Polo-like kinase 4 mediates epithelial\u2013mesenchymal transition in neuroblastoma via PI3K/Akt signaling pathway

Xiangdong Tian,Yalei Wang,Daowei Wang,Qiang Zhao,Meng Zhou,Huijuan Wang,Yanna Cao,Zhongyuan Li,Lianmin Zhang,Yao Tian,Dejun Zhou,Yanli Qiu,Jie Yan,Qiuping Dong,Benfu Zhong,Lu Chen,Guoguang Ying

doi:10.1038/s41419-017-0088-2

Xiangdong Tian, Yalei Wang + Show 15 more

Open Access

https://doi.org/10.1038/s41419-017-0088-2

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Abstract

Neuroblastoma (NB) is the most common malignant tumor in infancy and most common extracranial solid tumor in childhood. With the improvement of diagnosis and treatment, the survival rate of patients with low-risk and intermediate-risk NB can reach up to 90%. In contrast, for high-risk NBs, the long-term survival rate is still <40% because of heterogeneity of this tumor. The pathogenesis of NB is still not explicit, therefore it is of great significance to explore the mechanism of NB tumorigenesis and discover new therapeutic targets for NB. Polo-like kinase 4 (PLK4), one of the polo-like kinase family members, is an important regulator of centriole replication. The aberrant expression of PLK4 was found in several cancers and a recent study has unraveled a novel function of PLK4 as a mediator of invasion and metastasis in Hela and U2OS cells. However, the function of PLK4 in NB development and progression remains to be elucidated. The study showed the expression level of PLK4 in NB tissues was remarkably upregulated and high expression of PLK4 was negatively correlated with clinical features and survival, which suggested that PLK4 could be a potential tumor-promoting factor of NB. Functional studies indicated downregulation of PLK4 suppressed migration and invasion and promoted apoptosis in NB cells. Further experiments showed that downregulation of PLK4 in NB cells inhibited EMT through the PI3K/Akt signaling pathway. Animal experiments demonstrated that the downregulation of PLK4 in SK-N-BE(2) cells dramatically suppressed tumorigenesis and metastasis. PLK4 may be a promising therapeutic target for NB.

Highlights

Neuroblastoma (NB) is the most common malignant tumor in infancy and most common extracranial solid tumor in childhood
Polo-like kinase 4 (PLK4) was a poor prognostic factor We initially randomly collected seven pairs of freshly and untreated NB and adjacent normal tissues to analyze the protein expression level of PLK4 by western blot (WB), the results showed that when compared with adjacent normal tissues, PLK4 was elevated in 6/7 collected NB tissues (Fig. 1a)
The results showed that the PLK4 expression was elevated in SK-N-SH and SK-N-BE(2) cell lines as compared with Hela and Du145 cell lines, which were known to be positive (Supplementary Figure 1A)

Summary

Introduction

Neuroblastoma (NB) is the most common malignant tumor in infancy and most common extracranial solid tumor in childhood. The aberrant expression of PLK4 was found in several cancers and a recent study has unraveled a novel function of PLK4 as a mediator of invasion and metastasis in Hela and U2OS cells. Systemic multidisciplinary therapy has increased dren, which is the most commonly occurring extracranial the overall survival (OS) rate up to 90% or so for children solid tumor in childhood[1]. It accounts for 7–10% of all with NB.[4,5] But the extraordinary degree of heterogeneity. Relapse and metastasis remain common among patients with high-risk NB and the long-term survival rate is

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