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. 2022 Jun 4;14(11):2788.
doi: 10.3390/cancers14112788.

LncRNA ZNF582-AS1 Expression and Methylation in Breast Cancer and Its Biological and Clinical Implications

Junlong Wang  1   2 , Dionyssios Katsaros  3 , Nicoletta Biglia  4 , Yuanyuan Fu  1   2 , Chiara Benedetto  3 , Lenora Loo  1 , Zhanwei Wang  1 , Herbert Yu  1
Affiliations

LncRNA ZNF582-AS1 Expression and Methylation in Breast Cancer and Its Biological and Clinical Implications

Junlong Wang et al. Cancers (Basel). .

Abstract

Background: Long non-coding RNAs (lncRNAs) play an important role in cellular activities and functions, but our understanding of their involvement in cancer is limited. Methods: TCGA data on RNA expression and DNA methylation were analyzed for lncRNAs' association with breast cancer survival, using the Cox proportional hazard regression model. Fresh tumor samples and clinical information from 361 breast cancer patients in our study were used to confirm the TCGA finding on ZNF582-AS1. A RT-qPCR method was developed to measure ZNF582-AS1 expression. Survival associations with ZNF582-AS1 were verified with a meta-analysis. In silico predictions of molecular targets and cellular functions of ZNF582-AS1 were performed based on its molecular signatures and nucleotide sequences. Results:ZNF582-AS1 expression was lower in breast tumors than adjacent normal tissues. Low ZNF582-AS1 was associated with high-grade or ER-negative tumors. Patients with high ZNF582-AS1 had a lower risk of relapse and death. These survival associations were confirmed in a meta-analysis and remained significant after adjustment for tumor grade, disease stage, patient age, and hormone receptor status. Correlation analysis indicated the possible suppression of ZNF582-AS1 expression by promoter methylation. Bioinformatics interrogation of molecular signatures suggested that ZNF582-AS1 could suppress tumor cell proliferation via downregulating the HER2-mediated signaling pathway. Analysis of online data also suggested that HIF-1-related transcription factors could suppress ZNF582-AS1 expression, and the lncRNA might bind to hsa-miR-940, a known oncogenic miRNA in breast cancer. Conclusions: ZNF582-AS1 may play a role in suppressing breast cancer progression. Elucidating the lncRNA's function and regulation may improve our understanding of the disease.

Keywords: ZNF582-AS1; breast cancer; lncRNA; methylation; prognosis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Comparison of ZNF582-AS1 expression between breast cancer and adjacent normal tissues. (A) ZNF582-AS1 expression in breast cancer (n = 837) and adjacent breast tissues (n = 105). (B) ZNF582-AS1 expression in matched breast cancer (n = 105) and adjacent breast tissues (n = 105).
Figure 2
Figure 2
Kaplan–Meier survival curves by ZNF582-AS1 expression in tertile. (A) Overall survival (OS) curves by high, mid, and low expression of ZNF582-AS1. (B) Disease-free survival (DFS) curves by high, mid, and low expression of ZNF582-AS1.
Figure 2
Figure 2
Kaplan–Meier survival curves by ZNF582-AS1 expression in tertile. (A) Overall survival (OS) curves by high, mid, and low expression of ZNF582-AS1. (B) Disease-free survival (DFS) curves by high, mid, and low expression of ZNF582-AS1.
Figure 3
Figure 3
Meta-analysis of associations between ZNF582-AS1 expression and breast cancer survival. (A) ZNF582-AS1 expression (high vs. low) in association with overall survival (OS). (B) ZNF582-AS1 expression (high vs. low) in association with disease-free survival (DFS).
Figure 4
Figure 4
Ingenuity Pathway Analysis (IPA) prediction of the molecular and cellular functions of ZNF582-AS1 based on its expression and methylation signatures. (A) IPA prediction of the molecular and cellular functions related to the ZNF582-AS1 expression signature. (B) IPA prediction of the molecular and cellular functions related to the ZNF582-AS1 promoter methylation signature. (C) IPA prediction of the signal network related to the ZNF582-AS1 expression signature. (D) IPA prediction of the signal network related to the ZNF582-AS1 promoter methylation signature.
Figure 4
Figure 4
Ingenuity Pathway Analysis (IPA) prediction of the molecular and cellular functions of ZNF582-AS1 based on its expression and methylation signatures. (A) IPA prediction of the molecular and cellular functions related to the ZNF582-AS1 expression signature. (B) IPA prediction of the molecular and cellular functions related to the ZNF582-AS1 promoter methylation signature. (C) IPA prediction of the signal network related to the ZNF582-AS1 expression signature. (D) IPA prediction of the signal network related to the ZNF582-AS1 promoter methylation signature.
Figure 5
Figure 5
Analysis of hsa-miR-940 expression in breast cancer and adjacent normal breast tissues (n = 105), as well as its expression in association with overall survival in TCGA. (A) Comparison of hsa-miR-940 expression between breast cancer and match adjacent normal tissues (n = 105). (B) Kaplan–Meier overall survival (OS) curves by high, mid, and low expression of hsa-miR-940.
Figure 5
Figure 5
Analysis of hsa-miR-940 expression in breast cancer and adjacent normal breast tissues (n = 105), as well as its expression in association with overall survival in TCGA. (A) Comparison of hsa-miR-940 expression between breast cancer and match adjacent normal tissues (n = 105). (B) Kaplan–Meier overall survival (OS) curves by high, mid, and low expression of hsa-miR-940.
Figure 6
Figure 6
RNA network among lncRNA ZNF582-AS1, miRNA has-miR-940, and mRNA PTEN.
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