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首页> 外文期刊>Journal of experimental & clinical cancer research : >Hypoxia-dependent expression of MAP17 coordinates the Warburg effect to tumor growth in hepatocellular carcinoma
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Hypoxia-dependent expression of MAP17 coordinates the Warburg effect to tumor growth in hepatocellular carcinoma

机译：Map17的缺氧依赖表达坐标对肝细胞癌肿瘤生长的Warburg效应

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Reprogrammed glucose metabolism, also known as the Warburg effect, which is essential for tumor progression, is regarded as a hallmark of cancer. MAP17, a small 17-kDa non-glycosylated membrane protein, is frequently?dysregulated in human cancers. However, its role in hepatocellular carcinoma (HCC) remains largely unknown. Immunohistochemistry was used to analyze the expression pattern of MAP17 in HCC. Loss-of-function and gain-of-function studies were performed to investigate the oncogenic roles of MAP17 in vitro and in vivo. RNA sequencing, co-immunoprecipitation, immunofluorescence and western blotting were used to study the molecular mechanism of MAP17 affecting the tumor growth and glycolytic phenotype of HCC. An integrative analysis showed that MAP17, a small 17-kDa non-glycosylated membrane protein, is significantly related to the glycolytic phenotype of hepatocellular carcinoma (HCC). Firstly, we found that MAP17 expression is hypoxia-dependent and predicts a poor prognosis in HCC. Genetic silencing of MAP17 reduced the rate of glucose uptake, lactate release, extracellular acidification rate, and expression of glycolytic genes. Ectopic expression of wild type MAP17 but not its PDZ binding domain mutant MAP17-PDZm increased tumor glycolysis. Further research showed that MAP17 knockdown markedly retarded in vivo tumor growth in HCC. Importantly, attenuation of tumor glycolysis by galactose largely hijacked the growth-promoting role of MAP17 in HCC cells. RNA sequencing analysis revealed that MAP17 knockdown leads to transcriptional changes in the ROS metabolic process, cell surface receptor signaling, cell communication, mitotic cell cycle progression, and regulation of cell differentiation. Mechanistically, MAP17 exerted an increased tumoral phenotype associated with an increase in reactive oxygen species (ROS), which activates downstream effectors AKT and HIF1α to enhance the Warburg effect. In HCC clinical samples, there is a close correlation between MAP17 expression and HIF1α or phosphorated level of AKT. Our results show that MAP17 is a novel glycolytic regulator, and targeting MAP17/ROS pathway may be an alternative approach for the prevention and treatment of HCC.
机译：重新编程的葡萄糖新陈代谢，也称为Warburg效应，这对于肿瘤进展至关重要，被认为是癌症的标志。 MAP17，一种小型17-KDA非糖基化膜蛋白经常？在人类癌症中具有吸诵。然而，其在肝细胞癌（HCC）中的作用仍然很大程度上是未知的。免疫组织化学用于分析HCC中MAP17的表达模式。进行函数丧失和致功能性研究，以研究MAP17在体外和体内的致癌作用。使用RNA测序，共免疫沉淀，免疫荧光和蛋白质印迹研究MAP17的分子机制影响HCC的肿瘤生长和糖酵解表型。一致性分析表明，MAP17，小型17-KDA非糖基化膜蛋白，与肝细胞癌（HCC）的甘露糖表型显着相关。首先，我们发现Map17表达是缺氧依赖性，并预测HCC预后差。 MAP17的遗传沉默降低了葡萄糖摄取，乳酸释放，细胞外酸化率和糖酵解基因表达的速率。野生型MAP17的异位表达，但不是其PDZ结合结构域突变体MAP17-PDZM增加的肿瘤糖醇分解。进一步的研究表明，MAP17敲低在HCC的体内肿瘤生长中显着延迟。重要的是，通过半乳糖衰减肿瘤糖醇分解在很大程度上被劫持了MAP17在HCC细胞中的生长促进作用。 RNA测序分析显示，MAP17敲低导致ROS代谢过程，细胞表面受体信号，细胞通信，有丝分裂细胞周期进展和细胞分化调节的转录变化。机械地，MAP17施加了与活性氧物质（ROS）增加相关的增加的肿瘤表型，其激活下游作用AKT和HIF1α以增强Warburg效应。在HCC临床样本中，MAP17表达与HIF1α或磷酸含量的AKT之间存在紧密相关性。我们的结果表明，MAP17是一种新型糖酵解调节器，靶向MAP17 / ROS途径可能是预防和治疗HCC的替代方法。

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