The RUNX Family Defines Trk Phenotype and Aggressiveness of Human Neuroblastoma through Regulation of p53 and MYCN

Abstract

The Runt-related transcription factor (RUNX) family, which is essential for the differentiation of cells of neural crest origin, also plays a potential role in neuroblastoma tumorigenesis. Consecutive studies in various tumor types have demonstrated that the RUNX family can play either pro-tumorigenic or anti-tumorigenic roles in a context-dependent manner, including in response to chemotherapeutic agents. However, in primary neuroblastomas, RUNX3 acts as a tumor-suppressor, whereas RUNX1 bifunctionally regulates cell proliferation according to the characterized genetic and epigenetic backgrounds, including MYCN oncogenesis. In this review, we first highlight the current knowledge regarding the mechanism through which the RUNX family regulates the neurotrophin receptors known as the tropomyosin-related kinase (Trk) family, which are significantly associated with neuroblastoma aggressiveness. We then focus on the possible involvement of the RUNX family in functional alterations of the p53 family members that execute either tumor-suppressive or dominant-negative functions in neuroblastoma tumorigenesis. By examining the tripartite relationship between the RUNX, Trk, and p53 families, in addition to the oncogene MYCN, we endeavor to elucidate the possible contribution of the RUNX family to neuroblastoma tumorigenesis for a better understanding of potential future molecular-based therapies.

Keywords: MYCN; RUNX; Trk; neuroblastoma; p53; p63; p73.

Figure 1

RUNX family is associated with neuroblastoma aggressiveness through regulation of Trk family expression. (A) Neurotrophin signals define the cell fate in development of the dorsal root ganglion. The question mark indicates a hypothetical repressor of TrkC. (B) RUNX1 and RUNX3 have opposite impacts on regulation of TrkA and TrkC expression. (C) RUNX 1 and RUNX3 influence neuroblastoma biology and patient prognosis.

Figure 2

Characteristic alteration of TP53-family-related pathways in neuroblastoma. The red-colored or green-colored molecules indicate oncogenes or tumor-suppressors in neuroblastomas, respectively. The light-pink-colored or light-green-colored molecules could positively or negatively affect neuroblastoma proliferation, respectively. Interaction between TAp73 and MYCN is unknown. ATRA, All-trans-retinoic acid.

Figure 3

Proposed network of expressional and/or functional regulation between the RUNX1 or RUNX2 and p53 families. (A) In response to DNA damage, RUNX1 interacts with Yes-associated protein (Yap1) and collaborates to induce protein degradation of all the p63 and p73 isoforms through the transcriptional activation of Itch, one of the known E3 ligases for p63 and p73. (B) Inhibitory roles of RUNX2 on the p53 family. Interaction between RUNX2 and MYCN is unknown. The red-colored or green-colored molecules indicate oncogenes or tumor-suppressors in neuroblastomas, respectively. The pink-colored RUNX1 could positively affect neuroblastoma proliferation The light-pink-colored or light-green-colored molecules could positively or negatively affect neuroblastoma proliferation, respectively, and the non-colored molecules are undetermined.

Figure 4

Proposed network between RUNX3 and MYCN in neuroblastomas with presence or absence of functional p53. (A) Expressional and/or functional regulation between the RUNX3 and p53 families. (B) Enhancer of zeste 2 (EZH2)-mediated epigenetic regulation is associated with neuroblastoma aggressiveness through transcriptional repression of RUNX3. (C) RUNX1-dependency in p53 non-functional neuroblastomas. The red-colored or green-colored molecules indicate oncogenes or tumor-suppressors in neuroblastomas, respectively. The pink-colored RUNX1 could positively affect neuroblastoma proliferation. The light-pink-colored or light-green-colored molecules could positively or negatively affect neuroblastoma proliferation, respectively, and the non-colored molecules are undetermined.