摘要
目的：子宫颈癌的早期诊断、规范化治疗及有效病情监测是影响患者预后的关键。本研究首先检测并筛选与维吾尔族妇女子宫颈鳞状细胞癌发生、浸润和转移相关的特异性水通道蛋白（Aquaporin，AQPs）亚型；在基因转录水平和蛋白表达水平检测不同宫颈病变中特异性表达AQPs亚型的表达差异，通过分析AQPs表达与宫颈癌的临床病理资料的关系，寻找特异性AQPs亚型在维吾尔族妇女子宫颈鳞状上皮的恶变、肿瘤周围间质浸润和远处转移中的作用机制；收集与维吾尔族子宫颈癌预后相关的婚产因素、临床病理因素和AQPs表达因素资料，随访患者的无瘤生存时间，寻找对宫颈癌预后有影响的因素，探讨AQPs在维吾尔族子宫颈癌预后随访中的意义。为临床建立以AQPs为标准的分子指标进行子宫颈癌的早期诊断和疾病监控提供理论依据。方法：1）选取2例早期子宫颈癌、2例晚期子宫颈癌（实验组）和2例宫颈炎组织（对照组），TRIzol一步法提取组织中的总DNA，鉴定总RNA的质量，应用Real-time RT-PCR检测存在于女性生殖系统的AQPs亚型（AQP1，AQP2，AQP3，AQP4，AQP5和AQP8），从基因转录水平筛选在宫颈癌中特异性表达的AQPs亚型；2）选取10例宫颈炎（对照组）和18例宫颈癌（实验组）组织应用免疫荧光法检测存在于女性生殖系统的六种AQPs亚型，从蛋白表达水平筛选在宫颈癌中特异性表达的AQPs亚型；3）扩大样本量，选取10例宫颈炎，10例早期宫颈癌和10例晚期宫颈癌组织，应用RealtimeRT-PCR检测特异性AQPs亚型在基因转录水平的差异；4）选取所有进行RealtimeRT-PCR检测标本，即12例宫颈炎，12例早期宫颈癌和12例晚期宫颈癌组织，应用免疫印迹法（Western blot）检测特异性AQPs亚型在蛋白表达水平的差异；5）选取维吾尔族宫颈炎42例，宫颈上皮内瘤变（cervical intraepithelia neoplasiaCIN）I-Ⅱ级31例，CINⅢ级36例和子宫颈癌98例的石蜡标本，应用免疫组织化学法检测特异性AQPs亚型的定位表达，收集子宫颈癌患者的临床病理资料，分析AQPs表达与临床病理参数之间的关系；6）选取我院同期收治的维吾尔族子宫颈鳞癌患者196例，随访调查无瘤生存期，采用对数秩检验对可能影响患者预后的婚产因素、临床病理因素及AQP1、AQP3和AQP8表达因素与宫颈癌生存率的关系进行研究。将单因素分析有意义的因素引入Cox比例风险模型进行多因素分析。寻找与预后相关的独立因素，明确AQPs与维吾尔族子宫颈癌患者预后的关系，以期为临床治疗和判断预后提供依据。结果：1）基因转录水平筛选结果显示AQP1，AQP2，AQP3，AQP5，AQP8mRNA在宫颈炎及宫颈癌组织中均有表达，AQP4未表达。AQP1mRNA在宫颈炎和早期、晚期宫颈癌组织中的表达丰度为1.005±0.0217，1.94±0.18和3.45±1.22；AQP2mRNA在宫颈炎和早期、晚期宫颈癌组织中的表达量丰度1.001±0.0049，1.136±0.0604和1.65±0.134；AQP3mRNA在宫颈炎和早期、晚期宫颈癌组织中的表达丰度为1.047±0.17，1.82±0.0667和4.10±0.12；AQP5mRNA在宫颈炎和早期、晚期宫颈癌组织中的表达丰度为1.016±0.0662，0.899±0.169和1.82±0.815；AQP8mRNA在宫颈炎和早期、晚期宫颈癌组织的表达丰度为1.000±0.000312，2.33±1.32和5.29±5.04。AQP1，AQP2，AQP3和AQP8mRNA在宫颈炎和早期、晚期宫颈癌的表达呈递增趋势，差异均无统计学意义（P＞0.05）；AQP5mRNA在早期宫颈癌中的表达低于宫颈炎，差异无统计学意义（P＞0.05）。2）蛋白表达水平筛选结果显示AQP1，AQP3和AQP8蛋白在宫颈炎及宫颈癌组织中表达，AQP2，AQP4和AQP5在宫颈炎和子宫颈癌组织中未表达。AQP1表达于血管内皮细胞，AQP1微血管密度测定值（microvessel density，MVD）在宫颈炎和宫颈癌为49.94±4.07和76.51±3.31，差异有统计学意义（P＜0.05）。AQP3表达于正常鳞状上皮细胞和宫颈癌肿瘤细胞的胞膜，AQP3在宫颈炎和宫颈癌的阳性表达率分别为20%和66.67%，差异有统计学意义（P＜0.05）。AQP8表达于宫颈癌肿瘤细胞的胞膜，AQP8在宫颈炎和宫颈癌的阳性表达率分别为30%和72.22%，差异有统计学意义（P＜0.05）。3）扩大样本检测AQP1，AQP3和AQP8mRNA在宫颈炎、早期、晚期宫颈癌组织中的表达，结果显示AQP1，AQP3和AQP8的表达丰度呈上调趋势，差异有统计学意义（P＜0.05）。AQP1mRNA表达丰度分别为1.0067±0.01581，1.770±0.005518和3.954±0.2617，差异有统计学意义（P＜0.05）；AQP3mRNA表达丰度分别为1.008±0.01886，1.999±0.06361和3.721±0.1660，差异有统计学意义（P＜0.05）；AQP8mRNA表达丰度分别为1.0106±0.02255，1.874±0.02854和3.5447±0.1878，差异有统计学意义（P＜0.05）。4）AQP1，AQP3，AQP8蛋白在宫颈炎、早期、晚期宫颈癌组织中的表达浓度存在差异，均呈上调趋势。AQP1蛋白表达浓度为0.9195±0.1351，1.460±0.2963和2.624±0.6603，差异有统计学意义（P＜0.05）；AQP3蛋白表达浓度分别为0.0056±0.00293，0.6362±0.1452，0.9926±0.2173差异有统计学意义（P＜0.05）；AQP8蛋白表达浓度分别为1.113±0.2302，1.725±0.2362，2.607±0.6830差异有统计学意义（P＜0.05）。5）AQP1表达于血管内皮细胞，AQP1/MVD在宫颈炎、CINⅠ-Ⅱ级、CINⅢ和宫颈癌组织中的表达分别为37.51±14.62，40.1±15.32，56.05±27.51，69.84±34.93，呈递增趋势，差异有统计学意义（P＜0.05）。随着宫颈病变级别的升高，呈现逐渐升高的进行性趋势。AQP1高表达于宫颈癌临床分期晚、肿瘤直径大，浸润深，淋巴结转移阳性和外生型肿瘤。AQP3表达于宫颈炎鳞状上皮细胞、宫颈上皮内瘤变不典型鳞状细胞和宫颈鳞癌肿瘤细胞的细胞膜，AQP3在宫颈炎、CINⅠ-Ⅱ级、CINⅢ和宫颈癌组织中的阳性表达率为16.67%，18.6%，27.78%和44.9%，差异有统计学意义（P＜0.05）。AQP8表达于宫颈炎鳞状上皮细胞、宫颈上皮内瘤变不典型鳞状细胞和宫颈鳞癌肿瘤细胞的细胞膜，AQP8在宫颈炎、CINⅠ-Ⅱ级、CINⅢ级和宫颈癌组织中的阳性表达率为38.38%，41.93%，91.67%和56.12%，差异有统计学意义（P＜0.05）。虽然AQP8在宫颈癌中的表达高于宫颈炎、CINⅠ-Ⅱ级，但低于CINⅢ级中的表达。AQP8高表达于临床分期晚、肿瘤直径大，浸润深和淋巴结转移阳性的肿瘤。6）影响维吾尔族子宫颈癌患者预后的因素有临床分期、治疗方式、肿瘤直径、浸润深度、淋巴结转移、HPV感染、血清SCC-Ag、AQP1、AQP3和AQP8，其中临床分期，肿瘤直径和淋巴结转移是独立影响因素。