超声分子成像评价前列腺癌FoxM1表达及其促前列腺癌转移机制的研究

Prostate cancer is a life-threatening malignant tumor of senile male. Early recognition and intervention for prostate cancer metastasis tendency is of great significance in the process of diagnosis and treatment of prostate cancer. Transcription factor FoxM1 is becoming a hot spot of research in recent years because it is related with pathogenesis of a wide variety of malignancy. But the researches at home and abroad of the correlation between FoxM1expression level and prostate cancer progression and prognosis are still rarely reported. Our preliminary study found that the expression level of FoxM1 is up-regulated in prostate cancer samples and it has an important role in the process of EMT in prostate cancer. Nanometer carrier of ultrasound mediated gene delivery system has an important position in molecular imaging and targeted therapy. We hypothesize that FoxM1 could be an ultrasonic molecular imaging and targeted therapy technology target, which can provide more theoretical basis for early diagnosis of tumor and targeted therapy. So this topic is proposed to analyze FoxM1 expression in a large number of prostate cancer samples and the correlation with prognosis. And a further study of FoxM1 participating in prostate cancer metastasis will be designed. Last, we will use over-expression and silence techniques and ultrasonic nanoscale microbubble mediated gene delivery technology to investigate ultrasound molecular imaging and targeted therapy. We will demonstrate the role of FoxM1 in prostate cancer metastasis from the molecular level, cellular level and clinical level and inhibit the expression of FoxM1 through ultrasound targeted therapy.

前列腺癌是危及中老年男性生命的恶性肿瘤。对有转移倾向的前列腺癌进行早期识别和干预具有重要意义。转录因子FoxM1因其与多种肿瘤的致病机理密切相关，成为近年肿瘤基础研究的热点分子。但其对前列腺癌进展及预后的相关性研究国内外鲜有报道。本课题组前期研究发现FoxM1在前列腺癌组织中高表达并能够参与前列腺癌EMT的发生。超声介导的纳米载体基因递送系统在分子成像和基因靶向治疗中具有重要地位。本课题设想将FoxM1作为超声分子成像及靶向治疗的靶点，为肿瘤的早期诊断和靶向治疗提供更多的依据。本课题拟分析大量前列腺癌样本中FoxM1表达水平与临床预后的相关性，进一步研究FoxM1参与前列腺癌转移的机制，制备携载FoxM1和FoxM1 siRNA纳米微泡，通过离体、活体实验进行超声分子成像及靶向治疗，从分子机制、细胞水平和临床水平探讨FoxM1在前列腺癌致病转移中的作用并利用超声靶向治疗技术对其进行干预。

前列腺癌是威胁中老年男性生命的恶性肿瘤，近年在我国呈递增趋势。其发病隐匿，早期症状不明显，发展到中晚期肿瘤易发生转移，严重影响患者生活质量和生命。因此对前列腺癌的早期诊断和转移机制的研究具有重要意义。转录因子FoxM1 在恶性肿瘤的发生发展中起重要作用，在器官发育、细胞分化和增殖中意义重大，参与了肿瘤相关机制中多个环节的调控。本研究围绕FoxM1参与前列腺癌发生和转移中的重要作用，从分子机制、细胞水平、组织水平和超声分子成像四个层面展开研究，探讨了转录因子FoxM1通过参与上皮间质转化（EMT）这一过程而促进肿瘤细胞转移的机制，并对其在超声分子成像中的应用进行了探索，首次制备了携载FoxM1siRNA 的靶向阳离子（siFoxM1-Apt-CNBs）纳泡，评估超声介导靶向载基因阳离子纳泡转染FoxM1siRNA治疗前列腺癌的体内外治疗效果。本研究共发表相关学术论文9篇，其中SIC收录论文4篇，培养博士研究生3名。研究发现FoxM1在前列腺癌组织和良性前列腺增生组织表达存在差异，并与前列腺癌预后相关的Gleason评分具有一定相关性。机制方面通过体外建立前列腺癌EMT模型，证实FoxM1参与了EMT过程。进一步通过使用二甲双胍处理细胞，使内源性FoxM1表达下降，证实细胞增殖及迁移能力随之减低。成功建立FoxM1敲低的前列腺癌移植瘤模型，FoxM1敲低后成瘤能力弱，瘤体生长慢，转移灶明显减少。成功制备了携载siFoxM1-Apt-CNBs纳泡，体外研究证实其能抗核酸酶降解，在体外有较好的超声造影成像效果。细胞实验表明上述纳泡成功转染前列腺癌细胞，在超声介导下能高效转染入前列腺癌细胞，并发生较高的晚期凋亡和总凋亡，细胞内FoxM1表达下调，E-Cadherin表达上调。活体动物实验证实超声介导下siFoxM1-Apt-CNBs 转染治疗裸鼠移植瘤后，肿瘤组织内FoxM1表达受到抑制，治疗后肿瘤生长被抑制，裸鼠生存时间较长。综上，FoxM1在前列腺癌EMT过程中具有重要作用，超声介导siFoxM1-Apt-CNBs 纳泡转染治疗，有较高的体内、体外转染效率及生物学效应，能明显抑制前列腺癌细胞增殖和移植瘤生长，有望成为一种新的前列腺癌治疗方式。