Functional role of ALK-related signal cascades on modulation of epithelial-mesenchymal transition and apoptosis in uterine carcinosarcoma.
Functional role of ALK-related signal cascades on modulation of epithelial-mesenchymal transition and apoptosis in uterine carcinosarcoma.
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DOI：
10.1186/s12943-017-0609-8
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发表时间：
2017-02-14
期刊：
影响因子：
37.3
通讯作者：
Saegusa M
中科院分区：
文献类型：
--
作者：
Inoue H;Hashimura M;Akiya M;Chiba R;Saegusa M
间变性淋巴瘤激酶（ALK）是一种受体酪氨酸激酶，主要在发育中的神经系统中瞬时表达。近年来，在一些原发性实体瘤中观察到全长ALK的表达失调，但关于其参与子宫癌肉瘤（UCS）的肿瘤发生的情况知之甚少。在这里，我们研究了ALK基因在UC中的功能作用。使用两种子宫内膜癌细胞系评估ALK基因的调节和功能。还使用UC的临床样本研究了ALK及其相关分子的表达。在细胞系中，ALK启动子活性通过转染Sox 11和N-myc显著增加，这两种基因已知有助于神经元特性。稳定过表达全长ALK的细胞显示TGF-β1和HGF介导的EMT特性增强，沿着磷酸化（p）Akt和核p65增加。p65的过表达还导致Twist 1基因的反式激活，该基因被称为EMT诱导剂。最后，用阿霉素处理稳定的ALK过表达细胞导致细胞凋亡的抑制，pAkt和bcl 2相对于总Akt和bax的表达比率分别逐渐增加。在临床样本中，在UC中经常观察到强烈的细胞质ALK免疫反应性和mRNA信号，而ALK基因座没有重排或扩增，特别是在肉瘤组分中。此外，发现ALK IHC评分与Sox 11、N-myc、Twist 1和bcl 2评分呈正相关。包含Akt、NF-κB、Twist 1和bcl 2的ALK相关信号级联可能通过诱导EMT过程和抑制细胞凋亡特征参与UC中癌性成分驱动的不同肉瘤分化的初始信号传导。本文的在线版本（doi：10.1186/s12943-017-0609-8）包含补充材料，可供授权用户使用。
Anaplastic lymphoma kinase (ALK), which is a receptor tyrosine kinase, is essentially and transiently expressed in the developing nervous system. Recently, the deregulated expression of full-length ALK has been observed in some primary solid tumors, but little is known about its involvement in the tumorigenesis of uterine carcinosarcomas (UCSs). Here we examined the functional role of the ALK gene in UCSs. Regulation and function of the ALK gene were assessed using two endometrial carcinoma cell lines. Expression of ALK and its related molecules were also investigated using clinical samples of UCSs. In cell lines, ALK promoter activity was significantly increased by transfection of Sox11 and N-myc, which are known to contribute to neuronal properties. Cells stably overexpressing full-length ALK showed an enhancement of EMT properties mediated by TGF-β1 and HGF, along with an increase in phosphorylated (p) Akt and nuclear p65. Overexpression of p65 also led to transactivation of Twist1 gene, known as an EMT inducer. Finally, treatment of the stable ALK-overexpressing cells with doxorubicin resulted in inhibition of apoptosis with progressive increase in the expression ratio of both pAkt and bcl2 relative to total Akt and bax, respectively. In clinical samples, strong cytoplasmic ALK immunoreactivity and mRNA signals without rearrangement or amplification of the ALK locus were frequently observed in UCSs, particularly in the sarcomatous components. Further, ALK IHC score was found to be positively correlated with Sox11, N-myc, Twist1, and bcl2 scores. ALK-related signal cascades containing Akt, NF-κB, Twist1, and bcl2 may participate in initial signaling for divergent sarcomatous differentiation driven from carcinomatous components in UCSs through induction of the EMT process and inhibition of apoptotic features. The online version of this article (doi:10.1186/s12943-017-0609-8) contains supplementary material, which is available to authorized users.