miR-223促进胰腺癌恶性生物学行为的分子机制及临床意义研究

Pancreatic cancer (PC) is one of the common malignant tumors of digestive tract. Since incidence and mortality rates of PC are increased in the recent years in worldwide, it is pivotal to investigate the basic and clinical study in PC. Recently, the role of microRNAs as the therapeutic targets has been achieved an important progress and some of miRNAs are in clinical trial. Our previous study has demonstrated that miR-223 promotes PC cell growth, migration, and invasion, suggesting an oncogenic role of miR-223 in PC. Moreover, miR-223 is critically involved in gemcitabine resistant-triggered EMT in PC cells, indicating that miR-223 could be a potential target for the treatment of PC. Therefore, based on our preliminary results, we will further determine the role of miR-223 in the PC progression and drug resistance. Firstly, we will define whether SP1 regulates miR-223 and miR-223 controls PDS5B, leading to governing PC malignant biological behavior. Secondly, we will detect the relationship between expression of miR-223 and clinic pathological features of PC patients and dissect whether miR-223 inhibitors enhance the sensitivity of gemcitabine in PC patients. Our study will provide the insight onto evaluation of miR-223 as a new molecular target and obtain theoretical and experimental basis for using miR-223 inhibitors in clinical in the future.

胰腺癌是一种常见的恶性消化道肿瘤，近年来发病率及死亡率在全球呈现逐渐上升的趋势。因此加强胰腺癌的基础与临床研究意义重大。近年来，miRNA作为肿瘤治疗靶点的研究有重要进展，部分miRNA类药物已进入临床实验阶段。我们前期发现：miR-223促进胰腺癌细胞增殖、迁移及侵袭，发挥癌基因功能；胰腺癌细胞对吉西他滨产生耐药与miR-223表达增加并导致EMT发生有关，提示miR-223可能是胰腺癌的潜在治疗靶点。结合预实验，本课题拟围绕miR-223这一靶点，首先探讨SP1转录调控miR-223和miR-223调控PDS5B并进而促进胰腺癌恶性生物学行为的分子机制；其次探讨miR-223在胰腺癌组织中的表达及临床意义，及miR-223抑制剂加强化疗药物吉西他滨对胰腺癌疗效的作用及机制，以初步评价miR-223作为胰腺癌新的分子靶标的临床应用价值，从而为日后向临床应用转化提供理论和实验依据。

胰腺癌是一种常见的消化系统恶性肿瘤，具有较高的发病率和死亡率。因此，深入探寻胰腺癌发病的分子机制，加强胰腺癌的基础与临床研究意义重大。研究显示，miR-223在胰腺癌的发生发展中发挥重要的调控作用，但其分子机制还尚不清楚。因此，本课题旨在探索miR-223在胰腺癌恶性发生与进展中的作用及其可能分子机制，并初步探讨miR-223在胰腺癌临床治疗的应用价值，从而为胰腺癌的临床治疗提供新的分子靶标和治疗策略。本课题研究发现1. 体外实验中，miR-223明显能够促进胰腺癌细胞的生长和转移能力，体内实验同样显示miR-223升高后，小鼠肿瘤的生长明显增加。2. PDS5B是miR-223的靶基因，miR-223通过转录后调控的方式抑制胰腺癌细胞中PDS5B的表达。3. PDS5B在胰腺癌中发挥抑癌基因的功能，PDS5B能够抑制胰腺癌细胞的生长和转移，胰腺癌组织标本检测中发现肿瘤组织中PDS5B的表达低于癌旁对照组织，PDS5B的低表达与患者的生存相关。4. MiR-223可以通过下调PDS5B的表达而促进胰腺癌细胞的生长和转移。5. 前期我们已经发现miR-223在胰腺癌对吉西他滨的耐药中发挥调控作用，其原因可能与miR-223促进耐药细胞发生EMT有关，通过本课题的深入研究，我们发现miR-223抑制剂能够提高耐药的胰腺癌细胞对吉西他滨的敏感性，逆转耐药细胞EMT，尤其是miR-223与植物抗癌药大豆异黄酮联合应用时作用效果更为明显。这些研究结果提示miR-223可能是胰腺癌的有效的分子靶点，miR-223 抑制剂与化疗药物的联合应用可能是胰腺癌治疗的新策略。