外泌体介导ITGA6传递在乳腺癌细胞获得性放射抵抗中的作用及机制研究

Exploring the mechanism of impacting radiation sensitivity has great significance in enhancing the efficacy of radiotherapy. Our previous study verified that intergrin α6（ITGA6）can induce the radioresistance of breast cancer cells via regulating PI3K/AKT、MEK/ERK signal paths. It is still uncertain, however, that ITGA6 can influence the sensitivity of tumor cells through extracellular approach. Exosomes are membranous vesicles that sereted from cells, it is also a channel to let cells transmit signals to outsides. Reported in other literature, exosomes can achieve drug resistance through intercellur signaling molecules transporting in breast cancer cells. So we assume that: ITGA6 of breast cancer cells can be transmitted to radio-sensitive cells nearby through exosomes, and then lead to the overexpression of recipient cells, which will also make it achieve acquired radiation resistance effect. This program specified the extracelluar mechanism of ITGA6 inducing the radiation resistance of breast cancer cells through a research of tumor cells releasing exosomes. It laid a theoretical foundation of enlarging the influence of ITGA6 in curing breast cancer, it also provides a new thought and a new target in increasing the radio-sensitivity of breast cancer.

探寻影响放射敏感性机制对提高放疗疗效具有重要意义。我们前期研究首次发现整合素α6（integrin alpha6，ITGA6）可通过调控细胞内信号通路PI3K/AKT、MEK/ERK介导乳腺癌细胞放射抵抗。但ITGA6能否通过细胞外途径影响肿瘤细胞放射敏感性还不得而知。外泌体是由细胞分泌的膜性小囊泡，整合素存在于外泌体膜表面，可通过外泌体向细胞外传递信号。外泌体在乳腺癌细胞中能通过细胞间信号分子的传递介导获得性耐药。因此我们假设：乳腺癌细胞膜表面分子ITGA6，除了细胞内信号通路途径，还可能通过外泌体将ITGA6传递给邻近放射敏感细胞，使受体细胞过表达ITGA6，并产生获得性放射抵抗效应。本项目通过对外泌体的研究，明确ITGA6介导乳腺癌细胞放射抵抗的细胞外机制，为丰富ITGA6在乳腺癌治疗抵抗中的作用奠定理论基础，为乳腺癌放射增敏提供新思路及新靶点。

探寻影响放射敏感性机制对提高放疗疗效具有重要意义。我们前期研究首次发现整合素α6（integrin alpha6，ITGA6）可通过调控细胞内信号通路PI3K/AKT、MEK/ERK介导乳腺癌细胞放射抵抗。为了探索ITGA6能否通过细胞外途径影响肿瘤细胞放射敏感性，我们用siITGA6转染乳腺癌细胞，行lncRNA全转录组测序；同时收集放疗敏感和放疗后复发转移乳腺癌患者血液标本，提取血浆中外泌体，行血浆外泌体lncRNA全转录组测序测序。发现lncRNA PCAT6在两组测序结果中均显示出明显差异。本项目通过对外泌体的研究，明确lncRNA PCAT6介导乳腺癌细胞发生发展、侵袭转移和放射抵抗的细胞外机制，为丰富ITGA6在乳腺癌治疗抵抗中的作用奠定理论基础，为乳腺癌放射增敏提供新思路及新靶点。