AQP1，AQP3和AQP8表达是影响子宫颈癌预后的危险因素，但并非独立影响因素。分析AQPs影响维吾尔族子宫颈癌患者预后的原因，可能是通过促进肿瘤细胞增殖、迁移造成肿瘤体积增大，侵入周围间质，侵袭周围淋巴管并破坏淋巴管转移至淋巴结造成远处转移，从而影响维吾尔族子宫颈癌患者影响疾病预后。结论：1）本研究通过筛查存在于女性生殖系统并与维吾尔族妇女子宫颈鳞状细胞恶性转化相关的特异性AQPs亚型，发现AQP1，AQP3和AQP8可能在宫颈癌发生、浸润和转移过程中发挥一定的作用；2）AQP1，AQP3和AQP8在基因转录水平表达上调，导致转录、翻译的蛋白合成增加，导致子宫颈鳞状细胞恶变、浸润和远处转移。AQP1在子宫颈癌肿瘤间质内微、小血管内皮细胞的高表达可以引起肿瘤间质内新生血管生成增多，并通过促进新生微血管的通透性增高和内皮细胞迁移，满足肿瘤细胞高生长代谢的需要；AQP3和AQP8在宫颈癌肿瘤细胞中的高表达能促进癌细胞快速增殖，肿瘤细胞运动和侵袭能力增强；三者的协同作用，使肿瘤体积增大，通过血管、淋巴管向周围间质浸润，浸润至淋巴结向远处转移。AQP1，AQP3和AQP8在维吾尔族子宫颈癌发生、发展中可能是癌基因，在宫颈癌组织中的特异性分布、表达除了可能是宫颈癌发生的潜在因素，并在肿瘤细胞向周围间质浸润，并侵犯淋巴结造成远处转移过程中起了一定作用，并有望成为早期判定子宫颈癌和疾病监测的重要分子指标和治疗靶点；3）AQP1，AQP3和AQP8阳性表达患者预后差，但非独立影响因素。AQP1，AQP3和AQP8可能通过促进肿瘤体积增长、间质浸润和淋巴结转移影响患者预后，虽然并非独立影响因素，但是能为维吾尔族子宫颈癌患者的预后判断、制定治疗方案选择提供一定的理论依据。
Objective: It is very significant for patients of cervical carcinoma that earlydiagnosis, normalized treatment and efficient survey. To find the soecufuc aquaporinssubtypes which were differential expressed in occurrence, invasion and metastasis ofcervical squamous carcinoma.To analysis the significance and expression of theseaquaporin subtypes in gene transcription level and protein expression level.To investigatethe mechanism of the specific aquaporin subtypes in cervical carcinogenesis, invasionand metastasis of uygur patients.Select the marriage-pregnant factors, clinicalpathological factors and specific aquaporin expression factors which may be related withthe prognosis and analyzing the follow-up survival data of uygur patients with cervicalcarcinoma. To find the independent factors which affected the prognosis of cervicalcarcinoma and the relationship of specific AQPs expression with prognosis.To provideevidence and new approach for the molecular mechanism, servings standardizedaquaporin molecular index for early diagnosis, prognosis monitoring and curative effect.Methods:1) Total RNA was isolated from2fresh sample of early stage cervicalcarcinoma,2sample of late stage cervical carcinoma,2sample of cervicitis tissues byTRIzol. The mRNA expression of these aquaporin subtypes were detected by RealtimeRT-PCR on gene transcription level which were existed in female reproductive system(AQP1, AQP2, AQP3, AQP4, AQP5, AQP8).2) Select10sample of cervitis18sample ofcervical carcinoma.To screen the protein expression of aquaporin subtypes which wereexpressed in female reproductive system by immunofluorescence technique on proteinlevel.3) The mRNA expression of relavant aquaporin subtypes were detected by real timeRT-PCR on gene transcription level in10sample of cevitis tissue,10sample of earlystage cervical carcinoma and10sample of late-stage cervical carcinoma.4) The proteinexpression of these special aquaporin subtypes were detected by Western blot in12sample of cevitis tissue,12sample of early-stage cervical carcinoma and12sample of late-stage cervical carcinoma in protein level.5) Immunohistochemistry was used todetecte specific aquaporin subtypes protein expression in36sample of cevitis,31sampleof CINⅠ-Ⅱ,36sample of CINⅢ and98sample of cervical