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A DAAM1 3′-UTR SNP Mutation Regulates Breast Cancer Metastasis

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A DAAM1 3′-UTR SNP Mutation Regulates Breast Cancer Metastasis Mei et al. Cancer Cell Int (2019) 19:55 https://doi.org/10.1186/s12935-019-0747-8 Cancer Cell International PRIMARY RESEARCH Open Access A DAAM1 3′-UTR SNP mutation regulates breast cancer metastasis through afecting miR-208a-5p-DAAM1-RhoA axis Jie Mei1†, Ting Yan2†, Yifu Huang1,3, Tiansong Xia4, Fei Chang1, Shuning Shen1, Leiyu Hao1, Yin Chen1, Zhongyuan Wang1, Xiaozheng Jiang1, Bujie Xu1 and Yichao Zhu1,5* Abstract Background: Dishevelled-associated activator of morphogenesis 1 (DAAM1) is a member of microflament-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. Methods: A 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. Results: The expression and activation of DAAM1 increased markedly in lymphnode metastatic tissues. A genetic var- iant (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 afnity of miR-208a-5p for the DAAM1 3′-UTR. Further- more, the miR-208a-5p expression level was signifcantly 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. Conclusion: Overall, the rs79036859 G variant of DAAM1 3′-UTR was identifed as a relevant role in BrCa metastasis via the diversity of miR-208a-5p binding afnity. Keywords: DAAM1, 3′-UTR , rs79036859, miR-208a-5p, Metastasis Background actin flaments [2, 4]. DAAM1 is essential for Wnt-11/ Dishevelled-associated activator of morphogenesis 1 Frizzled-induced activation of RhoA and Xenopus gastru- (DAAM1) is a member of microflament-related form- lation [2]. DAAM1 directly collaborates to fascin in actin ins and is involved in cell motility through mediating flaments and thus controls the formation of flopodia [5]. Wnt signaling pathway [1–3]. In the cytoplasm, DAAM1 Our previous studies fnd that active DAAM1 is involved exists in an autoinhibited state by intramolecular interac- in Wnt5a/Dishevelled 2 and Collagen/Integrin αvβ3 sign- tion between its N-terminal GBD and C-terminal DAD aling pathways, resulting in the elevation of the migratory domains. When Dishevelled 2 binds to DAAM1, leading and haptotatic ability of breast cancer (BrCa) cells [3, 6]. to disrupting the interaction between the GBD and DAD However, the genetic mutation status of DAAM1 mRNA that mediates DAAM1 auto-inhibition, DAAM1 will and its correlation with pathological characteristics are exposure FH1 and FH2 domains to polymerize straight still unknown in BrCa patients. Single nucleotide polymorphisms (SNPs) located in untranslated region (UTR) have been reported to be *Correspondence: [email protected] associated with dysregulation of genes expression. A †Jie Mei and Ting Yan contributed equally to this work recent global transcriptional network study identifes 1 Department of Physiology, Nanjing Medical University, 101 Longmian Road, Nanjing 211166, China mutations at somatic expression quantitative trait locus Full list of author information is available at the end of the article (eQTL) located 5′-UTR of DAAM1, directly regulating © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Mei et al. Cancer Cell Int (2019) 19:55 Page 2 of 12 the expression of DAAM1 mRNA [7]. Nevertheless, non- intensity. Immunostained sections were scanned by a coding mutations in the 3′-UTR of DAAM1 has not been microscope (Olympus Corporation, Tokyo, Japan). reported. An increasing evidence revealed that functional 3′-UTR SNPs are participated in the progression of mul- Selection of SNPs and TaqMan genotyping tiple cancers [8–11]. Most 3′-UTR of mRNAs function A next-generation sequencing of metastatic BrCa tis- as the target sequences of microRNAs (miRNAs) by base sues (data not published) revealed some SNPs, includ- pairing, thereby leading to the degradation of mRNAs ing rs79036859 and rs45476291, locating in the 3′-UTR and decrease of their translation [12, 13]. SNPs in the of DAAM1. After a review of dbSNP database (https :// miRNA binding sites in the 3′-UTRs of target genes rep- www.ncbi.nlm.nih.gov/snp) and PolymiRTS Database resent their diferential binding afnities for correspond- 3.0 (http://compb io.uthsc .edu/miRSN P), we selected the ing miRNAs [14–16]. candidate SNP (rs79036859) suggested as a transcrip- Here, we demonstrate that DAAM1 is highly expressed tional regulation factor for the 3′-UTR of DAAM1. SNP in lymphnode metastatic BrCa tissues. We also elu- genotyping was conducted by allelic discrimination using cidate the