聚焦超声治疗对外阴低级别鳞状上皮内病变模型大鼠外阴皮肤缺氧诱导因子1α、血管内皮生长因子及突变型p53表达的影响
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摘要
目的探讨聚焦超声治疗对外阴低级别鳞状上皮内病变(LSIL)模型大鼠外阴皮肤中缺氧诱导因子1α(HIF-1α)、血管内皮生长因子(VEGF)及突变型p53(mtp53)表达的影响。方法建立28只外阴LSIL大鼠模型,随机分为治疗组(n=14)及对照组(n=14)。治疗组予以聚焦超声辐照,对照组予超声假辐照(治疗仪无功率输出)。4周后取模型大鼠外阴皮肤行组织病理学观察,并以免疫组织化学方法检测HIF-1α、VEGF及mtp53表达。结果聚焦超声辐照/假照后4周治疗组92.86%(13/14)外阴皮肤基本恢复正常生理结构,对照组71.43%(10/14)进展为高级别鳞状上皮内病变(HSIL)。治疗组大鼠外阴皮肤中HIF-1α、VEGF及mtp53表达均明显低于对照组(P均<0.05)。结论聚焦超声可通过降低HIF-1α、VEGF及mtp53表达,改善局部组织微环境而安全、有效治疗大鼠外阴LSIL。
Objective To explore the impact of focused ultrasound on expression of hypoxia inducible factor-1α(HIF-1α),vascular endothelial growth factor(VEGF) and mutant type p53(mtp53) in vulvar skin of rat models with low grade squamous intraepithelial lesion(LSIL). Methods A total of 28 rat models with LSIL were established and randomly divided into treatment group and control group(each n=14). The rat models in treatment group were treated with focused ultrasound, while in control group only received sham irradiation(no power output from ultrasonic therapeutic instrument). Histological changes of vulvar skin in SD rats were observed 4 weeks later. The expression of HIF-1α, VEGF and mtp53 protein were detected using immunohistochemistry. Results After 4 weeks of focused ultrasound irradiation/sham irradiation, there were 92.86%(13/14) rats return to normal in treatment group and 71.43%(10/14) rats progressed into high grade squamous intraepithelial lesion(HSIL) in control group. Compared with control group, HIF-1α, VEGF and mtp53 protein levels significantly decreased in treatment group(all P<0.05). Conclusion Focused ultrasound treatment can improve the microenvironment of local vulvar tissue by decreasing the expression of HIF-1α, VEGF and mtp53 in vulvar skin, therefore can be used to treat LSIL safely and effectively in rat models.
Objective To explore the impact of focused ultrasound on expression of hypoxia inducible factor-1α(HIF-1α),vascular endothelial growth factor(VEGF) and mutant type p53(mtp53) in vulvar skin of rat models with low grade squamous intraepithelial lesion(LSIL). Methods A total of 28 rat models with LSIL were established and randomly divided into treatment group and control group(each n=14). The rat models in treatment group were treated with focused ultrasound, while in control group only received sham irradiation(no power output from ultrasonic therapeutic instrument). Histological changes of vulvar skin in SD rats were observed 4 weeks later. The expression of HIF-1α, VEGF and mtp53 protein were detected using immunohistochemistry. Results After 4 weeks of focused ultrasound irradiation/sham irradiation, there were 92.86%(13/14) rats return to normal in treatment group and 71.43%(10/14) rats progressed into high grade squamous intraepithelial lesion(HSIL) in control group. Compared with control group, HIF-1α, VEGF and mtp53 protein levels significantly decreased in treatment group(all P<0.05). Conclusion Focused ultrasound treatment can improve the microenvironment of local vulvar tissue by decreasing the expression of HIF-1α, VEGF and mtp53 in vulvar skin, therefore can be used to treat LSIL safely and effectively in rat models.
引文
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[18] 杜善平,张键,段英梅,等.缺氧诱导因子-1α蛋白在外阴癌组织中的表达及临床意义.现代肿瘤医学,2013,21(10):2313-2315.
[19] Karaman S,Lepp?nen VM,Alitalo K.Vascular endothelial growth factor signaling in development and disease.Development,2018,145(14):dev151019.
[20] Li YZ,Li SL,Li X,et al.Expression of endogenous hypoxia markers in vulvar squamous cell carcinoma.Asian Pac J Cancer Prev,2012,13(8):3675-3680.
