Wang Yuan-Hsi, Suk Fat-Moon, Liao Yi-Jen
School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan.
Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan.
Cancers (Basel). 2020 Jul 4;12(7):1797. doi: 10.3390/cancers12071797.
Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor with limited treatment. The ketogenic diet (KD) emerged as a metabolic therapy for cancer; however, the antitumor effect on HCC remains controversial. We previously reported that the ketogenesis rate-limiting enzyme, 3-hydroxymethylglutaryl-CoA synthase 2 (HMGCS2), was downregulated in most patients with HCC. The knockdown of HMGCS2 enhanced the proliferation and metastasis ability of HCC cells. However, the role of HMGCS2 in affecting KD-mediated metabolic effects remains unclear. Here, we report that KD feeding upregulates HMGCS2 expression and inhibits HCC tumor growth, while a reverse correlation between tumor size and HMGCS2 expression was observed. We found that HCC cells with HMGCS2 downregulation possess altered lipid metabolism that increases fatty acid, triglyceride, and cholesterol synthesis. Under KD feeding, a higher tumor growth rate was observed in HMGCS2 knockdown tumors, which had increased lipid synthesis-related marker expression and a positive correlation between lipid quantity and tumor weight. In conclusion, these results demonstrate that the downregulation of HMGCS2 attenuates the protective effect of the KD by shifting ketone production to enhance de novo lipogenesis in HCC. Our study elucidates a new molecular mechanism underlying the crosstalk between HMGCS2 expression and the KD in cancer treatment, which provides more information for precision medicine in developing personalized treatment strategies.
肝细胞癌（HCC）是最常见的原发性恶性肝肿瘤，治疗手段有限。生酮饮食（KD）作为一种癌症代谢疗法应运而生；然而，其对HCC的抗肿瘤作用仍存在争议。我们之前报道过，生酮限速酶3-羟基-3-甲基戊二酰辅酶A合酶2（HMGCS2）在大多数HCC患者中表达下调。敲低HMGCS2可增强HCC细胞的增殖和转移能力。然而，HMGCS2在影响KD介导的代谢效应中的作用仍不清楚。在此，我们报道，给予KD可上调HMGCS2表达并抑制HCC肿瘤生长，同时观察到肿瘤大小与HMGCS2表达呈负相关。我们发现，HMGCS2下调的HCC细胞具有改变的脂质代谢，增加了脂肪酸、甘油三酯和胆固醇的合成。在给予KD的情况下，HMGCS2敲低的肿瘤中观察到更高的肿瘤生长速率，其脂质合成相关标志物表达增加，脂质含量与肿瘤重量呈正相关。总之，这些结果表明，HMGCS2的下调通过将酮生成转移以增强HCC中的从头脂肪生成，从而减弱了KD的保护作用。我们的研究阐明了HMGCS2表达与KD在癌症治疗中的相互作用的新分子机制，这为制定个性化治疗策略的精准医学提供了更多信息。
