Inhibition of BRD4 enhanced the tumor suppression effect of dasatinib in gastric cancer.
Inhibition of BRD4 enhanced the tumor suppression effect of dasatinib in gastric cancer.
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DOI：
10.1007/s12032-022-01831-8
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发表时间：
2022-11-09
期刊：
影响因子：
3.4
通讯作者：
Zheng, Shangyong
中科院分区：
文献类型：
--
作者：
Shen, Hao;Hu, Xuefei;Yang, Xinrui;Chen, Jiahui;Fu, Yating;He, Hongwei;Shi, Yongkang;Zeng, Rong;Chang, Wenjun;Zheng, Shangyong
BRD4是溴结构域和末端外（BET）家族的成员，在多种癌症组织中升高，包括胃癌（GC）。BRD4的靶向治疗可能有助于提高GC患者的总生存率。与此同时，最近报道了批准的多靶点激酶抑制剂达沙替尼在GC细胞中显示出不同的肿瘤抑制作用。本研究分别采用免疫组织化学和蛋白质印迹法研究了BRD4在体内和体外的表达。我们讨论了BRD4表达与患者预后的关系。接下来，在BRD4敲低的GC细胞中测量达沙替尼的抗肿瘤功效，以确定BRD4阻断在达沙替尼治疗中的作用。最后，使用BET抑制剂Molibresib来测量BRD4抑制和达沙替尼处理在三种GC细胞系中的协同作用。上皮BRD4表达在肿瘤和转移组织中更高，并且与不利的肿瘤、淋巴结和转移阶段以及存活率密切相关。在体外测试的三种GC细胞系中，BRD4表达是异质的。在BRD4高GC细胞系SGC7901中，使用特异性siRNA敲低BRD4单独抑制细胞生长，并与达沙替尼协同抑制细胞生长。此外，莫利布和达沙替尼在抑制BRD 4-高GC细胞的增殖方面显示出协同作用。总之，我们证实上皮BRD4表达增加与GC的疾病分期和预后不良相关，BRD4阻断可能是提高达沙替尼和其他药物在晚期GC化疗中的敏感性的有价值的策略。
BRD4, a member of the bromodomain and extraterminal (BET) family, is elevated in multiple cancer tissues, including gastric cancer (GC). Targeted therapy with BRD4 may help improve the overall survival of patients with GC. Meanwhile, the approved multi-target kinase inhibitor, dasatinib, was recently reported to show varied tumor-suppressive effects in GC cells. This study investigated BRD4 expression in vivo and in vitro using immunohistochemistry and western blotting, respectively. We discussed the relationship between BRD4 expression and patient prognosis. Next, the antitumor efficacy of dasatinib was measured in BRD4-knockdown GC cells to determine the role of BRD4 blockage in dasatinib treatment. Finally, molibresib, a BET inhibitor, was used to measure the cooperative function of BRD4 inhibition and dasatinib treatment in three GC cell lines. Epithelial BRD4 expression was higher in tumoral and metastatic tissues and was strongly associated with unfavorable tumor, node, and metastasis stages and survival. BRD4 expression was heterogeneous in the three GC cell lines tested in vitro. In SGC7901, a BRD4-high GC cell line, knockdown of BRD4 using specific siRNAs suppressed cell growth individually and cooperatively with dasatinib. Moreover, molibresib and dasatinib showed a cooperative effect in suppressing the proliferation of BRD4-high GC cells. In conclusion, we confirmed that increased epithelial BRD4 expression is associated with poor disease stage and prognosis in GC and BRD4 blockage might be a valuable strategy to improve the sensitivity of dasatinib and other drugs in the chemotherapy of advanced GC.
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影响因子：
37.3
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通讯作者：
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