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首页> 外文期刊>The journal of clinical investigation >Pregnane X receptor activation induces FGF19-dependent tumor aggressiveness in humans and mice
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Pregnane X receptor activation induces FGF19-dependent tumor aggressiveness in humans and mice

机译：孕烷X受体的激活在人类和小鼠中诱导FGF19依赖性肿瘤侵袭性

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The nuclear receptor pregnane X receptor (PXR) is activated by a range of xenochemicals, including chemotherapeutic drugs, and has been suggested to play a role in the development of tumor cell resistance to anticancer drugs. PXR also has been implicated as a regulator of the growth and apoptosis of colon tumors. Here, we have used a xenograft model of colon cancer to define a molecular mechanism that might underlie PXR-driven colon tumor growth and malignancy. Activation of PXR was found to be sufficient to enhance the neoplastic characteristics, including cell growth, invasion, and metastasis, of both human colon tumor cell lines and primary human colon cancer tissue xenografted into immunodeficient mice. Furthermore, we were able to show that this PXR-mediated phenotype required FGF19 signaling. PXR bound to the FGF19 promoter in both human colon tumor cells and “normal” intestinal crypt cells. However, while both cell types proliferated in response to PXR ligands, the FGF19 promoter was activated by PXR only in cancer cells. Taken together, these data indicate that colon cancer growth in the presence of a specific PXR ligand results from tumor-specific induction of FGF19. These observations may lead to improved therapeutic regimens for colon carcinomas.
机译：核受体孕烷X受体（PXR）被包括化学治疗药物在内的一系列异种化学物质激活，并被认为在肿瘤细胞对抗癌药物产生耐药性中发挥作用。 PXR还被认为是结肠肿瘤生长和凋亡的调节剂。在这里，我们使用了结肠癌的异种移植模型来定义可能是PXR驱动的结肠肿瘤生长和恶性肿瘤的分子机制。发现PXR的激活足以增强异种移植到免疫缺陷小鼠中的人结肠肿瘤细胞系和原发性人结肠癌组织的肿瘤特征，包括细胞生长，侵袭和转移。此外，我们能够证明该PXR介导的表型需要FGF19信号传导。 PXR在人结肠肿瘤细胞和“正常”肠道隐窝细胞中均与FGF19启动子结合。然而，尽管两种细胞都响应PXR配体而增殖，但FGF19启动子仅在癌细胞中被PXR激活。总而言之，这些数据表明在存在特定的PXR配体的情况下结肠癌的生长是由肿瘤特异性诱导的FGF19引起的。这些观察结果可能导致结肠癌的治疗方案得到改善。

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