PDCD4/JNK/ABCG2信号通路介导结直肠癌细胞5-FU耐药机制研究

Colorectal cancer (CRC) is one of the most common malignant tumors in China. 5-FU is widely used as the first-line systemic chemotherapy for CRC, but the response to the medicine becomes poorly as the time goes on, which may be resulted from primary or acquired resistance to 5-FU. The effect of 5-FU on the advanced colorectal cancer has only 10-15%. Therefore, how to reduce the chemo-resistance will be the key to improve the efficacy of 5-FU. Our previous study has showed that PDCD4/JNK/ABCG2 signaling has relationship with 5-FU chemo-resistance, and JNK/c-jun may play an importance role in it. In this project, we will intensive study the regulatory mechanism of PDCD4 on JNK/c-jun signaling, and how JNK/c-jun regulates ABCG2 expression and then the 5-FU chemo-resistance. We will also investigate the roles of JNK/c-jun signaling on 5-FU chemo-resistance from cell apoptosis and cell cycles, which will benefit future clinical study on increase of 5-FU effect and targeted inhibition of 5-FU chemo-resistance.

结直肠癌在我国是最常见的恶性肿瘤之一。临床上，5-FU是结直肠癌治疗的基本化疗药物，但由于产生原发性或获得性耐药，以5-FU为基础的化疗效益低至10-15%。因此，如何有效降低癌细胞对药物产生耐药性将是提高5-FU疗效的关键。本项目前期研究发现PDCD4/JNK/ABCG2信号通路与5-FU耐药性有关，而其中JNK/c-jun通路可能在5-FU耐药性产生中发挥着关键作用。因此，本课题将研究5-FU处理结肠癌细胞后，PDCD4调节JNK/c-jun的作用机制，以及JNK/c-jun如何调控ABCG2表达进而影响结肠癌细胞耐药性的产生。此外，本课题还将从细胞凋亡、细胞周期等方面深入探讨JNK/c-jun通路对结肠癌细胞产生5-FU耐药性的作用。该研究不仅能揭示5-FU耐药性的产生机制，还能为临床提高5-FU疗效以及靶向抑制5-FU耐药性的产生提供新思路。

结直肠癌是我国发病率和致死率都较高的肿瘤。晚期结直肠癌由于对化疗药物治疗的耐受性，是肿瘤复发和患者死亡的主要原因之一。因此，深入了解化学治疗耐受的分子机制，能为结直肠癌的有效治疗提供理论基础。. 五氟尿嘧啶(Fluorouracil，5-FU)是治疗结直肠癌的最常见药物，但由于耐药性，以5-FU为基础的化疗方案对晚期结直肠癌患者的有效治疗率仅约10%-15%。本研究通过建立5-FU获得性耐药结直肠癌细胞株HCT116/FUR，发现microRNA-21(miR-21)能够通过靶向抑制PDCD4(programmed cell death 4)激活JNK(c-Jun NH2 terminal kinase)通路，促进ABCG2(ATP-binding cassette G2)转录，从而促进5 -FU耐药性产生。裸鼠实验进一步证明，JNK信号通路能促进结直肠癌细胞产生5-FU耐药性。抑制该信号通路，可明显增强耐药性结直肠癌细胞对5-FU的敏感性。本项目还发现，miR-21通过PTEN/AKT通路抑制TFEB(transcription factor EB)活化入核，减少TFEB对VMP1(vacuole membrane protein 1)的表达激活，从而降低VMP1对miR-21表达产生的抑制效应，形成miR-21/VMP1/miR-21负反馈调控环。该研究结果揭示了结直肠癌细胞miR-21呈高表达的分子调控机制以及产生5-FU耐药性的新机制。. 综上，本项目通过构建5-FU耐药性结直肠癌细胞模型，首次发现miR-21/PDCD4/JNK/ABCG2信号通路以及miR-21/VMP1/miR-21负反馈环调控结直肠癌细胞产生5-FU耐药性的分子机制。研究结果不仅揭示了结直肠癌细胞产生5-FU耐药性的新机制，也为临床上有效克服结直肠癌5-FU获得性耐药提供新的理论基础。