Abstract
Simple SummaryNeuroblastoma is the most common extra-cranial tumor in children and despite medical advancements in cancer treatment, five-year survival for high-risk neuroblastoma remains less than 50%. Investigation of the mechanisms responsible for aggressive disease is necessary to identify novel therapeutic targets and improve survival. Serine-threonine kinase receptor associated protein (STRAP) is upregulated in several malignancies and plays an important role in tumor growth and metastasis. The role of STRAP in pediatric malignancies and specifically in neuroblastoma has not been explored. We sought to determine whether STRAP functions assisted to promote the malignant phenotype in neuroblastoma and could provide a potential target for future therapies.Background: Serine-threonine kinase receptor-associated protein (STRAP) plays an important role in neural development but also in tumor growth. Neuroblastoma, a tumor of neural crest origin, is the most common extracranial solid malignancy of childhood and it continues to carry a poor prognosis. The recent discovery of the role of STRAP in another pediatric solid tumor, osteosarcoma, and the known function of STRAP in neural development, led us to investigate the role of STRAP in neuroblastoma tumorigenesis. Methods: STRAP protein expression was abrogated in two human neuroblastoma cell lines, SK-N-AS and SK-N-BE(2), using transient knockdown with siRNA, stable knockdown with shRNA lentiviral transfection, and CRISPR-Cas9 genetic knockout. STRAP knockdown and knockout cells were examined for phenotypic alterations in vitro and tumor growth in vivo. Results: Cell proliferation, motility, and growth were significantly decreased in STRAP knockout compared to wild-type cells. Indicators of stemness, including mRNA abundance of common stem cell markers Oct4, Nanog, and Nestin, the percentage of cells expressing CD133 on their surface, and the ability to form tumorspheres were significantly decreased in the STRAP KO cells. In vivo, STRAP knockout cells formed tumors less readily than wild-type tumor cells. Conclusion: These novel findings demonstrated that STRAP plays a role in tumorigenesis and maintenance of neuroblastoma stemness.
Highlights
Despite advancements in pediatric cancer care, neuroblastoma, a childhood malignancy resulting from abnormal neural crest cell development, remains the cause of over15% of pediatric cancer related deaths [1]
Immunoblotting confirmed the presence of Serine-threonine kinase receptor-associated protein (STRAP) in five long-term passage neuroblastoma cell lines (Supplemental Figure S1)
We found that STRAP KO downregulated genes were involved in stemness, metastasis, and multiple oncogenic signaling pathways such as TGFβ and WNT/β-catenin signaling, while genes associated with apoptosis and differentiation were upregulated in the AS STRAP KO cells (Figure 4D)
Summary
Despite advancements in pediatric cancer care, neuroblastoma, a childhood malignancy resulting from abnormal neural crest cell development, remains the cause of over15% of pediatric cancer related deaths [1]. Despite advancements in pediatric cancer care, neuroblastoma, a childhood malignancy resulting from abnormal neural crest cell development, remains the cause of over. Current treatment regimens for high-risk disease include chemotherapy, surgical resection, autologous stem cell transplant, radiation, immunotherapy, and retinoic acid [2] Despite these extensive therapies, outcomes remain dismal for patients with high-risk disease as less than 50% will attain a 5 year survival [3]. STRAP is overexpressed in several malignancies, including colorectal [6] and lung cancer [7] and the pediatric bone cancer, osteosarcoma [8] In these malignancies, STRAP enhanced cancer cell proliferation and tumor growth. Serine-threonine kinase receptor-associated protein (STRAP) plays an important role in neural development and in tumor growth. Indicators of stemness, including mRNA abundance of common stem cell markers Oct, Nanog, and Nestin, the percentage of cells expressing CD133 on their surface, and the ability to form tumorspheres were significantly decreased in the STRAP
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