JCO: FOXR2 can stabilize MYCN protein and can be used as an independent predictor of adverse outcomes in patients with neuroblastoma

The clinical outcomes of patients with neuroblastoma range from spontaneous tumor regression to death
.

Therefore, understanding the mechanisms that lead to tumor progression is essential for the treatment of patients

The researchers analyzed a total of 1,030 primary neuroblastoma cases with complete clinical annotations from three independent transcription data sets, performed immunoprecipitation on FOXR2 and MYCN , and silenced them in two neuroblastoma cell lines FOXR2 expression to examine the effect on cellular processes, transcriptome and MYCN protein levels
.

In addition, the protein levels of FOXR2 and MYCN in tumor samples were also analyzed

immunity

OS and EFS in neuroblastoma patients with FOXR1, FOXR2, MYC, MYCN or other abnormal gene expression

OS and EFS in neuroblastoma patients with FOXR1, FOXR2, MYC, MYCN or other abnormal gene expression

In these three neuroblastoma data sets, 9% of tumors have FOXR2 expression , but MYCN mRNA levels are low
.

According to FOXR2 expression, a group of patients with poor prognosis was determined, and the 10-year overall survival rate was only 53%-59% ; FOXR2 expression is a predictor independent of known risk factors

9% of tumors have FOXR2 expression.

OS and EFS in patients with high-risk neuroblastoma

OS and EFS in patients with high-risk neuroblastoma

At the transcriptional level, tumors expressing FOXR2 are very similar to tumors carrying MYCN amplification , indicating that they may have a common tumor initiation mechanism
.

Knockdown of FOXR2 in neuroblastoma cell lines expressing FOXR2 can lead to cell cycle arrest, cell growth slowdown, cell death, and decreased MYCN protein levels, all suggesting that FOXR2 is essential for these tumors

At the transcriptional level, tumors expressing FOXR2 are very similar to tumors carrying MYCN amplification

The expression level of MYCN protein in tumors expressing FOXR2

The expression level of MYCN protein in tumors expressing FOXR2

Finally, the researchers also proved that FOXR2 can bind to and stabilize the MYCN protein.
The level of MYCN protein in tumors expressing FOXR2 was significantly increased, and in some samples it was even comparable to the samples carrying MYCN amplification
.

FOXR2 can bind to and stabilize MYCN protein.
The protein level of MYCN is significantly increased in tumors expressing FOXR2, and in some samples it is even comparable to samples carrying MYCN amplification.

In summary, FOXR2 stabilizing MYCN protein represents an alternative mechanism for MYCN amplification to increase MYCN protein levels
.

Therefore, it is sufficient to determine another group of neuroblastoma patients with unfavorable clinical outcomes based on FOXR2 expression

Stabilization of MYCN protein by FOXR2 represents an alternative mechanism for MYCN amplification to increase MYCN protein levels

Original source: Original source:

Schmitt-Hoffner Felix,van Rijn Sjoerd,Toprak Umut H et al.

FOXR2 Stabilizes MYCN Protein and Identifies Non- Amplified Neuroblastoma Patients With Unfavorable Outcome in this message