Exosome传输增强结直肠癌干细胞化疗耐药性及其分子机制

Recent studies have shown that tumor microenvironment and CSCs may cooperate to confer chemoresistance in colorectal cancers (CRCs), one recent study has shown that carcinoma-associated fibroblasts (CAFs) promote drug resistance through maintaining CSC pool; however, underlying mechanisms are not fully defined. Our preliminary data has demonstrated that CAFs are able to secret exosomes and their transfer to CSCs promotes chemoresistance in CRCs, in addition, inhibition of exosome secretion decreases chemoresistance. Further investigations have shown that CAF-secreted exosomes enrich for miRNA-374a and are able to enhance the activity of wnt in CSCs. Based on our preliminary data, we hypothesize that exosome miRNA-374a transfer from CAF to CSCs mediates wnt signaling and thus contributes to drug resistance. We proposed the following main aims: 1) To explore whether CAF-derived exosome miRNA-374a is transferred to CSCs in CRCs; 2) To find out whether overexpression or inhibition of miRNA-374a in CAFs promotes or decreases the chemoresistance of CSCs; 3) To explore whether wnt signaling pathway involves in conferring chemoresistance of CSCs upon exosome miRNA-374a transfer from CAF to CSCs, and to further investigate the underlying mechanisms. If the proposed aims are well accomplished, the findings will provide great benefit for patients suffering cancer, especially CRC.

研究表明结直肠癌肿瘤微环境、癌干细胞与化疗后复发密切相关，新近研究发现肿瘤微环境中的肿瘤相关性成纤维细胞（CAF）可增强结直肠癌干细胞的耐药性，但其分子机制还不十分清楚。我们的前期研究发现，CAF可分泌胞外体（exosome），并能被传输至结直肠癌干细胞从而增强其耐药性，而抑制CAF胞外体分泌可削弱癌干细胞的耐药性；进一步研究发现胞外体富集miR-374a并增强结直肠癌干细胞的Wnt信号通路。本课题将在我们前期工作的基础上，探讨胞外体miR-374a能否被传输至结直肠癌干细胞，CAF过表达或抑制miR-374a能否增强或削弱结直肠癌干细胞的耐药性；此外，探讨CAF胞外体miR-374a传输至结直肠癌干细胞后是如何调控Wnt信号通路，揭示CAF通过分泌胞外体miR-374a并传输到癌干细胞从而增强其耐药性，并初步阐明其分子机制，为治疗结直肠癌提供新思路。

研究表明结直肠癌肿瘤微环境、癌干细胞与化疗后复发密切相关，新近研究发现肿瘤微环境中的肿瘤相关性成纤维细胞（CAFs）可增强结直肠癌干细胞的耐药性，但其分子机制还不十分清楚。我们的前期研究发现，CAFs可分泌胞外体（exosome），并能被传输至结直肠癌干细胞从而增强其耐药性。在此基础上，我们深入地探讨后发现CAF来源的胞外体miR-21-5p促进结直肠转移更加明确，我们发现：（1）肿瘤相关性成纤维细胞通过旁分泌的作用可促进结直肠癌细胞浸润和转移；（2）肿瘤相关性成纤维细胞旁分泌来源的胞外体可促进结直肠癌细胞的浸润和转移；（3）肿瘤相关性成纤维细胞来源的胞外体富集miR-21-5p，并可能通过YAP1信号通路发挥效应；（4）hsa-miR-21-5p的表达越高结直肠癌患者的预后越差。我们的研究表明在治疗结直肠癌时，可能需要靶向肿瘤相关性成纤维细胞（CAF），而胞外体miR-21-5p是潜在的治疗靶点。