Autocrine Prolactin Stimulates Endometrial Carcinoma Growth and Metastasis and Reduces Sensitivity to Chemotherapy
Autocrine Prolactin Stimulates Endometrial Carcinoma Growth and Metastasis and Reduces Sensitivity to Chemotherapy
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自分泌催乳素刺激子宫内膜癌生长和转移并降低对化疗的敏感性
DOI：
10.1210/en.2016-1903
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发表时间：
2017-06-01
期刊：
影响因子：
4.8
通讯作者：
Zhu, Tao
中科院分区：
文献类型：
--
作者：
Ding, Keshuo;Yuan, Yan;Zhu, Tao
晚期复发性子宫内膜癌（EC）对化疗反应差，生存率低。先前已有报道称人催乳素（hPRL）在子宫内膜癌中表达上调，并与更差的生存结果相关。我们为hPRL在EC进展中的功能作用提供了证据。我们通过在人EC细胞中强制表达hPRL构建了一个研究自分泌hPRL介导的细胞功能效应的模型。自分泌hPRL表达刺激了EC细胞的增殖、非贴壁生长、迁移和侵袭，并在异种移植模型中促进了肿瘤生长、局部侵袭和转移性定植。此外，无论是在体外还是体内，hPRL的强制表达都降低了EC细胞对化疗药物（即多柔比星和紫杉醇）的敏感性。同样，小干扰RNA介导的hPRL缺失显著降低了EC细胞的致癌性并增强了其对化疗药物的敏感性。由于CD24受hPRL调控且与EC的耐药性有关，我们进一步表明CD24是hPRL刺激EC细胞对多柔比星和紫杉醇敏感性降低的关键介质。因此，抑制hPRL信号通路是治疗晚期EC的一种潜在治疗策略，可与化疗联合使用以提高化疗反应。
Advanced and recurrent endometrial carcinoma (EC) exhibits a poor response to chemotherapy and low survival rates. It has been previously reported that human prolactin (hPRL) is upregulated in endometrial cancer and is associated with worse survival outcomes. We provide evidence for the functional role of hPRL in EC progression. We generated a model for the study of autocrine hPRL-mediated cell functional effects through the forced expression of hPRL in human EC cells. Autocrine hPRL expression stimulated cell proliferation, anchorage-independent growth, migration, and invasion of EC cells and promoted tumor growth, local invasion, and metastatic colonization in xenograft models. In addition, forced expression of hPRL decreased sensitivity of EC cells to chemotherapeutic drugs (i.e., doxorubicin and paclitaxel), both in vitro and in vivo. Consistently, small interfering RNA-mediated depletion of hPRL significantly reduced oncogenicity and enhanced the chemosensitivity of EC cells. As CD24 is hPRL-regulated and has been implicated in drug resistance in EC, we further showed that CD24 is a critical mediator of hPRL-stimulated reduced sensitivity to doxorubicin and paclitaxel in EC cells. Therefore, inhibition of hPRL signaling is a potential therapeutic strategy for the treatment of late-stage EC, which can be used in combination with chemotherapy to improve the chemotherapeutic response.