Long Non-Coding RNAs in Pancreatic Cancer: Biologic Functions, Mechanisms, and Clinical Significance

Abstract

Despite tremendous efforts devoted to research in pancreatic cancer (PC), the mechanism underlying the tumorigenesis and progression of PC is still not completely clear. Additionally, ideal biomarkers and satisfactory therapeutic strategies for clinical application in PC are still lacking. Accumulating evidence suggests that long non-coding RNAs (lncRNAs) might participate in the pathogenesis of diverse cancers, including PC. The abnormal expression of lncRNAs in PC is considered a vital factor during tumorigenesis that affects tumor cell proliferation, migration, invasion, apoptosis, angiogenesis, and drug resistance. With this review of relevant articles published in recent years, we aimed to summarize the biogenesis mechanism, classifications, and modes of action of lncRNAs and to review the functions and mechanisms of lncRNAs in PC. Additionally, the clinical significance of lncRNAs in PC was discussed. Finally, we pointed out the questions remaining from recent studies and anticipated that further investigations would address these gaps in knowledge in this field.

Keywords: LncRNAs; biomarker; cancer diagnosis and therapy; pancreatic cancer.

Figure 1

Mechanisms underlying long noncoding RNA (lncRNA)-mediated regulation of gene expression. (1) Transcription regulation by lncRNAs. (a) LncRNAs can promote histone H3 Lys27 trimethylation (H3K27me3) of the promoter region of chromatin via the recruitment of histone complexes such as polycomb repressive complex 2 (PRC2), thereby leading to the silencing of gene transcription; (b) lncRNAs can also catalyze DNA methylation to modulate transcriptive activity; (c) lncRNAs can enhance the expression of protein coding genes (PCGs) by remodeling chromatin (for example, by forming chromatin loops). (2) LncRNAs interact with RNAs. (d) Together with alternative splicing factors, lncRNAs are engaged in the processing and maturation of mRNAs; (e) lncRNAs facilitate mRNA translation; (f) lncRNAs help to stabilize some mRNAs by binding to them; (g) lncRNAs can competitively bind to miRNAs by acting as ceRNAs, thereby blocking the inhibition of the target gene. (3) LncRNAs interact with proteins. (h) Through protein modulation (for example, phosphorylation), lncRNAs regulate protein activity; (i) lncRNAs mediate the interactions between proteins; (j) lncRNAs regulate the localization of proteins.

Figure 2

LncRNA Hox transcript antisense RNA (HOTAIR) regulates PC development in diverse pathways. LncRNA HOTAIR acts through histone modification, miRNA sponging, and protein interaction to regulate proliferation, apoptosis, migration, invasion, the cell cycle, drug resistance, and cell metabolism in PC. IGF2: insulin-like growth factor 2; DR5: death receptor 5; hexokinase-2 (HK2).

Figure 3

Overview of the role of lncRNAs with miRNAs in PC cells. By functioning as ceRNAs, lncRNAs can competitively bind to miRNAs, thereby blocking the inhibition of the target gene. PTBP1: polypyrimidine tract-binding protein 1; IRS1: insulin substrate receptor; CBX2: chromobox2; IGF1R: insulin-like growth factor 1 receptor; PTEN: phosphatase and tensin homolog deleted on chromosome ten; EGFR: epidermal growth factor receptor; FOXD1: forkhead box D1; BNIP3: Bcl-2/adenovirus E1B 19 kDa interacting protein 3; HDGF: hepatoma-derived growth factor; FOXO3: forkhead box O3; ITGA2: integrin subunit α 2; Muc6: mucin 6; STAT1: signal transducer and activator of transcription 1.