TAp73逆转自噬调控骨肉瘤作用的机制研究

Autophagy has dual role in promoting and inhibition on tumor, clarify the regulation mechanism of autophagy in tumor for the identification of new targets for cancer therapy is important. p53 family plays a switch roles in autophagy positive and negative regulation on tumor: autophagy of p53 wild-type tumor show tumor promoting effect, while in p53 null or p53 mutation tumor show inhibitory effect there. Osteosarcoma and other cancers often appear missing or mutated p53, we recently published in Cancer Research, Neoplasia magazine papers found: p53 family members TAp73 expression is relatively stable, dephosphorylation activating TAp73 can replace missing p53 by specific play anti-tumor effect. Thus hypothesis: in p53-deficient osteosarcoma cells by activating TAp73 to reverse autophagy regulation of osteosarcoma that autophagy inhibitor regain anti-osteosarcoma function. This project intends to use the signal path PCR microarray analysis, molecular biology experiments, autophagy inhibitors TAp73 anti-osteosarcoma and other methods to clarify TAp73 activate p53 family signaling pathway, the mechanism regulating autophagy. Explore a method for inhibiting osteosarcoma by regulating autophagy, to find a new target for the treatment of osteosarcoma.

自噬对肿瘤具有促进和抑制双重作用，阐明自噬对肿瘤的调控机制，对确定新的肿瘤治疗靶点有重要意义。p53家族在自噬对肿瘤正负调控中起着开关的作用：自噬对p53野生型肿瘤有促瘤作用，而对p53缺失或突变的肿瘤则有抑瘤作用。骨肉瘤等恶性肿瘤中p53常出现缺失或突变，我们最近发表在Cancer Research、Neoplasia等杂志上的论文发现：p53家族成员TAp73表达相对稳定，通过特异性去磷酸化激活TAp73可替代缺失的p53发挥抗瘤作用。由此假设：在p53缺失的骨肉瘤细胞中通过激活TAp73来逆转自噬对骨肉瘤的调节作用，使自噬抑制剂重获抗骨肉瘤功能。本课题拟采用信号通路PCR芯片分析，分子生物学实验验证，自噬抑制剂联合TAp73抗骨肉瘤等方法，旨在阐明TAp73激活p53家族信号通路，调控自噬的机制。探索一种通过调节自噬抑制骨肉瘤的方法，寻找治疗骨肉瘤的新靶点。

自噬对肿瘤具有促进和抑制双重作用，阐明自噬对肿瘤的调控机制，对确定新的肿瘤治疗靶点有重要意义。p53家族在自噬对肿瘤正负调控中起着开关的作用：自噬对p53野生型肿瘤有促瘤作用，而对p53缺失或突变的肿瘤则有抑瘤作用。骨肉瘤等恶性肿瘤中p53常出现缺失或突变，我们最近发表在Cancer Research、Neoplasia等杂志上的论文发现：p53家族成员TAp73表达相对稳定，通过特异性去磷酸化激活TAp73可替代缺失的p53发挥抗瘤作用。由此假设：在p53缺失的骨肉瘤细胞中通过激活TAp73来逆转自噬对骨肉瘤的调节作用，使自噬抑制剂重获抗骨肉瘤功能。本课题实验开展中，分别证实自噬抑制剂NVP-BEZ235通过PI3K-Akt-mTOR通路提高骨肉瘤化疗敏感性；线粒体自噬线粒体自噬在骨肉瘤化疗耐药中的作用机制研究；旨在阐明自噬调节骨肉瘤化疗耐药具体机制。探索一种通过调节自噬抑制骨肉瘤的方法，寻找治疗骨肉瘤的新靶点。