摘要
研究背景：子宫颈癌是女性生殖系统最常见的恶性肿瘤之一，在一些发展中国家妇女中其发病率仍居第一位。文献报道，从1980年至2010年，子宫颈癌患者每年从37.8万增加到45.4万，平均年增长率为0.6%。在发展中国家，76%的子宫颈癌发生在不发达地区。近年来随着宫颈癌普查普治工作的广泛开展，一些国家和地区的宫颈癌患病率和死亡率明显下降，但是年轻妇女宫颈癌的发病率有上升趋势。同处新疆的维吾尔族与哈萨克族相比，前者死亡率较后者（9.67/10万）高一倍左右。目前，手术、放化疗是宫颈癌的主要治疗手段。对于早期宫颈癌患者，手术治疗是较为有效的治疗方法；但是中晚期宫颈癌患者失去手术机会，不得不采用放化疗方法治疗，放化疗的副作用常常使治疗难以继续进行。浸润和转移是宫颈癌疗效差、预后不良的重要因素，因此深入研究宫颈癌浸润、转移的机制对其临床治疗具有重要的意义。多年研究表明，为满足快速增殖、分裂和侵袭转移的需要，肿瘤细胞内一系列酶的活性和表达会发生改变，细胞基本结构成分如蛋白质、脂类和核酸的合成加强。癌细胞所有生命活动都离不开水的微环境和参与，它比正常细胞更需要水分子的快速跨膜转运，同时癌细胞向周围基质浸润和进出血管（淋巴管）时需要其体积和细胞形态的改变。水通道蛋白（AQPs）是一组能选择性跨细胞质膜由渗透压驱动转运水分子的小而完整的糖蛋白，迄今为止共发现有13个成员（AQP0-12）。源于基因敲除小鼠的大量研究提示AQPs参与的生理病理功能有尿的浓缩、外分泌腺分泌、脑水肿、神经信号传导、皮肤水分增加、脂肪代谢等。近期对AQPs的一些研究提示AQPs参与细胞的迁移和增殖，可能增强肿瘤的局部侵袭力和通过血管（淋巴管）转移的能力。本研究应用荧光实时定量PCR（Real-Time PCR，RT-PCR）、免疫荧光及免疫组织化学初步筛选出在子宫颈癌中特异表达的AQP1、AQP3、AQP8三个亚型，选取AQP8基因作为目的基因，然后通过荧光蛋白标记的慢病毒载体转染入SiHa细胞基因组内，分别从AQP8基因过表达和表达沉默两方面，探讨AQP8基因对SiHa细胞迁移、增殖、基质贴附及局部浸润的影响。目的：筛选在子宫颈癌中特异表达的AQP亚型，探讨特异AQP亚型对子宫颈癌细胞体外、体内迁移增殖、基质贴附及局部浸润的影响。方法：1）通过水通透性实验比较四种人子宫颈癌细胞系SiHa、HeLa、Caski、ME-180水通透性差异，从中选择水通透性低的细胞系作为实验用细胞系，应用RT-PCR、免疫荧光筛选子宫颈癌细胞系中特异表达的AQP亚型，进一步通过免疫组化筛选子宫颈癌组织中特异表达的AQP亚型；2）构建AQP8过表达质粒pLVX-AQP8-IRES-tdTomato→用磷酸钙转染方法包装慢病毒→感染SiHa细胞→通过红色荧光蛋白（red fluorescence protein，RFP）报告基因筛选稳定过表达AQP8基因的SiHa细胞系；构建AQP8基因沉默质粒pLVX-shRNA2-AQP8-1、 pLVX-shRNA2-AQP8-2、 pLVX-shRNA2-AQP8-3和pLVX-shRNA2-AQP8-4→用lipofectamine2000转染293T细胞，通过Western Blot筛选基因沉默效率最高的质粒→用磷酸钙转染方法包装慢病毒→感染SiHa细胞→通过绿色荧光蛋白（green fluorescence protein，GFP）报告基因筛选稳定AQP8基因沉默的SiHa细胞系；3）通过Transwell侵袭和迁移实验、损伤愈合实验、细胞增殖及贴附实验和裸鼠皮下移植瘤等体外、体内实验探讨AQP8基因对SiHa细胞迁移及局部浸润的影响。结果：1）SiHa中100mOsm与300mOsm、200mOsm与300mOsm组间水通透性差异无统计学意义（P＞0.05），400mOsm与300mOsm、500mOsm与300mOsm组间水通透性差异有统计学意义（P＜0.05）；Caski中100mOsm与300mOsm、200mOsm与300mOsm、500mOsm与300mOsm组间水通透性差异有统计学意义（P＜0.05），400mOsm与300mOsm组间水通透性差异无统计学意义（P＞0.05）；HeLa中100mOsm与300mOsm、400mOsm与300mOsm组间水通透性差异有统计学意义（P＜0.05），200mOsm与300mOsm、500mOsm与300mOsm组间水通透性差异无统计学意义（P＞0.05）；ME-180中各组间水通透性差异均有统计学意义（P＜0.05）；SiHa中表达的特异AQPs亚型有AQP0、AQP1、AQP2、AQP3、AQP4、AQP5、AQP8。AQP1在慢性宫颈炎、CIN2～3和子宫颈癌组的微血管密度分别是43.6±17.8、56.2±11.6、70.8±21.1，三组间差异有统计学意义（P＜0.05）；AQP3在慢性宫颈炎、CIN2～3和子宫颈癌组的阳性率分别是13.33%、26.67%、48.57%，子宫颈癌组与慢性宫颈炎组间差异有统计学意义（P＜0.05）；AQP8在三组间的阳性率分别是46.67%、86.67%、54.29%，三组间差异有统计学意义（P＜0.05）；2）成功构建AQP8基因过表达的稳定转染SiHa细胞系和AQP8基因沉默的稳定转染SiHa细胞系；（3）AQP8-SiHa侵袭迁移率明显高于对照组（P＜0.05）；AQP8-SiHa愈合速度明显快于对照组（P＜0.05）；增殖及贴附能力AQP8-SiHa与对照组相比无明显差异（P＞0.05）；皮下移植瘤实验显示AQP8-SiHa组肿瘤向皮下脂肪及肌肉组织指样浸润，但对肿瘤大小无明显影响（P＞0.05）。AQP8shRNA-SiHa侵袭迁移率明显低于对照组（P＜0.05）；AQP8shRNA-SiHa愈合速度明显低于对照组（P＜0.05）；增殖及基质贴附能力AQP8shRNA-SiHa与对照组相比无明显差异（P＞0.05）。结论：1）SiHa细胞水通透性最低，在SiHa细胞中表达的AQP亚型可能与Siha细胞的迁移及转移有关；AQP1、AQP3和AQP8的表达可能与子宫颈癌的发生、发展有关；2）本实验建立的AQP8及AQP8shRNA稳定转染SiHa细胞系将用于后续实验宫颈癌中AQP8基因的功能研究，为从体外及体内研究AQP8在子宫颈癌细胞的迁移、浸润中的作用提供了基础；3）AQP8基因的过表达促进SiHa人子宫颈癌细胞的迁移及局部浸润，抑制AQP8基因表达可以抑制SiHa细胞的迁移和潜在的侵袭过程，AQP8可能参与肿瘤的侵袭过程。
Back ground: Cancer of cervix is the most common one of malignant tumors in thefemale genital system, it is still the first incidence in the women in some developpingcountries. Some documents reported that patients of cancer of cervix increased from378,000to454,000from1980to2010, the mean annual incremental rate was0.6%. In somedevelopping countries,76%of cervical cancer patients take residence in unde-veloppedareas. For the past few years, along with widespread mass screening for cancer of cervix,the prevalence and mortality for cancer of cervix descend obviously in some countriesand regions, but incidence of cancer of cervix for young women takes on increasingtendency. In Xinjiang, compared with Hazakh, the death rate of the Uygur nationalitywas higher about one time than Hazakh (9.67/100,000). Now, operation