A Novel Strategy for Identifying NSCLC MicroRNA Biomarkers and Their Mechanism Analysis Based on a Brand-New CeRNA-Hub-FFL Network

Abstract

Finding reliable miRNA markers and revealing their potential mechanisms will play an important role in the diagnosis and treatment of NSCLC. Most existing computational methods for identifying miRNA biomarkers only consider the expression variation of miRNAs or rely heavily on training sets. These deficiencies lead to high false-positive rates. The independent regulatory model is an important complement to traditional models of co-regulation and is more impervious to the dataset. In addition, previous studies of miRNA mechanisms in the development of non-small cell lung cancer (NSCLC) have mostly focused on the post-transcriptional level and did not distinguish between NSCLC subtypes. For the above problems, we improved mainly in two areas: miRNA identification based on both the NOG network and biological functions of miRNA target genes; and the construction of a 4-node directed competitive regulatory network to illustrate the mechanisms. NSCLC was classified as lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) in this work. One miRNA biomarker of LUAD (miR-708-5p) and four of LUSC (miR-183-5p, miR-140-5p, miR-766-5p, and miR-766-3p) were obtained. They were validated using literature and external datasets. The ceRNA-hub-FFL involving transcription factors (TFs), microRNAs (miRNAs), mRNAs, and long non-coding RNAs (lncRNAs) was constructed. There were multiple interactions among these components within the net at the transcriptional, post-transcriptional, and protein levels. New regulations were revealed by the network. Meanwhile, the network revealed the reasons for the previous conflicting conclusions on the roles of CD44, ACTB, and ITGB1 in NSCLC, and demonstrated the necessity of typing studies on NSCLC. The novel miRNA markers screening method and the 4-node directed competitive ceRNA-hub-FFL network constructed in this work can provide new ideas for screening tumor markers and understanding tumor development mechanisms in depth.