School of Life Science, Chongqing University, Chongqing, 400044, PR China.
Breast Cancer Center, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, 400044, PR China.
Exp Cell Res. 2019 Nov 1;384(1):111591. doi: 10.1016/j.yexcr.2019.111591. Epub 2019 Aug 31.
The high lactate production rate in hepatocellular carcinoma cells (HCC) have a profound impact on their malignant properties. In adaptation to the enhanced lactate stress, lactate-effusing monocarboxylate transporter 4(MCT4) is usually overexpressed in a broad range of HCC subtypes. In this study, the MCT4-mediated lactate efflux in HCC was blocked using microRNA-145(miR-145), which would force the endogenously generated lactate to accumulate within tumor cells in a self-regulated manner, resulting in the acidification of the cytoplasmic compartment as well as partial neutralization for pH in the tumor extracellular environment. Evaluations on multiple representative HCC subtypes (HepG2, Hep3B and HuH7) suggested that the disrupted pH homeostasis would amplify the lactate stress to initiate HCC apoptosis, while at the same time also suppressing their migration and invasion abilities. Moreover, safety tests on 7702 cells and living animals revealed that MCT4-blockade treatment has no cytotoxicity against healthy cells/tissues. The results indicate the MCT4-inhibition-induced disruption of tumor intracellular pH holds promise as a therapy against not only HCC, but a broader spectrum of MCT4-overexpressing hyperglycolytic tumors.
肝癌细胞（HCC）中高乳酸的产生速率对其恶性特性有深远的影响。在适应增强的乳酸应激中，乳酸外排单羧酸转运蛋白 4（MCT4）通常在广泛的 HCC 亚型中过表达。在这项研究中，使用 microRNA-145（miR-145）阻断 HCC 中的 MCT4 介导的乳酸外排，这将迫使内源性产生的乳酸以自我调节的方式在肿瘤细胞内积累，导致细胞质区室酸化以及肿瘤细胞外环境中 pH 的部分中和。对多种代表性 HCC 亚型（HepG2、Hep3B 和 HuH7）的评估表明，破坏的 pH 平衡会放大乳酸应激，引发 HCC 细胞凋亡，同时抑制其迁移和侵袭能力。此外，对 7702 细胞和活体动物的安全性测试表明，MCT4 阻断治疗对健康细胞/组织没有细胞毒性。这些结果表明，MCT4 抑制诱导的肿瘤细胞内 pH 破坏有望成为不仅针对 HCC 而且针对更广泛的 MCT4 过表达高糖酵解肿瘤的治疗方法。
