MicroRNAs and Corresponding Targets in Esophageal Cancer as Shown In Vitro and In Vivo in Preclinical Models

Abstract

Squamous cell carcinoma of the esophagus is associated with a dismal prognosis. Therefore, identification of new targets and implementation of new treatment modalities are issues of paramount importance. Based on a survey of the literature, we identified microRNAs conferring antitumoral activity in preclinical in vivo experiments. In the category of miRs targeting secreted factors and transmembrane receptors, four miRs were up-regulated and 10 were down-regulated compared with five out of nine in the category transcription factors, and six miRs were down-regulated in the category enzymes, including metabolic enzymes. The down-regulated miRs have targets which can be inhibited by small molecules or antibody-related entities, or re-expressed by reconstitution therapy. Up-regulated miRs have targets which can be reconstituted with small molecules or inhibited with antagomirs.

Keywords: miR-based target identification; miR-related treatment modalities; preclinical in vivo models; review; squamous cell esophageal cancer.

Figure 1. Up-regulated (A) and down-regulated (B) miRs targeting secreted factors and transmembrane receptors in esophageal cancer cells in preclinical in vivo systems. ADAMTS1: A disintegin and metalloprotease with thrombospondin motifs 1; CD44, 47, 133: cluster of differentiation 44, 47, 133; EGFR: epidermal growth factor receptor; EI24: etoposide-induced 2.4 transcript; HER2: human epidermal growth factor receptor 2; IGF1R: insulin growth factor-like receptor 1; INTα6: integrin α6; INTβ6: integrin β6; INV: invasion; MET: metastasis; PROL: proliferation; RAGE: receptor for advanced glycation end-products; SARA: SMAD anchor for receptor activation; TG: tumor growth; TGFβR2: transforming growth factor receptor 2; TNFα: tumor necrosis factor α; VEGFA: vascular endothelial growth factor A.

Figure 2. Up-regulated (A) and down-regulated (B) miRs targeting transcription factors in esophageal cancer cells in preclinical in vivo systems. AKT: Serine-threonine kinase AKT; ARID3A: AT-rich interactive domain-containing protein 3A; CXX5: CCX-type zinc finger protein 5; DDP res: cisplatin resistance; EMT: epithelial–mesenchymal transition; FOXK2: forkhead box protein K2; FOXO31: forkhead-box protein 31; FOXM1: forkhead box protein M1; GSK3β: glycogen synthase kinase 3β; INV: invasion; KLF4: Krüppel-like factor 4; MAPK: mitogen-activated protein kinase; MET: metastasis; MYC: transcription factor MYC; mTOR: mechanistic target of rapamycin; p38: mitogen-activated protein kinase p38; PITX2: paired-like homeodomain transcription factor 2; PPARγ: peroxisome proliferator-activated receptor γ; PROL: proliferation; SMAD4: signaling protein SMAD4; SNAI2: snail family transcriptional repressor 2; SOX4: sex determining region Y-box 4; STAT3: signal transducer and activator of transcription 3; TG: tumor growth; ZEB1: zinc finger E-box binding homeobox 2.

Figure 3. Down-regulated miRs targeting enzymes in esophageal cancer cells mediating efficacy in preclinical in vivo systems DNA polβ: DNA polymerase β; LDHB: lactate dehydrogenase B; MET: metastasis; MTDH1: metadherin 1; OGT: O-linked-N-acetylglucosaminacetylation transferase; PROL: proliferation; PSAT1: phosphoserine aminotransferase 1; INV: invasion; TG: tumor growth; TIGAR: p53-inducible glycolysis and apoptosis regulator; USP26: ubiquitin-specific protease 26.