Oncogene-dependent addiction to Carbohydrate-Responsive Element Binding Protein in hepatocellular carcinoma

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 <i>in vitro</i> and <i>in vivo</i> 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.

代谢重编程是包括肝细胞癌（hepatocellular carcinoma, HCC）在内的多种癌症的标志性特征。鉴定该过程中的关键调控因子，或可为开发新型高效的抗肿瘤治疗手段提供关键思路。本研究明确了碳水化合物反应元件结合蛋白（carbohydrate responsive element binding protein, ChREBP）——肝脏脂质与葡萄糖代谢调控的核心因子——在体外（in vitro）与体内（in vivo）模型中对肝细胞癌发生发展的影响。我们发现，ChREBP的基因敲除（本研究中将该小鼠模型称为ChREBP敲除小鼠，ChREBPKO mice）可分别显著延缓或抑制由AKT过表达以及AKT/c-Met过表达驱动的小鼠肝细胞癌变过程。与之相反，在共表达AKT与N-Ras原癌基因的小鼠中，ChREBP缺失并不会影响肝细胞癌的发生发展。在小鼠和人源肝细胞癌细胞系中，通过特异性小干扰RNA（small interfering RNAs, siRNAs）抑制ChREBP的表达，可降低细胞增殖并诱导细胞凋亡。值得注意的是，联合抑制丝裂原活化蛋白激酶（mitogen-activated protein kinase, MAPK）通路可显著增强上述细胞效应。本研究数据表明，ChREBP的活性对于肝细胞癌生长的必要性具有情境依赖性，具体取决于所涉及的癌基因类型。具体而言，Ras/MAPK信号通路的激活或许可作为此类肿瘤对ChREBP抑制产生抵抗的潜在机制。未来仍需开展进一步研究，以阐明使肝细胞癌细胞对ChREBP抑制产生不敏感性的分子机制。