carcinoma.And then variousclinical and pathological parameters in cervical carcinoma were investigated andanalysed with specific aquaporin subtypes protein expression.6) Choose196cases ofcervical squamous carcinoma who were treated in hospital and select the clinical andprognostic data.Survival curves were prepared according to the method of Kaplan andMeier, and statistical significance between curves was tested using the log-rank test. TheCox proportional hazard model was also performed to evaluate the independentprognostic value to investigate the correlation with specific aquaporin subtypes. Results:1) AQP1, AQP2, AQP3, AQP5, AQP8mRNA were expressed in cervitis and cervicalcarcinoma in gene transcription level. AQP4mRNA was not detected.The relativeabundance of AQP1were1.005±0.0217，1.94±0.18and3.45±1.22in cervitis, earlystage cervical carcinoma and late stage cervical carcinoma.The relative abundance ofAQP2were1.001±0.0049，1.13±0.0604and1.65±0.134in cervitis, early stagecervical carcinoma and late stage cervical carcinoma. The relative abundance of AQP3were1.04±0.17，1.82±0.0667and4.10±0.12in cervitis, early stage cervical carcinomaand late stage cervical carcinoma. The relative abundance of AQP5were1.016±0.0662，0.899±0.169and1.82±0.815in cervitis, early stage cervical carcinoma and late stagecervical carcinoma. The relative abundance of AQP8were1.000±0.000312，2.33±1.32and5.29±5.04in cervitis, early stage cervical carcinoma and late stage cervicalcarcinoma.The difference of AQP1, AQP2, AQP3, AQP8had no significant in cervitis,early stage cervical carcinoma and late stage cervical carcinoma (P＞0.05). The relativeabundance of AQP5in cervitis was higher than that of cervitis and late stage cervicalcarcinoma. The difference of AQP5was not significant between three groups.2) AQP1,AQP3and AQP8protein expressed in cervitis and cervical carcinoma tissues.AQP2,AQP4and AQP5did not express.AQP1was localized on vascular endothelial. TheAQP1/MVD (microvessel density, MVD) were49.94±4.07and76.51±3.31in cervitisand cervical carcinoma. AQP3was localized on tumor cell membrane. The positive rateof AQP3was20%and66.67%in cervitis and cervical carcinoma.AQP8was localized ontumor cell membrane. The positive rate of AQP8was30%and72.22%in cervitis andcervical carcinoma. The expression of these three protein were all significant different (P＜0.05).3) The relative abundance of AQP1mRNA were1.0067±0.01581,1.770±0.005518and3.954±0.2617; The relative abundance of AQP3mRNA were1.008±0.01886,1.999±0.06361and3.721±0.1660; the relative abundance ofAQP8mRNA were1.0106±0.02255,1.874±0.02854,3.5447±0.1878. The relativeabundanceof AQP1, AQP3and AQP8mRNA were increased and had significantdifference (P＜0.05);4)The protein expression concentration of AQP1were0.9195±0.1351,1.460±0.2963and2.624±0.6603; The protein expression concentration ofAQP3were0.0056±0.002930,0.6362±0.1452,0.9926±0.2173; The protein expressionconcentration of AQP8were1.113±0.2302,1.725±0.2362,2.607±0.6830. Theexpression of AQP1, AQP3and AQP8protein were increased and had