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Integrated Bioinformatics Data Analysis Reveals Prognostic Significance of SIDT1 in Triple-Negative Breast Cancer

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Integrated Bioinformatics Data Analysis Reveals Prognostic Significance of SIDT1 in Triple-Negative Breast Cancer OncoTargets and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Integrated Bioinformatics Data Analysis Reveals Prognostic Significance Of SIDT1 In Triple-Negative Breast Cancer This article was published in the following Dove Press journal: OncoTargets and Therapy Ya Wang 1 Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease with a Hanning Li2 worse prognosis. However, current therapies have rarely improved the outcome of patients Jingjing Ma1 with TNBC. Here we sought to identify novel biomarkers or targets for TNBC. Tian Fang1 Materials and methods: Patients GSE76275 clinic traits and their corresponding mRNA fi Xiaoting Li1 pro les for 198 TNBC and 67 non-TNBC were obtained from the GEO database. Weighted gene co-expression network analysis (WGCNA) of the GSE76275 keyed out hub genes, and Jiahao Liu1 the differentially expressed genes (DEGs) were identified with the cut-off of adjusted P (adj. Henok Kessete Afewerky 3 4 P) <0.01 and |log2 fold-change (FC)| > 1.5. The hub - DEGs overlapping genes, as key Xiong Li genes, were considered for further study using Kaplan-Meier plotter online analysis. 1 Qinglei Gao Subsequently, Breast Cancer Gene-Expression Miner v4.0 and tissue microarray analysis 1Cancer Biology Research Center (Key were applied to determine the transcriptional and translational levels of every key gene. Laboratory of the Ministry of Education), Following plasmid transfection for overexpression, the proliferation of TNBC cells was Tongji Hospital, Tongji Medical College, Huazhong University of Science and determined by CCK8 and colony formation assay. Moreover, xenograft tumor models were Technology, Wuhan, People’s Republic of canvassed to investigate their effect upon in vivo tumor growth. 2 China; Department of Thyroid and Results: Four genes (SIDT1, ANKRD30A, GPR160,andCA12) were found to be associated Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of with relapse-free survival (RFS) in TNBC through WGCNA and DEGs integrated analysis. Science and Technology, Wuhan, People’s Patients with a higher level of SIDT1 had significantly better RFS compared to those with Republic of China; 3Department of lower levels. The transcriptional and translational levels of SIDT1 were validated as down- Pathology and Pathophysiology, School of Basic Medicine, Tongji Medical College, regulated in patients with triple-negative status, negative estrogen receptor (ER), progesterone Huazhong University of Science and receptor (PR), and human epidermal growth factor receptor 2 (HER2). Furthermore, SIDT1 Technology, Wuhan, People’s Republic of China; 4Department of Gynecology and inhibited proliferation of breast cancer cells (MDA-MB-231 and MDA-MB-468) and xenograft Obstetrics, Central Hospital of Wuhan, studies demonstrated that SIDT1 can suppress tumor growth in vivo. Tongji Medical College, Huazhong Conclusion: This study suggests that SIDT1 may play a crucial role in TNBC progression University of Science and Technology, Wuhan, People’s Republic of China and has the potential as a prognostic biomarker of TNBC. Keywords: triple-negative breast cancer, WGCNA, prognosis, SIDT1 Introduction Breast cancer remains the most commonly diagnosed cancer and a leading cause of 1 Correspondence: Qinglei Gao cancer death among females. Approximately 2.1 million new cases were diagnosed Cancer Biology Research Center (Key Laboratory of the Ministry of Education), with breast cancer in 2018 globally, accounting for 24.2% of total novel cancer Tongji Hospital, Tongji Medical College, cases among females.1 Triple-negative breast cancer (TNBC), which is defined by Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan no expression of the estrogen receptor (ER), progesterone receptor (PR), and human 430000, People’s Republic of China epidermal growth factor receptor 2 (HER2), accounts for 10–20% of all breast Tel/fax +86-27-83662681 2,3 Email [email protected] cancers. Patients with TNBC typically have a higher recurrence and mortality submit your manuscript | www.dovepress.com OncoTargets and Therapy 2019:12 8401–8410 8401 DovePress © 2019 Wang 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 and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the http://doi.org/10.2147/OTT.S215898 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). Wang et al Dovepress rate than all other breast