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Transcriptome Analysis Reveals Key Genes and Pathways Associated with Metastasis in Breast Cancer

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Transcriptome Analysis Reveals Key Genes and Pathways Associated with Metastasis in Breast Cancer OncoTargets and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Transcriptome Analysis Reveals Key Genes and Pathways Associated with Metastasis in Breast Cancer This article was published in the following Dove Press journal: OncoTargets and Therapy Wei Li 1,* Background: Metastasis is the major cause of death in breast cancer patients. Although the Jianling Liu2,* strategies targeting metastasis have promoted survival, the underlying mechanisms still Bin Zhang3 remain unclear. In this study, we used microarray data of primary breast tumor, tumor Qingli Bie3 derived from bone and liver, and skin metastatic tissue, to identify the key genes and Hui Qian1 pathways that are involved in metastasis in breast cancer. Methods: We first calculated the differentially expressed genes (DEGs) between three Wenrong Xu1 metastatic tissues and primary tumor tissue, and then used it to perform Gene Ontology 1Key Laboratory of Laboratory Medicine (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analy- of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, sis. Further, we analyzed the correlation of genes enriched in GO terms and KEGG pathways People’s Republic of China; 2Central Lab, with survival of breast cancer patients. To identify the key genes and pathways associated fi The First Af liated Hospital of Hebei with metastasis, we overlapped the DEGs and KEGG pathways. In our in vitro experiments, North University, Zhangjiakou, Hebei, People’s Republic of China; 3Department we knocked down the key gene, ERLIN2, and detected the PI3K expression in tumor cells to of Laboratory Medicine, Affiliated evaluate their effect on tumor metastasis. Hospital of Jining Medical University, Results: We identified six genes (ALOX15, COL4A6, LMB13, MTAP, PLA2G4A, TAT) that Jining, Shandong, People’s Republic of China correlated with survival. Seven key genes (SNRPN, ARNT2, HDGFRP3, ERO1LB, ERLIN2, YBX2, EBF4) and seven signaling pathways (metabolic pathways, phagosome pathway, *These authors contributed equally to this work PI3K-AKT signaling pathway, focal adhesion, ECM-receptor interaction, pancreatic secre- tion, human papillomavirus infection) associated with metastasis were also identified. Our in vitro experiments revealed that ERLIN2 was highly expressed in MDA-MB231 cells compared to MCF-7 cells. Moreover, knockdown of ERLIN2 increased apoptosis, while inhibiting the proliferation, invasion, and migration ability of breast cancer cells. The PI3K/ AKT signaling pathway was also found to be highly expressed in MDA-MB231 cells. Conclusion: Our results reveal the key genes and signaling pathways that contribute to metastasis, and highlight that strategic targeting of ENLIN2 and PI3K/AKT signaling path- ways could inhibit metastasis of breast cancer. Keywords: breast cancer, metastasis, transcriptome microarray data, key genes, signaling pathways Introduction Globally, breast cancer is the leading cause of cancer-related deaths in women.1 Correspondence: Wenrong Xu; Hui Qian School of Medicine, Jiangsu University, Although surgery at an early stage has been reported to prolong the survival of the 301 Xuefu Road, Zhenjiang, Jiangsu ’ patients, the recurrence and metastasis pose critical challenges to the treatment of 212013, People s Republic of China 2 Tel +86 511 85038215; breast cancer. Common metastasis organs of breast cancer include brain, liver, lung, +86 511 85038334 bone, and skin.3,4 Metastasis, a process occasioned by tumor cells detaching from the Fax +86 511 85038483 Email [email protected]; [email protected] original tumor tissue and entering the metastatic site, is a complex process. The submit your manuscript | www.dovepress.com OncoTargets and Therapy 2020:13 323–335 323 DovePress © 2020 Li et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php – http://doi.org/10.2147/OTT.S226770 and incorporate the Creative Commons Attribution Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Li et al Dovepress disseminated tumor cells may undergo four fates: death, process which is strongly associated with mRNA expres- cellular dormancy, dormant micrometastasis, or invasive sion changes. Kimbung et al12 found that Claudin-2 could growth.5,6 Over the past decades, strategies targeting breast predict early liver metastasis in breast cancer. Moreover, cancer have focused on every stage and subpopulation. For expressions of