ALK(R1275Q) perturbs extracellular matrix, enhances cell invasion and leads to the development of neuroblastoma in cooperation with MYCN.
T UedaY NakataN YamasakiH OdaK SentaniA KanaiN OnishiK IkedaY SeraZ-I HondaK TanakaM SataS OgawaW YasuiHideyuki SayaJ TakitaH HondaPublished in: Oncogene (2016)
Overexpression of MYCN is a hallmark of neuroblastoma (NB). ALK(R1275Q), an activating mutation of ALK (anaplastic lymphoma kinase), has been found in sporadic and familial NB patients. In this report, we demonstrated that ALK(R1275Q) knock-in, MYCN transgenic compound mice developed NB with complete penetrance. Transcriptome analysis revealed that ALK(R1275Q) globally downregulated the expression of extracellular matrix (ECM)- and basement membrane (BM)-associated genes in both primary neuronal cells and NB tumors. Accordingly, ALK(R1275Q)/MYCN tumors exhibited reduced expression of ECM/BM-related proteins as compared with MYCN tumors. In addition, on MYCN transduction, ALK(R1275Q)-expressing neuronal cells exhibited increased migratory and invasive activities. Consistently, enhanced invasion and metastasis were demonstrated in ALK(R1275Q)/MYCN mice. These results collectively indicate that ALK(R1275Q) confers a malignant potential on neuronal cells that overexpress MYCN by impairing normal ECM/BM integrity and enhancing tumor growth and dissemination. Moreover, we found that crizotinib, an ALK inhibitor, almost completely inhibited the growth of ALK(R1275Q)/MYCN tumors in an allograft model. Our findings provided insights into the cooperative mechanism of the mutated ALK and overexpressed MYCN in the pathogenesis of NB and demonstrated the effectiveness of crizotinib on ALK(R1275Q)-positive tumors.
Keyphrases
- advanced non small cell lung cancer
- extracellular matrix
- epidermal growth factor receptor
- randomized controlled trial
- cell cycle arrest
- poor prognosis
- gene expression
- end stage renal disease
- dna methylation
- signaling pathway
- genome wide
- cell death
- cell proliferation
- climate change
- adipose tissue
- transcription factor
- diffuse large b cell lymphoma
- endoplasmic reticulum stress
- chronic kidney disease
- high fat diet induced
- late onset
- peritoneal dialysis
- prognostic factors
- human health
- subarachnoid hemorrhage
- cerebral ischemia
- kidney transplantation