Abstract
Mounting evidence indicates that hotspot p53 mutant proteins often possess gain-of-function property in promoting cell mobility and tumor metastasis. However, the molecular mechanisms are not totally understood. In this study, we demonstrate that the hotspot mutation, p53-R273H, promotes cell migration, invasion in vitro and tumor metastasis in vivo. p53-R273H significantly represses expression of DLX2, a homeobox protein involved in cell proliferation and pattern formation. We show that p53-R273H-mediated DLX2 repression leads to upregulation of Neuropilin-2 (NRP2), a multifunctional co-receptor involved in tumor initiation, growth, survival and metastasis. p53-R273H-induced cell mobility is effectively suppressed by DLX2 expression. Furthermore, knockdown of NRP2 significantly inhibits p53-R273H-induced tumor metastasis in xenograft mouse model. Together, these results reveal an important role for DLX2-NRP2 in p53-R273H-induced cell mobility and tumor metastasis.
Highlights
Tumor suppressor protein p53 is activated in response to various cellular stresses to transactivate a set of target genes involved in cell cycle arrest, apoptosis, senescence, DNA repair and cancer cell metabolism.[1]
Our study reveals a new pathway with which mutant p53-R273H suppresses Distal-less homeobox 2 (DLX2) transcription, resulting in downregulation of NRP2 expression, which in turn leads to attenuation of signaling transduction pathway involved in TGFβ, SEMA3 and vascular endothelial growth factor in epithelial-mesenchymal transition, cell mobility and cancer metastasis (Figure 6e)
Hotspot mutations, including R175H, R248W and R273H, are closely associated with human tumorigenesis. While these mutations have lost their transcription activity in regulation of genes involved in cell cycle progression and apoptosis, it is clear that these mutations have exhibited gain of functions associated with cancer development, most strikingly, with cancer metastasis
Summary
Tumor suppressor protein p53 is activated in response to various cellular stresses to transactivate a set of target genes involved in cell cycle arrest, apoptosis, senescence, DNA repair and cancer cell metabolism.[1]. DNA-binding domain are frequently found in cancers, refereed as ‘hotspot’ mutations, which include R175, G245, R248, R249, R273 and R282.5 Mutant p53 proteins usually have lost its DNA sequence-specific transcription function, they can inhibit wild-type p53 function in a dominant negative fashion,[6] since p53 protein usually exerts as a tetramer. R175H exhibits a gain of oncogenic function in driving cell migration and invasion.[4,8] Studies from animal models have confirmed that mice bearing a mutant p53 allele show more aggressive and metastatic tumor than p53 null.[9,10,11] In human cancers, mutant p53 expression has been linked to poorer prognosis.[12]. It has recently become widely acknowledged that upregulation of NRP2 expression is associated with tumorigenesis and, in particular, tumor metastasis.[23]
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