Abstract
BackgroundAnaplastic 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.MethodsRegulation 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.ResultsIn 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.ConclusionALK-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.
Highlights
Anaplastic lymphoma kinase (ALK), which is a receptor tyrosine kinase, is essentially and transiently expressed in the developing nervous system
FIuorescence in situ hybridization (FISH) assay revealed no rearrangement or amplification of the ALK locus in 5 Uterine carcinosarcoma (UCS) cases with strong immunoreactivity (Fig. 1d and Table 2). These findings indicated that overexpression of full-length ALK at both mRNA and protein levels was frequently observed in UCSs
ALK enhances Epithelial-mesenchymal transition (EMT) phenotype by up-regulation of Twist1 through NF-κB/p65 The investigation of ALK signaling in UCSs was carried out using two endometrial carcinoma (Em Ca), but not UCS, cell lines, since we focused on an association between the functional roles of ALK with induction of EMT features in the carcinomatous components of UCSs
Summary
Anaplastic lymphoma kinase (ALK), which is a receptor tyrosine kinase, is essentially and transiently expressed in the developing nervous system. 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). Full-length ALK is expressed in the developing central and peripheral nervous system during embryogenesis and is associated with the balance of cell proliferation and differentiation [11,12,13]. While several fusion genes involving ALK produced by chromosomal rearrangements have been found in a subset of lymphomas and lung carcinomas,[7, 14] recently, deregulated expression of full-length ALK has been observed in some primary solid tumors derived from various tissues [15]. Carcinosarcomas are considered to represent a true example of complete EMT [23, 24]
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