p27kip1在宫颈癌组织中的表达及意义

目的 研究p27^kip1在宫颈癌组织中的表达并探讨其在宫颈癌发生发展过程中的变化及意义。方法 采用免疫组化SP法对57例浸润性宫颈癌(IC)、11例宫颈原位癌(CLS)、18例宫颈上皮重度不典型增生(SD)和15例正常宫颈组织(NE)进行了细胞周期蛋白依赖性激酶抑制剂(CDKI）p27^kip1的检测。结果 15例正常宫颈上皮中p27^kip1蛋白全部高表达，而在SD和CLS以及浸润性宫颈癌中，其蛋白表达水平随病变的发展呈现了有意义的下降。在宫颈癌进展期，p27^kip1表达与宫颈癌的临床分期、组织分级、淋巴结转移呈显著负相关，单因素生存分析显示p27^kip1蛋白高表达组生存率明显优于低表达组。结论 p27^kip1蛋白表达的下降参与了宫颈癌的发生发展。其蛋白水平检测是宫颈癌早期诊断及判定预后的一个有价值的指标。     

HIF-1α和Glut-1蛋白在中老年宫颈癌组织中的表达及其意义北大核心CSCD

目的探讨葡萄糖转运蛋白1（Glut-1）、缺氧诱导因子-1α（HIF-1α）在中老年宫颈癌组织中的表达及其临床意义。方法选取2013年1月至2015年12月在河南省南阳市中心医院收集的宫颈癌病理组织标本80例、正常宫颈组织标本40例,采用免疫组织化学染色检测两组标本中Glut-1、HIF-1α蛋白的表达水平并探讨其与临床病理学特征的关系。结果中老年宫颈癌组织中Glut-1蛋白的阳性表达率为58.75%、HIF-1α蛋白的阳性表达率为73.75%,正常宫颈组织中Glut-1蛋白的阳性表达率为25.00%、HIF-1α蛋白的阳性表达率为10.00%,两组比较差异有统计学意义（P〈0.05）;宫颈癌组织中HIF-1α蛋白的阳性表达在不同的肿瘤组织学分级、FIGO分期中差异有统计学意义（P〈0.05）,宫颈癌组织中Glut-1蛋白的阳性表达在不同年龄段的宫颈癌患者、肿瘤肌层浸润深度、是否伴有淋巴结转移的患者中差异具有统计学意义（P〈0.05）。结论 Glut-1、HIF-1α在中老年宫颈癌组织中表达上调,并且与患者的临床病理学特征密切相关,对于指导临床诊断和治疗具有一定的价值。     

Dicer1在宫颈肿瘤组织中的表达及意义

目的:探讨Dicer1在正常宫颈上皮、宫颈上皮内瘤变和宫颈鳞癌的表达及意义。方法:Western blot和RT-PCR法检测正常细胞系(End1/E6E7)、宫颈内瘤变细胞系(S12)及宫颈癌细胞系(Ca Ski、He La、Si Ha和C33A)中Dicer1蛋白及其mRNA表达水平,免疫组织化学技术检测Dicer1在正常宫颈、宫颈上皮内瘤变和宫颈鳞癌中的表达水平。结果:正常宫颈上皮细胞系Dicer1表达水平低于宫颈癌细胞系表达量。随着恶性程度增加,Dicer1呈驼峰状表达,即在正常宫颈组织及Grade III级宫颈鳞癌中表达较低,但在宫颈上皮内瘤变及高分化宫颈肿瘤(grade I级)中表达较高。结论:Dicer1在正常宫颈、宫颈上皮内瘤变和宫颈鳞癌中的表达有差异,为进一步研究Dicer1在宫颈癌发生发展中的作用及分子机制提供依据。     

