Malic Enzyme 1 Is Associated with Tumor Budding in Oral Squamous Cell Carcinomas.
Malic Enzyme 1 Is Associated with Tumor Budding in Oral Squamous Cell Carcinomas.
复制标题
DOI：
10.3390/ijms21197149
复制
发表时间：
2020-09-28
影响因子：
5.6
通讯作者：
Kuniyasu H
中科院分区：
文献类型：
--
作者：
Nakashima C;Kirita T;Yamamoto K;Mori S;Luo Y;Sasaki T;Fujii K;Ohmori H;Kawahara I;Mori T;Goto K;Kishi S;Fujiwara-Tani R;Kuniyasu H
肿瘤侵袭前沿的出芽与许多癌症的恶性特性相关。苹果酸酶 1 (ME1) 促进癌细胞中的 Warburg 效应，并诱导口腔鳞状细胞癌 (OSCC) 中的上皮-间质转化 (EMT)。因此，我们研究了 ME1 在 OSCC 肿瘤出芽中的作用。通过上皮标记物 (AE1/AE3) 的免疫染色测量 96 个人类 OSCC 中的肿瘤出芽，并将其表达与 ME1 的表达进行比较。肿瘤出芽和 ME1 表达之间观察到显着相关性。这种相关性随着癌症的进展而增加。在人 OSCC 细胞中，当通过敲低 ME1 和乳酸脱氢酶 A 或抑制丙酮酸脱氢酶 (PDH) 激酶来抑制乳酸发酵时，乳酸分泌会减少。此外，细胞外pH值升高，EMT表型受到抑制。相反，当PDH敲低抑制氧化磷酸化时，乳酸分泌增加，细胞外pH值降低，并且促进EMT表型。 CoCl2 处理诱导 OSCC 细胞化学缺氧，导致 ME1 表达增加以及 HIF1α 表达增加，并促进 EMT 表型。缺氧条件还会增加基质金属蛋白酶的表达，降低线粒体膜电位、线粒体氧化应激和细胞外 pH 值。此外，低氧处理导致 Yes 相关蛋白 (YAP) 的激活，而 ME1 敲除则消除了该蛋白的激活。这些发现表明，由于 ME1 过度表达、细胞外 pH 值降低和 YAP 激活，缺氧环境中肿瘤前部的癌细胞通过将能量代谢从氧化磷酸化转变为糖酵解来增加乳酸分泌。这些改变增强了 EMT 和随后的肿瘤出芽。因此，肿瘤出芽和 ME1 表达被认为是 OSCC 恶性肿瘤的有用标志物，ME1 有望成为分子治疗的相关靶点。
Budding at the tumor invasive front has been correlated with the malignant properties of many cancers. Malic enzyme 1 (ME1) promotes the Warburg effect in cancer cells and induces epithelial–mesenchymal transition (EMT) in oral squamous cell carcinoma (OSCC). Therefore, we investigated the role of ME1 in tumor budding in OSCC. Tumor budding was measured in 96 human OSCCs by immunostaining for an epithelial marker (AE1/AE3), and its expression was compared with that of ME1. A significant correlation was observed between tumor budding and ME1 expression. The correlation increased with the progression of cancer. In human OSCC cells, lactate secretion decreased when lactate fermentation was suppressed by knockdown of ME1 and lactate dehydrogenase A or inhibition of pyruvate dehydrogenase (PDH) kinase. Furthermore, the extracellular pH increased, and the EMT phenotype was suppressed. In contrast, when oxidative phosphorylation was suppressed by PDH knockdown, lactate secretion increased, extracellular pH decreased, and the EMT phenotype was promoted. Induction of chemical hypoxia in OSCC cells by CoCl2 treatment resulted in increased ME1 expression along with HIF1α expression and promotion of the EMT phenotype. Hypoxic conditions also increased matrix metalloproteinases expression and decreased mitochondrial membrane potential, mitochondrial oxidative stress, and extracellular pH. Furthermore, the hypoxic treatment resulted in the activation of Yes-associated protein (YAP), which was abolished by ME1 knockdown. These findings suggest that cancer cells at the tumor front in hypoxic environments increase their lactate secretion by switching their energy metabolism from oxidative phosphorylation to glycolysis owing to ME1 overexpression, decrease in extracellular pH, and YAP activation. These alterations enhance EMT and the subsequent tumor budding. Tumor budding and ME1 expression are thus considered useful markers of OSCC malignancy, and ME1 is expected to be a relevant target for molecular therapy.
登录
查看更多内容
影响因子：
3.4
作者：
Liu HL;Liu D;Ding GR;Liao PF;Zhang JW
通讯作者：
Zhang JW
影响因子：
5.7
作者：
Nakashima C;Yamamoto K;Fujiwara-Tani R;Luo Y;Matsushima S;Fujii K;Ohmori H;Sasahira T;Sasaki T;Kitadai Y;Kirita T;Kuniyasu H
通讯作者：
Kuniyasu H
影响因子：
11.1
作者：
Greenhough A;Bagley C;Heesom KJ;Gurevich DB;Gay D;Bond M;Collard TJ;Paraskeva C;Martin P;Sansom OJ;Malik K;Williams AC
通讯作者：
Williams AC
影响因子：
6
作者：
Kuniyasu, H;Yano, S;Ohmori, H
通讯作者：
Ohmori, H
影响因子：
3.4
作者：
Kanazawa, H.;Mitomi, H.;Watanabe, M.
通讯作者：
Watanabe, M.