Prolactin prevents hepatocellular carcinoma by restricting innate immune activation of c-Myc in mice
Prolactin prevents hepatocellular carcinoma by restricting innate immune activation of c-Myc in mice
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DOI：
10.1073/pnas.1404267111
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发表时间：
2014-08-05
影响因子：
11.1
通讯作者：
Rogers, Arlin B.
中科院分区：
文献类型：
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作者：
Hartwell, Hadley J.;Petrosky, Keiko Y.;Rogers, Arlin B.
尽管女性同样面临乙型肝炎或丙型肝炎病毒感染等主要危险因素，但女性对肝细胞癌 (HCC) 的抵抗力比男性更强。女性抵抗力依赖于激素，不接受激素替代治疗的绝经后女性 HCC 发病率急剧增加就证明了这一点。在啮齿动物模型中，性别二态性 HCC 表型依赖于垂体，这表明性激素通过性腺-垂体轴发挥作用。我们发现雌激素反应性垂体激素催乳素 (PRL) 通过肝细胞主导的短型催乳素受体 (PRLR-S) 发出信号，限制由 IL-1 β、TNF-α 和 LPS/Toll 样受体 4 (TLR4) 引发的 TNF 受体相关因子 (TRAF) 依赖性先天免疫反应，但 不依赖 TRIF 的聚 (I:C)/TLR3。 PRL 泛素化并加速由 IRAK1、TRAF6 和 MAP3K 蛋白组成的“trafasome”的刺激后衰减，消除 c-Myc 相互作用途径的下游激活，包括 PI3K/AKT、mTORC1、p38 MAPK 和 NF-kappa B。与这一发现一致，我们记录了男性肝脏对免疫的夸大反应 对小鼠和人类的刺激。通过 Alb-Myc 转基因小鼠中性别无关的 HCC 萌发，证明了 c-Myc 水平可促进肿瘤，但其调节作用高于 c-Myc 水平。 PRL 缺乏加速了两性 Prl(-/-) 小鼠的肝癌发生。相反，使用多巴胺 D2 受体拮抗剂多潘立酮药物动员 PRL 可预防易患肿瘤的 C3H/HeN 男性的 HCC。综合来看，我们的结果表明，PRL 通过在特拉法体水平抑制 MAP3K 依赖性 c-Myc 激活来抑制肿瘤促进性肝脏炎症。 PRL 靶向治疗有望减轻高危男性和女性的肝癌负担。
Women are more resistant to hepatocellular carcinoma (HCC) than men despite equal exposure to major risk factors, such as hepatitis B or C virus infection. Female resistance is hormone-dependent, as evidenced by the sharp increase in HCC incidence in postmenopausal women who do not take hormone replacement therapy. In rodent models sex-dimorphic HCC phenotypes are pituitary-dependent, suggesting that sex hormones act via the gonadal-hypophyseal axis. We found that the estrogen-responsive pituitary hormone prolactin (PRL), signaling through hepatocyte-predominant short-form prolactin receptors (PRLR-S), constrained TNF receptor-associated factor (TRAF)-dependent innate immune responses invoked by IL-1 beta, TNF-alpha, and LPS/Toll-like receptor 4 (TLR4), but not TRIF-dependent poly(I:C)/TLR3. PRL ubiquitinated and accelerated poststimulatory decay of a "trafasome" comprised of IRAK1, TRAF6, and MAP3K proteins, abrogating downstream activation of c-Myc-interacting pathways, including PI3K/AKT, mTORC1, p38 MAPK, and NF-kappa B. Consistent with this finding, we documented exaggerated male liver responses to immune stimuli in mice and humans. Tumor promotion through, but regulation above, the level of c-Myc was demonstrated by sex-independent HCC eruption in Alb-Myc transgenic mice. PRL deficiency accelerated liver carcinogenesis in Prl(-/-) mice of both sexes. Conversely, pharmacologic PRL mobilization using the dopamine D2 receptor antagonist domperidone prevented HCC in tumor-prone C3H/HeN males. Viewed together, our results demonstrate that PRL constrains tumor-promoting liver inflammation by inhibiting MAP3K-dependent activation of c-Myc at the level of the trafasome. PRL-targeted therapy may hold promise for reducing the burden of liver cancer in high-risk men and women.