LATS1在宫颈癌中的表达及其生物学特性的实验研究

目的:探讨LATS1在宫颈癌中表达的临床意义及生物学特性。方法:免疫组化法检测80例宫颈癌组织中LATS1蛋白表达;分别以Si Ha及Caski细胞系为媒介,进行LATS1转染及干扰实验;MTT及基质胶侵袭实验检测细胞增殖和侵袭能力。结果:80例宫颈癌组织中LATS1低表达的比例约为45%(36/80);LATS1过表达抑制了宫颈癌细胞的增殖和侵袭,LATS1过表达上调p27表达量的同时下调cyclin E及MMP-9的表达量。LATS1过表达刺激了YAP的磷酸化过程。敲除LATS1的Caski细胞系中则呈现相反的结果。结论:在宫颈癌中,LATS1发挥肿瘤抑制剂的功能,在肿瘤细胞增殖和侵袭过程中发挥重要作用。     

lncRNA XIST/miR-153/SNAI1在宫颈癌迁移、侵袭和上皮间质转化中的表达及意义#br#

Objective?To investigate the role of lncRNAXIST/miR-153/SNAI1 signal axis in the migration, invasion and epithelial-mesenchymal transformation of cervical cancer. Methods?The samples of 42 patients with cervical cancer were collected and cultured in vitro. The effects of lncRNAXIST and miR-153 on the proliferation, invasion, migration and epithelial-mesenchymal transformation (EMT) of cervical cancer cells were detected. Results?The expression of lncRNAXIST was increased in cervical cancer. Silencing lncRNAXIST and adding miR-153 simulator significantly reduced the invasion, migration and proliferation of cervical cancer cells, inhibited the expression of proliferation protein CDK4, CyclinD1 and invasive protein MMP-9, MMP-2, reduced the expression of EMT-related gene SNAI1 and related protein N-cadherin, Vimentin, IL-6, SNAI1, and promoted the increase of E-cadherin. Conclusion?Silencing lncRNAXIST targets could up-regulate of miR-153 and inhibit the migration, invasion and EMT of cervical cancer cells, which may be related to the inhibition of downstream signal pathway IL-6/SNAI1.     

宫颈癌中MTA1蛋白的表达及临床意义

目的:研究转移相关基因1(MTA1)在宫颈癌中的表达及临床意义.方法:采用免疫组化法检测20例正常宫颈组织,50例宫颈癌以及淋巴结转移癌组织中MTA1蛋白的表达情况,并与临床病理特征相比较.结果:与正常宫颈上皮相比,宫颈癌与淋巴结转移癌组织中MTA1阳性细胞数量及染色强度均明显增高.正常宫颈中MTA1蛋白定位于细胞核;宫颈癌及淋巴结转移癌组织中MTA1出现了细胞核、细胞浆、细胞膜的多种形式的蛋白定位.宫颈癌中MTA1蛋白的过表达与淋巴转移、浸润深度及脉管浸润有关,与组织学类型、分化程度无关.Kaplan-Meier生存分析未发现MTA1是宫颈癌的不良预后因素.结论:MTA1蛋白的过表达可能与宫颈癌的发生发展、浸润转移密切相关,其与宫颈癌预后的关系还有待于进一步研究.     

血清CYFRA21-1与宫颈癌患者临床病理特征及预后的关系

目的:探讨治疗前血清CYFRA21-1水平与宫颈癌患者临床病理特征及预后的关系。方法:对90例FIGOⅠB1～ⅡB期宫颈癌患者行治疗前CYFRA21-1检测,结合临床资料及随访结果对其与临床病理特征及预后的关系进行分析。结果:90例患者CYFRA21-1的检测值为0.61～30.30mg/L(3.15±3.57mg/L)。以3.30mg/L为阈值,CYFRA21-1升高者占26.7%。不同FIGO期别、肿瘤大小、大体类型、病理类型,术后有或无盆腔淋巴结转移、宫颈深肌层浸润、淋巴血管间隙浸润的患者间的CYFRA21-1均值及升高率比较,差异均无统计学意义(P>0.05)。经过42个月中位随访期,不同CYFRA21-1值(0.10～3.30mg/Lvs>3.30mg/L)患者间的复发率(19.7%vs25.0%)比较,差异均无统计学意义(P>0.05)。治疗前血清CYFRA21-1值对预测治疗后复发无价值,曲线下面积(AUC)为0.456±0.087。CYFRA21-1升高与否患者间的总生存率(79.0%vs82.0%)比较,差异无统计学意义(P>0.05)。结论:FIGOⅠB1～ⅡB期宫颈癌患者血清CYFRA2...     

