Institut Cochin, Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique, Unité Mixte De Recherché 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale Unité Mixte De Recherche 1138, Equipe Labellisée Ligue Contre le Cancer, Paris, France.
Institut Cochin, Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique, Unité Mixte De Recherché 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Gastroenterology. 2019 Sep;157(3):807-822. doi: 10.1053/j.gastro.2019.05.069. Epub 2019 Jun 10.
BACKGROUND & AIMS: In one-third of hepatocellular carcinomas (HCCs), cancer cells have mutations that activate β-catenin pathway. These cells have alterations in glutamine, bile, and lipid metabolism. We investigated whether positron emission tomography (PET) imaging allows identification of altered metabolic pathways that might be targeted therapeutically.
We studied mice with activation of β-catenin in liver (Apc mice) and male C57Bl/6 mice given injections of diethylnitrosamine, which each develop HCCs. Mice were fed a conventional or a methionine- and choline-deficient diet or a choline-deficient (CD) diet. Choline uptake and metabolism in HCCs were analyzed by micro-PET imaging of mice; livers were collected and analyzed by histologic, metabolomic, messenger RNA quantification, and RNA-sequencing analyses. Fifty-two patients with HCC underwent PET imaging with F-fluorodeoxyglucose, followed by F-fluorocholine tracer metabolites. Human HCC specimens were analyzed by immunohistochemistry, quantitative polymerase chain reaction, and DNA sequencing. We used hepatocytes and mouse tumor explants for studies of incorporation of radiolabeled choline into phospholipids and its contribution to DNA methylation. We analyzed HCC progression in mice fed a CD diet.
Livers and tumors from Apc mice had increased uptake of dietary choline, which contributes to phospholipid formation and DNA methylation in hepatocytes. In patients and in mice, HCCs with activated β-catenin were positive in F-fluorocholine PET, but not F-fluorodeoxyglucose PET, and they overexpressed the choline transporter organic cation transporter 3. The HCC cells from Apc mice incorporated radiolabeled methyl groups of choline into phospholipids and DNA. In Apc mice, the methionine- and choline-deficient diet reduced proliferation and DNA hypermethylation of hepatocytes and HCC cells, and the CD diet reduced long-term progression of tumors.
In mice and humans, HCCs with mutations that activate β-catenin are characterized by increased uptake of a fluorocholine tracer, but not F-fluorodeoxyglucose, revealed by PET. The increased uptake of choline by HCCs promotes phospholipid formation, DNA hypermethylation, and hepatocyte proliferation. In mice, the CD diet reverses these effects and promotes regression of HCCs that overexpress β-catenin.
在三分之一的肝细胞癌（HCC）中，癌细胞存在激活β-连环蛋白途径的突变。这些细胞的谷氨酰胺、胆汁和脂质代谢发生改变。我们研究了正电子发射断层扫描（PET）成像是否可以识别可能成为治疗靶点的改变的代谢途径。
我们研究了肝脏中β-连环蛋白激活的 Apc 小鼠和接受二乙基亚硝胺注射的雄性 C57Bl/6 小鼠，它们都发展为 HCC。小鼠分别用常规饮食或蛋氨酸和胆碱缺乏饮食或胆碱缺乏（CD）饮食喂养。通过对小鼠进行微 PET 成像分析 HCC 中的胆碱摄取和代谢；收集肝脏并通过组织学、代谢组学、信使 RNA 定量和 RNA 测序分析进行分析。52 例 HCC 患者行 F-氟脱氧葡萄糖 PET 成像，随后行 F-氟胆碱示踪代谢物 PET 成像。用人 HCC 标本进行免疫组织化学、定量聚合酶链反应和 DNA 测序分析。我们使用肝细胞和小鼠肿瘤外植体研究放射性标记的胆碱掺入磷脂及其对 DNA 甲基化的贡献。我们分析了 CD 饮食喂养的小鼠中的 HCC 进展。
Apc 小鼠的肝脏和肿瘤摄取了更多的膳食胆碱，这有助于肝细胞中磷脂的形成和 DNA 甲基化。在患者和小鼠中，β-连环蛋白激活的 HCC 在 F-氟胆碱 PET 中呈阳性，但 F-氟脱氧葡萄糖 PET 中呈阴性，并且它们过度表达胆碱转运蛋白有机阳离子转运蛋白 3。Apc 小鼠的 HCC 细胞将放射性标记的胆碱的甲基掺入磷脂和 DNA 中。在 Apc 小鼠中，蛋氨酸和胆碱缺乏饮食减少了肝细胞和 HCC 细胞的增殖和 DNA 过度甲基化，而 CD 饮食减少了肿瘤的长期进展。
在小鼠和人类中，激活β-连环蛋白的 HCC 表现为通过 PET 检测到的氟胆碱示踪剂摄取增加，但 F-氟脱氧葡萄糖摄取不增加。HCC 对胆碱的摄取增加促进了磷脂的形成、DNA 过度甲基化和肝细胞增殖。在小鼠中，CD 饮食逆转了这些效应，并促进了过度表达β-连环蛋白的 HCC 的消退。
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