Liu Feng, Liu Bin, Qian Jianmin, Wu Gang, Li Jiawei, Ma Zhenyu
Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China.
Institute of Integrated Traditional Chinese and Western Medicine, Fudan University, Shanghai 200040, China.
Acta Biochim Biophys Sin (Shanghai). 2017 Jun 1;49(6):520-529. doi: 10.1093/abbs/gmx039.
Pancreatic cancer (PC) is one of the most lethal cancers, with an overall 5 years survival rate of <5%. The clinical benefit of gemcitabine based chemotherapeutic strategy on PC was limited by its high drug resistance rate. Snail, one of the master regulators of epithelial-mesenchymal transition, has been implicated in the progression of various cancers. However, whether it is also linked to the development of chemosensitivity to gemcitabine in PC is unknown, and the regulatory pathways controlling Snail also need to be explored. Cell apoptosis analysis was performed using flow cytometry assay. Quantitative real-time PCR was used to investigate the level of microRNA and the mRNA expression of its target, Snail. Snail expression was measured by immunoblotting and immunohistochemistry. A xenografted tumor model was used to test the in vivo effects of miR-153 on chemosensitivity to gemcitabine. The results of this study demonstrated the decrease of miR-153 expression in PC tumor tissue, which is correlated with a poor prognosis. miR-153 mimic transfection enhanced gemcitabine sensitivity in gemcitabine-resistant PC cells, while downregulation of miR-153 decreased gemcitabine sensitivity. In addition, miR-153 was found to target the 3'-UTR of Snail mRNA. Furthermore, we found that the increase of apoptosis in gemcitabine-resistant PC cells resulted from miR-153 mimic transfection was reversed by overexpression of Snail. miR-153 reverses the resistance of PC cells to gemcitabine by directly targeting Snail, and it may be a potential novel therapeutic target for overcoming gemcitabine resistance in human PC.
胰腺癌（PC）是最致命的癌症之一，总体5年生存率<5%。基于吉西他滨的化疗策略对PC的临床益处受到其高耐药率的限制。Snail是上皮-间质转化的主要调节因子之一，与多种癌症的进展有关。然而，它是否也与PC对吉西他滨的化疗敏感性发展有关尚不清楚，控制Snail的调控途径也有待探索。使用流式细胞术分析进行细胞凋亡分析。定量实时PCR用于研究微小RNA水平及其靶标Snail的mRNA表达。通过免疫印迹和免疫组织化学测量Snail表达。使用异种移植肿瘤模型测试miR-153对吉西他滨化疗敏感性的体内作用。本研究结果表明，PC肿瘤组织中miR-153表达降低，这与预后不良相关。miR-153模拟物转染增强了吉西他滨耐药PC细胞对吉西他滨的敏感性，而miR-153的下调降低了吉西他滨敏感性。此外，发现miR-153靶向Snail mRNA的3'-UTR。此外，我们发现Snail过表达逆转了miR-153模拟物转染导致的吉西他滨耐药PC细胞凋亡增加。miR-153通过直接靶向Snail逆转PC细胞对吉西他滨的耐药性，它可能是克服人类PC中吉西他滨耐药性的潜在新型治疗靶点。
