DJ-1/FGFR1信号通路参与肝细胞癌索拉非尼耐药的机制研究

Anti-apoptosis of tumor cells and angiogenesis of vascular endothelial cells are both involved in hepatocellular carcinoma (HCC) sonafenib resistance. Whether there are undefined mediators play a cross-talk regulatory role between tumor cells and vascular endothelial cells in HCC sonafenib resistance. . Pre-experimental results have revealed that up-regulated intracellular oncogene DJ-1 mediated the proliferation and apoptosis phenotype of HCC, and DJ-1 associated with resistance to chemotherapeutic drugs of breast cancer cell line MCF-7/ADM. As a tumor antigen, DJ-1 was secreted by breast cancer cells and uveal melanoma tumor cells. Moreover, it was detected as a circulating promising marker in the serum of breast cancer and uveal melanoma patients. Recently, extracellular DJ-1 stimulated the differentiation of human mesenchymal stem cells to osteoblasts, and induced angiogenesis in human umbilical vein endothelial cells through activation of fibroblast growth factor receptor-1 (FGFR-1) signaling pathways. Tumors with sorafenib-acquired resistance were enriched with FGFR-1 signaling cascades. . Therefore, we hypothesize that extracellular DJ-1 may be a cross-talk regulatory between tumor cells and vascular endothelial cells in HCC sonafenib resistance: extracellular DJ-1 secreted by HCC cells activates the FGFR-1 signaling cascades, and promotes anti-apoptosis and angiogenesis in tumor cells and vascular endothelial cells of HCC, respectively. Furthermore, the presence of circulating DJ-1 protein in sera from patients with HCC sonafenib resistance may have clinical utility.

肝细胞癌（Hepatocellular carcinoma，HCC）细胞的凋亡失控、HCC血管内皮细胞的血管生成参与HCC索拉非尼的耐药机制。HCC中肿瘤细胞与血管内皮细胞之间，是否存在某种媒介相互串话、共同参与HCC索拉非尼耐药？申请者研究发现：细胞内DJ-1调控HCC细胞的凋亡，与乳腺癌细胞的耐药相关。研究显示，细胞外DJ-1蛋白是肿瘤细胞分泌的循环抗原；细胞外DJ-1以配体形式直接与FGFR1结合，激活下游信号通路，促进血管内皮细胞的血管生成；FGFR1 下游信号通路的活化参与HCC索拉非尼耐药机制。据此，申请者提出：细胞外DJ-1可能是HCC中肿瘤细胞与血管内皮细胞之间串话的媒介。HCC细胞分泌的DJ-1蛋白，直接结合FGFR1，激活下游信号通路，抑制HCC细胞凋亡、促进HCC血管内皮细胞血管生成，参与索拉非尼耐药机制。血清DJ-1蛋白可能为HCC索拉非尼耐药的分子标记物。

肝细胞癌（Hepatocellular carcinoma，HCC）细胞的凋亡失控、HCC血管内皮细胞的血管生成参与HCC索拉非尼的耐药机制。HCC中肿瘤细胞与血管内皮细胞之间可能存在“串话”、共同参与HCC索拉非尼耐药。项目研究发现：1) 人HCC细胞具有分泌DJ-1蛋白的功能；2) 分泌性DJ-1蛋白促进人肝癌血管内皮细胞（ECDHCC-1）的增殖与迁移能力；3) DJ-1蛋白调节FGFR信号通路以及促进ECDHCC-1细胞发生EMT表型改变；4) 通过药物浓度梯度筛选，获得索拉非尼耐药的HepG2细胞（sHepG2）； 5) 鸡胚胎绒毛膜尿囊膜（chorioallantoic membrane，CAM）动物移植瘤模型体内研究显示，sHepG2细胞在体增殖速度较非耐药细胞显著；sHepG2细胞通过抑制PTEN基因表达、调节PI3K/AKT信号通路以及关键靶点FGFR1，参与肿瘤细胞凋亡的恶性生物学特征的调控。结合前期研究显示：分泌性DJ-1蛋白是HCC中肿瘤细胞与血管内皮细胞之间串话的媒介，其调节 FGFR1激活下游信号通路，抑制HCC细胞凋亡、促进HCC血管内皮细胞EMT，参与索拉非尼耐药机制。