Abstract
The proposed competing endogenous RNA (ceRNA) mechanism suggested that diverse RNA species, including protein-coding messenger RNAs and non-coding RNAs such as long non-coding RNAs, pseudogenes and circular RNAs could communicate with each other by competing for binding to shared microRNAs. The ceRNA network (ceRNET) is involved in tumor progression and has become a hot research topic in recent years. To date, more attention has been paid to the role of non-coding RNAs in ceRNA crosstalk. However, coding transcripts are more abundant and powerful than non-coding RNAs and make up the majority of miRNA targets. In this study, we constructed a mRNA-mRNA related ceRNET of lung adenocarcinoma (LUAD) and identified the highlighted TWIST1-centered ceRNET, which recruits SLC12A5 and ZFHX4 as its ceRNAs. We found that TWIST1/SLC12A5/ZFHX4 are all upregulated in LUAD and are associated with poorer prognosis. SLC12A5 and ZFHX4 facilitated proliferation, migration, and invasion in vivo and in vitro, and their effects were reversed by miR-194–3p and miR-514a-3p, respectively. We further verified that SLC12A5 and ZFHX4 affected the function of TWIST1 by acting as ceRNAs. In summary, we constructed a mRNA-mRNA related ceRNET for LUAD and highlighted the well-known oncogene TWIST1. Then we verified that SLC12A5 and ZFHX4 exert their oncogenic function by regulating TWIST1 expression through a ceRNA mechanism.
Highlights
With approximately 2.1 million new cases diagnosed every year, lung cancer is the most common cause of cancer deaths worldwide and lung adenocarcinoma (LUAD) accounts for almost 40% of lung cancer deaths[1]
In this study, we investigated whether SLC12A5 and ZFHX4 could exert their oncogenic function by regulating TWIST1 expression through a competing endogenous RNA (ceRNA) mechanism in LUAD
Construction of ceRNA networks in LUAD A central tenet of our hypothesis is that trans-regulatory ceRNA crosstalk increased with the high miRNA regulatory similarity between mRNAs and their strong co-expression relationships
Summary
With approximately 2.1 million new cases diagnosed every year, lung cancer is the most common cause of cancer deaths worldwide and lung adenocarcinoma (LUAD) accounts for almost 40% of lung cancer deaths[1]. A novel regulatory mechanism of RNA transcripts, known as competing endogenous RNA (ceRNA), was proposed by Pandolfi in 20112. This proposed mechanism suggested that microRNAs (miRNAs), approximately 22 nucleotides in length, bind to miRNA response elements (MREs) in target mRNA molecules, resulting in decreased stability of the target mRNAs and repressed expression of the target RNA transcripts, such as mRNAs, long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), pseudogenes like BRAF and HMGA1, which may modulate each other’s expression by competing for common miRNAs3–8.
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