MMP-1/PAR-1通路在宫颈癌侵袭转移中的作用

目的:探索基质金属蛋白酶-1(MMP-1)/蛋白酶活化受体-1(PAR-1)通路在宫颈癌侵袭转移中的作用。方法:RT-PCR法检测59例临床宫颈鳞癌组织和15例正常宫颈组织的MMP-1mRNA表达;Transwell实验检测添加重组人MMP-1及干扰PAR-1对宫颈癌Hela细胞转移侵袭能力的影响。结果:宫颈癌组织中的MMP-1(rhMMP-1)表达高于正常宫颈组织,并与侵袭转移程度相关;rhMMP-1能促进Hela细胞的转移能力,并与浓度相关;干扰PAR-1后能抑制MMP-1介导的Hela细胞转移能力。结论:MMP-1/PAR-1通路参与宫颈癌的侵袭转移,可能成为宫颈癌治疗的新靶点。     

EGFR、蛋白激酶B在宫颈癌中表达及EGFR胞外区基因突变的研究

目的:探讨宫颈癌中表皮生长因子受体(EGFR)、蛋白激酶B(PKB/Akt)的表达及EGFR胞外区基因突变的规律和临床意义,为宫颈癌的发生发展机制和靶向个性化治疗提供实验依据。方法:采用免疫组化SP法检测EGFR、Akt蛋白在16例正常宫颈组织、40例宫颈上皮内瘤变(CIN)组织和60例宫颈癌组织中的表达,并分析其与宫颈癌临床病理的关系。采用酚氯仿法抽提60例宫颈癌组织中DNA,PCR+DNA双向测序法检测EGFR胞外IV亚区基因突变。结果:正常宫颈组、CIN组及宫颈癌组中EGFR蛋白的阳性表达率分别为13.33%、43.33%及76.67%,Akt蛋白的阳性表达率分别为6.25%、35.00%及68.33%,差异有统计学意义(P0.05)。宫颈癌组织中,EGFR表达水平与病理类型、细胞分化程度和临床分期有关(P0.05),但与患者年龄和淋巴结转移无关(P0.05);Akt表达水平与细胞分化程度和临床分期有关(P0.05),但与患者年龄、病理类型和淋巴结转移无关(P0.05)。60例宫颈癌中EGFR基因外显子15突变率为3.33%(2/60),突变类型G→A,未发现外显子14突变。宫颈癌组织中EGFR、Akt表达呈正相关性(r=0.556,P0.05)。结论:EGFR、Akt可作为检测宫颈癌及癌前病变的重要参考指标,也为宫颈癌的多靶点联合治疗提供新思路;宫颈癌中EGFR胞外区可有基因突变,但突变率很低,关于其突变的规律和意义有待进一步研究。     

介入治疗前后宫颈癌组织局部肿瘤细胞Th1/Th2类因子表达动态变化的研究

目的:研究动脉介入化疗前后宫颈癌组织内肿瘤细胞Th1/Th2类细胞因子表达的动态变化。方法:用免疫组化法检测21例宫颈癌介入治疗前后标本IL-2、IFN-γ和IL-4的表达率及表达强度。结果:介入前,介入治疗后第7天及介入治疗后第14天,IL-2表达率为19.05%、85.71%、19.05%;IFN-γ表达率为28.57%、90.48%、38.10%;IL-4表达率为57.14%、76.19%、28.57%。各项指标3个时间点两两的比较,除介入前与介入后14天无统计学差异(P>0.05),其余均有统计学意义(P<0.01)。结论:介入治疗能有效地逆转癌组织局部肿瘤细胞Th1/Th2类细胞因子的表达,增强肿瘤局部免疫。     

