文章：

乳酸是乳腺癌细胞侵袭性的主要促进因子

Lactate Is a Major Promotor of Breast Cancer Cell Aggressiveness

原文发布日期：27 May 2025

DOI: 10.3390/cancers17111793

类型: Article

开放获取: 是

英文摘要：

Background: Lactate dehydrogenase (LDH) activity, producing high levels of lactate from pyruvate in cancer cells, is often associated with poor patient prognosis. We previously showed enhanced LDH/lactate levels in estrogen receptor (ER) compared to ER + breast cancer cells; lactate or pyruvate supplementation to ER + cells significantly enhanced their motile ability, while LDHB gene knockout (KO) or treatment with LDH inhibitors reduced the motility of the highly aggressive ER breast cancer cells.Aims: To investigate the molecular mechanisms by which lactate, LDHB KO, or treatment with LDH inhibitors can modulate the motile capabilities of breast cancer cell lines.Methods: KO experiments were performed using siRNA, and global expression was determined by proteomic profiling with Proteome Profiler Human XL Oncology arrays, Western blot, and immunofluorescence.Results: Lactate supplementation to ER + breast cancer cells enhanced expression of vimentin, N-cadherin, and snail, while reducing the expression of JAM-A, E-cadherin, and nectin-4. This expression profile was reversed with LDHB KO in ER cells. LDHB KO, or treatment with LDH inhibitors in ER cells, also reduced the expression of IL-6, IL-8, and MMP-2. The expressions of other markers such as PECAM-1, CCL20, and ENPP-2 were differentially modulated with LDH B KO in de novo ER cells (MDA-MB-231) vs. those that had ER knockout (pII).Conclusions: Our data show a novel role for lactate in modulating the EMT status in breast cancer cells and highlight the important role of lactate in breast cancer motility in part through modulating EMT status and the expression profile of cytokines, adhesion molecules, MMP-2, and nectin-4.

摘要翻译： 

背景：乳酸脱氢酶（LDH）在癌细胞中催化丙酮酸生成大量乳酸，其活性常与患者不良预后相关。我们前期研究发现，与ER+乳腺癌细胞相比，ER-细胞中LDH/乳酸水平显著升高；向ER+细胞补充乳酸或丙酮酸可显著增强其运动能力，而LDH B基因敲除或LDH抑制剂处理则能降低高侵袭性ER-乳腺癌细胞的运动能力。 目的：探究乳酸、LDH B敲除或LDH抑制剂处理调控乳腺癌细胞系运动能力的分子机制。 方法：采用siRNA进行基因敲除实验，通过蛋白质组学分析（使用Proteome Profiler Human XL Oncology芯片）、Western blot及免疫荧光技术检测全局蛋白表达变化。 结果：向ER+乳腺癌细胞补充乳酸可上调波形蛋白、N-钙黏蛋白和Snail的表达，同时降低JAM-A、E-钙黏蛋白及nectin-4的表达。在ER-细胞中进行LDH B敲除可逆转该表达谱。LDH B敲除或LDH抑制剂处理还能降低ER-细胞中IL-6、IL-8和MMP-2的表达。在新生ER-细胞（MDA-MB-231）与ER敲除细胞（pII）中，PECAM-1、CCL20和ENPP-2等其他标志物的表达受LDH B敲除的调控呈现差异性变化。 结论：本研究揭示了乳酸在调控乳腺癌细胞上皮-间质转化状态中的新功能，并阐明乳酸通过部分调控EMT状态及细胞因子、黏附分子、MMP-2和nectin-4的表达谱，在乳腺癌细胞运动能力中发挥重要作用。

原文链接：

Lactate Is a Major Promotor of Breast Cancer Cell Aggressiveness