Abstract
High-risk neuroblastoma (NB) remains an extremely difficult subgroup to cure and is associated with MYCN amplification. Serine hydroxymethyltransferase 2 (SHMT2) regulates serine metabolism in a myc-dependent manner; it is upregulated in several cancers and is associated with tumor aggressiveness. Akt-2, an important regulator of MYCN via the PI3K/Akt pathway, induces metastatic potential in NB. The association between SHMT2 and PI3K/Akt in hepatocyte regeneration has been well established but its mechanistic interaction in cancer has yet to be clearly elucidated. Herein, we evaluated the exact role of SHMT2 on the PI3K/Akt pathway, in addition to NB tumorigenesis and metastatic potential in vitro. SHMT2 gene expression and overall survival (OS) were assessed. Two human NB cell lines were examined. SHMT2 silencing and overexpression were performed. The downstream effects were analyzed with immunoblotting, RT-qPCR and functional assays were performed. We found SHMT2 gene expression is associated with decreased OS and MYCN amplification. SHMT2 protein and mRNA expression are increased in MYCN-amplified cells. SHMT2 expression has a direct interaction with Akt-2 and MYCN. Induction of SHMT2 increased cellular proliferation, colony formation and cellular migration and SHMT2 expression was increased in metastatic NB cells. We conclude that SHMT2 regulates N-Myc via phosphorylation of Akt-2 and plays an important role in NB tumorigenesis by contributing to cell growth, migration, colony formation and metastasis in vitro.
Highlights
Neuroblastoma (NB) is a pediatric tumor derived from neural crest cells
Serine hydroxymethyltransferase 2 (SHMT2) expression is associated with MYCN amplification and decreased overall survival
Given the role of SHMT2 as an independent predictor of prognosis in breast cancer and glioma, we sought to determine the potential relationship between SHMT2 gene expression and overall survival in NB patients [8, 9]
Summary
Neuroblastoma (NB) is a pediatric tumor derived from neural crest cells. It is the most common pediatric, extracranial solid tumor. The high-risk group of NB remains one of the most difficult subgroups of NB to treat with resistance to therapeutic regimens and high disease relapse. Children with high-risk NB tumors have a long-term survival rate of less than 50%. Surgical resection is a viable treatment option for patients with low-risk NB. High-risk NBs require multi-modality treatment including chemotherapy, radiation, stem-cell transplant and recently, immunotherapy. Despite these treatment advances, highrisk NB has a low disease-free survival and increased rate of relapse or remission with many tumors developing chemotherapy and radiation resistance [2]
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