lncRNA-UCA1在前列腺癌发生发展中的作用及其机制

Our preliminary work showed that the lncRNA-UCA1 expression level in prostate cancer malignant cells was significantly decreased and lncRNA-UCA1 effectively stabilized the E-cadherin protein which is closely related to prostate cancer metastasis. These results may be inferred that lncRNA-UCA1 may play an important role in prostate cancer progression. Therefore, this project will focus on elucidating the functions and the underlying molecular mechanisms of lncRNA-UCA stabilizing E-cadherin in prostate cancer development. lncRNA-UCA1 directly binds to E-cadherin protein, which blocks the binding of the ubiquitin E3 ligase MDM2 to E-cadherin, thereby inhibiting the ubiquitin degradation of E-cadherin protein mediated by MDM2. This will be a new action mode of lncRNA mediating transfer of genetic information and regulatory network of gene expression. We will further in-depth study the roles and mechanisms of lncRNA-UCA1 in prostate cancer development, and explore the upstream regulatory pathways of lncRNA-UCA1 expression, and analyze the molecular mechanism underlying the significant decreased expression in the development of prostate cancer. The project will also screen a large number of clinical samples to assess the value of the abnormal expressions of both lncRNA-UCA1 and E-cadherin in the early diagnosis, treatment and prognosis of clinical prostate cancer, which finally provides a new target for precision/molecule therapy of prostate cancer.

在前期工作中我们发现lncRNA-UCA1在前列腺癌恶性细胞中的表达水平显著下降，且lncRNA-UCA1能有效地稳定与前列腺癌转移密切相关的E-cadherin蛋白，据此推测，lncRNA-UCA1可能在前列腺癌发生发展中发挥着重要作用。在预结果基础上，本项目将重点阐明lncRNA-UCA1稳定E-cadherin蛋白在前列腺癌发生发展中的功能及其分子机制。lncRNA-UCA1可能与E-cadherin蛋白直接结合，这可以阻断E-cadherin与其泛素化E3连接酶MDM2之间的结合，从而进一步抑制由MDM2所介导的E-cadherin的泛素化降解。这种作用方式目前尚未报道，可能是lncRNA一种全新的分子机制。我们还将深入研究lncRNA-UCA1在前列腺癌发生发展及转移中的生物学功能及其上游调节机制，评估lncRNA-UCA1潜在临床应用价值，试图为前列腺癌精准分子治疗提供新靶点。

长链非编码RNAs在肿瘤中扮演着重要的角色，其表达失调与肿瘤的发生、增殖、侵袭和转移密切相关。尿路上皮癌抗原1 (Urothelial carcinoma antigen1，UCA1)最早是在膀胱移行上皮细胞癌中被发现并因此而命名的一个lncRNA分子，研究发现lncRNA-UCA1通过促进细胞增殖和迁移在许多类型肿瘤中发挥促癌功能。在本项目中，我们发现了lncRNA-UCA1的全新功能，即抑制细胞恶性转化，在维持原发前列腺癌细胞的低成瘤性和低迁移性中发挥重要作用。LncRNA-UCA1通过阻止E-cadherin蛋白与其泛素化修饰E3连接酶MDM2相结合，进而抑制MDM2所介导的E-cadherin蛋白泛素化降解，从而稳定E-cadherin蛋白。此外，我们还发现lncRNA-UCA1可以作为一种“分子海绵”，有效减弱或屏蔽miR-296-3p在转录后水平对其靶标CDH1 mRNA的抑制作用。综上所述，本项目的研究工作表明lncRNA-UCA1通过上述双重机制有效地使细胞内E-cadherin蛋白维持在高水平，进而使原发前列腺癌细胞保持低致瘤性和非转移状态。本项目阐明了lncRNA-UCA1在前列腺癌发生发展中的功能及作用机制，有望为前列腺癌的精准治疗提供新的靶点。