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Neuroblastoma tumorigenesis is regulated through the Nm23-H1/h-Prune C-terminal interaction.

Carotenuto M, Pedone E, Diana D, de Antonellis P, Džeroski S, Marino N, Navas L, Di Dato V, Scoppettuolo MN, Cimmino F, Correale S, Pirone L, Monti SM, Bruder E, Zenko B, Slavkov I, Pastorino F, Ponzoni M, Schulte JH, Schramm A, Eggert A, Westermann F, Arrigoni G, Accordi B, Basso G, Saviano M, Fattorusso R, Zollo M - Sci Rep (2013)

Bottom Line: H-Prune is the most characterized Nm23-H1 binding partner, and its overexpression has been shown in different human cancers.We developed a competitive permeable peptide (CPP) to impair the formation of the Nm23-H1/h-Prune complex and demonstrated that CPP causes impairment of cell motility, substantial impairment of tumor growth and metastases formation.We also identified two other proteins (PTPRA and TRIM22) with expression levels significantly affected by CPP.

View Article: PubMed Central - PubMed

Affiliation: Centro di Ingegneria Genetica e Biotecnologie Avanzate-CEINGE, Naples, Italy.

ABSTRACT
Nm23-H1 is one of the most interesting candidate genes for a relevant role in Neuroblastoma pathogenesis. H-Prune is the most characterized Nm23-H1 binding partner, and its overexpression has been shown in different human cancers. Our study focuses on the role of the Nm23-H1/h-Prune protein complex in Neuroblastoma. Using NMR spectroscopy, we performed a conformational analysis of the h-Prune C-terminal to identify the amino acids involved in the interaction with Nm23-H1. We developed a competitive permeable peptide (CPP) to impair the formation of the Nm23-H1/h-Prune complex and demonstrated that CPP causes impairment of cell motility, substantial impairment of tumor growth and metastases formation. Meta-analysis performed on three Neuroblastoma cohorts showed Nm23-H1 as the gene highly associated to Neuroblastoma aggressiveness. We also identified two other proteins (PTPRA and TRIM22) with expression levels significantly affected by CPP. These data suggest a new avenue for potential clinical application of CPP in Neuroblastoma treatment.

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Related in: MedlinePlus

Nm23-H1 and h-Prune gene expression and NBL overall survival.(a) NME1 expression in human NBL tissues (88 samples) compared to normal adrenal gland (13 samples) searched through a public database (Versteeg database). (b) H-prune expression in human NBL tissues compared to normal adrenal gland (Versteeg database). (c) In the Essen Affymetrix database, Nm23-H1 was detected with a probe which does not discriminate between Nm23-H1 and Nm23-H2. High expression of Nm23-H1/H2 in tumors promotes worse overall survival. (d) High expression of h-Prune in NBL tissues shows a trend towards worse overall survival that does not reach significance.
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f1: Nm23-H1 and h-Prune gene expression and NBL overall survival.(a) NME1 expression in human NBL tissues (88 samples) compared to normal adrenal gland (13 samples) searched through a public database (Versteeg database). (b) H-prune expression in human NBL tissues compared to normal adrenal gland (Versteeg database). (c) In the Essen Affymetrix database, Nm23-H1 was detected with a probe which does not discriminate between Nm23-H1 and Nm23-H2. High expression of Nm23-H1/H2 in tumors promotes worse overall survival. (d) High expression of h-Prune in NBL tissues shows a trend towards worse overall survival that does not reach significance.

Mentions: To determine the expression levels of Nm23-H1 and h-Prune in human NBL, we searched through a public database (http://r2.amc.nl). This search revealed that Nm23-H1 (Fig. 1a) and h-Prune (Fig. 1b) are significantly overexpressed in NBL tissues compared to normal adrenal gland (p = 2.7 e−12 and 1.3 e−11, respectively). Moreover, we analyzed a cohort of 101 NBL samples (Essen database) showing that high expression of Nm23 (both H1 and H2) correlates significantly to poor survival (p = 9.9 e−10) (Fig. 1c). These results are in agreement with studies performed previously1336. Although at the RNA level, h-Prune expression has not yet been significantly correlated to NBL survival from the previously analyzed cohorts, a positive association trend (p = 0.072) was seen (Fig. 1d). Taken together, these findings allow us to assume that the formation of the Nm23-H1/h-Prune complex is likely to have a role in cancer progression in NBL.


