Clear Cell Renal Carcinoma: MicroRNAs With Efficacy in Preclinical In Vivo Models

Abstract

In order to identify new targets and treatment modalities for clear cell renal carcinoma, we surveyed the literature with respect to microRNAs involved in this disease. In this review, we have focused on up- and down-regulated miRs which mediate efficacy in preclinical clear-cell renal carcinoma-related in vivo models. We have identified 10 up-regulated and 33 down-regulated micro-RNAs according to this criterion. As proof-of-concept, micro-RNAs interfering with VEGF (miR-205p) and mTOR (mir-99a) pathways, which are modulated by approved drugs for this disease, have been identified. miRs targeting hypoxia induced factor-2α (HIF-2α) (miR-145), E3 ubiquitinylases speckle-type POZ protein (SPOP) (miR 520/372/373) and casitas B-lineage lymphoma (CBL) (miR-200a-3p), interfere with druggable targets. Further identified miRs interfere with cell-cycle dependent kinases, such as CDK2 (miR-200c), CDK4, 6 (miR-1) and CDK4, 9 (206c). Transmembrane receptor Ral interacting protein of 76 kD (RLIP76), targeted by mir-137, has emerged as another important target for ccRCC. Additional miRs and their targets merrying further preclinical validation are discussed.

Keywords: HIF-2α; SPOP; VEGF pathway; VHL; hypoxia-inducible factor 2α; mTOR; mechanistic target of rapamycin; microRNA-based therapy; review; speckle-type POZ protein; target identification; von Hippel Lindau tumor suppressor.

Figure 1. Up-regulated microRNAs mediating efficacy in kidney-cancer related in vivo models. miRs, targets and corresponding effectors are shown. (A) miRs with transmembrane receptors and signaling-related proteins as targets. (B) miRs covering transcription-related targets, enzymes and other targets. CADM2: Cell adhesion molecule 2; DKK2: dickkopf-related protein 2; E-Cad: E-cadherin; LZTFL1: leucine zipper transcription factor like 1; mTOR: mechanistic target of rapamycin; PTEN: phosphatase and tensin homolog; PTENP1: pseudogene 1 of PTEN; SFRP1: secreted frizzled-related protein 1; WNT: WNT signaling; AKT: ser-thr kinase AKT; ARID-1A: AT-rich interactive domain-containing protein 1A; DICER: endoribonuclease DICER; FOXO3: forkhead box O3; PI3K: phosphoinosite 3-kinase; ST3Gal IV: α 2,3 sialyltransferase IV; SWI/SNF: SWI/sucrose non fermentable.

Figure 2. Down-regulated miRs targeting transmembrane receptors with efficacy in preclinical kidney cancer-related in vivo systems. AKT: Ser-thr kinase AKT; EPHA2: erythropoietin-producing human hepatocellular receptor A2; ERK: extracellular signal-regulated kinase; FAK: focal adhesion kinase; FLOT-1: flotilin 1; FOXO3: forkhead box 3; IGF1R: insulin growth factor 1 receptor; PI3K: phosphoinositide 3-kinase; MAPK: mitogenactivated protein kinase; RLIP76: Ral interaction protein of 76D.

Figure 3. Down-regulated miRs targeting signaling-related proteins with efficacy in preclinical kidney cancer-related in vivo systems. 4E-BP1: Eukaryotic translation initiation factor (eIF4E) binding protein 1; AKT2: ser-thr kinase AKT2; ERK: extracellular signal regulated kinase; GLUT1: glucose transporter 1; KRAS: Kirsten rat sarcoma viral oncogene homolog; MAPK: mitogen-activated protein kinase; mTOR: mechanistic target of rapamycin; NFĸB: nuclear factor ĸB; p38: p38 mitogen-activated kinase; p53: protein 53; p70S6K: p70 ribosomal protein S6 kinase; PAK5: p21 activated protein kinase 5; RAP-1B: ras-related protein 1B; AKT: ser-thr kinase AKT; CCND1: cyclin D1; HGF: hepatocyte growth factor; HIF-2α: hypoxia-inducible factor 2α; MET: transmembrane tyrosine kinase receptor MET; p19ARF: ARF tumor suppressor p19; PI3K: phosphoinositide 3-kinase; SNAI-1: zinc finger protein SNAI-1; TR4: testicular nuclear receptor 4; VEGF: vascular endothelial growth factor; ZBTB7A: zinc finger and BTB domain containing protein 7.

Figure 4. Down-regulated miRs targeting cell-cycle, extracellular matrix and ubiquitinylation related enzymes with efficacy in preclinical kidney cancer-related in vivo systems. (A) miRs targeting cell-cycle related proteins. (B) miRs targeting extracellular matrix and ubiquitinylation-related proteins. CDK2,4,6,9: Cyclin-dependent kinases 2,4,6,9; CCND1: cyclin D1; SLUG: transcription factor SLUG (SNAI-2); EMT: epithelial mesenchymal transition; RNA pol II: RNA polymerase II; CBL: Casitas B-lineage lymphoma; CCC7: chemokine (C-C motif) ligand 7; COL3A1: α1 chain of type III collagen, DAXX6: death-associated protein 6; DUSP7: dual specificity phosphatase 7; EGFR: epidermal growth factor receptor 7; ERK: extracellular signal-regulated kinase; FAK: focal adhesion kinase; ILK: integrin-linked kinase; LAMA4: laminin subunit 4; MAPK: mitogenactivated protein kinase; MET: transmembrane receptor tyrosine kinase MET; PDGFR: platelet-derived growth factor receptor; PTEN: phosphatase and tensin homolog; SPOP: speckle-type POZ protein.

Figure 5. Down-regulated miRs targeting apoptosis-related and other proteins with efficacy in preclinical kidney cancer-related in vivo systems. (A) Apoptosis-related targets. (B) Other exploratory targets. BID: BH3 interacting domain death agonist; CAPN4: calpain small regulatory subunit; FAK: focal adhesion kinase; FLIP: caspase FLICE-like inhibitory protein; LC3B: autophagy protein LC3B; MMP2: matrix metallo-proteinase 2; MYC: transcription factor MYC; NFĸB; nuclear factor ĸB; VEGFR2; vascular endothelial growth factor receptor 2; EMT: epithelial mesenchymal transition; ERK: extracellularly-regulated kinase; JNK: c-jun N-terminal kinase; KIF1C: kinesin family member 1; NOB1: nin one binding protein; p38: p38 mitogen-activated protein kinase; VIM: vimentin.