LDLR inhibition promotes hepatocellular carcinoma proliferation and metastasis by elevating intracellular cholesterol synthesis through the MEK/ERK signaling pathway.
LDLR inhibition promotes hepatocellular carcinoma proliferation and metastasis by elevating intracellular cholesterol synthesis through the MEK/ERK signaling pathway.
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DOI：
10.1016/j.molmet.2021.101230
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发表时间：
2021-09
影响因子：
8.1
通讯作者：
Guo H
中科院分区：
文献类型：
--
作者：
Chen Z;Chen L;Sun B;Liu D;He Y;Qi L;Li G;Han Z;Zhan L;Zhang S;Zhu K;Luo Y;Chen L;Zhang N;Guo H
癌症能量代谢的适应性重新布线已经受到越来越多的关注。通过与LDL结合，LDLR使大部分循环胆固醇可供细胞利用。然而，LDLR如何通过影响胆固醇代谢在HCC发展中起作用仍不清楚。数据库分析和免疫组化染色用于确定LDLR在HCC中的临床意义。通过转录组分析揭示LDLR异常在HCC进展中的机制。肝原位移植模型用于评估LDLR在体内HCC进展中的作用。LDLR的下调被确定为人HCC的负性预后因素。在体外和体内，肝癌细胞系中低密度脂蛋白受体的表达降低损害LDL摄取，但促进增殖和转移。从机制上讲，增加细胞内从头胆固醇生物合成是由LDLR抑制引起的恶性行为的主要贡献者，辛伐他汀可以挽救这种恶性行为。通过LDLR下调激活MEK/ERK通路部分促进了HCC细胞内胆固醇的合成。LDLR的下调可能通过部分归因于MEK/ERK信号通路刺激的机制提高细胞内胆固醇合成以加速增殖和运动。他汀类药物对细胞内胆固醇合成的抑制可能在HCC中LDLR表达较低的背景下构成一种靶向倾向。LDLR的下调被确定为人HCC的负性预后因素。LDLR抑制促进HCC细胞的增殖和转移。胆固醇合成增加主要促成由LDLR减少引起的恶性行为。辛伐他汀阻断胆固醇合成可在低LDLR条件下减缓HCC进展。通过LDLR下调激活MEK/ERK通路促进HCC中胆固醇合成。
Adaptive rewiring of cancer energy metabolism has received increasing attention. By binding with LDLs, LDLRs make most of the circulating cholesterol available for cells to utilize. However, it remains unclear how LDLR works in HCC development by affecting cholesterol metabolism. Database analyses and immunohistochemical staining were used to identify the clinical significance of LDLR in HCC. A transcriptome analysis was used to reveal the mechanism of LDLR aberration in HCC progression. A liver orthotopic transplantation model was used to evaluate the role of LDLR in HCC progression in vivo. Downregulation of LDLR was identified as a negative prognostic factor in human HCC. Reduced expression of LDLR in HCC cell lines impaired LDL uptake but promoted proliferation and metastasis in vitro and in vivo. Mechanistically, increasing intracellular de novo cholesterol biosynthesis was the chief contributor to malignant behaviors caused by LDLR inhibition, which could be rescued by simvastatin. Activation of the MEK/ERK pathway by LDLR downregulation partially contributed to intracellular cholesterol synthesis in HCC. Downregulation of LDLR may elevate intracellular cholesterol synthesis to accelerate proliferation and motility through a mechanism partially attributed to stimulation of the MEK/ERK signaling pathway. Repression of intracellular cholesterol synthesis with statins may constitute a targetable liability in the context of lower LDLR expression in HCC. Downregulation of LDLR is identified as a negative prognostic factor in human HCC. LDLR inhibition facilitates the proliferation and metastasis of HCC cells. Increased cholesterol synthesis chiefly contributes to the malignant behaviors caused by LDLR reduction. Blockade of cholesterol synthesis by simvastatin attenuates HCC progression under lower LDLR. Activation of the MEK/ERK pathway by LDLR downregulation promotes cholesterol synthesis in HCC.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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