肿瘤再增殖是指放化疗后残存的肿瘤细胞生长形成新的肿瘤的过程。课题组前期研究发现放化疗所致凋亡细胞可通过caspase 3-iPLA2-AA-PGE2通路刺激残存肿瘤细胞增殖。本人最近的研究发现放疗所致濒死肿瘤细胞中激活的caspase 3还可激活PKCδ，后者可增加Akt磷酸化。抑制PKCδ活性可在体内外显著抑制肿瘤再增殖！然而PKCδ是通过哪些下游分子调控肿瘤再增殖并不清楚。鉴于PI3K/Akt/mTOR通路可上调HIF1α促进VEGF生成，我们设想濒死肿瘤细胞可能存在caspase 3-PKCδ-PI3K/Akt/mTOR-HIF1α-VEGF通路，并与肿瘤细胞再增殖有关。我们拟在前期制备的PKCδ显性负性突变体细胞及裸鼠模型的基础上，研究PI3K/Akt/mTOR-HIF1α-VEGF与PKCδ及肿瘤再增殖的关系，为阐明肿瘤再增殖的分子机制提供新的实验证据。

After radiotherapy or chemotherapy, surviving tumor cells growth and reestablish the tumor is referred as tumor repopulation. Our previous studies demonstrated that radiotherapy- or chemotherapy-induced apoptotic cells significantly stimulate the proliferation of surviving tumor cells through the caspase 3-iPLA2-AA-PGE2 signaling pathway. My latest study showed that radiation-induced activation of caspase 3 could further activate protein kinase Cδ (PKCδ), which increases the phosphorylation of Akt in dying tumor cells, and the inhibition of PKCδ activity significantly decreased the growth-stimulating effect of dying tumor cells on surviving tumor cell repopulation both in vitro and in vivo. However, the downstream molecules mediated by PKCδ in tumor repopulation remains unclear. Since PI3K/Akt/mTOR signaling pathway could increase the expression of hypoxia-inducible factor 1α (HIF1α) to stimulate the production of vascular endothelial growth factor (VEGF), we assume that there may be a tumor cell repopulation-related caspase 3-PKCδ-PI3K/Akt/mTOR-HIF1α-VEGF signaling pathway presented in dying tumor cells. We intend to explore the relationship of PI3K/Akt/mTOR-HIF1α-VEGF with PKCδ as well as tumor cell repopulation, using the PKCδ dominant negative mutant-transduced tumor cells and the radiation-induced in vivo tumor repopulation model in Balb/c nude mice. This study will provide some new data for elucidating the mechanism of tumor repopulation.