Abstract
Long noncoding RNA (lncRNA)/microRNA(miRNA)/mRNA triplets contribute to cancer biology. However, identifying significative triplets remains a major challenge for cancer research. The dynamic changes among factors of the triplets have been less understood. Here, by integrating target information and expression datasets, we proposed a novel computational framework to identify the triplets termed as “lncRNA-perturbated triplets”. We applied the framework to five cancer datasets in The Cancer Genome Atlas (TCGA) project and identified 109 triplets. We showed that the paired miRNAs and mRNAs were widely perturbated by lncRNAs in different cancer types. LncRNA perturbators and lncRNA-perturbated mRNAs showed significantly higher evolutionary conservation than other lncRNAs and mRNAs. Importantly, the lncRNA-perturbated triplets exhibited high cancer specificity. The pan-cancer perturbator OIP5-AS1 had higher expression level than that of the cancer-specific perturbators. These lncRNA perturbators were significantly enriched in known cancer-related pathways. Furthermore, among the 25 lncRNA in the 109 triplets, lncRNA SNHG7 was identified as a stable potential biomarker in lung adenocarcinoma (LUAD) by combining the TCGA dataset and two independent GEO datasets. Results from cell transfection also indicated that overexpression of lncRNA SNHG7 and TUG1 enhanced the expression of the corresponding mRNA PNMA2 and CDC7 in LUAD. Our study provides a systematic dissection of lncRNA-perturbated triplets and facilitates our understanding of the molecular roles of lncRNAs in cancers.
Highlights
Transcriptomic studies have shown that the human genome contains an abundance of non-coding RNAs that are often multiexonic and polyadenylated but lack obvious protein-coding capacity [1,2]
By integrating miRNA-target information and matched expression profiles, we investigated the landscape of Long noncoding RNA (lncRNA)-perturbated triplets across five cancer types
The process mainly involved the following three steps (Figure 1): (i) Since low tumor purity may influence the results of genomic analysis [20], we first filtered 1,370 high tumor purity patient samples from the five cancer types and collected their matched expression profiles. (ii) We collected Ago CLIP-supported miRNA-target interactions and filtered significant triplets for further analysis by hypergeometric test. (iii) LncRNA-perturbated triplets were identified through the dynamic change among lncRNA, miRNA and mRNA
Summary
Transcriptomic studies have shown that the human genome contains an abundance of non-coding RNAs that are often multiexonic and polyadenylated but lack obvious protein-coding capacity [1,2]. HOTAIR is known as an oncogenic lncRNA in various cancer types [10] which affects cancer progress via forming HOTAIR/miRNA/mRNA axes It was identified as an lncRNA-directed biomarker in gastric cancer that regulates HER2 by sponging miR-331-3p [11]. Song et al [14] identified novel functional lncRNAs associated with progression and prognosis of cholangiocarcinoma; Fan et al [15] developed an lncRNA/miRNA/mRNA network to further understand the lncRNA working mechanism and pathogenesis in colorectal cancer. These studies contributed to the understanding of the roles of lncRNA/miRNA/mRNA axes in cancer but still need to be improved. Taking LUAD as an example, we proved the overexpression of the identified lncRNA perturbators enhanced the expression of their corresponding mRNAs
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