Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome
Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome
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DOI：
10.1038/nature12347
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发表时间：
2013-07-04
期刊：
影响因子：
64.8
通讯作者：
Ohtani, Naoko
中科院分区：
文献类型：
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作者：
Yoshimoto, Shin;Loo, Tze Mun;Ohtani, Naoko
过去几十年来，肥胖在大多数发达国家变得更加普遍，并且越来越多地被认为是几种常见癌症类型的主要危险因素(1)。由于全球肥胖流行病没有显示出减弱的迹象(2)，因此迫切需要更好地了解肥胖相关癌症的潜在机制。尽管一些事件被认为与肥胖相关癌症有关1,3，但整合这些事件的确切分子机制仍不清楚。在此，我们证明衰老相关分泌表型 (SASP)(4,5) 在促进小鼠肥胖相关肝细胞癌 (HCC) 的发展中发挥着至关重要的作用。饮食或遗传性肥胖会引起肠道微生物群的改变，从而增加脱氧胆酸 (DCA) 的水平，脱氧胆酸 (DCA) 是一种已知会导致 DNA 损伤的肠道细菌代谢物 (6)。 DCA 的肠肝循环会引起肝星状细胞 (HSC) (7) 中的 SASP 表型，进而在肝脏中分泌各种炎症和肿瘤促进因子，从而促进接触化学致癌物的小鼠发生 HCC。值得注意的是，阻断 DCA 的产生或减少肠道细菌可以有效预防肥胖小鼠的 HCC 发展。在缺乏 SASP 诱导剂 (8) 或衰老 HSC 耗尽的小鼠中也观察到类似的结果，表明 HSC 中的 DCA-SASP 轴在肥胖相关 HCC 的发展中发挥着关键作用。此外，在非酒精性脂肪性肝炎患者的 HCC 区域的 HSC 中也观察到了 SASP 的迹象(3)，这表明类似的途径可能至少在人类肥胖相关 HCC 发展的某些方面也有贡献。 These findings provide valuable new insights into the development of obesity-associated cancer and open up new possibilities for its control.
Obesity has become more prevalent in most developed countries over the past few decades, and is increasingly recognized as a major risk factor for several common types of cancer(1). As the worldwide obesity epidemic has shown no signs of abating(2), better understanding of the mechanisms underlying obesity-associated cancer is urgently needed. Although several events were proposed to be involved in obesity-associated cancer1,3, the exact molecular mechanisms that integrate these events have remained largely unclear. Here we show that senescence-associated secretory phenotype (SASP)(4,5) has crucial roles in promoting obesity-associated hepatocellular carcinoma (HCC) development in mice. Dietary or genetic obesity induces alterations of gut microbiota, thereby increasing the levels of deoxycholic acid (DCA), a gut bacterial metabolite known to cause DNA damage(6). The enterohepatic circulation of DCA provokes SASP phenotype in hepatic stellate cells (HSCs)(7), which in turn secretes various inflammatory and tumour-promoting factors in the liver, thus facilitating HCC development in mice after exposure to chemical carcinogen. Notably, blocking DCA production or reducing gut bacteria efficiently prevents HCC development in obese mice. Similar results were also observed in mice lacking an SASP inducer(8) or depleted of senescent HSCs, indicating that the DCA-SASP axis in HSCs has key roles in obesity-associated HCC development. Moreover, signs of SASP were also observed in the HSCs in the area of HCC arising in patients with non-alcoholic steatohepatitis(3), indicating that a similar pathway may contribute to at least certain aspects of obesity-associated HCC development in humans as well. These findings provide valuable new insights into the development of obesity-associated cancer and open up new possibilities for its control.