4-phenylbutyric acid promotes hepatocellular carcinoma via initiating cancer stem cells through activation of PPAR-α.
4-phenylbutyric acid promotes hepatocellular carcinoma via initiating cancer stem cells through activation of PPAR-α.
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4-苯基丁酸通过激活 PPAR-α 启动癌症干细胞促进肝细胞癌
DOI：
10.1002/ctm2.379
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发表时间：
2021-04
影响因子：
10.6
通讯作者：
Wang HY
中科院分区：
文献类型：
--
作者：
Chen SZ;Ling Y;Yu LX;Song YT;Chen XF;Cao QQ;Yu H;Chen C;Tang JJ;Fan ZC;Miao YS;Dong YP;Tao JY;Monga SPS;Wen W;Wang HY
4-苯基丁酸(4-PBA)是一种低分子脂肪酸，临床上用于治疗遗传性尿素循环障碍。在以往的报道中，它作为一种化学伴侣抑制内质网(ER)应激和未折叠的蛋白质反应信号。一些研究表明其在小鼠模型中具有抗肝纤维化的作用。然而，它在肝癌发生中的作用仍不清楚。4-PBA单独或与二乙基亚硝胺合用，观察其对肝脏肿瘤形成的长期影响。并观察了4-PBA对HMET和β-catenin点突变(S45Y)共表达的睡美人系统诱导的小鼠肝癌模型的作用。采用RNA-seq和聚合酶链式反应(PCR)芯片筛选相关途径和基因。通过体内外实验，探讨4-PBA对小鼠肝脏的影响及其作用机制。长期来看，4-PBA单独作用不会引起肝脏肿瘤。然而，它通过Wnt5b-Fzd5介导β-catenin信号通路启动肝癌干细胞(LSCs)，从而促进肝癌模型小鼠的肝肿瘤发生。4-苯丁酸诱导的过氧化物酶体增殖物激活受体-α参与了β-连环蛋白信号的激活。因此，PPAR-α的干预逆转了4-PBA诱导的LC的启动和体内肝细胞癌的发展。进一步的研究表明，4-PBA不仅在转录水平上上调PPAR-α基因的表达，而且通过保护其不被蛋白降解而增强其稳定性。此外，PPAR-α的高表达预示着肝细胞癌患者预后不良。4-PBA可通过激活α-连环蛋白信号通路，上调PPAR-β启动肝干细胞，促进肝细胞癌的早期发生。因此，在肝细胞癌诱导环境下，4-PBA的潜在促肿瘤作用应采取更谨慎的态度。4-PBA在体内肿瘤发生的早期阶段对肝癌有促进作用。4-PBA通过激活依赖于PPAR-β的Wnt5b-Fzd5-α-Catenin信号通路来启动CSCs。4-PBA不仅可以在转录水平上调节PPAR-α的表达，而且还可以通过直接结合来稳定它。
4‐phenylbutyric acid (4‐PBA) is a low molecular weight fatty acid that is used in clinical practice to treat inherited urea cycle disorders. In previous reports, it acted as a chemical chaperone inhibiting endoplasmic reticulum (ER) stress and unfolded protein response signaling. A few studies have suggested its function against hepatic fibrosis in mice models. However, its role in hepatocarcinogenesis remained unknown. 4‐PBA was administered alone or in combination with diethylnitrosamine to investigate its long‐term effect on liver tumorigenesis. The role of 4‐PBA in oncogene‐induced hepatocellular carcinoma (HCC) mice model using sleeping beauty system co‐expressed with hMet and β‐catenin point mutation (S45Y) was also observed. RNA‐seq and PCR array were used to screen the pathways and genes involved. In vitro and in vivo studies were conducted to explore the effect of 4‐PBA on liver and validate the underlying mechanism. 4‐PBA alone didn't cause liver tumor in long term. However, it promoted liver tumorigenesis in HCC mice models via initiation of liver cancer stem cells (LCSCs) through Wnt5b‐Fzd5 mediating β‐catenin signaling. Peroxisome proliferator‐activated receptors (PPAR)‐α induced by 4‐PBA was responsible for the activation of β‐catenin signaling. Thus, intervention of PPAR‐α reversed 4‐PBA‐induced initiation of LCSCs and HCC development in vivo. Further study revealed that 4‐PBA could not only upregulate the expression of PPAR‐α transcriptionally but also enhance its stabilization via protecting it from proteolysis. Moreover, high PPAR‐α expression predicted poor prognosis in HCC patients. 4‐PBA could upregulate PPAR‐α to initiate LCSCs by activating β‐catenin signaling pathway, promoting HCC at early stage. Therefore, more discretion should be taken to monitor the potential tumor‐promoting effect of 4‐PBA under HCC‐inducing environment. 4‐PBA could promote HCC at early stage of tumor development in vivo. 4‐PBA initiated CSCs via activating Wnt5b‐Fzd5‐β‐catenin signaling pathway dependent of PPAR‐α activation. 4‐PBA could not only regulate the expression of PPAR‐α transcriptionally, but also stabilize it via direct binding.
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影响因子：
64.5
作者：
He G;Dhar D;Nakagawa H;Font-Burgada J;Ogata H;Jiang Y;Shalapour S;Seki E;Yost SE;Jepsen K;Frazer KA;Harismendy O;Hatziapostolou M;Iliopoulos D;Suetsugu A;Hoffman RM;Tateishi R;Koike K;Karin M
通讯作者：
Karin M
影响因子：
4.6
作者：
Honda Y;Kessoku T;Ogawa Y;Tomeno W;Imajo K;Fujita K;Yoneda M;Takizawa T;Saito S;Nagashima Y;Nakajima A
通讯作者：
Nakajima A
影响因子：
4.5
作者：
Gonzalez, Frank J.;Shah, Yatrik A.
通讯作者：
Shah, Yatrik A.
影响因子：
13.5
作者：
Clouston, AD;Powell, EE;Jonsson, JR
通讯作者：
Jonsson, JR
影响因子：
11.2
作者：
Cheung, C;Akiyama, TE;Gonzalez, FJ
通讯作者：
Gonzalez, FJ