肿瘤再增殖是导致肿瘤治疗失败的主要原因！我们在前期研究中发现肿瘤经放化疗后产生的凋亡细胞中caspase3激活，进而激活iPLA2及PKC-δ，前者促进PGE2产生，后者增加Akt或p38磷酸化，最终刺激肿瘤细胞再增殖。然而，放化疗后除凋亡外，还有大量坏死细胞！生理状态下HMGB1主要存在于细胞核中；当细胞受到刺激或病理状态时，可被主动或被动释放到细胞外，细胞外的HMGB1可作为细胞因子、趋化因子、生长因子等促进或抑制肿瘤细胞生长。我们假设放疗后的坏死细胞及其所释放的HMGB1参与了肿瘤再增殖，坏死细胞与凋亡细胞间可能存在相互影响。拟采用CRISPR/Cas9技术分别敲除人及小鼠乳腺癌细胞中HMGB1基因，或联合敲除HMGB1与Caspase3双基因，采用体内外肿瘤再增殖模型研究其对肿瘤再增殖的影响，相关的调控分子及信号传导通路。帮助阐明肿瘤再增殖的机理，指导临床合理使用放化疗治疗肿瘤。

Cancer cell repopulation is a major reason causing treatment failure. Data from our previous study suggested that activated caspase3 in apoptotic cells could activate iPLA2 and promote the production of PGE2. The PGE2 is a major growth factor which resulted in cancer cell proliferation. The new results from our study showed that activated caspase3 in apoptotic cells could activate PKC-delta and phospholate downstream Akt and/or p38. Which can also cause cancer cell repopulation. However, the apoptosis is not merely manner of cell death after radiotherapy or chemotherapy. Thear are a lot of necrosis or aponecrosis cells in tumor mass after radiotherapy or chemotherapy. HMGB1 is a gene with wide biologic functions. It is normally located in nuclei and acts as a DNA chaperone to help maintain nuclear homeostasis and genome stability in several ways. It can be activelly or passivelly released to extrocellular when cells suffer from stress or in pathphysical conditions. HMGB1 in extrocellular matrix acts as an anti- or protumor protein in tumor development and therapy. Extracellular HMGB1 promotes proliferation, inflammation, energy metabolism, and angiogenesis and inhibits host anticancer immunity, which contributes to tumorigenesis. In contrast, extracellular-HMGB1 is important for the immunogenic cell death of cancer cells and stimulates antitumor immunity response during chemotherapy or radiotherapy. In this study, we plan to use CRISPR/Cas9 technology to knock out HMGB1 or both HMGB1 and Caspase3 and investigate the role of HMGB1 plays in cancer repopulation. We will further study whether HMGB1 interacts with Caspase3 and explore downstream moleculars and pathwaies. The results from this study will be helpful to understand the mechanism of cancer repopulation and advise the doctors to properally treat cancers via radiotherapy or chemotherapy .