Monocarboxylate transporters (MCT) are transmembrane proteins that control the lactate metabolism and are associated with poor prognosis in solid tumors, including colorectal cancer. Here, we aimed to investigate the biological and clinical role of MCTs in colorectal cancer and to assess the potential of therapeutic application. A total of 16 human colorectal cancer cell lines, 11 patient-derived cells from malignant ascites [patient-derived cells (PDC)], and 39 matched pairs of primary colorectal cancer and normal colorectal tissues were used to assess the role of MCT in vitro and in vivo. siRNA methodology was used to determine the effect of MCT inhibition and molecular mechanism of hypoxia- and angiogenesis-related factors in addition to MCT4. The effect of MCT inhibition was confirmed in mouse xenograft models. MCT4 expression in surgical tissue was evaluated by IHC and used for survival analysis. Expression of MCTs was demonstrated in colorectal cancer cell lines. siRNA-mediated MCT silencing caused significant decline of cell proliferation both in vitro and in vivo. An additive effect of MCT inhibition was induced by combined treatment with chemotherapy or radiotherapy. In particular, the expression of MCT4 was markedly increased in PDCs, and MCT4 inhibition significantly decreased PDC proliferation. Hypoxia-inducible factor 1-α (HIF1α) was also highly expressed in PDCs, whereas HIF1α knockdown reduced MCT4 expression and of other angiogenesis-related mediators. The patients with high MCT4 expression by IHC showed shorter relapse-free survival compared with low expression. These findings suggest that MCT4 may represent a new therapeutic target for colorectal cancer with peritoneal carcinomatosis and serve as a prognostic indicator. Mol Cancer Ther; 17(4); 838–48. ©2018 AACR.

中文翻译：

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MCT4 表达是结直肠癌腹膜癌的潜在治疗靶点

单羧酸转运蛋白 (MCT) 是控制乳酸代谢的跨膜蛋白，与实体瘤（包括结直肠癌）的不良预后有关。在这里，我们旨在研究 MCT 在结直肠癌中的生物学和临床作用，并评估治疗应用的潜力。共使用16个人结直肠癌细胞系、11个来自恶性腹水的患者来源细胞[患者来源细胞(PDC)]和39对匹配的原发性结直肠癌和正常结直肠组织用于体外评估MCT的作用和体内。除了 MCT4 外，还使用 ​​siRNA 方法确定 MCT 抑制的效果和缺氧和血管生成相关因子的分子机制。在小鼠异种移植模型中证实了 MCT 抑制的作用。通过 IHC 评估手术组织中的 MCT4 表达并用于生存分析。在结直肠癌细胞系中证明了 MCT 的表达。siRNA 介导的 MCT 沉默导致体外和体内细胞增殖的显着下降。通过与化学疗法或放射疗法的联合治疗诱导了 MCT 抑制的累加效应。特别是，MCT4 在 PDC 中的表达显着增加，并且 MCT4 抑制显着降低了 PDC 增殖。缺氧诱导因子 1-α (HIF1α) 在 PDC 中也高度表达，而 HIF1α 敲低降低了 MCT4 的表达和其他血管生成相关介质的表达。与低表达相比，IHC 高表达 MCT4 的患者显示出更短的无复发生存期。这些发现表明 MCT4 可能代表结直肠癌腹膜转移癌的新治疗靶点，并作为预后指标。摩尔癌症治疗; 17(4); 838-48。©2018 AACR。