外泌体传输cicrRNA诱导结直肠癌细胞去分化在化疗耐药中的作用和机制

Chemotherapy resistance in colorectal cancer (CRC) may be related to the presence of cancer stem cells (CSCs), and their proportion substantially increases in clinically chemotherapy-refractory tumor specimens but the cell-of-origin of CSCs remains unclear. Cancer-associated fibroblasts (CAFs) can promote drug resistance through inducing differentiated cells dedifferentiate into CSCs in CRC. Our preliminary data has demonstrated that CAFs-derived exosome-transfer to differentiated cells promotes chemoresistance via Wnt pathway in CRC. In addition, inhibition of exosome secretion blocks this effect. Further investigations have shown that CAF-derived exosomes enrich for ciRS-7, one type of circle RNAs, and are able to promote the self-renewal capacity of differentiated cells in CRC. Based on our preliminary data, we hypothesize that exosomal ciRS-7 transfer from CAFs to differentiated CRC cells mediates Wnt signaling and thus contributes to drug resistance. We proposed the following main aims: 1) To explore whether CAF-derived exosomal ciRS-7 is transferred to differentiated cells in CRCs; 2) To find out whether overexpression or inhibition of ciRS-7 in CAFs promotes or suppresses the chemoresistance of differentiated cells; 3) To explore whether exosomal ciRS-7-transfer inducing chemoresistance of differentiated cells via Wnt signaling pathway in CRC, and to further investigate the underlying mechanisms. If the proposed aims are well accomplished, the findings will help design new therapeutic strategies targeting chemotherapy in colorectal cancer.

研究表明结直肠癌干细胞与化疗耐药密切相关，化疗后复发的肿瘤标本中肿瘤干细胞显著增加，但其来源并不清楚。研究发现，肿瘤相关成纤维细胞（CAFs）可诱导结直肠癌分化细胞去分化为癌干细胞，CAFs的外泌体可促进肿瘤化疗耐药。我们前期研究发现，CAFs外泌体可传输至结直肠癌分化细胞，通过调控Wnt通路诱导其去分化从而促进化疗耐药，而抑制CAFs分泌外泌体可阻断这一效应；进一步研究发现外泌体中的效应分子可能为环状RNA，高通量测序发现外泌体富含一种环状RNA—ciRS-7。本课题将在前期基础上，探讨外泌体ciRS-7能否被传输至结直肠癌分化细胞，CAFs过表达或抑制ciRS-7对分化细胞耐药性的影响；此外，探讨外泌体ciRS-7是如何调控结直肠癌分化细胞的Wnt通路，揭示CAFs通过传输外泌体ciRS-7至癌分化细胞诱导其去分化从而增强其耐药性，初步阐明其分子机制，为治疗结直肠癌提供新思路。

研究表明结直肠癌干细胞与化疗耐药密切相关，化疗后复发的肿瘤标本中肿瘤干细胞显著增加，但其来源并不清楚。研究发现，肿瘤相关成纤维细胞（CAFs）可诱导结直肠癌分化细胞去分化为癌干细胞，CAFs的外泌体可促进肿瘤化疗耐药。我们前期研究发现，CAFs外泌体可传 输至结直肠癌分化细胞，通过调控Wnt通路诱导其去分化从而促进化疗耐药，而抑制CAFs分泌外泌体可阻断这一效应；进一步研究发现外泌体中的效应分子可能为环状RNA，高通量测序发现外泌体富含一种环状RNA—ciRS-7。本课题在前期基础上进一步发现，（1）CAFs来源外泌体ciRS-7能被传输至结直肠癌分化细胞，促进其化疗耐药性；（2）外泌体ciRS-7通过miR-7海绵作用诱导结直肠癌分化细胞的去分化从而调控化疗耐药性；（3）结直肠癌组织中ciRS-7的表达水平越高，患者的预后越差；揭示CAFs通过传输外泌体ciRS-7至癌分化细胞诱导其去分化从而增强其耐药性，初步阐明其分子机制，为治疗结直肠癌提供新思路。