乳房外Paget病中错配修复基因功能异常与PI3K/AKT通路在侵袭中的作用

Extramammary Paget's disease (EMPD), a rare skin malignant tumor, is predisoposed to misdiagnosed, since there is lack of biomarker for its early diagnosis. We applied high-throughput pralleled seuqncing strategy to screen the genetic alternations in the malignant tissues of EMPD patients, and found 30% of the patients harbored the mutations in MLH1 and MSH2 gene. The PIK3CA and AKT mutations were detected in 35% of the maligancies, which were validated to be relevent to the tumor migration. Given these data, we are justifed to induce that imperiled DNA mismatch repare (MMR) gene function and mutation caused PIK3CA/AKT pathway hyperactivation may play an important role in the pathogenesis and development of EMPD. In this study, we will make a thorough genetic and epigenetic screen on the MMR system, and explain the molecular background and genetic vulnerability of EMPD with a perspective of MMR mutation and silence. This study will also shed a light on the mechanism of the PI3K/AKT pathway activation mediated E-cadherin modulation and its downstream molecular network, providing the diagnosis and treatment of EMPD with a new target and strategy.

乳房外Paget病(extramammary paget's disease，EMPD)是一少见的皮肤恶性肿瘤。由于缺乏分子标志物，患者常被误诊且容易伴发或者继发其他部位的恶性肿瘤，严重影响了患者的预后和生存。我们曾采用二代测序等技术发现30% EMPD患者携有MLH1或MSH2基因的突变；且肿瘤组织中PIK3CA和AKT1的突变率为35%，与肿瘤的侵袭密切相关， 提示DNA错配修复（MMR）基因功能异常以及PIK3CA和AKT1突变引起的PI3K/AKT信号通路异常活化在EMPD发生、发展中起了重要作用。本项目将在EMPD患者中全面筛查MMR系统，首次尝试从MMR基因突变和沉默导致遗传不稳定的角度来阐述EMPD发病的遗传学背景和其易伴发肿瘤的分子机理，揭示EMPD发展过程中PI3K/AKT通路激活后对E-cadherin调控作用和相关的下游效应分子，为该病的诊断和治疗提供新靶点和新策略。

乳房外Paget病(extramammary paget's disease，EMPD)是一少见的皮肤恶性肿瘤，由于缺乏分子标志物，患者常被误诊且容易伴发或者继发其他部位的恶性肿瘤，严重影响了患者的预后和生存。我们在本项目中采用二代测序等技术发现部分EMPD患者携有MLH1、MSH2、MSH6和PMS2等DNA错配修复基因的突变，并证实主要突变MLH1 V384D和R217C可通过降低与PMS2的结合而显著降低DNA修复能力；通过分析MLH1、MSH2、MSH6和PMS2在EMPD中的表达，发现EMPD存在较高频率的MSH2蛋白表达下降和基因启动子甲基化，这些发现证实DNA错配修复（MMR）基因功能异常在EMPD发生、发展中起了重要作用，对于EMPD的诊断和治疗指导具有重要意义；同时探索EMPD中PI3K/AKT通路的相关蛋白，并发现通过抑制剂抑制PI3K/AKT通路，可显著降低原代培养EMPD细胞生长，为该病的治疗提供新靶点和新策略。

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