School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, PR China.
Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, 55455, USA.
Oncogene. 2023 Sep;42(39):2892-2904. doi: 10.1038/s41388-023-02757-9. Epub 2023 Jun 26.
Hepatic cholesterol accumulation and hypercholesterolemia are implicated in hepatocellular carcinoma (HCC). However, the therapeutic effects of cholesterol-lowering drugs on HCC are controversial, indicating that the relationship between cholesterol metabolism and HCC is more complex than anticipated. A positive feedback between cholesterol synthesis and the pentose phosphate pathway (PPP) rather than glycolysis was formed in tumors of c-Myc mice. Blocking the PPP prevented cholesterol synthesis and thereby HCC in c-Myc mice, while ablating glycolysis did not affect cholesterol synthesis and failed to prevent c-Myc-induced HCC. Unexpectedly, HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase) and G6PD (glucose-6-phosphate dehydrogenase), the rate-limiting enzymes of cholesterol synthesis and the PPP, were identified as direct targets of microRNA-206. By targeting Hmgcr and G6pd, microRNA-206 disrupted the positive feedback and fully prevented HCC in c-Myc mice, while 100% of control mice died of HCC. Disrupting the interaction of microRNA-206 with Hmgcr and G6pd restored cholesterol synthesis, the PPP and HCC growth that was inhibited by miR-206. This study identified a previously undescribed positive feedback loop between cholesterol synthesis and the PPP, which drives HCC, while microRNA-206 prevents HCC by disrupting this loop. Cholesterol synthesis as a process rather than cholesterol itself is the major contributor of HCC.
肝内胆固醇积累和高胆固醇血症与肝细胞癌（HCC）有关。然而，降脂药物对 HCC 的治疗效果存在争议，这表明胆固醇代谢与 HCC 之间的关系比预期的更为复杂。c-Myc 小鼠肿瘤中形成了胆固醇合成与戊糖磷酸途径（PPP）之间而不是糖酵解之间的正反馈。阻断 PPP 可防止胆固醇合成并因此阻止 c-Myc 小鼠的 HCC，而糖酵解的缺失不会影响胆固醇合成并且不能阻止 c-Myc 诱导的 HCC。出乎意料的是，胆固醇合成和 PPP 的限速酶 HMGCR（3-羟-3-甲基戊二酰辅酶 A 还原酶）和 G6PD（葡萄糖-6-磷酸脱氢酶）被鉴定为 microRNA-206 的直接靶标。通过靶向 Hmgcr 和 G6pd，microRNA-206 破坏了正反馈并完全阻止了 c-Myc 小鼠的 HCC，而 100%的对照小鼠死于 HCC。破坏 microRNA-206 与 Hmgcr 和 G6pd 的相互作用恢复了被 miR-206 抑制的胆固醇合成、PPP 和 HCC 生长。这项研究确定了胆固醇合成与 PPP 之间以前未描述的正反馈环，该环驱动 HCC，而 microRNA-206 通过破坏该环来预防 HCC。胆固醇合成作为一个过程而不是胆固醇本身是 HCC 的主要原因。
