些脂类在炎症、血栓形成和肿瘤演进过程中发挥着重要的作用。LOX按照组织分布被分为5- 、8- 、12 -、15- LOX4 个家族,血小板型12 LOX是LOX的一种,催化花生四烯酸转化为廿碳四烯酸。血小板型12 -LOX在正常组织中主要分布在血小板、人皮肤表皮细胞细胞质和微粒体中。近来研究发现,在多种肿瘤组织和肿瘤细胞系中不仅可检测到血小板型12- LOX的表达,且随着肿瘤级别的增高,瘤细胞表达增强。血小板型12 -LOX催化的代谢产物,如12(S) 羟廿碳四烯酸,已被证明涉及肿瘤细胞凋亡、肿瘤血管形成,因此血小板型12 LOX也成为肿瘤治疗的潜在目标。多项研究表明,血小板型12 -LOX的抑制剂能有效抑制肿瘤,如去甲二氢愈创木酸能有效抑制胶质瘤。对血小板型12- LOX与肿瘤细胞增殖、凋亡和血管生成之间的关系以及其机制进行讨论,另外,对血小板型12- LOX抑制剂预防和治疗肿瘤予以综述。     

Pin1在宫颈癌中过表达及其与Ki67关系的研究

目的:探讨宫颈癌中肽基脯氨酰顺反异构酶Pin1表达、与Ki67的相关性及其临床意义。方法:应用RT-PCR和免疫组化技术检测宫颈癌组织中Pin1mRNA和蛋白表达水平及其与Ki67蛋白表达的相关性。结果:1)宫颈癌组织中Pin1mRNA表达明显高于正常宫颈组织(P<0.05);2)从正常宫颈到CIN再到浸润癌Pin1蛋白表达逐渐增强(P<0.05);3)Pin1蛋白过表达与临床分期、病理分级、淋巴结转移无明显相关(P>0.05);但宫颈腺癌Pin1表达明显高于宫颈鳞癌(P<0.05);4)Pin1过表达与Ki67表达呈显著正相关(P<0.05)。结论:1)Pin1过表达与宫颈癌细胞增殖有关,参与宫颈癌发生发展;2)Pin1过表达可作为宫颈癌诊断的辅助指标。     

宫颈癌组织PAR-2和MMP-2表达及其与侵袭转移关系的研究

目的:探讨蛋白酶激活受体-2(PAR-2)及基质金属蛋白酶-2(MMP-2)在正常宫颈组织、宫颈原位癌、宫颈浸润癌组织中的表达及临床意义。方法:采用免疫组化SP法分别检测PAR-2、MMP-2在15例正常宫颈组织,20例宫颈原位癌组织,70例宫颈浸润癌组织中的表达。结果:PAR-2及MMP-2在宫颈浸润癌组织中阳性表达率分别为45.71%及71.43%,明显高于宫颈原位癌及正常宫颈组织(P<0.01),PAR-2在宫颈癌盆腔淋巴结转移组和未转移组中的阳性表达率分别为72.41%和26.83%,MMP-2的阳性表达率分别为93.10%和56.10%,两组比较差异有统计学意义,P<0.01。结论:PAR-2及MMP-2与宫颈癌的侵袭和淋巴结转移密切相关。