Loss of PKM2 in Lgr5+ intestinal stem cells promotes colitis-associated colorectal cancer
Loss of PKM2 in Lgr5+ intestinal stem cells promotes colitis-associated colorectal cancer
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DOI：
10.1038/s41598-019-42707-8
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发表时间：
2019-04-17
影响因子：
4.6
通讯作者：
Kweon, Mi-Na
中科院分区：
文献类型：
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作者：
Kim, Yeji;Lee, Yong-Soo;Kweon, Mi-Na
丙酮酸激酶 M2 同工型 (PKM2)（关键的糖酵解酶）的调节特性影响能量代谢的改变，包括癌症中的糖酵解。在这项研究中，我们发现 PKM2 在溃疡性结肠炎或结直肠癌 (CRC) 患者中高表达。然后，我们使用结肠炎相关 CRC 小鼠模型（AOM 加 DSS）研究了在 Lgr5(+) 肠道干细胞 (ISC) 中条件性消除 PKM2 的有效性。与媒介物治疗小鼠 (PKM2(Delta Lgr5)-Veh) 中的发现相比，ISC 中他莫昔芬诱导的 Lgr5 驱动的 PKM2 缺失 (PKM2(Delta Lgr5)-Tx) 显着促进结肠肿瘤发生率和大小，并降低体重。组织病理学分析显示，PKM2(Delta Lgr5)-Tx 小鼠的结肠中有相当多的高度不典型增生和腺癌，而 PKM2(Delta Lgr5)-Veh 小鼠则有低度和高度不典型增生。 PKM2 的缺失与 Lgr5(+) ISC 及其子代细胞中 PKM1 的显性表达相关。此外，与PKM2(Delta Lgr5)-Veh小鼠相比，从PKM2(Delta Lgr5)-Tx小鼠的结肠息肉中获得的全癌细胞或Lgr5(+)细胞的类器官形成效率显着增加。 PKM2(Delta Lgr5)-Tx 小鼠的癌症类器官表现出线粒体耗氧量增加以及参与能量代谢的代谢物的变化。这些发现表明 ISC 中 PKM2 功能的丧失会促进结肠炎相关的 CRC。
The regulatory properties of pyruvate kinase M2 isoform (PKM2), the key glycolytic enzyme, influence altered energy metabolism including glycolysis in cancer. In this study, we found that PKM2 was highly expressed in patients with ulcerative colitis or colorectal cancer (CRC). We then investigated the effectiveness of conditionally ablating PKM2 in Lgr5(+) intestinal stem cells (ISC) using a mouse model of colitis-associated CRC (AOM plus DSS). Tamoxifen-inducible Lgr5-driven deletion of PKM2 in ISC (PKM2(Delta Lgr5)-Tx) significantly promoted tumor incidence and size in the colon and lower body weight compared with findings in vehicle-treated mice (PKM2(Delta Lgr5)-Veh). Histopathologic analysis revealed considerable high-grade dysplasia and adenocarcinoma in the colon of PKM2(Delta Lgr5)-Tx mice while PKM2(Delta Lgr5)-Veh mice had low-and high-grade dysplasia. Loss of PKM2 was associated with dominant expression of PKM1 in Lgr5(+) ISC and their progeny cells. Further, the organoid-forming efficiency of whole cancer cells or Lgr5(+) cells obtained from colon polyps of PKM2(Delta Lgr5)-Tx mice was significantly increased when compared with PKM2(Delta Lgr5)-Veh mice. Cancer organoids from PKM2(Delta Lgr5)-Tx mice exhibited increased mitochondrial oxygen consumption and a shift of metabolites involved in energy metabolism. These findings suggest that loss of PKM2 function in ISC promotes colitis-associated CRC.