andchemoradiation are the leading therapeutic tools for cance of cervix. For cervical cancerpatients in the early stage, operation is more effective therapy, chemoradiation has to beused because the cervical cancer patients in the middle or advanced stage have nooperation opportunity, but the side-effects of chemoradiation often make therapies not tokeep going. Metastasis and infiltration are the important factors of mal-curative effectand unfavourable prognosis for cancer of cervix, so further study on the mechanism ofmetastasis and infiltration of cancer of cervix is of the considerable significance for itsclinical treatment. Researches of many years show that enzymatic active and expressionin tumor cells can change to adapt to their fast proliferation, mitoses, infilitration andmetastasis, for example, synthesis of protein, lipids and nucleic acid enhance. All vitalmovements of cancer cells depend on water microenvironment, which furtherly needsfast water transmembrane transport compared with normal cells, and the volume andmorphology of cancer cells will change when they infiltrate surrounding substrates andblood or lymphatic vessels. A lot of studies from knockout mice implicate AQPs to takepart in many expected physiological functions, including urine concentration andexocrine gland secretion, as well as, including brain swelling, neural signal transduction, skin moisturization, and fat metabolism. The aquaporins (AQPs) are a family of small,integrate glucoproteins, facilitating osmotically driven water transport selectively acrosscell plasma membranes. Up to now, there are13members (AQP0～12). Recently somestudies on AQPs indicated that AQPs took part in cell migration and proliferation andenhanced local invasiveness and metastasis via blood and lymph vessels. In this study,preliminarily screening AQP1, AQP3, and AQP8subtypes expressing in cancer of cervixby using flourescent real-time PCR (RT-PCR), immunofluorescence and immunohisto-chemistry, and then selecting AQP8gene as the aim gene, transfecting aim gene AQP8into SiHa cells by lentivirus vector, probing the AQP8influence on migration, prolifera-tion, substrate adherence and local invasiveness of SiHa cells according to AQP8geneoverexpression and expression silence, respectively. Objective: To screen AQPssubtypes idio-expressing in cancer of cervix, and to investigate AQP subset effects onmigration, proliferation, substrate adherence and local invasiveness of SiHa cells in vivoand in vitro. Methods:1) Comparing the difference of osmotic water permeability in4kinds of cervical carcinoma cell lines SiHa, HeLa, Caski, ME-180by osmotic waterpermeability measurement and selecting cervical carcinoma cell line of low waterpermeability for the experiment, and then examining expression of isoforms ofaquaporins by Real-Time PCR and immunofluorescence, furtherly selecting idio-aquaporins expressing in cervical carcinoma tissues by immunohistochemistry;2)Building AQP8overexpression plasmid pLVX-AQP8-IRES-tdTomato, packaginglentivirus particles by calcium phosphate transfection, then infect SiHa cells, screeningstably expressing AQP8SiHa cell line by RFP (red fluorescence protein) reporter gene;building AQP8gene silent plasmids, pLVX-shRNA2-AQP8-1, pLVX-shRNA2-AQP8-2,pLVX-shRNA2-AQP8-3and pLVX-shRNA2-AQP8-4, transfecting293T cells usinglipofectamine2000, screening highest silent rate plasmid by Western Blot, packaginglentivirus particles by calcium phosphate transfection, then infecting SiHa cells,screening stably expressing AQP8gene silence SiHa