Inoue H, Hashimura M, Akiya M, Chiba R, Saegusa M
Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan.
Mol Cancer. 2017 Feb 14;16(1):37. doi: 10.1186/s12943-017-0609-8.
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.
间变性淋巴瘤激酶（ALK）是一种受体酪氨酸激酶，在发育中的神经系统中基本呈瞬时表达。最近，在一些原发性实体瘤中观察到全长ALK的表达失调，但对其在子宫癌肉瘤（UCS）发生中的作用知之甚少。在此，我们研究了ALK基因在UCS中的功能作用。
使用两种子宫内膜癌细胞系评估ALK基因的调控和功能。还使用UCS的临床样本研究了ALK及其相关分子的表达。
在细胞系中，已知有助于神经元特性的Sox11和N-myc转染可显著增加ALK启动子活性。稳定过表达全长ALK的细胞显示由转化生长因子-β1（TGF-β1）和肝细胞生长因子（HGF）介导的上皮-间质转化（EMT）特性增强，同时磷酸化（p）Akt和核p65增加。p65的过表达还导致已知为EMT诱导剂的Twist1基因的反式激活。最后，用阿霉素处理稳定过表达ALK的细胞导致细胞凋亡受到抑制，pAkt和bcl2相对于总Akt和bax的表达比率逐渐增加。在临床样本中，在UCS中经常观察到强烈的细胞质ALK免疫反应性和mRNA信号，而ALK基因座无重排或扩增，特别是在肉瘤成分中。此外，发现ALK免疫组化评分与Sox11、N-myc、Twist1和bcl2评分呈正相关。
包含Akt、核因子-κB（NF-κB）、Twist1和bcl2的ALK相关信号级联可能通过诱导EMT过程和抑制凋亡特征参与UCS中癌成分驱动的不同肉瘤分化的初始信号传导。
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