PTBP1-associated microRNA-1 and -133b suppress the Warburg effect in colorectal tumors.
PTBP1-associated microRNA-1 and -133b suppress the Warburg effect in colorectal tumors.
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PTBP1相关的microRNA-1和-133B抑制了结直肠肿瘤的WARBUR效应。
DOI：
10.18632/oncotarget.8005
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发表时间：
2016-04-05
期刊：
影响因子：
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通讯作者：
Akao Y
中科院分区：
文献类型：
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作者：
Taniguchi K;Sakai M;Sugito N;Kumazaki M;Shinohara H;Yamada N;Nakayama T;Ueda H;Nakagawa Y;Ito Y;Futamura M;Uno B;Otsuki Y;Yoshida K;Uchiyama K;Akao Y
已知肌肉中的丙酮酸激酶（PKM）（其是限速糖酵解酶）在瓦尔堡效应中具有重要作用，并且癌症显性PKM 2的表达通过多聚嘧啶片段结合蛋白1（PTBP 1）增加，所述PTBP 1是PKM基因的剪接体。换句话说，PKM 2充当瓦尔堡效应的启动子。以前，我们证明了瓦尔堡效应部分是通过下调与PTBP 1结合的几种microRNA（miR）建立的，并且这些miR的异位表达抑制了瓦尔堡效应。在本研究中，我们从大肠癌中的瓦尔堡效应的角度研究了众所周知的肌肉特异性miR-1和-133 b的功能。miR-1和-133b在除肌肉外的结肠组织中的表达水平相对较高，并且与邻近正常组织样品相比，在75个临床结肠直肠肿瘤样品中，甚至在腺瘤中，miR-1和-133b的表达水平频繁下调。这些miR的异位表达通过在体外和体内沉默PTBP 1表达将PKM同种型表达从PKM 2转换为PKM 1而诱导生长抑制和自噬性细胞死亡。此外，我们还表明细胞内活性氧（ROS）水平的增加也参与了这一机制。此外，PTBP 1在检查的30个临床结直肠肿瘤样品中的大多数中高度表达，甚至在腺瘤中也是如此。我们的研究结果表明，PTBP 1和PTBP 1相关的miR-1和-133 b是维持结直肠肿瘤中瓦尔堡效应的关键分子。
It is known that pyruvate kinase in muscle (PKM), which is a rate-limiting glycolytic enzyme, has essential roles in the Warburg effect and that expression of cancer-dominant PKM2 is increased by polypyrimidine tract-binding protein 1 (PTBP1), which is a splicer of the PKM gene. In other words, PKM2 acts as a promoter of the Warburg effect. Previously, we demonstrated that the Warburg effect was partially established by down-regulation of several microRNAs (miRs) that bind to PTBP1 and that ectopic expression of these miRs suppressed the Warburg effect. In this study, we investigated the functions of miR-1 and -133b, which are well known as muscle-specific miRs, from the viewpoint of the Warburg effect in colorectal tumors. The expression levels of miR-1 and -133b were relatively high in colon tissue except muscle and very frequently down-regulated in 75 clinical colorectal tumors samples, even in adenomas, compared with those of the adjacent normal tissue samples. The ectopic expression of these miRs induced growth suppression and autophagic cell death through the switching of PKM isoform expression from PKM2 to PKM1 by silencing PTBP1 expression both in vitro and in vivo. Also, we showed that the resultant increase in the intracellular level of reactive oxygen species (ROS) was involved in this mechanism. Furthermore, PTBP1 was highly expressed in most of the 30 clinical colorectal tumor samples examined, even in adenomas. Our results suggested that PTBP1 and PTBP1-associated miR-1 and -133b are crucial molecules for the maintenance of the Warburg effect in colorectal tumors.