[21] Molchadsky A,Rotter V.p53 and its mutants on the slippery road from stemness to carcinogenesis.Carcinogenesis,2017,38(4):347-358.
[22] 侯学涛,王丽君,李敏,等.HPV、突变型p53和COX-2在外阴HPV感染相关疾病的表达及意义.现代妇产科进展,2013,22(7):575-577.
[2] Kurman RJ,Carcangiu ML,Herrington CS,et al.WHO classification of tumours of female reproductive organs.4th ed.Lyon:IARC Press,2014:228-253.
[3] Xue X,Yi BM,Peng B,et al.Vulvar cancer in China:Epidemiological features and risk analysis.J Cancer,2017,8(15):2950-2958.
[4] ?sterg?rd S,Vorbeck CS,Meinert M.Vulvar intraepithelial neoplasia.Ugeskr Laeger,2018,180(20):V12170931.
[5] 何小丽,肖松舒,邓新粮,等.HIFU治疗VINⅠ～Ⅱ的临床分析(附病例18例).临床医学工程,2014,21(10):1234-1235.
[6] 罗桂娟,肖松舒,邓新粮.高强度聚焦超声治疗外阴上皮内瘤变Ⅰ级的临床分析.临床超声医学志,2014,16(12):857-859.
[7] 陈丽萍,刘毅,范秀芳,等.聚焦超声治疗129/J小鼠外阴上皮内瘤变模型的实验研究.科技导报,2009,27(9):34-38.
[8] Jia Y,Wu J,Chen L,et al.Focused ultrasound therapy for vulvar intraepithelial neoplasia in a mice model.Am J Med Sci,2013,346(4):303-307.
[9] Jia Y,Wu J,Xu M,et al.Clinical responses to focused ultrasound applied to women with vulval intraepithelial neoplasia.J Ultrasound Med,2014,33(11):1903-1908.
[10] 范艺巾,唐华均,刘瑶,等.二甲基苯并蒽诱导外阴鳞状上皮内病变大鼠模型的建立.南方医科大学学报,2018,38(11):1318-1324.
[11] 王智彪.聚焦超声治疗技术在妇科领域的研究与应用.中华妇产科杂志,2006,41(9):638-640.
[12] Ji Y,Hu K,Zhang Y,et al.High-intensity focused ultrasound (HIFU) treatment for uterine fibroids:A meta-analysis.Arch Gynecol Obstet,2017,296(6):1181-1188.
[13] Tang X,Gao Z,Li Y,et al.Efficacy and safety of focused ultrasound versus microwave therapy for cervical ectopy:A meta-analysis.J Evid Based Med,2015,8(2):61-74.
[14] Zhang L,Zhang W,Orsi F,et al.Ultrasound-guided high intensity focused ultrasound for the treatment of gynaecological diseases:A review of safety and efficacy.Int J Hyperthermia,2015,31(3):280-284.
[15] Wu C,Zou M,Xiong Y,et al.Short- and long-term efficacy of focused ultrasound therapy for non-neoplastic epithelial disorders of the vulva.BJOG,2017,124(Suppl 3):87-92.
[16] 李继强,陈谦学.缺氧诱导因子1α相关信号通路与肿瘤关系的研究进展.医学综述,2015,21(24):4460-4464.
[17] Semenza GL.Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics.Oncogene,2010,29(5):625-634.
[18] 杜善平,张键,段英梅,等.缺氧诱导因子-1α蛋白在外阴癌组织中的表达及临床意义.现代肿瘤医学,2013,21(10):2313-2315.
[19] Karaman S,Lepp?nen VM,Alitalo K.Vascular endothelial growth factor signaling in development and disease.Development,2018,145(14):dev151019.
[20] Li YZ,Li SL,Li X,et al.Expression of endogenous hypoxia markers in vulvar squamous cell carcinoma.Asian Pac J Cancer Prev,2012,13(8):3675-3680.
[21] Molchadsky A,Rotter V.p53 and its mutants on the slippery road from stemness to carcinogenesis.Carcinogenesis,2017,38(4):347-358.
[22] 侯学涛,王丽君,李敏,等.HPV、突变型p53和COX-2在外阴HPV感染相关疾病的表达及意义.现代妇产科进展,2013,22(7):575-577.