CD44v7/8基因表达与宫颈癌关系的探讨

目的探讨宫颈癌组织中CD44v7/8基因的异常表达及临床意义。方法1986～2000年沈阳医学院附属中心医院采用免疫组化的方法随机测定59例宫颈癌、18例尖锐湿疣和18例慢性宫颈炎组织中CD44v7/8基因的表达情况。结果宫颈癌、尖锐湿疣及慢性宫颈炎3种疾病中CD44v7/8表达阳性率分别为76.27%、11.11%和11.11%,宫颈癌组的CD44v7/8表达分别高于慢性宫颈炎组及尖锐湿疣组,且差异非常显著(P<0.01)。慢性宫颈炎组及尖锐湿疣组比较差异无显著性(P>0.05)。结论CD44v7/8蛋白的表达增强与宫颈癌的发生、发展及和局部浸润转移有关。     

Molecularly targeted therapies in cervical cancer. A systematic review

Cervical cancer represents the third most common cause of female cancer mortality. Even with the best currently available treatment, a significant proportion of patients will experience recurrence and eventually die. Evidently, there is a clear need for the development of new agents with novel mechanisms of action in this disease. A number of biological agents modulating different signal transduction pathways are currently in clinical development, inhibiting angiogenesis, targeting epidermal growth factor receptor, cell cycle, histone deacetylases, cyclooxygenase-2 (COX-2), or mammalian target of rapamycin (mTOR). This is the first systematic review of the literature to synthesize all available data emerging from trials and evaluate the efficacy and safety of molecularly targeted drugs in cervical cancer. However, it should be stressed that relatively fewer molecularly targeted agents have been tested in cervical cancer in comparison with other cancer types; of note, no related phase 3 trials have been published and consequently no agent has been approved for use in clinical practice. Nevertheless, the promising results of bevacizumab in therapeutic trials for cervical cancer have shown that targeting the VEGF pathway is an attractive therapeutic strategy. As knowledge accumulates on the molecular mechanisms underlying carcinogenesis in the cervix, the anticipated development and assessment of molecularly targeted agents may offer a promising perspective for cervical cancer.     

EFEMP1 expression promotes angiogenesis and accelerates the growth of cervical cancer in vivo

Objective

The study was to investigate the role of EFEMP1 in angiogenesis and growth of cervical carcinoma in vivo.

Methods

Effects of EFEMP1 on proliferation of Hela cells and HUVECs, invasion of Hela cells and migration of HUVECs, and adhesion of Hela cells to HUVECs were evaluated by MTT, Transwell chamber assay and adhesion assay, respectively. EFEMP1 overexpression in Hela cells was achieved by stable EFEMP1 gene transfection into Hela cells by Lipofectamin™ 2000 and the effectiveness of transfection was verified with western-blotting. The effect of EFEMP1 transfection upon the VEGF expression of Hela cells was detected with ELISA. The nude mouse models bearing cervical cancer were established with Hela cells transfected with EFEMP1 gene to observe the role of EFEMP1 in angiogenesis and growth of cervical cancer in vivo. VEGF expression and microvascular density of cervical cancer tissues were detected with immunohistochemistry and CD34 labeling respectively to elucidate the pathway by which EFEMP1 influences the growth of cervical cancer.

Results

Proliferation and invasion of Hela cells were promoted by the EFEMP1 protein. The EFEMP1 gene transfection into Hela cells was successful and EFEMP1 gene obtained stable high expression in Hela cells. Compared to the control, the tumors with EFEMP1 overexpression showed a faster growth rate and had a higher level of VEGF expression and microvascular density. EFEMP1 gene transfection elevated the VEGF protein level in Hela cells and EFEMP1 protein facilitated the adhesion of Hela cells to HUVECs. However, no direct effect of EFEMP1 was observed on proliferation, migration and tube formation of HUVECs.

Conclusions

EFEMP1 promoted the angiogenesis and accelerated the growth of cervical carcinoma in vivo through a VEGF up-regulation pathway.     

