Dedifferentiation of neuroendocrine carcinoma of the uterine cervix in hypoxia
Dedifferentiation of neuroendocrine carcinoma of the uterine cervix in hypoxia
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DOI：
10.1016/j.bbrc.2020.01.024
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发表时间：
2020-04-02
影响因子：
3.1
通讯作者：
Inoue, Masahiro
中科院分区：
文献类型：
--
作者：
Kubota, Satoshi;Tanaka, Mie;Inoue, Masahiro
小细胞型神经内分泌癌（SCNEC）是宫颈癌中一种罕见的病理亚型，其预后比其他组织学细胞类型差。由于其发病率低和缺乏实验平台，宫颈SCNEC的分子特征在很大程度上仍然未知。使用癌组织起源的球体（CTOS）方法-一种保留原始肿瘤分化状态的离体3D培养系统-我们建立了一组SCNEC的CTOS系。我们证明，异种移植肿瘤和CTOS，分别表现出显着的肿瘤内和CTOS内的嗜铬粒蛋白A（CHGA），神经内分泌肿瘤标志物的表达水平的变化。由于缺氧影响各种肿瘤和干细胞的分化，我们还研究了缺氧如何影响宫颈SCNEC的神经内分泌分化。在CTOS细胞系cerv 21中，缺氧抑制神经内分泌标志物CHGA和突触素（SYP）的表达。使用CD 99（SCNEC的膜蛋白标记物）的流式细胞术分析揭示了在缺氧条件下细胞亚群中CD 99表达的降低。这些表达变化被HIF-1 α敲低和Notch抑制剂减弱，表明这些分子在神经内分泌分化的调节中发挥作用。在多个CTOS系中，所检查的SCNEC标记物在缺氧下被抑制。总之，我们目前的研究结果表明，神经内分泌分化在SCNEC的子宫是一个可变的表型，缺氧可能是调节分化状态的因素之一。(C)2020爱思唯尔公司All rights reserved.
Neuroendocrine carcinoma of small cell type (SCNEC) is a rare pathological subtype in cervical cancer, which has a worse prognosis than other histological cell types. Due to its low incidence and the lack of experimental platforms, the molecular characteristics of SCNEC in the cervix remain largely unknown. Using the cancer tissue-originated spheroid (CTOS) method-an ex vivo 3D culture system that preserves the differentiation status of the original tumors-we established a panel of CTOS lines of SCNEC. We demonstrated that xenograft tumors and CTOSs, respectively, exhibited substantial intra-tumor and intra-CTOS variation in the expression levels of chromogranin A (CHGA), a neuroendocrine tumor marker. Since hypoxia affects differentiation in various tumors and in stem cells, we also investigated how hypoxia affected neuroendocrine differentiation of SCNEC of the uterine cervix. In the CTOS line cerv21, hypoxia suppressed expression of the neuroendocrine markers CHGA and synaptophysin (SYP). Flow cytometry analysis using CD99 (a membrane protein marker of SCNEC) revealed decreased CD99 expression in a subset of cells under hypoxic conditions. These expression changes were attenuated by HIF-1 alpha knockdown, and by a Notch inhibitor, suggesting that these molecules played a role in the regulation of neuroendocrine differentiation. The examined SCNEC markers were suppressed under hypoxia in multiple CTOS lines. Overall, our present results indicated that neuroendocrine differentiation in SCNEC of the uterus is a variable phenotype, and that hypoxia may be one of the factors regulating the differentiation status. (C) 2020 Elsevier Inc. All rights reserved.