贝他斯汀抑制人结肠癌和鼠结肠癌中 LTA4H 的活性。
Inhibition of LTA4H by bestatin in human and mouse colorectal cancer.
机构信息
The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, United States of America; Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, PR China; China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, PR China; Henan Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan, PR China.
The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, United States of America; China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, PR China.
出版信息
EBioMedicine. 2019 Jun;44:361-374. doi: 10.1016/j.ebiom.2019.05.008. Epub 2019 May 10.
BACKGROUND
Our preclinical data showed that the leukotriene A4 hydrolase (LTA4H) pathway plays a role in colorectal cancer (CRC). High expression of LTA4H and leukotriene B4 receptor type 1 (BLT1) were also associated with CRC survival probability. Clinical samples were evaluated to determine whether LTA4H could serve as a therapeutic target and whether leukotriene B4 (LTB4) could be used as a biomarker for evaluating the efficacy of bestatin in CRC.
METHODS
Patients with Stage I-III CRC did or did not receive bestatin prior to surgery. Evaluable pairwise CRC patient blood samples were collected to evaluate LTB4 concentration. Tissues were processed by immunohistochemistry to detect the LTA4H pathway and Ki-67 expression. We also determined whether LTA4H or BLT1 was associated with CRC survival probability and explored the mechanism of bestatin action in CRC.
FINDINGS
Samples from 13 CRC patients showed a significant decrease in LTB4, the LTA4H signaling pathway, and Ki-67 in the bestatin-treated group compared with the untreated group. LTA4H and BLT1 are overexpressed in CRC and associated with CRC survival probability. Bestatin effectively inhibited LTB4 and tumorigenesis in the Apc and CRC patient-derived xenograft mouse model.
INTERPRETATION
These results demonstrate that LTB4 could serve as a biomarker for evaluating bestatin efficacy in CRC and the antitumor effects of bestatin through its targeting of LTA4H and support further studies focusing on LTA4H inhibition in CRC.
背景
我们的临床前数据表明，白三烯 A4 水解酶（LTA4H）途径在结直肠癌（CRC）中发挥作用。LTA4H 和白三烯 B4 受体 1（BLT1）的高表达也与 CRC 的生存概率相关。评估临床样本，以确定 LTA4H 是否可以作为治疗靶点，以及白三烯 B4（LTB4）是否可以作为评估贝司他汀在 CRC 中疗效的生物标志物。
方法
I-III 期 CRC 患者在手术前接受或未接受贝司他汀治疗。收集可评估的配对 CRC 患者血液样本以评估 LTB4 浓度。通过免疫组织化学检测 LTA4H 通路和 Ki-67 表达来处理组织。我们还确定了 LTA4H 或 BLT1 是否与 CRC 的生存概率相关，并探讨了贝司他汀在 CRC 中的作用机制。
发现
与未治疗组相比，贝司他汀治疗组 13 例 CRC 患者的 LTB4、LTA4H 信号通路和 Ki-67 明显降低。LTA4H 和 BLT1 在 CRC 中过度表达，与 CRC 的生存概率相关。贝司他汀能有效抑制 Apc 和 CRC 患者来源异种移植小鼠模型中的 LTB4 和肿瘤发生。
解释
这些结果表明，LTB4 可作为评估贝司他汀在 CRC 中疗效的生物标志物，以及贝司他汀通过靶向 LTA4H 发挥抗肿瘤作用，并支持进一步研究 LTA4H 抑制在 CRC 中的作用。
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