Nuclear DDX3 expression predicts poor outcome in colorectal and breast cancer.
Nuclear DDX3 expression predicts poor outcome in colorectal and breast cancer.
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DOI：
10.2147/ott.s140639
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发表时间：
2017
影响因子：
4
通讯作者：
Raman V
中科院分区：
文献类型：
--
作者：
Heerma van Voss MR;Vesuna F;Bol GM;Meeldijk J;Raman A;Offerhaus GJ;Buerger H;Patel AH;van der Wall E;van Diest PJ;Raman V
死亡盒蛋白3(DEAD BOX Protein 3，DDX3)是一种穿梭于细胞质和细胞核之间的具有致癌特性的RNA解旋酶。大多数DDX3存在于细胞质中，但部分肿瘤有明显的核DDX3定位，其生物学意义尚不清楚。本研究旨在探讨核DDX3在结直肠癌和乳腺癌中表达的意义及其机制。应用免疫组织化学方法检测304例结直肠癌和292例乳腺癌组织中核DDX3和核出口体染色体区域维持1(CRM1)的表达。研究DDX3和CRM1的亚细胞定位与有核和无核DDX3患者总体生存率差异之间的关系。此外，还创建了DDX3突变体，用于体外评估DDX3核保留背后的机制。在35%的结直肠癌和48%的乳腺癌患者的细胞核中存在DDX3，并且在核仁中的表达尤其强烈。在结直肠癌(风险比[HR]2.34，P<；0.001)和乳腺癌患者(风险比[HR]2.39，P=0.004)中，核DDX3与较差的总体生存率相关。核DDX3表达的结直肠癌更多的是胞浆表达核出口蛋白CRM1(相对危险度1.67，P=0.04)。对DDX3缺失突变体的体外分析表明，CRM1介导的输出最依赖于N末端的核输出信号。总体而言，我们得出结论，核DDX3部分是由CRM1介导的，并预测结直肠癌和乳腺癌患者的生存率更差，将其作为正在开发的DDX3抑制剂对这些癌症类型进行治疗干预的靶点。
DEAD box protein 3 (DDX3) is an RNA helicase with oncogenic properties that shuttles between the cytoplasm and nucleus. The majority of DDX3 is found in the cytoplasm, but a subset of tumors has distinct nuclear DDX3 localization of yet unknown biological significance. This study aimed to evaluate the significance of and mechanisms behind nuclear DDX3 expression in colorectal and breast cancer. Expression of nuclear DDX3 and the nuclear exporter chromosome region maintenance 1 (CRM1) was evaluated by immunohistochemistry in 304 colorectal and 292 breast cancer patient samples. Correlations between the subcellular localization of DDX3 and CRM1 and the difference in overall survival between patients with and without nuclear DDX3 were studied. In addition, DDX3 mutants were created for in vitro evaluation of the mechanism behind nuclear retention of DDX3. DDX3 was present in the nucleus of 35% of colorectal and 48% of breast cancer patient samples and was particularly strong in the nucleolus. Nuclear DDX3 correlated with worse overall survival in both colorectal (hazard ratio [HR] 2.34, P<0.001) and breast cancer (HR 2.39, P=0.004) patients. Colorectal cancers with nuclear DDX3 expression more often had cytoplasmic expression of the nuclear exporter CRM1 (relative risk 1.67, P=0.04). In vitro analysis of DDX3 deletion mutants demonstrated that CRM1-mediated export was most dependent on the N-terminal nuclear export signal. Overall, we conclude that nuclear DDX3 is partially CRM1-mediated and predicts worse survival in colorectal and breast cancer patients, putting it forward as a target for therapeutic intervention with DDX3 inhibitors under development in these cancer types.