cancer subtypes owing to biolo- #739406, Roche) following the manufacturer instructions. To gically more aggressive behavior and the lack of hormone generate the lentiviral vector for overexpression of SIDT1, the receptors and HER2 expression for targeted therapy.4–7 FUGW-H1-GFP-neomycin (Cat. #37632, Addgene) was mod- Hence, identifying reliable biomarkers and effective tar- ified by inserting a target gene downstream from HIV-1 flap gets for TNBC is urgently needed for enhancing overall into a unique EcoRI-BamHI site. The lentivirus was con- prognosis. structed and produced by Taitool Bioscience Co. Ltd. The wealth of molecular information from public data- (Shanghai, China). base resources, such as The Cancer Genome Atlas (TCGA: https://www.cancer.gov/tcga) and Gene Expression Omnibus Animal Studies (GEO) database,8 offers insight upon the mechanism of Four-week-old 24 female athymic nude (nu/nu) mice were cancer progression and an opportunity for discovering new purchased from HFK Bio-Technology Co. Ltd. (Beijing, biomarkers. Furthermore, reanalyzing of these data based on China). MDA-MB-231 (1×106) and MDA-MB-468 bioinformatics methods could also provide new clues for (1×106) cells with indicated lentivirus were suspended in discovering valuable targets. Among these bioinformatics 50 µl of PBS and injected subcutaneously into the caudal methods, differentially expressed genes (DEGs) analysis is thigh of each mouse. Tumor volumes were calculated a widely used tool riveted on gene upregulation and down- every 7 days according to the formula: volume = (the 2 regulation independently. As genome is a complicated and longest diameter) × (the maximum width) /2 and the highly interconnected network, there is a need to analyze weight of tumors were recorded at the end of the experi- from different perspectives.9 Weighted gene co-expression ment. The animal experiment was performed in accor- network analysis (WGCNA), based on a scale-free network, dance with the Animal Welfare Act, “Guidelines for the is used for identifying modules or clusters of highly corre- Care and Use of Laboratory Animals”, approved by the lated genes.10 Thus,WGCNAisapowerfultooltoidentify Committee for Ethics on Animal Experiments of Tongji key genes that contribute to phenotypic traits and referenc- Hospital, Tongji medical college, Huazhong University of able candidate biomarkers or therapeutic targets. Science and Technology. In this study, we selected candidate genes related to TNBC by combining DEGs and WGCNA algorithms. We Immunohistochemistry further explored their prognostic value and expression in Two human breast cancer tissue chips (BR2082a and breast cancer. Then, we chose SIDT1 for further study and BR487c, Alenabio, China) were utilized for SIDT1 immu- verified its correlation with clinicopathological progres- nostaining in accord to the Specimens in Tissue Chips sion by tissue microarray. Moreover, we investigated its Collection and Use guideline approved by the Ethics ’ effect on tumor growth both in vitro and in vivo. Committee of People s Hospital of Xutong County, Henan Province and subsequent approval by the Ethical Management Committee of Tongji Hospital - Tongji Materials And Methods Medical College. A human paraffin-embedded tissue array Cell Culture And Transfection of BR2082a and BR487c contained 44 cases with benign Human breast cancer lines MDA-MB-231 and MDA-MB-468 breast lesion, 52 cases diagnosed with TNBC, and 108 were purchased from ATCC and cultured in DMEM medium cases with non-TNBC. Tissue sections were subjected to with 10% fetal bovine serum (FBS) and 1% penicillin/strepto- immunohistochemical (IHC) analysis using the Avidin- mycinat37°Cwith5%CO2. A plasmid expressing SIDT1 Biotin Complex (ABC) Vectastain Kit (SP-9001, Zsgb- (pENTER-CMV-SIDT1-flag) and an empty plasmid control Bio) according to the manufacturer’s protocol. Anti-human (pENTER) were constructed by inserting target gene into SIDT1 (55352-1-AP, Proteintech) was used as a primary plasmid pENTER using restriction enzyme AsisI/MluI antibody. Further, SIDT1 immunostaining was evaluated obtained from Vigene Bioscience (Shangdong, China). To independently by two pathologists who were blinded to all confirm the insertion, two primers (primerF: CGCAA clinical information. A semi-quantitative scoring system 'ATGGGCGGTAGGCGTG and primerR: CCTCTACAAA was used for evaluation as described previously.11 In brief, TGTGGTATGGC) were constructed by sequencing the target the staining intensity was marked (0 = absence; 1 = weak; 2 gene. The plasmid transfections were performed using = moderate; 3 = strong). The HSCORE
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