Loss of cell-surface heparan sulfate expression in both cervical intraepithelial neoplasm and invasive cervical cancer

OBJECTIVE: Syndecan-1 binds to various extracellular matrix components via its heparan sulfate glycosaminoglycans (HS-GAG) and most of its biological functions are considered to be associated with this process. The aims of this study are to investigate its expression in cervical neoplasms. METHODS: We investigated the expression of both the syndecan-1 core protein and cell-surface HS-GAG by immunohistochemistry in 53 cervical intraepithelial neoplasm (CIN), 19 microinvasive, 143 invasive cervical cancers, and 29 metastatic lymph node samples, and analyzed correlations with various clinicopathological features. RESULTS: The progression of CIN to early invasive cancer was found to associate with reduced levels of both syndecan-1 and HS-GAG expression. In squamous cell carcinomas, HS-GAG expression was significantly lower in cases with lymph-vascular space invasion. Additionally, the overall survival rates for patients exhibiting low HS-GAG expression was significantly lower than patients exhibiting high HS-GAG expression (P = 0.019). Low HS-GAG expression in positive nodes was determined to be a disease-free and overall survival prognostic factor (P = 0.028 and P = 0.018, respectively). CONCLUSION:The loss of syndecan-1 and HS-GAG expression is an early event in cervical carcinogenesis. The loss of HS-GAG expression particularly in positive nodes can serve as an indicator of aggressive disease potential and poor prognosis in patients with invasive cervical cancer.     

BCL-2, in combination with MVP and IGF-1R expression, improves prediction of clinical outcome in complete response cervical carcinoma patients treated by radiochemotherapy

Objectives

To investigate whether BCL-2 expression would improve MVP/IGF-1R prediction of clinical outcome in cervix carcinoma patients treated by radiochemotherapy, and suggest possible mechanisms behind this effect.

Methods

Fifty consecutive patients, who achieved complete response to treatment, from a whole series of 60 cases suffering from non-metastatic localized cervical carcinoma, were prospectively included in this study from July 1999 to December 2003. Follow-up was closed in January 2011. All patients received pelvic radiation (45-64.80 Gy in 1.8-2 Gy fractions) with concomitant cisplatin at 40 mg/m2/week doses followed by brachytherapy. Oncoprotein expression was studied by immunohistochemistry in paraffin-embedded tumour tissue.

Results

No relation was found between BCL-2 and clinicopathological variables. High MVP/IGF-1R/BCL-2 tumour expression was strongly related to poor local and regional disease-free survival (P < 0.0001), distant disease-free survival (P = 0.010), disease-free survival (P < 0.0001), and cause-specific survival (P < 0.0001). NHEJ repair protein Ku70/80 expression was significantly repressed in tumours overexpressing all three oncoproteins (P = 0.047). No differences were observed in proliferation (Ki67 expression) or P53 alteration.

Conclusions

BCL-2, MVP, and IGF-1R overexpression were related to poorer clinical outcome in cervical cancer patients who achieved clinical complete response to radiochemotherapy. The NHEJ repair protein Ku70/80 expression could be involved in the regulation of these oncoproteins.     

Prevalence and clinical relevance of cyclooxygenase-1 and -2 expression in stage IIB cervical adenocarcinoma

Objective

The objective of this study was to determine the relationship between cyclooxygenase (COX)-1 and -2 and prognosis in patients diagnosed with FIGO stage IIB cervical adenocarcinoma who underwent concurrent chemoradiotherapy.

Study design

Twenty-three patients diagnosed with stage IIB cervical adenocarcinoma and treated with concurrent chemoradiotherapy between 1990 and 1995 were included in this study. COX-1 and -2 expression and clinicopathologic features were evaluated. COX-1 and -2 expression was determined by immunohistochemistry.

Results

The prevalence of COX-1 and -2 expression was similar at 73.9%. Significant COX-1 and -2 expression was 47.8 and 60.9%, respectively. COX-2 expression was associated with poor response to treatment and cancer-related death (P = 0.043 and 0.012, respectively). Poor survival was identified in patients who showed high COX-2 expression (P = 0.016). There was no correlation between COX-1 expression and patient prognosis.

Conclusion

Only COX-2 was found to be a potent prognostic factor in patients treated with concurrent chemoradiotherapy for stage IIB cervical adenocarcinoma. However, further studies with more samples are needed to definitely demonstrate the relationship between COX expression and cervical adenocarcinoma.