分泌型HMGB1介导自噬促进肿瘤放疗后发生Neosis细胞新生的分子机制

Tumor recurrence and repopulation is the main reason for the failure of radiotherapy. Previously, the changing process from cell death to regeneration was observed in breast cancer cell lines following x-ray irradiation, We found the process of cell regeneration called Neosis after radiotherapy, We also preliminarily confirmed that secretory HMGB1 could significantly increase the capacity of Neosis after radiotherapy. Here, We would further investigate the possible molecular mechanism that HMGB1 promote cell regeneration with Neosis, that secreted HMGB1 from irradiated dying cells could promote cell autophagy by activating its receptor RAGE, and autophagy contributes to stemness maintenance in tumor cells, thus promote Neosis and production of newborn cells with strong proliferative activity. This research would clarify the role of HMGB1 and autophagy in Neosis, the mechanism that HMGB1 regulates cell autophagy, the relationship of cell coexistence with autophagy and stemness from the molecular, cellular, and animal models. This research would reveal the molecular and cellular mechanisms of tumor recurrence after radiotherapy in a certain extent.

肿瘤复发及再增殖一直是放射治疗失败的主要原因，前期我们在体外观察乳腺癌细胞经x射线照射后从死亡到细胞再生的变化过程，观察到被称之为Neosis的细胞新生过程，并初步证明分泌型高迁移率蛋白1（HMGB1）能显著增加放疗后Neosis能力。该课题在此基础上进一步揭示HMGB1促进Neosis的可能分子机制，即放疗所致濒死细胞分泌的HMGB1通过激活其受体RAGE促进细胞自噬的发生，细胞自噬增强有利于维持肿瘤细胞干性特征，进而促进细胞新生即Neosis，产生具有较强增殖活性的新生细胞。本课题将从分子、细胞、动物多方面阐明HMGB1及细胞自噬对Neosis的促进作用、HMGB1对细胞自噬的调节机制、细胞内自噬与干性特征的共存关系。该研究一定程度上揭示了放疗后肿瘤复发的分子和细胞学机制。