Explore the Neural Crest from Embryonic Development to Paediatric Tumour
Chengdong Wang1, Tianfeng Li1, Hui Wang1 and Hui Zhao1,2*
1. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, P. R. China.
2. CUHK-CAS KIZ Joint Laboratory of Bioresources and Molecular Research in Common Diseases
The neural crest (NC) is a transient, migratory cell population that differentiates into a large variety of tissues including craniofacial cartilage, melanocytes, and peripheral nervous system. NC is initially induced at the border of neural plate and non-neuralectoderm by balanced regulation of multiple signaling pathways, among which an intermediate bone morphogenetic protein (BMP) signalings is essential for NC formation. Ets1, a proto-oncogene playing important roles in tumor invasion, has also been implicated in delamination of NC cells. In this study, we investigated Ets1 function in NC formation using Xenopus. Overexpression of ets1 repressed NC formation through down-regulation of BMP signaling. Moreover, ets1 repressed the BMP-responsive gene id3 that is essential for NC formation. Conversely, overexpression of id3 can partially rescue the phenotype of NC inhibition induced by ectopic ets1. Mechanistically, we found that Ets1 binds to id3 promoter as well as Histone Deacetylase 1 (HDAC1), suggesting that Ets1 recruits HDAC1 to the promoter of id3, thereby inducing Histone deacetylation of the id3 promoter. Thus, our studies indicate that Ets1 regulates NC formation through attenuating BMP signaling epigenetically. We further generated ets-/- knockout X. tropicalis line and identified ets1 target genes using RNA-seq. Functional analysis of these genes are on-going.
Neuroblastoma is paediatric tumour of neural crest-derived tissues. Aberrant activation of anaplastic lymphoma kinase (ALK) can cause sporadic and familial neuroblastoma. Using a proteomics approach, we identified Bruton’s tyrosine kinase (BTK) as a novel ALK interaction partner, and the physical interaction was confirmed by co-immunoprecipitation. BTK is expressed in neuroblastoma cell lines and tumor tissues. Its high expression correlates with poor relapse free survival probability of neuroblastoma patients. Mechanistically, we demonstrated that BTK potentiates ALK-mediated signaling in neuroblastoma, and increases ALK stability by reducing ALK ubiquitination. Both ALKWT and ALKF1174L can induce BTK phosphorylation and higher capacity of ALKF1174L is observed. Furthermore, the BTK inhibitor Ibrutinib can effectively inhibit the growth of neuroblastoma xenograft in nude mice, and the combination of Ibrutinib and the ALK inhibitor Crizotinib further enhances the inhibition. Our study provides strong rationale for clinical trial of ALK positive neuroblastoma using Ibrutinib or the combination of Ibrutinib and ALK inhibitors.
Acknowledgement: Research Grants Council of Hong Kong CUHK413/12, CUHK24100414 and CUHK 14167017 to HZ
Chengdong Wang1, Tianfeng Li1, Hui Wang1 and Hui Zhao1,2*
1. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, P. R. China.
2. CUHK-CAS KIZ Joint Laboratory of Bioresources and Molecular Research in Common Diseases
The neural crest (NC) is a transient, migratory cell population that differentiates into a large variety of tissues including craniofacial cartilage, melanocytes, and peripheral nervous system. NC is initially induced at the border of neural plate and non-neuralectoderm by balanced regulation of multiple signaling pathways, among which an intermediate bone morphogenetic protein (BMP) signalings is essential for NC formation. Ets1, a proto-oncogene playing important roles in tumor invasion, has also been implicated in delamination of NC cells. In this study, we investigated Ets1 function in NC formation using Xenopus. Overexpression of ets1 repressed NC formation through down-regulation of BMP signaling. Moreover, ets1 repressed the BMP-responsive gene id3 that is essential for NC formation. Conversely, overexpression of id3 can partially rescue the phenotype of NC inhibition induced by ectopic ets1. Mechanistically, we found that Ets1 binds to id3 promoter as well as Histone Deacetylase 1 (HDAC1), suggesting that Ets1 recruits HDAC1 to the promoter of id3, thereby inducing Histone deacetylation of the id3 promoter. Thus, our studies indicate that Ets1 regulates NC formation through attenuating BMP signaling epigenetically. We further generated ets-/- knockout X. tropicalis line and identified ets1 target genes using RNA-seq. Functional analysis of these genes are on-going.
Neuroblastoma is paediatric tumour of neural crest-derived tissues. Aberrant activation of anaplastic lymphoma kinase (ALK) can cause sporadic and familial neuroblastoma. Using a proteomics approach, we identified Bruton’s tyrosine kinase (BTK) as a novel ALK interaction partner, and the physical interaction was confirmed by co-immunoprecipitation. BTK is expressed in neuroblastoma cell lines and tumor tissues. Its high expression correlates with poor relapse free survival probability of neuroblastoma patients. Mechanistically, we demonstrated that BTK potentiates ALK-mediated signaling in neuroblastoma, and increases ALK stability by reducing ALK ubiquitination. Both ALKWT and ALKF1174L can induce BTK phosphorylation and higher capacity of ALKF1174L is observed. Furthermore, the BTK inhibitor Ibrutinib can effectively inhibit the growth of neuroblastoma xenograft in nude mice, and the combination of Ibrutinib and the ALK inhibitor Crizotinib further enhances the inhibition. Our study provides strong rationale for clinical trial of ALK positive neuroblastoma using Ibrutinib or the combination of Ibrutinib and ALK inhibitors.
Acknowledgement: Research Grants Council of Hong Kong CUHK413/12, CUHK24100414 and CUHK 14167017 to HZ