Wang Yong-Hui, Sui Ya-Na, Yan Kai, Wang Li-Shan, Wang Fei, Zhou Jia-Hua
Department of General Surgery, The Affiliated Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu, P.R. China.
Emergency Department of Weifang Traditional Chinese Hospital, Weifang, Shandong, P.R. China.
Oncol Rep. 2015 Apr;33(4):1699-706. doi: 10.3892/or.2015.3774. Epub 2015 Jan 30.
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive carcinoma with a poor prognosis. To date, there is no effective treatment for this fatal disease. The manipulation of epigenetic proteins, such as BRD4, has recently emerged as an alternative therapeutic strategy. Our objective was to analyze the effect of BRD4 on the cell progression and chemoresistance of PDAC and the novel mechanisms involved. In the present study, we firstly revealed that the expression of BRD4 was significantly upregulated in PDAC cell lines, compared to that in human pancreatic duct epithelial cells. An in vitro assay showed that the suppression of BRD4 impaired PDAC cell viability and proliferation. Similarly, the tumor growth rate was also decreased in vivo after silencing of BRD4. Furthermore, we showed that the expression of BRD4 was increased after treatment with gemcitabine (GEM). Combination treatment of GEM and BRD4 silencing had a synergistic effect on the chemotherapeutic efficacy in the PANC-1 and MIAPaCa-2 cell lines, and significantly promoted apoptosis. In particular, we demonstrated that BRD4 activated the Sonic hedgehog (Shh) signaling pathway members in a ligand-independent manner in the PDAC cells. Together, our results indicate the important role of BRD4 in PDAC cell proliferation and chemoresistance and suggests that BRD4 is a promising target directed against the transcriptional program of PDAC.
胰腺导管腺癌（PDAC）是一种侵袭性很强的癌症，预后很差。迄今为止，对于这种致命疾病尚无有效的治疗方法。对表观遗传蛋白（如BRD4）的调控最近已成为一种替代治疗策略。我们的目的是分析BRD4对PDAC细胞进展和化疗耐药性的影响以及其中涉及的新机制。在本研究中，我们首先发现，与人类胰腺导管上皮细胞相比，BRD4在PDAC细胞系中的表达显著上调。体外实验表明，抑制BRD4会损害PDAC细胞的活力和增殖。同样，在体内沉默BRD4后肿瘤生长速率也降低。此外，我们发现吉西他滨（GEM）处理后BRD4的表达增加。GEM与BRD4沉默的联合治疗对PANC-1和MIAPaCa-2细胞系的化疗疗效具有协同作用，并显著促进细胞凋亡。特别是，我们证明BRD4在PDAC细胞中以不依赖配体的方式激活了音猬因子（Shh）信号通路成员。总之，我们的结果表明BRD4在PDAC细胞增殖和化疗耐药性中起重要作用，并表明BRD4是针对PDAC转录程序的一个有前景的靶点。
