Parathyroid hormone‐like hormone plays a dual role in neuroblastoma depending on PTH1R expression. Issue 9 (19th July 2019)

• Record Type: Journal Article
• Authors: García, Marta; Rodríguez‐Hernández, Carlos Javier; Mateo‐Lozano, Silvia; Pérez‐Jaume, Sara; Gonçalves‐Alves, Eliana; Lavarino, Cinzia; Mora, Jaume; de Torres, Carmen
• Is Part Of: Molecular oncology. Volume 13:Issue 9(2019)
• Page Start: 1959
• Page End: 1975
• Publication Date: 2019-07-19
• Subjects: epidermal growth factor receptor -- invasion -- neuroblastoma -- parathyroid hormone type 1 receptor -- parathyroid hormone‐like hormone; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.12542
• Languages: English
• ISSNs: 1574-7891

Abstract

Abstract : We have previously reported the expression of parathyroid hormone‐like hormone (PTHLH) in well‐differentiated, Schwannian stroma‐rich neuroblastic tumors. The aim of this study was to functionally assess the role of PTHLH and its receptor, PTH1R, in neuroblastoma. Stable knockdown of PTHLH and PTH1R was conducted in neuroblastoma cell lines to investigate the succeeding phenotype induced both in vitro and in vivo . Downregulation of PTHLH reduced MYCN expression and subsequently induced cell cycle arrest, senescence, and migration and invasion impairment in a MYCN ‐amplified, TP53 ‐mutated neuroblastoma cell line. These phenotypes were associated with reduced tumorigenicity in a murine model. We also show that PTHLH expression is not under the control of the calcium‐sensing receptor in neuroblastoma. Conversely, its production is stimulated by epidermal growth factor receptor (EGFR). Accordingly, irreversible EGFR inhibition with canertinib abolished PTHLH expression. The oncogenic role of PTHLH appeared to be a consequence of its intracrine function, as downregulation of its receptor, PTH1R, increased anchorage‐independent growth and induced a more undifferentiated, invasive phenotype. Respectively, high PTH1R mRNA expression was found in MYCN nonamplified primary tumors and also significantly associated with other prognostic factors of good outcome. This study provides the first evidence of the dual role of PTHLH in the behavior of neuroblastomas. Moreover, the identification of EGFR as a transcriptional regulator of PTHLH in neuroblastoma provides a novel therapeutic opportunity to promote a less aggressive tumor phenotype through irreversible inhibition of EGFR tyrosine kinase activity. Abstract : Parathyroid hormone‐like hormone (PTHLH) is expressed in neuroblastic tumors. A dual role of PTHLH seems to influence the behavior of neuroblastomas. The oncogenic functions of PTHLH appear to be a consequence of its intracrine action in aggressive, undifferentiated neuroblastomas, whereas the paracrine activities of PTHLH are predominant in benign neuroblastic tumors, which express high levels of its receptor PTH1R.