Abstract
Long non-coding RNAs (lncRNAs) play an important role in many diseases and are involved in the post-transcriptional regulatory network of tumors. The purpose of this study is to mine new lncRNA–mRNA regulatory pairs and analyze the new mechanism of lncRNA involvement in breast cancer progression. Using breast cancer miRNA and mRNA expression profiling from The Cancer Genome Atlas (TCGA), we identified 59 differentially expressed lncRNAs, 88 differentially expressed miRNAs, and 1,465 differentially expressed mRNAs between breast cancer tissue and adjacent normal breast cancer. Whereafter, four candidate lncRNAs (FGF14-AS2, LINC01235, AC055854.1, and AC124798.1) were identified by the Kaplan–Meier (K–M) plotter. Furthermore, we screened the hub lncRNA (LINC01235) through univariate Cox analysis, multivariate Cox analysis, and qPCR validation, which was significantly correlated with breast cancer stage, ER status, and pathological N. Subsequently, 107 LINC01235-related mRNAs were obtained by combining differentially expressed miRNAs, differentially expressed mRNAs, and LINC01235 targeting miRNAs and mRNAs. The protein–protein interaction (PPI) network was established by Cytoscape software, and 53 key genes were screened. Function and pathway enrichment showed that LINC01235-related key genes might be involved in the process of cell differentiation, cell proliferation, and p53 signal pathway. In addition, LINC01235 has been confirmed to regulate the proliferation, migration, and invasion of MCF-7 cells in in vitro experiments. Furthermore, we screened three mRNAs (ESR1, ADRA2A, and DTL) associated with breast cancer drug resistance from key genes. Through RNA interference experiments in vitro and correlation analysis, we found that there was a negative feedback mechanism between LINC01235 and ESR1/ADRA2A. In conclusion, our results suggest that LINC01235-ESR1 and LINC01235-ADRA2A could serve as important co-expression pairs in the progression of breast cancer, and LINC01235 plays a key role as an independent prognostic factor in patients with breast cancer. The findings of this work greatly increase our understanding of the molecular regulatory mechanisms of lncRNA in breast cancer.
Highlights
MATERIALS AND METHODSLong non-coding RNAs are a class of RNA molecules that are over 200 nucleotides in length, which have no proteincoding function but have epigenetic regulation and other biological functions (Peng et al, 2017)
In order to study the potential role of RNAs in the development of breast cancer, we identified the differentially expressed RNAs using the limma package in R
The prognosis of breast cancer according to the expression of differentially expressed Long non-coding RNAs (lncRNAs) was performed based on the dates obtained from the The Cancer Genome Atlas (TCGA) database by GEPIA database
Summary
MATERIALS AND METHODSLong non-coding RNAs (lncRNAs) are a class of RNA molecules that are over 200 nucleotides in length, which have no proteincoding function but have epigenetic regulation and other biological functions (Peng et al, 2017). In breast cancer (BRCA), high levels of BCRT1, SPRY4-IT1, RP11-19E11, and FAM83H-AS1 were associated with clinical stage and prognosis (Giro-Perafita et al, 2020; Han et al, 2020; Liang et al, 2020; Song et al, 2020) These studies indicated that lncRNAs could be regarded as valuable biomarkers and therapeutic targets for cancer therapy. The high expression of LINC01235 was associated with poor prognosis of breast cancer patients (Li et al, 2021; Zhang K. et al, 2021). These results are consistent with the data we analyzed. There is no relevant experimental data to explain this problem
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