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Review
. 2021 Jul 3;1(4):245-263.
doi: 10.21873/cdp.10033. eCollection 2021 Sep-Oct.

Bladder Cancer-related microRNAs With In Vivo Efficacy in Preclinical Models

Ulrich H Weidle  1 , Fabian Birzele  2
Affiliations
Review

Bladder Cancer-related microRNAs With In Vivo Efficacy in Preclinical Models

Ulrich H Weidle et al. Cancer Diagn Progn. .

Abstract

Progressive and metastatic bladder cancer remain difficult to treat. In this review, we critique seven up-regulated and 25 down-regulated microRNAs in order to identify new therapeutic entities and corresponding targets. These microRNAs were selected with respect to their efficacy in bladder cancer-related preclinical in vivo models. MicroRNAs and related targets interfering with chemoresistance, cell-cycle, signaling, apoptosis, autophagy, transcription factor modulation, epigenetic modification and metabolism are described. In addition, we highlight microRNAs targeting transmembrane receptors and secreted factors. We discuss druggability issues for the identified targets.

Keywords: Apoptosis; bladder cancer-related targets; cell cycle; epigenetic modifiers; invasion and proliferation; migration; orthotopic and xenograft models; review; tumor growth and metastasis.

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Conflict of interest statement

FB is and UHW was an employee of Roche.

Figures

Figure 1
Figure 1. MicroRNAs up-regulated in bladder cancer with efficacy in preclinical in vivo systems. AKT: AKT serine-threonine kinase; BECN1: beclin 1; DEED: death-effector domain-containing protein; ERK: extracellular signal-regulated kinase; GSK-3β: glycogen synthase kinase-3β; mTOR: mechanistic target of rapamycin; PHLPP2: PH domain leucine rich containing protein phosphatase; PI3K: phosphatidylinositol-4,5-bisphosphate 3-kinase; PPP2R2A: protein phosphatase 2 regulatory subunit Bα; PTEN: phosphatase and tensin homolog deleted on chromosome 10; TS: tumor suppressor; WNT: WNT signaling.
Figure 2
Figure 2. MicroRNAs down-regulated in bladder cancer which mediate chemoresistance, with context-dependent activity and affecting several targets, with efficacy in preclinical in vivo systems. miR-193a-3p: Chemoresistance; miR-145: context-dependent efficacy. CCND1/2: Cyclin D1/2; FOXO1: forkhead box protein 1; HIC2: hypermethylated in cancer 2; HOXC9: transcription factor homeobox C9; LOXL4: lysyl oxidase-like 4; p27: protein 27; PLAU: plasminogen activator urokinase; SRSF2: splicing factor serine/arginine rich; T24, T24T: bladder cancer cell lines.
Figure 3
Figure 3. Expression of miR-1, miR-100 and miR-145 in bladder cancer and corresponding normal bladder tissues at the RNA level. Data from 409 bladder cancer samples and 19 matching normal samples derived from The Cancer Genome Atlas (TCGA) are shown. miRNA expression was quantified by RNA sequencing and is shown as log2 of normalized read counts. The red lines indicate low versus higher expression (indicated by more or less than 100 normalized read counts, respectively). Expression data are shown as box plots. The line in the middle of the box represents the median values, the rectangles show the upper and lower quartiles, and 50% of all data points are included in the rectangle. All other data points, except for outliers are located within the upper and lower whiskers. The whiskers extend 1.5 times the interquartile range from the top and bottom of the box. If there are values that fall above or below the end of the whiskers, they are plotted as dots.
Figure 4
Figure 4. MicroRNAs down-regulated in bladder cancer which affect cell cycle-related targets with in vivo efficacy in related preclinical models. AURKA: Aurora kinase A; CCND1/2: cyclin D1/2; CDK2/4/6: cyclin-dependent kinases 2/4/6; G1/S: G1/S phases of the cell cycle; p21: protein 21; P2RY1: P2Y purinoreceptor 1; PTTG1: pituitary tumor transforming gene 1; WNT: WNT signaling.
Figure 5
Figure 5. MicroRNAs down-regulated in bladder cancer which target transmembrane receptors and secreted factors with efficacy in preclinical in vivo models. AKT: AKT serine-threonine kinase; ERK: extracellular signal-regulated kinase; EGFR: epidermal growth factor receptor; FGFRL1: fibroblast growth factor like-1; INTα5: integrin α5; MAPK: mitogen-activated protein kinase; MET: metastasis; mTOR: mechanistic target of rapamycin; PI3K: phosphatidylinositol-4,5-bisphosphate 3-kinase; RAS: GTPase RAS; VEGF-C: vascular endothelial growth factor C.
Figure 6
Figure 6. MicroRNAs down-regulated in bladder cancer which affect signaling, apoptosis, autophagy and transcription factors with efficacy in preclinical in vivo models. Signaling: miR-100, miR-608 and miR-4324; apoptosis: miR-138-5p and miR-200c; autophagy: miR154; transcription factors: miR-15 and miR-370. AKT: AKT serine-threonine kinase; ATG7: autophagy-related 7; ATPH: autophagy; BMI-1: B-lymphoma Moloney murine insertion region 1; CDC24: cell division control protein 24; CSP 3, 7, 9: capase 3, 7, 9; FLOT-1: flotilin-1; FOXO3A: forkhead-box-protein 3A; mTOR: mechanistic target of rapamycin; p16, 19, 21, 27: protein 16, 19, 21, 27; PI3K: phosphatidylinositol-4,5-bisphosphate 3-kinase; RAC: RAS-related C3 botulinum toxin substrate 1; RACGAP1: RAC GTPase activating protein-1; S6K: ribosomal protein S6 kinase; SOX12: transcription factor SOX12; STAT3: signal transducer and activator of transcription 3; XIAP: X-linked inhibitor of apoptosis.
Figure 7
Figure 7. MicroRNAs down-regulated in bladder cancer which affect epigenetic modifiers, metabolism and several targets with in vivo efficacy in bladder cancer-related preclinical models. Epigenetic modifiers: miR-124 and miR-411; metabolism: miR-1-3p, miR-145, miR-153, miR-612; several targets: miR-582-3p, miR-5p, miR-502. CCND1: Cyclin D1; CRRM: chromatin remodeling modifier; DIXDC1: DIX domain containing 1; DNMT3B: DNA methyltransferase 3B; EMT: epithelial–mesenchymal transition; GLS: glutaminase; GLUmet: glutamine metabolism; HOX: homeobox transcription factor; IL6: interleukin 6; IDO1: indoleamine 2,3 dioxygenase1; PKM1/2: muscle pyruvate kinase isoenzymes 1/2; LIPOG: lipogenesis; LRRK2: leucine-rich repeat kinase 2; meth: methylation; ME1: malic enzyme 1; MLLT1: myeloid/lymphoid or mixed lineage translocated to 1; MYC: transcription factor MYC; NADPH: nicotinamide dinucleotide phosphate; NOP14: nucleolar protein 14; PGGT1B: geranylgeranyl transferase type 1 subunit; RAB27A: RAS-related GTP binding protein 27A; STAT3: signal transducer and activator of transcription 3; TRYP met: tryptophan metabolism; VEGF: vascular endothelial growth factor; UHRF1: ubiquitin-like containing PH and ring finger domains, 1.
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