蟾毒灵介导miR-338-5p调节肿瘤微环境逆转结肠癌多药耐药的机制研究

Tumor microenvironment (TME) plays an important role in the process of tumor multidrug resistance (MDR), and some research showed that miRNA is an important link between the tumor cell and its, but the the mechanism of miRNA during TME mediated MDR is unclear. In the previous work, we found miR-338-5p had a lower expression in MDR colon cancer cell and its corresponding tumor microenvironment. Bufalin can reverse MDR in colon cancer, and also increase miR-338-5p expression. Based on our previous study, we conducted the following three areas studied: (1) Reveal the pharmacological effect and molecular mechanisms of miR-338-5p in colon cancer tumor microenvironment mediated multidrug resistance (2) Clarify the mechanism of Bufalin mediated miR-338-5p regulate colon cancer TME and reverse multidrug resistance. (3) Proposed a integrated Traditional and Western Theory based on Traditional Chinese medicine-miRNA-TME-MRD. The research has an important significance of revealing molecular mechanism of the tumor microenvironment mediated multidrug resistance in colon cancer and defining the important target of Traditional Chinese medicine reverse colon cancer MDR.

肿瘤微环境在肿瘤产生多药耐药的过程中起到了关键的作用，研究发现miRNA是肿瘤与肿瘤微环境之间重要的关联环节，但是miRNA在肿瘤微环境介导肿瘤多药耐药过程中的机制尚不清楚。前期发现，miR-338-5p在结肠癌多药耐药细胞株及其相应的肿瘤微环境中相对于亲本株均成低表达，蟾毒灵能够逆转结肠癌多药耐药，并对miR-338-5p具有正向调节作用。本项目旨在我们前期研究基础上，以体外肿瘤微环境模型、原位结肠癌小鼠、人结肠癌组织为研究对象，开展以下三个方面的研究:揭示miR-338-5p在结肠癌肿瘤微环境介导结肠癌多药耐药的过程中药理学作用及分子机制;阐明蟾毒灵介导miR-338-5p调节肿瘤微环境逆转结肠癌多药耐药的机制;提出基于中药-miRNA-肿瘤微环境-多药耐药的中西医结合理论。该研究成果对于揭示肿瘤微环境介导结肠癌多药耐药的分子机制，明确中药逆转结肠癌多药耐药的重要靶点有着重要的意义。

肿瘤微环境在肿瘤产生多药耐药的过程中起到了关键的作用，外泌体miRNA是肿瘤与肿瘤微环境之间重要的关联环节。前期研究发现，我们发现蟾毒灵可以逆转结肠癌多药耐药，并释放外泌体miRNA，但蟾毒灵逆转肿瘤微环境介导的多药耐药的作用及机制尚未见报道。本研究中，我们发现肿瘤相关成纤维细胞（CAFs）通过释放IL6进而激活结肠癌细胞的Stat3/Bcl2途径，产生耐药；通过体外内实验，证实蟾毒灵能够增加miR-338-5p的表达，促进外泌体miR-338-5p传递到CAFs，抑制其IL6的表达，从而逆转CAFs介导的化疗耐药；更为重要的是，我们还发现结肠癌临床标本中miR-338-5p的低表达与结肠癌生存率降低有相关性，同时miR-338-5p的表达与IL6的表达水平呈负相关。综上，该研究成果对于揭示肿瘤微环境介导结肠癌多药耐药的分子机制，明确中药逆转结肠癌多药耐药的重要靶点有着重要的意义。