前列腺癌长链非编码RNA表达谱构建及PRCAT38在前列腺癌中的功能和分子机制研究

Prostate cancer seriously endangers the health of the majority of men, and the molecular understanding of prostate cancer based on coding gene has made great progression. In such investigations, the potential importance of long-noncoding RNAs (lncRNAs) in multiple kinds of cancer has been gradually revealed. However, the molecular basis of lncRNAs in prostate cancer remains poorly understood. Here, we present the systematic analysis of the aberrant expression of lncRNAs in prostate cancer. We identified that PRCAT38 is significantly upregulated in prostate cancer. The expression level of PRCAT38 was able to predict the poor outcome of prostate cancer, including tumor size, invasion, and metastasis, indicating PRCAT38 is a potential diagnostic biomarker. We will further use molecular, cellular and biochemical methods to study the function and the underlying mechanism of PRCAT38 in prostate cancer on cell and animal level. Preliminary data have shown knockdown of PRCAT38 led to a severe decrease in prostate cancer cell proliferation, survival and migration, suggesting PRCAT38 is a potential driver mutation in prostate cancer. We are confirming these phenotypes and furthermore investigate the mechanism. This study will provide a comprehensive landscape of aberrant lncRNA expression and a rich resource for lncRNA study in prostate cancer. This study will pave a way for the clinic application of PRCAT38 as either a diagnostic biomarker or a therapeutic target, thus this will benefit the prostate cancer patients.

前列腺癌严重危害广大男性健康，基于编码基因在前列腺癌的分子基础研究已取得很大进展，近来显示长链非编码RNA（lncRNA)在癌症发生和发展中扮演重要角色，但我们对其在前列腺癌的功能和分子机制研究相对不深。随着lncRNA预测数量的提升，使我们能够系统性研究这类基因的功能和机制。本课题用生物信息学系统性构建前列腺癌的lncRNA表达谱。其中一个全新lncRNA，即PRCAT38和前列腺癌的发生和发展高度相关，并在前列腺癌特异性高表达。我们进一步使用分子、细胞、生化手段研究其在前列腺癌发生发展的功能和潜在的分子机制。前期数据显示敲低PRCAT38，会降低细胞的增殖和迁移能力，相反过表达该基因会导致细胞的增殖。我们正进一步细化其功能以及深挖相关分子机制。这个研究将为前列腺癌的系统性功能基因解读提供一个视角以及为PRCAT38作为诊断生物标志物和治疗靶点提供理论基础，前列腺癌患者将会因此受益。

全基因组和转录组测序揭示肿瘤患者的癌细胞存在大量的异常表达非编码基因，然而lncRNA在癌症的关键功能研究仍不足。本项目系统性构建了组蛋白乙酰化调控和DNA甲基化调控的lncRNA表达图谱，并以其中4个lncRNA为例子（LCDR、DMDRMR、PCSEAT和MYU），阐明lncRNA在调控肿瘤发生发展中的作用和分子机制。基于分子/细胞生物学、动物模型和若干组学技术，本项目阐明：1、LCDR结合一个RNA结合蛋白hnRNP K，共同调控溶酶体跨膜蛋白LAPTM5的转录本稳定性，协同调控溶酶体膜完整性，促进癌细胞生存，阐明LCDR/hnRNP K/LAPTM5调控轴为靶向溶酶体的肿瘤治疗提供理论基础；2、DMDRMR协同IGF2BP3，以m6A依赖的方式调控CDK4的稳定性，促进癌细胞生长，提出DMDRMR/IGF2BP3/CDK4调控轴为肾透明细胞癌新的治疗靶向策略； 3、PCSEAT作为与EZH2相关的竞争性内源RNA在前列腺癌发挥致癌作用；4、MYU通过介导miR-184/c-Myc轴促进前列腺癌增殖；5、另外，我们还首次发现肿瘤细胞内源性表达PD-1和PD-L1能抑制肿瘤细胞生长，并能介导拮抗PD-1/PD-L1抗体治疗，为临床超进展和假进展提供了一个潜在科学理论，为肿瘤患者接受免疫抗体治疗提供新思路。本研究主要系统性研究了异常表达的lncRNAs的功能与机制，为lncRNA的研究提供一个新思路。