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首页> 外文期刊>Cell cycle >Oncogene-dependent addiction to carbohydrate-responsive element binding protein in hepatocellular carcinoma
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Oncogene-dependent addiction to carbohydrate-responsive element binding protein in hepatocellular carcinoma

机译：肝细胞癌血红蛋水响应元件结合蛋白的癌烯类依赖性成瘾

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摘要

Metabolic reprogramming is a hallmark of many cancer types, including hepatocellular carcinoma (HCC). Identifying the critical players in this process might be crucial for the generation of novel and effective anti-neoplastic therapies. In the present investigation, we determined the importance of carbohydrate responsive element binding protein (ChREBP), a central player in the regulation of lipid and glucose metabolism in the liver, on the development of HCC in in vitro and in vivo models. We found that genetic deletion of ChREBP (that will be referred to as ChREBPKO mice) strongly delays or impairs hepatocarcinogenesis driven by AKT or AKT/c-Met overexpression in mice, respectively. In contrast, HCC development was found to be completely unaffected by ChREBP depletion in mice co-expressing AKT and N-Ras protooncogenes. In mouse and human HCC cell lines, suppression of ChREBP via specific small interfering RNAs (siRNAs) resulted in decreased proliferation and induction of apoptosis. Of note, these cellular events were strongly augmented by concomitant inhibition of the mitogen-activated protein kinase (MAPK) pathway. The present data indicate that ChREBP activity might be required or dispensable for HCC growth, depending on the oncogenes involved. In particular, the activation of Ras/MAPK signaling might represent a possible mechanism of resistance to ChREBP depletion in this tumor type. Additional studies are needed to unravel the molecular mechanisms rendering HCC cells insensitive to ChREBP suppression.
机译：代谢重编程是许多癌症类型的标志，包括肝细胞癌（HCC）。识别该过程中的关键球员可能对新颖和有效的抗肿瘤疗法产生至关重要。在本研究中，我们确定了碳水化合物响应元件结合蛋白（CHREBP），中央参与者在肝脏中脂质和葡萄糖代谢的调节中的重要性的重要性，在体外和体内模型中的HCC发育。我们发现CHREBP的遗传缺失（将被称为CHREBPKO小鼠）分别强烈延迟或损害由小鼠的AKT或AKT / C-MET过表达驱动的肝癌发生。相比之下，发现HCC开发完全不受Chrebp耗尽在共同表达的AKT和N-RAS Protooncogenses的影响。在小鼠和人HCC细胞系中，通过特定的小干扰RNA（siRNA）抑制CHREBP，导致细胞凋亡的增殖和诱导降低。值得注意的是，通过伴随含有丝裂原激活的蛋白激酶（MAPK）途径的抑制强烈地增强了这些细胞事件。目前的数据表明，根据所涉及的癌素，可能需要CHREBP活性或分配HCC生长。特别地，RAS / MAPK信号传导的激活可能代表这种肿瘤类型中的抗CHREBP耗尽的可能机制。需要进行额外的研究来解开对CHREBP抑制不敏感的HCC细胞的分子机制。

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