Development of a circHIPK3-based ceRNA network and identification of mRNA signature in breast cancer patients harboring BRCA mutation

PeerJ

article

Qi-xin Lian¹  Yang Song²  Lili Han³  Zunxian Wang⁴  Yinhui Song⁵ 

[1] Oncology Department, First Affiliated Hospital of Jiamusi University;Pathology Department, First Affiliated Hospital of Jiamusi University;General Surgery, The Seventh Medical Center of the General Hospital of the Chinese People’s Liberation;Chemoradiotherapy, First Affiliated Hospital of Jiamusi University;Department of Breast Surgery, The First Hospital of Qiqihar, The Affiliate Qiqihar Hospital of Southern Medical University

关键词: Breast cancer;    BRCA;    Competing endogenous RNA;    Circular RNA homeodomain-interacting protein kinase 3;    Messenger RNA;    Prognosis;    Risk model;   

DOI  :  10.7717/peerj.15572

学科分类：社会科学、人文和艺术（综合）

来源: Inra

【 摘 要 】

BackgroundExploring the regulatory network of competing endogenous RNAs (ceRNAs) as hallmarks for breast cancer development has great significance and could provide therapeutic targets. An mRNA signature predictive of prognosis and therapy response in BRCA carriers was developed according to circular RNA homeodomain-interacting protein kinase 3 (circHIPK3)-based ceRNA network.MethodWe constructed a circHIPK3-based ceRNA network based on GSE173766 dataset and identified potential mRNAs that were associated with BRCA mutation patients within this ceRNA network. A total of 11 prognostic mRNAs and a risk model were identified and developed by univariate Cox regression analysis and the LASSO regression analysis as well as stepAIC method. Genomic landscape was treated by mutect2 and fisher. Immune characteristics was analyzed by ESTIMATE, MCP-counter. TIDE analysis was conducted to predict immunotherapy. The clinical treatment outcomes of BRCA mutation patients were assessed using a nomogram. The proliferation, migration and invasion in breast cancer cell lines were examined using CCK8 assay and transwell assay.ResultWe found 241 mRNAs within the circHIPK3-based ceRNA network. An 11 mRNA-based signature was identified for prognostic model construction. High risk patients exhibited dismal prognosis, low response to immunotherapy, less immune cell infiltration and tumor mutation burden (TMB). High-risk patients were sensitive to six anti-tumor drugs, while low-risk patient were sensitive to 47 drugs. The risk score was the most effective on evaluating patients’ survival. The robustness and good prediction performance were validated in The Cancer Genome Atlas (TCGA) dataset and immunotherapy datasets, respectively. In addition, circHIPK3 mRNA level was upregulated, and promoted cell viability, migration and invasion in breast cancer cell lines.ConclusionThe current study could improve the understanding of mRNAs in relation to BRCA mutation and pave the way to develop mRNA-based therapeutic targets for breast cancer patients with BRCA mutation.

【 授权许可】

CC BY