| Background and ObjectiveCervical carcinoma is the most common threat of gynecology malignant tumorswhich severely endangers Chinese women health and life. Although it is clear that90%of the patients with cervical cancer are linked with Human papilloma virus(HPV), only a small fraction of patients infected with HPV would develop intocervical cancer. Persistent high-risk types HPV infection is the first step; however, themolecular mechanisms which contribute to cervical cancer progression anddevelopment have not been established. Therefore, it is an urgent problem to establisha multistep model to find out more sufficient and necessary mechanisms that couldaffect the final outcome of cancer. In addition, for some cervical adenocarcinoma anda small part of cervical squamous carcinoma patients, it is uneasy to detect. It is notenough to screen high-risk patients to rely on the cervical lesions three ladderdiagnosis (cytology, colposcope and histologic examination). In the treatment, it islimited to use operations and operations may damage the reproductive function ofyoung patients. Chemotherapy and radiotherapy have not absolutely affect onadenocarcinoma patients, because these types of tissue may be non-sensitive toradical therapy and chemical drugs. Carcinoma has multicellular-meditated resistance, which could plus a poor prognosis. Thus, to find out more higher sensitive andspecific test methods for early patients and more practical and effective targetedtreatments, it is an important and essential subject for the treatment of cervicalcarcinoma.Recent most international studies show that the activation of canonicalWnt/β-catenin pathway maybe involve in the progression of HPV-infected cervicaltissue cells to cervical cancer, as the second hit in the multistep carcinogenesis. Acritical hallmark in this pathway is the stabilization of β-catenin in cell plasma and itsaberrant accumulation into the nucleus. In fact, there are many studies betweenaberrant regulation of classical Wnt pathway and some cancer, which related to breastcancer, colon cancer and oral squamous cell carcinoma. However, exploring therelationship between cervical cancer and Wnt pathway is still in the initial stage. Atpresent many scholars have been trying to regulate and interfere withWnt/beta-catenin pathway to adjust the expression of targeted gene, finally to achievethe purpose of preventing cancerous tumors and development of cervical cancer.The expression of telomerase in the early stages of cervical lesions could beassayed, and is closely related to the occurrence and development of cervical lesiondevelopment. Many scholars at home and abroad verified the conclusions bytelomerase amplification method and fluorescence in situ hybridization method, andpointed out that as much as90%cervical cancer tissues have expressed telomerasepositive and hTERC was important for the judgement of the progress and outcome ofcervical lesions. At present telomerase could be not only used as a biological markerof cervical cancer, but also could be effectively used in early screening of cervicalcancer, auxiliary diagnosis and prognosis.Think commonly, tankyrase is an important positive regulating factor ofWnt/beta-catenin pathway, and a telomere binding protein to the core that couldmediate telomere and telomerase in combination and maintain the balance and lengthof telomere. Short telomere and high levels of telomerase have become anearly-detection and late-development signal of an increased risk of cervical tissuemalignant transformation. In2009《Nature》mentioned a chemical smll moleculenamed XAV939, which was identified by a chemical genetic screen manner, and this drugs could selectively prevent beta-catenin-mediated transcription and inhibit thePARP enzymes tankyrase1/2.This study, by means of exploring the effects of XAV939inhibitor onproliferation and apoptosis of cervical cancer cells and studying the relatedmechanisms of the anti-tumor effect, it was to investigate the feasibility of tankyraseinhibitorfors the treatment of cervical carcinoma.Materials and MethodsFirst of all added to the correlative drugs to Hela cells of post-exponential phasein vitro, including different concentrations of sole medication XAV939, nedaplatinand united medication; then observed and detected the apoptosis rate and the cellcycle distribution of Hela cell by MTT assay and flow cytometry; in the end we usewestern blot to evaluate the expression of tankyrase and β-catenin in cervicalcarcinoma cells in vitro treated by different concentrations of XAV939acting48hours.SPSS19.0Statistical analysis software was used to analysis related experientaldata. α=0.05was considered as the detection standard.Results1、With the increasing of XAV939concentration and with the extension of drugaction time, the apoptosis rate of Hela cells actually gradually increased, exhibitingconcentration-and time-dependent manners（P＜0.05）.The combination action athigher concentration and long term between XAV939and NDP could bring inhibitoryaction to the of Hela cells (CI＞1)while at lower concentrationand short term theircombined action was additive effect(CI＜1).2、 In analyses of Hela cultures by flow cytometry, with the increaseofconcentration and drug action timeof XAV939，the presence of anterior G0/G1phase cell accounted for higher proportion than control team（P＜0.05），and thepercentage of S phase showed a trend of decline（P＜0.05）；G0/G1and G2/M phasecells in the fluorescent signal expressed no significant difference.3、According to the westernblottest analysis，we examined the upregulatedexpressions of tankyrase and beta-catenin. At the same time, it revealed that tankyraseand β-catenin was significantly declined in cells under the influence of XAV939. Conclusions1、 XAV939, as a inhibitor of tankyrase1/2, could effectively inhibit theproliferation and induce apoptosis of cervical cancer Hela cells. XAV939couldincrease the sensitivity of nadaplatin at low concentration in the short time; if usingunited drugs in the long time could reduce the effects of NDP2、XAV939could prevent from synthesizing DNA and induce apoptosis ofcervical cancer Hela cells.3、Tankyrase could be used as a potential molecule target for the treatment ofcervical cancer. |
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