A DAAM1 3\u2032-UTR SNP mutation regulates breast cancer metastasis through affecting miR-208a-5p-DAAM1-RhoA axis

Jie Mei,Yin Chen,Yichao Zhu,Leiyu Hao,Fei Chang,Bujie Xu,Zhongyuan Wang,Shuning Shen,Xiaozheng Jiang,Tiansong Xia,Ting Yan,Yifu Huang

doi:10.1186/s12935-019-0747-8

Abstract

BackgroundDishevelled-associated activator of morphogenesis 1 (DAAM1) is a member of microfilament-related formins and mediates cell motility in breast cancer (BrCa). However, the genetic mutation status of DAAM1 mRNA and its correlation with pathological characteristics are still unclearly.MethodsA patient cohort and BrCa cells were recruited to demonstrate the role of functional SNP in microRNA-208a-5p binding site of DAAM1 3′-UTR and underlying mechanism in BrCa metastasis.ResultsThe expression and activation of DAAM1 increased markedly in lymphnode metastatic tissues. A genetic variant (rs79036859 A/G) was validated in the miR-208a-5p binding site of DAAM1 3′-UTR. The G genotype (AG/GG) was a risk genotype for the metastasis of BrCa by reducing binding affinity of miR-208a-5p for the DAAM1 3′-UTR. Furthermore, the miR-208a-5p expression level was significantly suppressed in lymphnode metastatic tissues compared with that in non-lymphnode metastatic tissues. Overexpression of miR-208a-5p inhibited DAAM1/RhoA signaling pathway, thereby leading to the decrease of the migratory ability.ConclusionOverall, the rs79036859 G variant of DAAM1 3′-UTR was identified as a relevant role in BrCa metastasis via the diversity of miR-208a-5p binding affinity.

Highlights

Dishevelled-associated activator of morphogenesis 1 (DAAM1) is a member of microfilament-related formins and mediates cell motility in breast cancer (BrCa)
DAAM1 expression positively correlates with lymphnode metastasis and associates with prognosis in BrCa Our previous studies reported that DAAM1 regulates the re-organization of microfilaments for oriented the migration and haptotaxis of BrCa cells [3, 6]
Because of limited amount of IHC sections, we further examined the transcriptional level of DAAM1 in 157 BrCa samples

Summary

Introduction

Dishevelled-associated activator of morphogenesis 1 (DAAM1) is a member of microfilament-related formins and mediates cell motility in breast cancer (BrCa). Dishevelled-associated activator of morphogenesis 1 (DAAM1) is a member of microfilament-related formins and is involved in cell motility through mediating Wnt signaling pathway [1,2,3]. DAAM1 exists in an autoinhibited state by intramolecular interaction between its N-terminal GBD and C-terminal DAD domains. When Dishevelled 2 binds to DAAM1, leading to disrupting the interaction between the GBD and DAD that mediates DAAM1 auto-inhibition, DAAM1 will exposure FH1 and FH2 domains to polymerize straight. Single nucleotide polymorphisms (SNPs) located in untranslated region (UTR) have been reported to be associated with dysregulation of genes expression. Mei et al Cancer Cell Int (2019) 19:55 the expression of DAAM1 mRNA [7]. SNPs in the miRNA binding sites in the 3′-UTRs of target genes represent their differential binding affinities for corresponding miRNAs [14,15,16]

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Discussion

Conclusion