Midkine Promotes Neuroblastoma through Notch2 Signaling

Abstract

Midkine is a heparin-binding growth factor highly expressed in various cancers, including neuroblastoma, the most common extracranial pediatric solid tumor. Prognosis of patients with neuroblastoma in which MYCN is amplified remains particularly poor. In this study, we used a MYCN transgenic model for neuroblastoma in which midkine is highly expressed in precancerous lesions of sympathetic ganglia. Genetic ablation of midkine in this model delayed tumor formation and reduced tumor incidence. Furthermore, an RNA aptamer that specifically bound midkine suppressed the growth of neuroblastoma cells in vitro and in vivo in tumor xenografts. In precancerous lesions, midkine-deficient MYCN transgenic mice exhibited defects in activation of Notch2, a candidate midkine receptor, and expression of the Notch target gene HES1. Similarly, RNA aptamer-treated tumor xenografts also showed attenuation of Notch2-HES1 signaling. Our findings establish a critical role for the midkine-Notch2 signaling axis in neuroblastoma tumorigenesis, which implicates new strategies to treat neuroblastoma. Cancer Res; 73(4); 1318-27. Ó2012 AACR.

The Multifunctional Growth Factor Midkine Promotes Proliferation and Migration in Pancreatic Cancer

“…Recently, we and others have shown that the secretion of MK in tumor cells may serve as biomarker for gastrointestinal tumors and glioblastomas (10,11). Therefore, the development of MK inhibitors has been considered as an attractive idea to prevent tumor growth and antiapoptosis in cancer cells (12,13).…”

Functional Receptors and Intracellular Signal Pathways of Midkine (MK) and Pleiotrophin (PTN)

“…67) Midkine-notch2-HES1 signal axis also plays a critical role in neuroblastoma tumorigenesis. 93) Similarly, notch-HES signal was found to be active in the PTN promoted hematopoietic stem cell expansion and regeneration, while the downstream signal of HES here is PI3K/AKT. 21) Nuclear Targeting Pathway The mitogenic and antiapoptotic function of MK are also realized though its internalization, cell nuclear targeting and the subsequent transcription promotion.…”

Neighbours of cancer-related proteins have key influence on pathogenesis and could increase the drug target space for anticancer therapies

“…NOTCH2 is a first neighbour of the NSCLC-related Midkine (MDK) protein, which is expressed only in NSCLC and not in normal lung, and it is a known NSCLC biomarker 52. MDK can also cause neuroblastoma through activating specifically NOTCH2 53. LFNG acts like a double-edged sword: by promoting both the Delta1 ligand activated NOTCH1/2 receptors and decreasing the Jagged1 ligand activated NOTCH1 signalling, it contributes to the normal and tumour suppressor effect of NOTCH1 51.…”