cell line by GFP (greenfluorescence protein) reporter gene;3) Probing AQP8gene influence on migration andlocal invasion of SiHa cells by transwell migration and invasion assays, wound healingassay, tumor cell growth, substrate adherence assays and subcutaneous xenografts assay.Results:1) In SiHa, osmotic water permeability differences between100mOsm and300mOsm groups,200mOsm and300mOsm groups were not significant (P＞0.05),osmotic water permeability differences between400mOsm and300mOsm groups,500mOsm and300mOsm groups were significant (P＜0.05); In Caski, osmotic water permeability differences between100mOsm and300mOsm groups,200mOsm and300mOsm,500mOsm and300mOsm groups were significant (P＜0.05), osmotic waterpermeability differences between400mOsm and300mOsm groups were not significant(P＞0.05); In HeLa, osmotic water permeability differences between100mOsm and300mOsm groups,400mOsm and300mOsm groups were significant (P＜0.05), osmoticwater permeability differences between200mOsm and300mOsm,500mOsm and300mOsm groups were not significant (P＞0.05); In ME-180, osmotic water permeabilitydifferences among groups were significant (P＜0.05); AQP0, AQP1, AQP2, AQP3,AQP4, AQP5, AQP8were isoforms of aquaporins expressing in SiHa cells; MVD ofAQP1were43.6±17.8,56.2±11.6,70.8±21.1, respectively, in control group, CIN3and cervical carcinoma group. Difference among three groups was significant (P＜0.05);Positive rates of AQP3were13.33%,26.67%,48.57%, respectively, in control group,CIN3and cervical carcinoma group. Difference between cervical carcinoma and controlgroup was significant (P＜0.05); Positive rates of AQP8were46.67%,86.67%,54.29%,respectively, in the three groups. Difference among three groups was significant (P＜0.05);2) Sucessfully building stable infection SiHa cell lines expressing AQP8gene andsilencing AQP8gene;3) Migration and invasion rate of AQP8-SiHa was obviouslyquicker than control groups (P＜0.05); Wound healing speed of AQP8-SiHa wasobviously quicker than control groups (P＜0.05); The difference of proliferation andsubstrate adherence between AQP8-SiHa and control groups was not significant (P＞0.05); The xenografts with AQP8showed finger-like local invasiveness intosubcutaneous adipose and muscle, but had no effects on tumor volumes (P＞0.05);Migration and invasion rate of AQP8shRNA-SiHa was obviously lower than controlgroups (P＜0.05); Wound healing speed of AQP8shRNA-SiHa was obviously lower thancontrol groups (P＜0.05); The difference of proliferation and substrate adherencebetween AQP8shRNA-SiHa and control groups was not significant (P＞0.05); Thexenografts with AQP8shRNA showed no significance in local invasion and tumorvolumes compared with control group (P＞0.05). Conclusions:1) Osmotic waterpermeability of SiHa cells is the lowest, and subsets of aquaporins expressing in Sihacells may be related with their migration and infiltration; Expression of AQP1, AQP3andAQP8in cervical carcinoma may be related with cervical carcinogenesis anddevelopment;2) Stable infection SiHa cell lines expressing AQP8gene and AQP8shRNA are used to study AQP8gene function in cervical carcinoma, and provide theresearch basis for AQP8gene effects on the migration and invasion of SiHa cells in vivo and in vitro;3) Overexpression of AQP8gene facilitates the migration and localinvasiveness potential of SiHa cells, suppression of AQP8gene expression can inhibit themigration and local invasiveness potential of SiHa cells, AQP8gene may participate inthe invasive process of tumors.
引文
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