Neuroblastoma tumorigenesis is regulated through the Nm23-H1/h-Prune C-terminal interaction.

Carotenuto M, Pedone E, Diana D, de Antonellis P, Džeroski S, Marino N, Navas L, Di Dato V, Scoppettuolo MN, Cimmino F, Correale S, Pirone L, Monti SM, Bruder E, Zenko B, Slavkov I, Pastorino F, Ponzoni M, Schulte JH, Schramm A, Eggert A, Westermann F, Arrigoni G, Accordi B, Basso G, Saviano M, Fattorusso R, Zollo M - Sci Rep (2013)

Nm23-H1 and h-Prune gene expression and NBL overall survival.(a) NME1 expression in human NBL tissues (88 samples) compared to normal adrenal gland (13 samples) searched through a public database (Versteeg database). (b) H-prune expression in human NBL tissues compared to normal adrenal gland (Versteeg database). (c) In the Essen Affymetrix database, Nm23-H1 was detected with a probe which does not discriminate between Nm23-H1 and Nm23-H2. High expression of Nm23-H1/H2 in tumors promotes worse overall survival. (d) High expression of h-Prune in NBL tissues shows a trend towards worse overall survival that does not reach significance.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3584926&req=5

f1: Nm23-H1 and h-Prune gene expression and NBL overall survival.(a) NME1 expression in human NBL tissues (88 samples) compared to normal adrenal gland (13 samples) searched through a public database (Versteeg database). (b) H-prune expression in human NBL tissues compared to normal adrenal gland (Versteeg database). (c) In the Essen Affymetrix database, Nm23-H1 was detected with a probe which does not discriminate between Nm23-H1 and Nm23-H2. High expression of Nm23-H1/H2 in tumors promotes worse overall survival. (d) High expression of h-Prune in NBL tissues shows a trend towards worse overall survival that does not reach significance.
Mentions: To determine the expression levels of Nm23-H1 and h-Prune in human NBL, we searched through a public database (http://r2.amc.nl). This search revealed that Nm23-H1 (Fig. 1a) and h-Prune (Fig. 1b) are significantly overexpressed in NBL tissues compared to normal adrenal gland (p = 2.7 e−12 and 1.3 e−11, respectively). Moreover, we analyzed a cohort of 101 NBL samples (Essen database) showing that high expression of Nm23 (both H1 and H2) correlates significantly to poor survival (p = 9.9 e−10) (Fig. 1c). These results are in agreement with studies performed previously1336. Although at the RNA level, h-Prune expression has not yet been significantly correlated to NBL survival from the previously analyzed cohorts, a positive association trend (p = 0.072) was seen (Fig. 1d). Taken together, these findings allow us to assume that the formation of the Nm23-H1/h-Prune complex is likely to have a role in cancer progression in NBL.

Bottom Line: H-Prune is the most characterized Nm23-H1 binding partner, and its overexpression has been shown in different human cancers.We developed a competitive permeable peptide (CPP) to impair the formation of the Nm23-H1/h-Prune complex and demonstrated that CPP causes impairment of cell motility, substantial impairment of tumor growth and metastases formation.We also identified two other proteins (PTPRA and TRIM22) with expression levels significantly affected by CPP.

View Article: PubMed Central - PubMed

Affiliation: Centro di Ingegneria Genetica e Biotecnologie Avanzate-CEINGE, Naples, Italy.

ABSTRACT
Nm23-H1 is one of the most interesting candidate genes for a relevant role in Neuroblastoma pathogenesis. H-Prune is the most characterized Nm23-H1 binding partner, and its overexpression has been shown in different human cancers. Our study focuses on the role of the Nm23-H1/h-Prune protein complex in Neuroblastoma. Using NMR spectroscopy, we performed a conformational analysis of the h-Prune C-terminal to identify the amino acids involved in the interaction with Nm23-H1. We developed a competitive permeable peptide (CPP) to impair the formation of the Nm23-H1/h-Prune complex and demonstrated that CPP causes impairment of cell motility, substantial impairment of tumor growth and metastases formation. Meta-analysis performed on three Neuroblastoma cohorts showed Nm23-H1 as the gene highly associated to Neuroblastoma aggressiveness. We also identified two other proteins (PTPRA and TRIM22) with expression levels significantly affected by CPP. These data suggest a new avenue for potential clinical application of CPP in Neuroblastoma treatment.

Show MeSH
Related in: MedlinePlus