PHLPP1, UBC, ACACB, TGFB1, and instance, chemotherapy kills the rapidly growing tumor ACTB were positively correlated with brain metastasis.13 cells, while blocking agents of oestrogen receptor (ER+) MicroRNAs (miRNAs) have also been shown to play an and human epidermal growth factor receptor-2 (HER2+) important role in metastasis. Zhao et al14 demonstrated benefit the patients with ER+ and HER2+ breast tumor.7,8 that miR-665 promoted metastasis by targeting NR4A3. In recent years, immunotherapy has also been used for the Therefore, extensive studies on gene expression could treatment of advanced stages of breast cancer with greatly enhance the understanding of tumor metastasis metastasis.9 However, the prognosis of metastatic breast mechanisms. cancer still remains poor. Thus, it is important to investigate In the present study, we aimed to identify the key genes the mechanisms of metastasis in breast cancer. and pathways involved in metastasis by multiple strategies Recent advancement in RNA detection technology (Figure 1). We first compared the difference in gene such as RNA sequencing and microarray, has facilitated expression level between samples from metastatic and the understanding of the biological and genomic altera- primary tissues. The DEGs identified were subjected to tions involved in the formation and metastasis of breast GO and KEGG enrichment analysis for each group. We cancer. The genomic landscape analysis revealed that then evaluated the relationship between expression of the TP53 and PIK3CA mutations are the most frequent geno- genes enriched in GO and KEGG pathways, and survival mic alterations in all subtypes of breast cancer.10 in breast cancer. To classify the key genes and pathways, Currently, relatively few studies have comprehensively we overlapped the DEGs and KEGG pathways. analyzed the genomic alterations leading to metastasis in Subsequently, the role of the key gene and pathways, breast cancer. Toy et al11 revealed that TP53, PIK3CA, and ERLIN2 and PI3K/AKT, in breast cancer cells were vali- GATA3 were the most frequent mutations in metastatic dated in vitro. Our results revealed the underlying mechan- breast cancer. In addition, Massard et al suggested that isms of metastasis of breast cancer, and showed that PTEN/PI3K/AKT and FGFR/FGF signaling pathways ERLIN2 and PI3K/AKT signaling pathway are potential were dysregulated. Breast cancer metastasis is an evolving therapeutic targets for breast cancer metastasis. Figure 1 Multiple strategies used in the study. 324 submit your manuscript | www.dovepress.com OncoTargets and Therapy 2020:13 DovePress Dovepress Li et al Materials and Methods Real-Time RT-PCR Microarray Data Total RNA was extracted from MCF-7 and MDA-MB231 R package (GEOquery) was used to download microarray cells using Trizol (Invitrogen, Carlsbad, CA, USA, ’ data GSE46141 from the GEO database (https://www.ncbi. #15596018), according to the manufacturer sprotocol.The nlm.nih.gov/geo/). The data were then normalized by RNA concentration and purity were detected using NanoDrop fi normalizeBetweenArrays function in limma package. 2000 (Thermo Scienti c, Waltham, MA, USA). One micro A total of 88 breast tumor samples were used for this gram of total RNA was reverse-transcribed to cDNA using analysis, comprising 11 primary tumor tissues, 5 bone Prime Script RT reagent kit (TaKaRa, Tokyo, Japan, metastatic tumor tissues, 16 liver metastatic tumor tissues, #RR037A). Real-time quantitative PCR was performed 17 skin metastatic tumor tissues, and 39 lymph node using Agilent Mx3005P (Santa Clara, CA, USA). All primers metastatic tissues. were purchased from Sangon Biotech (Shanghai, China) and are listed in Supplementary Table 1. Glyceraldehyde 3-phos- Identification and Clustering of DEGs phate dehydrogenase (GAPDH) was used as the control, and 2−ΔΔCt method used to calculate the relative gene expression RVM t-test was used to filter the DEGs between the meta- level. Each experiment was independently performed in static tissue and primary tumor tissue due to its ability to triplicates. effectively raise the degrees of freedom in small microarray data samples. We selected the differentially expressed genes according to the p-value threshold and fold change. Invasion and Migration Assay 5 Differences with p value < 0.05 and fold change > 1.5 were To perform the cell invasion and migration assay, 2 × 10 considered significant. Hierarchical clustering was per- cells were suspended in 200μL serum-free RPMI-1640 and formed by EPCLUST.15 added to the upper chamber of an 8-um pore transwell (Corning, New York, USA, #3422) with (invasion
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