significantdifference(P＜0.05).5).AQP1and AQP3protein expression showed a increased tendencygradually from cervitis, precancerous process and cervical cancer.AQP1/MVD were37.51±14.62,40.1±15.32,56.05±27.51,69.84±34.93in in cevitis, CINⅠ-Ⅱ, CINⅢ,cervical carcinoma (P＜0.05). The positive rate of AQP3was16.67%,18.6%,27.78%and44.9%in cervitis, CINⅠ-Ⅱ, CINⅢ and cervical carcinoma (P＜0.05). The positiverate of AQP8was38.38%,41.93%,91.67%and56.12%in cevitis, CINⅠ-Ⅱ, CINⅢ andcervical carcinoma (P＜0.05). The AQP1protein expression was correlated with clinicalstage, diameter of tumor, invasive depth, lymph node metastasis and pathologicalclassification.AQP3protein expression was correlated with clinical stage, diameter oftumor, invasive depth and lymph node metastasis. AQP8protein expression wascorrelated with clinical stage, diameter of tumor, invasive depth and lymph nodemetastasis.6) The proportional hazard factors were clinical stage, treatment,diameter oftumor, depth of invasion, lymph nodal metastasis, HPV infection, SCC-Ag, AQP1, AQP3and AQP8expression. Cox model with stepwise multivariable analysis showed lymphnodal metastasis, clinical stage and diameter of tumor were important factor affecting theprognosis of cervical carcinoma (P＜0.05). The survival rates of AQP1, AQP3and AQP8negative-expression group and positive-expression had significant differences (P＜0.01).AQP1,AQP3and AQP8were one of the factors which affected prognosisi of cervicalcarcinoma,but were not the independent factors.Aquaporins might affect the prognosis ofuygur patients of cervical carcinoma by promoting lymph nodal metastasis and tumorgrowth.Conclusion:1) The study found that AQP1, AQP3, AQP8play important role incervical carcinogenesis of uygur patients. These three special aquaporin subtypes wereselected from the aquaporin subtypes that existed in reproductive system.2) Theexpression of AQP1,AQP3and AQP8upregulated and translated corresponding proteinupregulated,too.And all play important role in carcinogenesis, tumor growth andmetastasis.AQP1were expressed in the endothelial cells of tumor vascular, which increase the expression the angiogenesis and promote tumor growth, mesenchymalinvasion and lymph node metastasis. AQP3and AQP8were expressed in cellularmembrane and/or cytoplasm in tumor cells.which enhanced the movement and invasionability and promote the invasion and metastasis of tumor.These three subtypes showed asynergism.AQP1, AQP3and AQP8may be oncongene and play significant role incarcinogenesis and metastasis of uygur patients and may be a molecular index fordiagnosis, disease survey of uygur patients of cervical carcinoma.3) The survival rates ofAQP1, AQP3and AQP8negative-expression group and positive-expression hadsignificant differences (P＜0.05). Aquaporin may affect the prognosisi of uygur patientsof cervical carcinoma by promoting lymph nodal metastasis and tumor growth.Althoughthey were not independent factor, but provided molecular biology evidence for judgmentand treatment.
引文
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