Gut flora disequilibrium promotes the initiation of liver cancer by modulating tryptophan metabolism and up-regulating SREBP2.
Gut flora disequilibrium promotes the initiation of liver cancer by modulating tryptophan metabolism and up-regulating SREBP2.
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肠道菌群不平衡通过调节色氨酸代谢和上调SREBP2促进肝癌的发生
DOI：
10.1073/pnas.2203894119
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发表时间：
2022-12-27
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
目前，原发性肝癌是全球第六大常见癌症和第四大癌症相关死亡原因。原发性肝癌患者的治疗选择有限，预后较差，这凸显了制定癌症预防策略的重要性。我们的发现确定了肠道菌群失衡通过色氨酸代谢平衡的AhR-SREBP2轴在肠道和肝脏之间促进肝癌发生的机制。我们的结果可能有助于开发通过肠道菌群调控预防肝癌的策略。肠道微生物区系与肝癌之间存在复杂的相互作用。然而，肠道微生物群在肝脏肿瘤发生中的作用仍不清楚。本实验采用流体动力基因转染法诱导小鼠肝癌，以探讨小鼠肝肿瘤的发生机制。肠道微生物区系枯竭促进了肝脏肿瘤的发生，但不能促进进展。在肠道菌群失调的小鼠中观察到固醇调节元件结合蛋白2(SREBP2)的升高。SREBP2或SREBF2 RNA干扰的药理抑制减轻肠道菌群失衡下小鼠肝癌的发生。此外，肠道微生物区系枯竭损害了肠道色氨酸代谢以激活芳香烃受体(AhR)。AHR激动剂FICZ翻译后抑制SREBP2，逆转小鼠肿瘤形成。而且，AhR基因敲除小鼠重现了加速的肝脏肿瘤形成。补充产生色氨酸代谢物的雷氏乳杆菌可抑制肠道菌群失调小鼠SREBP2的表达和肿瘤的发生。因此，肠道菌群失衡通过调节色氨酸代谢和上调SREBP2来促进肝癌的发生。
Primary liver cancer is currently the sixth most common cancer and fourth leading cause of cancer-related death globally. The limited therapeutic options and poor prognosis of patients with primary liver cancer highlight the significance of developing cancer prevention strategies. Our findings identified a mechanism of gut flora disequilibrium-promoted liver cancer initiation via a tryptophan metabolism-balanced AhR-SREBP2 axis between the gut and liver. Our results might contribute to developing strategies for liver cancer prevention through gut flora manipulation. The gut microbiota and liver cancer have a complex interaction. However, the role of gut microbiome in liver tumor initiation remains unknown. Herein, liver cancer was induced using hydrodynamic transfection of oncogenes to explore liver tumorigenesis in mice. Gut microbiota depletion promoted liver tumorigenesis but not progression. Elevated sterol regulatory element-binding protein 2 (SREBP2) was observed in mice with gut flora disequilibrium. Pharmacological inhibition of SREBP2 or Srebf2 RNA interference attenuated mouse liver cancer initiation under gut flora disequilibrium. Furthermore, gut microbiota depletion impaired gut tryptophan metabolism to activate aryl hydrocarbon receptor (AhR). AhR agonist Ficz inhibited SREBP2 posttranslationally and reversed the tumorigenesis in mice. And, AhR knockout mice recapitulated the accelerated liver tumorigenesis. Supplementation with Lactobacillus reuteri, which produces tryptophan metabolites, inhibited SREBP2 expression and tumorigenesis in mice with gut flora disequilibrium. Thus, gut flora disequilibrium promotes liver cancer initiation by modulating tryptophan metabolism and up-regulating SREBP2.
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影响因子：
32.4
作者：
Hezaveh K;Shinde RS;Klötgen A;Halaby MJ;Lamorte S;Ciudad MT;Quevedo R;Neufeld L;Liu ZQ;Jin R;Grünwald BT;Foerster EG;Chaharlangi D;Guo M;Makhijani P;Zhang X;Pugh TJ;Pinto DM;Co IL;McGuigan AP;Jang GH;Khokha R;Ohashi PS;O'Kane GM;Gallinger S;Navarre WW;Maughan H;Philpott DJ;Brooks DG;McGaha TL
通讯作者：
McGaha TL
影响因子：
5.2
作者：
Ni, Jiajia;Huang, Rong;Gao, Yi
通讯作者：
Gao, Yi
影响因子：
64.5
作者：
Moon, Sung-Hwan;Huang, Chun-Hao;Prives, Carol
通讯作者：
Prives, Carol
影响因子：
5.6
作者：
Chen YH;Wu WK;Wu MS
通讯作者：
Wu MS
影响因子：
50.3
作者：
Dapito DH;Mencin A;Gwak GY;Pradere JP;Jang MK;Mederacke I;Caviglia JM;Khiabanian H;Adeyemi A;Bataller R;Lefkowitch JH;Bower M;Friedman R;Sartor RB;Rabadan R;Schwabe RF
通讯作者：
Schwabe RF