Zhang Yiyin, Lei Yubin, Xu Jin, Hua Jie, Zhang Bo, Liu Jiang, Liang Chen, Meng Qingcai, Yu Xianjun, Shi Si
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai 200032, China.
Department of Oncology, Shanghai Medical College, Fudan University, No. 270 Dong'An Road, Shanghai 200032, China.
Cancers (Basel). 2019 Dec 12;11(12):1998. doi: 10.3390/cancers11121998.
Damaged DNA-binding protein 1 (DDB1) recruits nucleotide excision pathway proteins to form the UV-damaged DNA-binding protein complex and is required for DNA repair. DDB1 was reported to participate in apoptosis and chemoresistance regulation in several cancers. However, little is known about the function of DDB1 in pancreatic adenocarcinoma (PDAC). In this study, we reported that DDB1 functions as a tumor-promoting factor in PDAC by regulating cancer cell proliferation, epithelial-mesenchymal transition (EMT) and chemoresistance. Compared to normal pancreatic tissues, PDAC tissues had high expression levels of DDB1, and this high expression was positively correlated with poor prognosis. Furthermore, reductions in cell proliferation and EMT were observed in DDB1-deficient PDAC cell lines. Intriguingly, we also found that abrogation of DDB1 expression increased PDAC cell sensitivity to gemcitabine (GEM). Mechanistically, DDB1 knockdown was associated with an increase in deoxycytidine kinase expression in vivo and in vitro. In summary, our work demonstrated that DDB1 promotes PDAC progression and chemoresistance and may serve as a potential predictive marker and therapeutic target for PDAC treatment.
损伤DNA结合蛋白1（DDB1）招募核苷酸切除途径蛋白以形成紫外线损伤的DNA结合蛋白复合物，是DNA修复所必需的。据报道，DDB1参与多种癌症的细胞凋亡和化疗耐药性调节。然而，关于DDB1在胰腺腺癌（PDAC）中的功能知之甚少。在本研究中，我们报道DDB1通过调节癌细胞增殖、上皮-间质转化（EMT）和化疗耐药性，在PDAC中发挥肿瘤促进因子的作用。与正常胰腺组织相比，PDAC组织中DDB1表达水平较高，且这种高表达与预后不良呈正相关。此外，在DDB1缺陷的PDAC细胞系中观察到细胞增殖和EMT减少。有趣的是，我们还发现DDB1表达的缺失增加了PDAC细胞对吉西他滨（GEM）的敏感性。从机制上讲，DDB1敲低与体内外脱氧胞苷激酶表达增加有关。总之，我们的研究表明DDB1促进PDAC进展和化疗耐药性，可能作为PDAC治疗的潜在预测标志物和治疗靶点。