functional role of SNP rs79036859 in the the TaqMan SNP Genotyping Assays according to the miR-208a-5p binding site of DAAM1 3′-UTR and its manufacturer’s instructions (Applied Biosystems). Spe- involvement in BrCa metastasis. Overall these data iden- cifc primers (TAT CTC CTG AAA GAG ATA AGA, GTT tify miR-208a-5p/DAAM1 axis as a potential therapeutic TTT CCA ACA ACT CCA GT) and FAM/VIC-labeled target in limiting BrCa metastasis and reducing death TaqMan probes (FAM-labeled CAA ACA AAC AAA AAA from this disease. AGCT TGC AAA ATA TTTT, VIC-labeled CAA ACA AAC AAA AAA GGCT TGC AAA ATA TTTT) were designed Methods and supplied by Synbio Technologies (Soochow, China). Clinical information Te PCR conditions were as follows: initiation at 98 °C 157 BrCa patients were recruited by the First Afliated for 10 min, followed by 40 cycles of denaturation at 95 °C Hospital with Nanjing Medical University and Afliated for 30 s and annealing/extension at 60 °C for 60 s. PCR Cancer Hospital to Nanjing Medical University (NJMU) application was undergoing in a StepOnePlus Real-Time from 2015 to 2018. All cases had been diagnosed with PCR System (Applied Biosystems). BrCa by a pathologist on the basis of hematoxylin–eosin (HE) staining. Relevant clinicopathological character- Cell culture and transfection istics record for each case were collected by review of MCF-10A, MDA-MB-231, MCF-7, and COS-7 cell lines patients’ medical fles. Ethical approval for the study was were purchased from the Cell Bank of Chinese Academy obtained from the Clinical Research Ethics Committee, of Sciences (Shanghai, China). MCF-7, MDA-MB-231, NJMU. Pathologic staging was determined by a patholo- and COS-7 cells were maintained in Dulbecco’s modi- gist based on AJCC Cancer Staging Manual 8th classif- fed Eagle’s medium (DMEM, high glucose) (Hyclone, cation criteria. All the participants voluntarily joined this Termo Scientifc, Waltham, MA) supplemented with study with informed contents. 10% (v/v) fetal bovine serum (FBS) (Hyclone) at 37 °C with 5% CO 2. MCF-10A cells were cultured in DMEM/ Immunohistochemistry (IHC) F12 media supplemented with 5% (v/v) horse serum, A total of 46 BrCa sections were deparafnised at 55 °C 20 ng/mL human EGF, 10 μg/mL insulin, 0.5 μg/mL for 30 min. Te sections were then washed with xylene hydrocortisone, penicillin, streptomycin and 100 ng/mL for three 5-min. Te sections were rehydrated by succes- cholera toxin (Sigma-Aldrich, St. Louis, MO). sive washes in 100, 90 and 70% graded ethanol. Hydro- For subsequent assays, cells were transfected with miR- gen peroxidase (0.3%, ZSGB-Bio, Beijing, China) was 208a-5p mimic, miR-208a-5p inhibitor (an anti-sense of used to block endogenous peroxidase activity for 20 min. miR-208a-5p), or miRNA mimic control, which is syn- Te primary anti-DAAM1 (1:100 dilution, Cat. 14876-1- thesized in RiboBio Co., Ltd. (Guangzhou, China), using AP, ProteinTech, Wuhan, China) antibody and DAB and Lipofectamine 2000 Reagent (Invitrogen, Carlsbad, CA) hematoxylin counterstain (ZSGB-Bio) were used to visu- according to the manufacturer’s instructions. alize its expression. Te percentage of positively stained cells was scored as 0–4: 0 (< 5%), 1 (6–25%), 2 (26–50%), Western blotting analysis and pulldown assays 5 3 (51–75%) and 4 (> 75%). Te staining intensity was Cells were placed in 35-mm dishes (6 × 10 cells/dish) scored as 0–3: 0 (negative), 1 (weak), 2 (moderate), and and transfected with synthesized miR-208a-5p mimic, 3 (strong). Te immunoreactivity score (IRS) equals to miR-208a-5p inhibitor (anti-sense of miR-208a-5p), the percentages of positive cells multiplied with staining or miRNA mimic control. 72 h after transfection, all cells were harvested the proteins with lysis bufer. Mei et al. Cancer Cell Int (2019) 19:55 Page 3 of 12 SDS–polyacrylamide gel electrophoresis and Western amplifed genes. Te 2−ΔΔCt method was used for miR- blotting analysis were performed as standard protocols. 208a-5p or DAAM1 expression analysis. Te primary antibodies for DAAM1 (1:1000 dilution, Cat. 14876-1-AP, ProteinTech), RhoA (1:1000 dilution, RhoA GTPase activation assays (G‑LISA small GTPase Cat. 10749-1-AP, ProteinTec), β-actin (1:5000 dilution, activation assays) Cat. 60008-1-Ig, ProteinTec) were used. DAAM1 protein Total protein lysates extracted from BrCa cells were levels were normalized to β-actin for each sample. turned to measure RhoA activity by using RhoA GTPase To detect the active level of DAAM1, we employed activation assays (Cat.
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