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. 2022 Jul 4:12:904865.
doi: 10.3389/fonc.2022.904865. eCollection 2022.

Multi-Omics Integration-Based Prioritisation of Competing Endogenous RNA Regulation Networks in Small Cell Lung Cancer: Molecular Characteristics and Drug Candidates

Xiao-Jun Wang  1   2 , Jing Gao  1   2   3   4 , Qin Yu  2 , Min Zhang  5 , Wei-Dong Hu  1
Affiliations

Multi-Omics Integration-Based Prioritisation of Competing Endogenous RNA Regulation Networks in Small Cell Lung Cancer: Molecular Characteristics and Drug Candidates

Xiao-Jun Wang et al. Front Oncol. .

Abstract

Background: The competing endogenous RNA (ceRNA) network-mediated regulatory mechanisms in small cell lung cancer (SCLC) remain largely unknown. This study aimed to integrate multi-omics profiles, including the transcriptome, regulome, genome and pharmacogenome profiles, to elucidate prioritised ceRNA characteristics, pathways and drug candidates in SCLC.

Method: We determined the plasma messenger RNA (mRNA), microRNA (miRNA), long noncoding RNA (lncRNA) and circular RNA (circRNA) expression levels using whole-transcriptome sequencing technology in our SCLC plasma cohort. Significantly expressed plasma mRNAs were then overlapped with the Gene Expression Omnibus (GEO) tissue mRNA data (GSE 40275, SCLC tissue cohort). Next, we applied a multistep multi-omics (transcriptome, regulome, genome and pharmacogenome) integration analysis to first construct the network and then to identify the lncRNA/circRNA-miRNA-mRNA ceRNA characteristics, genomic alterations, pathways and drug candidates in SCLC.

Results: The multi-omics integration-based prioritisation of SCLC ceRNA regulatory networks consisted of downregulated mRNAs (CSF3R/GAA), lncRNAs (AC005005.4-201/DLX6-AS1-201/NEAT1-203) and circRNAs (hsa_HLA-B_1/hsa_VEGFC_8) as well as upregulated miRNAs (hsa-miR-4525/hsa-miR-6747-3p). lncRNAs (lncRNA-AC005005.4-201 and NEAT1-203) and circRNAs (circRNA-hsa_HLA-B_1 and hsa_VEGFC_8) may regulate the inhibited effects of hsa-miR-6747-3p for CSF3R expression in SCLC, while lncRNA-DLX6-AS1-201 or circRNA-hsa_HLA-B_1 may neutralise the negative regulation of hsa-miR-4525 for GAA in SCLC. CSF3R and GAA were present in the genomic alteration, and further identified as targets of FavId and Trastuzumab deruxtecan, respectively. In the SCLC-associated pathway analysis, CSF3R was involved in the autophagy pathways, while GAA was involved in the glucose metabolism pathways.

Conclusions: We identified potential lncRNA/cirRNA-miRNA-mRNA ceRNA regulatory mechanisms, pathways and promising drug candidates in SCLC, providing novel potential diagnostics and therapeutic targets in SCLC.

Keywords: circular RNA (circRNA); competing endogenous RNA (ceRNA); long noncoding RNA (lncRNA); microRNA (miRNA); multi-omics integration; small cell lung cancer (SCLC).

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Illustration of multi-omics–based prioritisation of ceRNAs and pathways. CLCGP, Clinical Lung Cancer Genome Project; CIRI, circRNA identifier; ceRNA, competitive endogenous RNA; circRNA, circular RNAs; DE, differentially expressed; SCLC, small cell lung cancer; lncRNA, long noncoding RNA; miRNA, microRNA; mRNA, messenger RNA; cBioPortal database (https://www.cbioportal.org/datasets); DrugBank database (https://go.drugbank.com/); Genecards database (https://www.genecards.org/); PubMed (https://pubmed.ncbi.nlm.nih.gov/).
Figure 2
Figure 2
Identification of differentially expressed mRNAs, miRNAs, lncRNAs and circRNAs in SCLC. (A) Common differentially expressed mRNAs (Co-DEmRNAs) in the in-house SCLC plasma cohort and the SCLC lung tissue cohort (GSE40275). (B) Up- and downregulated mRNAs in our cohort. (C) Up- and downregulated miRNAs in our cohort. (D) Up- and downregulated lncRNAs in our cohort. (E) Up- and downregulated circRNAs in our cohort. Red indicates upregulated and green indicates downregulated; circRNA, circular RNAs; lncRNA, long noncoding RNA; miRNA, microRNA; mRNA, messenger RNA; SCLC, small cell lung cancer.
Figure 3
Figure 3
The lncRNA-miRNA-mRNA ceRNAs network in SCLC. lncRNA, long noncoding RNA; miRNA, microRNA; mRNA, messenger RNA; SCLC, small cell lung cancer.
Figure 4
Figure 4
The circRNA-miRNA-mRNA ceRNAs network in SCLC. circRNA, circular RNA; miRNA, microRNA; mRNA, messenger RNA; SCLC, small cell lung cancer.
Figure 5
Figure 5
Illustration of multi-omics–based prioritisation of the ceRNA subnetwork, drug candidates and pathways. ATP, adenosine triphosphatase; AMPK, AMP-activated protein kinase; BCAAs, branched-chain amino acids; CoA, coenzyme A; ceRNA, competitive endogenous; RNA; circRNA, circular RNA; CSF3R, colony-stimulating factor 3 receptor; GAA, acid alpha-glucosidase; lncRNA, long noncoding RNA; miRNA, microRNA; mRNA, messenger RNA; SCLC, small cell lung cancer; TCA, tricarboxylic acid.
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