Organ-Specific MicroRNAs (MIR122, 137, and 206) Contribute to Tissue Characteristics and Carcinogenesis by Regulating Pyruvate Kinase M1/2 (PKM) Expression.
Organ-Specific MicroRNAs (MIR122, 137, and 206) Contribute to Tissue Characteristics and Carcinogenesis by Regulating Pyruvate Kinase M1/2 (PKM) Expression.
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DOI：
10.3390/ijms19051276
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发表时间：
2018-04-24
影响因子：
5.6
通讯作者：
Akao Y
中科院分区：
文献类型：
--
作者：
Taniguchi K;Sugito N;Shinohara H;Kuranaga Y;Inomata Y;Komura K;Uchiyama K;Akao Y
丙酮酸激酶被称为糖酵解酶，催化糖酵解的最后一步。在哺乳动物中，它存在两种不同的形式，即，丙酮酸激酶M1/2（PKM）和丙酮酸激酶L/R（PKLR）。此外，PKM有两种亚型，即，PKM 1和PKM 2。这些基因具有组织特异性分布。即PKM 1分布在高能量需求的器官，如大脑和肌肉。此外，PKM 2分布在各种其他器官中，例如结肠。另一方面，PKLR分布在肝脏和红细胞（RBC）中。有趣的是，PKM 2已被认为是癌症特异性能量代谢的必需基因之一，称为“瓦尔堡效应”。然而，这一事实背后的机制在很大程度上仍不清楚。最近，我们发现一些器官特异性microRNAs（miRNAs，MIR）通过直接靶向多聚嘧啶束结合蛋白1（PTBP 1）来调节PKM亚型的表达，PTBP 1是负责PKM 2显性表达的剪接体。在这项研究中，我们研究了这种机制是否在其他PTBP 1和PKM靶向miRNA的情况下是保守的。我们重点研究了MIRs 122、137和206，并研究了这些miRNAs在小鼠和人体器官组织中的表达谱。此外，我们通过在人类癌细胞系中测试这些miRNA中的每一个来检查PKM同种型表达的调节机制。目前，我们发现脑特异性MIR 137和肌肉特异性MIR 206主要通过直接靶向PTBP 1诱导PKM 1表达。此外，肝脏特异性MIR 122抑制PKM 1和PKM 2的表达，其作用通过直接靶向PKM以使PKLR能够表达而发生。此外，这些miRNA的表达水平在源自这些组织的癌细胞中下调，导致PKM 2占优势。我们的研究结果表明，miRNA的器官特异性分布是miRNA建立组织特征的主要手段之一，这些miRNA的失调通过PKM亚型表达比例的变化导致癌症的发展。此外，我们的研究结果有助于癌症的诊断，并将在不久的将来用于癌症特异性治疗的瓦尔堡效应。
Pyruvate kinase is known as the glycolytic enzyme catalyzing the final step in glycolysis. In mammals, two different forms of it exist, i.e., pyruvate kinase M1/2 (PKM) and pyruvate kinase L/R (PKLR). Also, PKM has two isoforms, i.e., PKM1 and PKM2. These genes have tissue-specific distribution. Namely, PKM1 is distributed in high-energy-demanding organs, such as brain and muscle. Also, PKM2 is distributed in various other organs, such as the colon. On the other hand, PKLR is distributed in liver and red blood cells (RBCs). Interestingly, PKM2 has been recognized as one of the essential genes for the cancer-specific energy metabolism termed the “Warburg effect”. However, the mechanism(s) underlying this fact have remained largely unclear. Recently, we found that some organ-specific microRNAs (miRNAs, MIR) regulate PKM isoform expression through direct targeting of polypyrimidine tract binding protein 1 (PTBP1), which is the splicer responsible for PKM2-dominant expression. In this study, we examined whether this machinery was conserved in the case of other PTBP1- and PKM-targeting miRNAs. We focused on the MIRs 122, 137, and 206, and investigated the expression profiles of each of these miRNAs in tissues from mouse and human organs. Also, we examined the regulatory mechanisms of PKM isoform expression by testing each of these miRNAs in human cancer cell lines. Presently, we found that brain-specific MIR137 and muscle-specific MIR206 predominantly induced PKM1 expression through direct targeting of PTBP1. Also, liver-specific MIR122 suppressed the expression of both PKM1 and PKM2, which action occurred through direct targeting of PKM to enable the expression of PKLR. Moreover, the expression levels of these miRNAs were downregulated in cancer cells that had originated from these tissues, resulting in PKM2 dominance. Our results suggest that the organ-specific distribution of miRNAs is one of the principal means by which miRNA establishes characteristics of a tissue and that dysregulation of these miRNAs results in cancer development through a change in the ratio of PKM isoform expression. Also, our results contribute to cancer diagnosis and will be useful for cancer-specific therapy for the Warburg effect in the near future.
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影响因子：
5.6
作者：
Takai T;Yoshikawa Y;Inamoto T;Minami K;Taniguchi K;Sugito N;Kuranaga Y;Shinohara H;Kumazaki M;Tsujino T;Takahara K;Ito Y;Akao Y;Azuma H
通讯作者：
Azuma H
影响因子：
--
作者：
He X;Du S;Lei T;Li X;Liu Y;Wang H;Tong R;Wang Y
通讯作者：
Wang Y
miR-124、miR-137 和 miR-340 通过抑制 Warburg 效应来调节结直肠癌的生长。
影响因子：
4.2
作者：
Sun, Yan;Zhao, Xiaoping;Hu, Yu
通讯作者：
Hu, Yu
影响因子：
37.3
作者：
Hsu MC;Hung WC
通讯作者：
Hung WC
miR-124和miR-137抑制多形性胶质母细胞瘤细胞的增殖并诱导脑肿瘤干细胞的分化。
影响因子：
9.3
作者：
Silber J;Lim DA;Petritsch C;Persson AI;Maunakea AK;Yu M;Vandenberg SR;Ginzinger DG;James CD;Costello JF;Bergers G;Weiss WA;Alvarez-Buylla A;Hodgson JG
通讯作者：
Hodgson JG