Identification of CREB3L1 as a Biomarker Predicting Doxorubicin Treatment Outcome.
Identification of CREB3L1 as a Biomarker Predicting Doxorubicin Treatment Outcome.
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将CREB3L1鉴定为预测阿霉素治疗结果的生物标志物。
DOI：
10.1371/journal.pone.0129233
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Ye J
中科院分区：
文献类型：
--
作者：
Denard B;Pavia-Jimenez A;Chen W;Williams NS;Naina H;Collins R;Brugarolas J;Ye J
阿霉素已被证明通过蛋白水解激活CREB 3L 1（cAMP反应元件结合蛋白3样1）（一种作为膜结合前体合成的转录因子）来抑制癌细胞增殖。在阿霉素处理后，CREB 3L 1被切割，使得蛋白质的N-末端结构域可以到达细胞核，在那里它激活抑制细胞增殖的基因的转录。这些结果表明，癌细胞中CREB 3L 1的水平可能决定了它们对阿霉素的敏感性。用阿霉素（Doxorubicin）对6株肾细胞癌（RCC）移植瘤小鼠进行化疗，观察其对肿瘤生长的影响。进行免疫组织化学和生物信息学分析，以比较已知对多柔比星有反应的癌症类型与对多柔比星有抗性的癌症类型中的CREB 3L 1水平。较高水平的CREB 3L 1蛋白与异种移植RCC肿瘤的阿霉素敏感性增加相关（Pearson分析p = 0.017）。从我们分析的患者肿瘤活检来看，CREB 3L 1在19%的RCC中表达，RCC通常对阿霉素耐药，但在70%的弥漫性大B细胞淋巴瘤中对阿霉素敏感。多柔比星被用作表达最高水平的CREB 3L 1的癌症的标准治疗，例如骨肉瘤和恶性纤维组织细胞瘤，但通常不用于治疗表达最低水平的CREB 3L 1的癌症，例如RCC。CREB 3L 1作为阿霉素敏感性的生物标志物的鉴定可以通过仅将阿霉素应用于表达CREB 3L 1的癌症患者来显著改善阿霉素应答率。
Doxorubicin has been shown to inhibit proliferation of cancer cells through proteolytic activation of CREB3L1 (cAMP response element binding protein 3-like 1), a transcription factor synthesized as a membrane-bound precursor. Upon doxorubicin treatment, CREB3L1 is cleaved so that the N-terminal domain of the protein can reach the nucleus where it activates transcription of genes that inhibit cell proliferation. These results suggest that the level of CREB3L1 in cancer cells may determine their sensitivity to doxorubicin. Mice transplanted with 6 lines of renal cell carcinoma (RCC) were injected with doxorubicin to observe the effect of the chemotherapy on tumor growth. Immunohistochemistry and bioinformatics analyses were performed to compare CREB3L1 levels in types of cancer known to respond to doxorubicin versus those resistant to doxorubicin. Higher levels of CREB3L1 protein are correlated with increased doxorubicin sensitivity of xenograft RCC tumors (p = 0.017 by Pearson analysis). From patient tumor biopsies we analyzed, CREB3L1 was expressed in 19% of RCC, which is generally resistant to doxorubicin, but in 70% of diffuse large B-cell lymphoma that is sensitive to doxorubicin. Doxorubicin is used as the standard treatment for cancers that express the highest levels of CREB3L1 such as osteosarcoma and malignant fibrous histiocytoma but is not generally used to treat those that express the lowest levels of CREB3L1 such as RCC. Identification of CREB3L1 as the biomarker for doxorubicin sensitivity may markedly improve the doxorubicin response rate by applying doxorubicin only to patients with cancers expressing CREB3L1.
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影响因子：
7.7
作者：
Denard B;Lee C;Ye J
通讯作者：
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影响因子：
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作者：
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