Expression profiles and clinical relationships of ID2, CDKN1B, and CDKN2A in primary neuroblastoma

Abstract

Despite considerable research into the etiology of neuroblastoma, the molecular basis of this disease has remained elusive. In contrast to the absence of expression of the known tumor suppressor CDKN2A (also known as p16 and INK4A) in a wide variety of tumor types we have found in previous studies that CDKN2A protein is paradoxically highly expressed in many advanced stage neuroblastomas and unrelated to RB1 status. In the present study, we sought to identify the mechanistic relationships that might influence CDKN2A expression and negate its influence on tumor cell proliferation. In this regard, we examined the role of the tumor-suppressor gene CDKN1B (also known as p27 and Kip1) and the oncogene ID2 in relationship to CDKN2A expression, MYCN amplification, and neuroblastoma pathogenesis in 17 neuroblastoma cell lines and 129 samples of primary tumors of all stages. All neuroblastoma cell lines expressed the ID2 transcript and protein. However, although the majority of primary neuroblastomas also expressed the ID2 transcript, expression of the ID2 protein was undetectable or only barely detectable, regardless of transcript expression. In both cell lines and primary tumors, ID2 expression was independent of both CDKN2A and MYCN expression. In primary neuroblastomas, CDKN1B protein was expressed in significantly fewer advanced-stage neuroblastomas than early-stage neuroblastomas, but its expression had no relationship with CDKN2A expression or MYCN amplification. We concluded that the paradoxical expression of CDKN2A in neuroblastoma cannot be explained by inactivation of the tumor-suppressor gene CDKN1B or overexpression of the oncogene ID2. We further concluded that ID2 is not a target of MYCN regulation nor is it a prognostic factor for neuroblastoma. Finally, the loss of CDKN1B in advanced-stage neuroblastoma suggests this protein may play a role in the neuroblastoma disease process.

A c-Myc-regulated stem cell-like signature in high-risk neuroblastoma: A systematic discovery (Target neuroblastoma ESC-like signature)

“…Furthermore, the LR genes CDKN2D, CDK19 and CDKN1B were among the ENSC down-regulated genes, suggesting that they represent the differentiated status of NB cells. Consistent with these observations, CDKN1B and CDKN2D have been reported as NB tumour suppressors 45, 46 . Therefore, we expected the relative expression levels of these two sets of biomarkers to indicate an unfavourable outcome in HR-NB.

Figure 4Identification of prognostic biomarkers and clinical evaluation.

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Gravin gene expression in acute leukaemias: Clinical importance and review of the literature

“…However, its expression was found to be increased in cases with advanced stage neuroblastoma. In these cases compensatory nonfunctional over expression of CDKN2A by RB1 against the other activated factors has been speculated [19]. Gravin is a gene associated with cyclins.…”

Structural analysis of the human neuroblastoma DNA replication complex: insights into faulty proliferation

“…For example, cell cycle proteins are a level of cellular control that ensures precise DNA replication. In NB, the overexpression and/or aberrations in the following cell cycle regulatory proteins, cyclin D1, p16, p21, and p27, have each been implicated in the pathogenesis of NB [5][6][7][8][9][10]. An additional highly conserved mechanism of DNA replication control involves minichromosome maintenance (MCM) proteins.…”