PAPSS2基因调节雌激素硫酸化失活途径介导子宫内膜异位症恶变的研究

批准号:
81471435
项目类别:
面上项目
资助金额:
73.0 万元
负责人:
徐冰
依托单位:
学科分类:
H0412.子宫内膜异位症与子宫腺肌症
结题年份:
2019
批准年份:
2014
项目状态:
已结题
项目参与者:
谌兵来、付菲、韩扬、钱颖、强素凤、陈文勤、支云清
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中文摘要
研究表明卵巢子宫内膜异位症(EM)可恶变成卵巢癌,但机制未明。前期研究发现,染色体杂合性缺失(LOH)可能与EM 恶变有关;位于高频LOH 位点附近的基因3-磷酸腺苷-5-磷酸腺苷合成酶-2(PAPSS2)可能通过影响雌激素硫酸化参与恶变发生。本课题继续收集符合EM 恶变标准的卵巢癌病例,从DNA、RNA及蛋白水平检测 PAPSS2及雌激素代谢关键酶基因,临床验证在异位上皮细胞、癌细胞及不典型细胞中的差异;进而构建三维培养细胞和PAPSS2基因敲除鼠模型,进行雌激素干预,通过子宫内膜干细胞、基因转染、siRNA等技术,围绕雌激素硫酸化代谢及失活途经研究PAPSS2基因功能。研究将揭示PAPSS2基因可能通过影响雌激素硫酸化关键性底物合成,介导雌激素失活途径受阻,进而诱使局部活性雌激素异常增高, EM恶变发生。为阐明EM 恶变分子机制提供新思路。
英文摘要
Although previous studies have suggested that ovarian endometriosis has malignant potential, the molecular mechanism underlying the malignant transformation is poorly understood. We previously reported that high frequency LOH on some chromosome loci may play an important role during the malignant transformation, and the gene PAPSS2 located on chromosome 10q23-24 may be involved in the process via imbalance of estrogen sulfation. In the present study, we examine PAPSS2 and related estrogen metabolizing genes at the levels of DNA, RNA and proteins using specimens of ovarian cancer arising from endometriosis that fulfill the histological criteria and compare the differences between the epithelial cells, cancer cells and atypical cells in the same cases. Furthermore, we establish the models of spheroid cell culture and PAPSS2 gene knockout mice. We focus study on PAPSS2's functions regugulating to estrogen sulfation and metabolism pathways using stem cell, gene transfection, siRNA and gene knockout techniques. The study will help to clarify that PAPSS2 gene may mediate the malignant transformation of endometriosis via blocking sulfation substrate synthesis, which in turn induces abberant estrogen inactivation and high local estrogen accumulation.The study will supply new perspectives for elucidating the genetic mechanisms of malignant transformation of endometriosis.
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