神經母細胞瘤的形成主要是由於神經嵴細胞無法正常分化成交感神經系統所產生的胚胎腫瘤。NDPK-A由nm23-H1基因編碼，在神經母細胞瘤中扮演促進腫瘤轉移的功能。然而，其分子機制目前還未知。實驗室先前發現在神經母細胞瘤NB69細胞與子宮頸癌HeLa細胞中NDPK-A會結合至c-myc基因啟動子上的nuclease hypersensitive element (NHE) III1，進而抑制了c-myc基因啟動子的活性。此外，發現c-myc啟動子NHE III1上游也參與NDPK-A所調控抑制的c-myc的轉錄。基於實驗室先前的cDNA微陣列數據，發現FBP-1是一個可能的調控因子。FBP-1已知結合於c-myc的啟動子的上游區域（FUSE）進而促進c-myc基因的轉錄。在神經母細胞瘤SH-SY5Y細胞中抑制NDPK-A的表達則增加c-myc的轉錄與FBP-1的表現。另一方面，SH-SY5Y細胞中抑制FBP-1的表達會降低的c-myc的表現，進一步也發現c-myc的表現的降低也會受到異位表達NDPK-A的影響。而在SH-SY5Y細胞中加入視黃酸 (retinoic acid)誘導神經細胞分化的過程中，c-myc表達下降，FBP-1和nm23-H1也下降。另外，抑制FBP-1的表達會增加視黃酸誘導的神經細胞分化，而抑制NDPK-A 的表現則會降低神經細胞的分化。雖然異位表達NDPK-A會增加視黃酸誘導的神經細胞分化，但同時抑制FBP-1的表現未能進一步提升神經細胞分化。另外也發現異位表達NDPK-A 會抑制其network 之可能成員，如HOXA9、RIN2及RIT2，在表現下降時所增加的神經分化。已知的是，c-myc在爪蟾神經嵴的發育中扮演重要的角色。在mRNA全覆式原位雜交實驗中發現nm23-H1與c-myc的同源基因nme2b1和myca在斑馬魚早期發育過程的表現位置與時間極為相似。因而，在斑馬魚中nme2b1也可能調控myca的基因的轉錄。以上的研究結論是，FBP-1參與NDPK-A所調控的c-myc基因轉錄和神經元分化。與腫瘤轉移有關的NDPK-A過度表現藉由導致c-myc基因轉錄的失調，很可能抑制有高度轉移及侵襲能力的早期神經嵴細胞的正常分化，因而產生高侵襲力的神經母細胞瘤。

Neuroblastoma is an embryonic tumor arising from neural crest cells that fail to differentiate into the sympathetic nervous system. Encoded by the nm23-H1 gene, human NDPK-A acts as a metastasis promoter in neuroblastoma. However, its molecular mechanism is largely unknown. Our lab has found that NDPK-A binds to nuclease hypersensitive element (NHE) III1 in the c-myc promoter and down-regulates the c-myc promoter activity in neuroblastoma NB69 and non-neuroblastoma HeLa cells. In addition, an element upstream of NHE III1 in the c-myc promoter is also involved in NDPK-A mediated down-regulation of c-myc transcription. Based on the cDNA microarray data in our lab, FBP-1 was identified as a potential collaborator of NDPK-A since it is known to bind to a single-stranded far upstream element (FUSE) in the c-myc promoter and activates c-myc transcription. In this study, knocking down NDPK-A expression increased c-myc transcription and FBP-1 expression in neuroblastoma SH-SY5Y cells. On the other hand, knockdown of FBP-1 expression reduced the c-myc promoter activity, and the latter was further decreased by ectopic NDPK-A expression in NB69 and SH-SY5Y cells. Moreover, the expression of c-myc, FBP-1 and nm23-H1 was down-regulated during neuronal differentiation of SH-SY5Y cells as induced by retinoic acid (RA). Although knockdown of FBP-1 expression increased RA-induced neuronal differentiation of SH-SY5Y cells, knockdown of NDPK-A expression decreased such differentiation. RA-induced neuronal differentiation was increased by ectopic expression of NDPK-A, but failed to be further elevated by knocking down FBP-1 expression. Furthermore, ectopic NDPK-A also abrogated neuronal differentiation of SH-SY5Y cells enhanced by knocking down the expression of candidates in the NDPK-A network, such as HOXA9, RIN2, and RIT2. It is known that c-Myc participates in neural crest development in Xenopus. Based on whole mount in-situ hybridization, nme2b1 (a highly homologous nm23-H1 ortholog) and myca (a c-myc ortholog) transcripts were spatially and temporally co-localized during early development of zebrafish, indicating a potential role of NME2b1 in regulating myca transcription. In conclusion, FBP-1 was involved in NDPK-A mediated regulation of c-myc transcription and neuronal differentiation. By deregulating c-myc transcription, metastasis-associated NDPK-A overexpression likely arrest neural crest at its migratory/invasive stage during differentiation into sympathetic neurons, thereby leading to aggressive neuroblastoma.

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