Good or not good: Role of miR-18a in cancer biology

Abstract

miR-18a is a member of primary transcript called miR-17-92a (C13orf25 or MIR17HG) which also contains five other miRNAs: miR-17, miR-19a, miR-20a, miR-19b and miR-92a. This cluster as a whole shows specific characteristics, where miR-18a seems to be unique. In contrast to the other members, the expression of miR-18a is additionally controlled and probably functions as its own internal controller of the cluster. miR-18a regulates many genes involved in proliferation, cell cycle, apoptosis, response to different kinds of stress, autophagy and differentiation. The disturbances of miR-18a expression are observed in cancer as well as in different diseases or pathological states. The miR-17-92a cluster is commonly described as oncogenic and it is known as 'oncomiR-1', but this statement is a simplification because miR-18a can act both as an oncogene and a suppressor. In this review we summarize the current knowledge about miR-18a focusing on its regulation, role in cancer biology and utility as a potential biomarker.

Keywords: 5-FU, 5-fluorouracyl; ACVR2A, activin A receptor type 2A; AKT, AKT serine/threonine kinase; AR, androgen receptor; ATG7, autophagy related 7; ATM, ATM serine/threonine kinase; BAX, BCL2 associated Xapoptosis regulator; BCL2, BCL2 apoptosis regulator; BCL2L10, BCL2 like 10; BDNF, brain derived neurotrophic factor; BLCA, bladder urothelial carcinoma; BRCA, breast cancer; Biomarker; Bp, base pair; C-myc (MYCBP), MYC binding protein; CASC2, cancer susceptibility 2; CD133 (PROM1), prominin 1; CDC42, cell division cycle 42; CDKN1, Bcyclin dependent kinase inhibitor 1B; COAD, colon adenocarcinoma; Cancer; Circulating miRNA; DDR, DNA damage repair; E2F family (E2F1, E2F2, E2F3), E2F transcription factors; EBV, Epstein-Barr virus; EMT, epithelial-to-mesenchymal transition; ER, estrogen receptor; ERBB (EGFR), epidermal growth factor receptor; ESCA, esophageal carcinoma; FENDRR, FOXF1 adjacent non-coding developmental regulatory RNA; FER1L4, fer-1 like family member 4 (pseudogene); GAS5, growth arrest–specific 5; HIF-1α (HIF1A), hypoxia inducible factor 1 subunit alpha; HNRNPA1, heterogeneous nuclear ribonucleoprotein A1; HNSC, head and neck squamous cell carcinoma; HRR, homologous recombination-based DNA repair; IFN-γ (IFNG), interferon gamma; IGF1, insulin like growth factor 1; IL6, interleukin 6; IPMK, inositol phosphate multikinase; KIRC, clear cell kidney carcinoma; KIRP, kidney renal papillary cell carcinoma; KRAS, KRAS proto-oncogene, GTPase; LIHC, liver hepatocellular carcinoma; LMP1, latent membrane protein 1; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; Liquid biopsy; MAPK, mitogen-activated protein kinase; MCM7, minichromosome maintenance complex component 7; MET, mesenchymal-to-epithelial transition; MTOR, mechanistic target of rapamycin kinase; N-myc (MYCN), MYCN proto-oncogene, bHLH transcription factor; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NOTCH2, notch receptor 2; Oncogene; PAAD, pancreatic adenocarcinoma; PERK (EIF2AK3), eukaryotic translation initiation factor 2 alpha kinase 3; PI3K (PIK3CA), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PIAS3, protein inhibitor of activated STAT 3; PRAD, prostate adenocarcinoma; RISC, RNA-induced silencing complex; SMAD2, SMAD family member 2; SMG1, SMG1 nonsense mediated mRNA decay associated PI3K related kinase; SNHG1, small nucleolar RNA host gene 1; SOCS5, suppressor of cytokine signaling 5; STAD, stomach adenocarcinoma; STAT3, signal transducer and activator of transcription 3; STK4, serine/threonine kinase 4; Suppressor; TCGA; TCGA, The Cancer Genome Atlas; TGF-β (TGFB1), transforming growth factor beta 1; TGFBR2, transforming growth factor beta receptor 2; THCA, papillary thyroid carcinoma; TNM, Classification of Malignant Tumors: T - tumor / N - lymph nodes / M – metastasis; TP53, tumor protein p53; TP53TG1, TP53 target 1; TRIAP1, p53-regulating inhibitor of apoptosis gene; TSC1, TSC complex subunit 1; UCA1, urothelial cancer associated 1; UCEC, uterine corpus endometrial carcinoma; UTR, untranslated region; WDFY3-AS2, WDFY3 antisense RNA 2; WEE1, WEE1 G2 checkpoint kinase; WNT family, Wingless-type MMTV integration site family/Wnt family ligands; ZEB1/ZEB2, zinc finger E-box binding homeobox 1 and 2; ceRNA, competitive endogenous RNA; cncRNA, protein coding and non-coding RNA; lncRNA, long-non coding RNA; miR-17-92a; miR-18a; miRNA.

Fig. 1

(A) The localization of the members within the miR-17-92a cluster and paralogs miR-106a-363 and miR-106b-25. (B) The sequence similarities and differences among 15 miRNAs that share four “seed” regions: the miR-17, miR-18, miR-19, and miR-92 families; framed nucleotides indicate the “seed” regions.

Fig. 2

Expression of miR-18a-5p in different types of human cancer according to TCGA database. StarBase v3.0 data - modified; COAD (colon adenocarcinoma), UCEC (uterine corpus endometrial carcinoma), BLCA (bladder urothelial carcinoma), HNSC (head and neck squamous cell carcinoma), LUAD (lung adenocarcinoma), STAD (stomach adenocarcinoma), KIRC (clear cell kidney carcinoma), PRAD (prostate adenocarcinoma), BRCA (breast cancer), ESCA (esophageal carcinoma), LUSC (lung squamous cell carcinoma), LIHC (liver hepatocellular carcinoma), KIRP (kidney renal papillary cell carcinoma), PAAD (pancreatic adenocarcinoma), THCA (papillary thyroid carcinoma).

Fig. 3

Predicted miR-18a-5p targets according to miRDB database. (A) Participation of miR-18a-5p targets in specific biological processes. (B) Similarity of cancers in terms of miR-18a-5p targets expression and heat-map and clustering of the top 50 miR-18a-5p targets in 15 different types of cancers. Based on miRDB, PANTHER and StarBase v3.0 databases.

Fig. 4

Overall survival depending on miR-18a-5p expression level in different types of human cancer according to TCGA database. StarBase v3.0 data - modified; COAD (colon adenocarcinoma), UCEC (uterine corpus endometrial carcinoma), BLCA (bladder urothelial carcinoma), HNSC (head and neck squamous cell carcinoma), LUAD (lung adenocarcinoma), STAD (stomach adenocarcinoma), KIRC (clear cell kidney carcinoma), PRAD (prostate adenocarcinoma), BRCA (breast cancer), ESCA (esophageal carcinoma), LUSC (lung squamous cell carcinoma), LIHC (liver hepatocellular carcinoma), KIRP (kidney renal papillary cell carcinoma), PAAD (pancreatic adenocarcinoma), THCA (papillary thyroid carcinoma).