国内团队:膳食叶酸或促进肝癌进展
创作:芥末 审核:章台柳 06月27日
  • 在DEN/高脂食物(HFD)诱导的肝癌(HCC)小鼠模型中,高叶酸饮食以依赖于甲硫氨酸腺苷转移酶MATIIα的方式促进HCC的发生;
  • 机制上,去泛素化酶VCIP135响应叶酸信号,去泛素化并稳定MATIIα,驱动HCC细胞中甲硫氨酸及一碳代谢从而促进癌细胞增殖;
  • 敲除小鼠肝脏的MAT IIA可消除叶酸对HFD诱导HCC发生的促进作用;
  • 肝癌患者肿瘤组织中MATIIα及VCIP135表达增加,甲硫氨酸及其代谢物水平升高,导致HCC患者预后不良。
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章台柳
复旦大学上海医学院的雷群英、尹淼和王鲁合作在Signal Transduction and Targeted Therapy发表文章,发现肝癌(HCC)小鼠模型中,膳食叶酸通过甲硫氨酸腺苷转移酶MATIIα,驱动HCC细胞中甲硫氨酸及一碳代谢,促进肿瘤进展。提示高表达MATIIα的HCC病人或应该少摄入叶酸。
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Dietary folate drives methionine metabolism to promote cancer development by stabilizing MAT IIA

叶酸饮食通过稳定MATIIα驱动甲硫氨酸代谢促进肿瘤进展

10.1038/s41392-022-01017-8

06-22, Article

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Folic acid, served as dietary supplement, is closely linked to one-carbon metabolism and methionine metabolism. Previous clinical evidence indicated that folic acid supplementation displays dual effect on cancer development, promoting or suppressing tumor formation and progression. However, the underlying mechanism remains to be uncovered. Here, we report that high-folate diet significantly promotes cancer development in mice with hepatocellular carcinoma (HCC) induced by DEN/high-fat diet (HFD), simultaneously with increased expression of methionine adenosyltransferase 2A (gene name, MAT2A; protein name, MATIIα), the key enzyme in methionine metabolism, and acceleration of methionine cycle in cancer tissues. In contrast, folate-free diet reduces MATIIα expression and impedes HFD-induced HCC development. Notably, methionine metabolism is dynamically reprogrammed with valosin-containing protein p97/p47 complex-interacting protein (VCIP135) which functions as a deubiquitylating enzyme to bind and stabilize MATIIα in response to folic acid signal. Consistently, upregulation of MATIIα expression is positively correlated with increased VCIP135 protein level in human HCC tissues compared to adjacent tissues. Furthermore, liver-specific knockout of Mat2a remarkably abolishes the advocating effect of folic acid on HFD-induced HCC, demonstrating that the effect of high or free folate-diet on HFD-induced HCC relies on Mat2a. Moreover, folate and multiple intermediate metabolites in one-carbon metabolism are significantly decreased in vivo and in vitro upon Mat2a deletion. Together, folate promotes the integration of methionine and one-carbon metabolism, contributing to HCC development via hijacking MATIIα metabolic pathway. This study provides insight into folate-promoted cancer development, strongly recommending the tailor-made folate supplement guideline for both sub-healthy populations and patients with cancer expressing high level of MATIIα expression.

First Authors:
Jin-Tao Li,Hai Yang,Ming-Zhu Lei,Wei-Ping Zhu

Correspondence Authors:
Lu Wang,Miao Yin,Qun-Ying Lei

All Authors:
Jin-Tao Li,Hai Yang,Ming-Zhu Lei,Wei-Ping Zhu,Ying Su,Kai-Yue Li,Wen-Ying Zhu,Jian Wang,Lei Zhang,Jia Qu,Lei Lv,Hao-Jie Lu,Zheng-Jun Chen,Lu Wang,Miao Yin,Qun-Ying Lei

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