Challenges and Opportunities of MicroRNAs in Lymphomas
Abstract
:1. Introduction
2. MicroRNA Biogenesis and Mechanism of MicroRNA Gene Regulation
3. MicroRNAs as Regulators of Lymphoid Maturation
- Evaluation of global expression patterns of miRNAs in specific cell lineages, and comparison of these profiles in several stages of differentiation and/or in normal cells vs. lymphoma cells.
- In vitro and in vivo functional and mechanistic studies of miRNAs carried out by (a) replacing or knockdown of miRNAs or (b) silencing only specific single miRNA-mRNA target interactions through a mutation in complementary sites to the 3′-UTR or (c) using chemically-modified antisense oligonucleotides, termed antimiRs, which hold the mature miRNA in competition withtarget mRNAs leading to functional inhibition of the miRNA and repression of the direct targets.
4. Role of miRNAs in B-Cell Maturation
4.1. miRNA Control of B-Cell Development in Bone Marrow
miRNAs | Direct/Indirect Target | Function/Ref. | Regulation | Lymphomas/miRNAs involved/Ref. |
---|---|---|---|---|
miR-17-92 |
| Control of transition from proB- to preB-cells. Enhancement of cell survival and inhibition of apoptosis by targeting PTEN and Bim, antagonizing with BCL2 [29,30]. Positive regulation by MYC and simultaneous repression of E2F1 expression by miR-17-5p and miR-20a: generation of MYC/miR-17-92/E2F1 circuit that accelerates the development and increases the aggressiveness of the tumor [31,32,33,34,35]. miR-19b represses apoptosis and promotes cell proliferation and angiogenesis by repressing PTEN expression and function, thus resulting a functional activation of Akt/mTOR pathway via PI3K pathway [36]. Induction of chemoresistance in MCL by activating the PI3K/AKT pathway trough targeting of PHLPP2 [37]. VEGF up-regulate the expression levels of only miR-18, miR-19 and miR-20 to participate in the control of angiogenic phenotypes [9]. Selective miR-17-92 biogenesis and likely post-transcriptional silencing mediated by each miRNA component within miR-17-92 may be regulated in a cell type- and context- dependent manner [9,38]. | ||
miR-181a |
| Involvement in commitment to Lymphoid cell fate, B and T-cell differentiation, and specifically promotion of early B-cell development [19,45]. Block of human progenitor cell differentiation [46]. | ||
miR-181b |
| Modulation of somatic hyper-mutation and class-switch recombination together with miR-155 but at different stage of B-cell activation [48,49]. | B-CLL [48] | |
miR-150 |
| Control of transition from proB- to preB-cells [50,51]. Down-regulation of c-MYB, expression [18,51]: interaction important for oncogenesis and (or) tumor progression [52,53,54]. Regulation of the NK and iNKT cell development [55]. Reduction of phosphorylated AKT (ser473/4) levels and increasing Bim and TP53 by directly down-regulating the DKC1 and AKT2 expression [56]. |
| |
miR-185 |
| BCR development. | ||
miR-155 |
| Control of B-cell differentiation and GC reaction: activation and function of B cell in germinal centres and for T-cell dependent antibody responses [19,46,60,61,62] by negatively modulating somatic hypermutation and class-switch recombination through the targeting of AID [62] and PU.1 [63]. Down-regulation of HGAL expression, leading to a decreasing of RhoA activation and increasing of spontaneous and chemoattractant-induced lymphoma cell motility [64] Oncomir that regulates proliferation and enhances cell survival by:
|
| |
miR-34a |
| Growth suppressive function and pro-apoptotic effect in pro-B cells of which it controls the transition to pre-B stage by targeting FOXP1 [77,78] know as B cell on cogene. [79] It is negatively regulated by c-MYC [80] and positively regulated by TP53 [80,81,82,83,84]. In turn, by inhibiting SIRT1, it actives TP53 resulting apoptotic effects mediated by TP53/SIRT1/miR-34a pathway. Epigenetically silenced in many lymphomas, mainly NK/T-NHL [55]. |
| |
miR-9 |
| Regulation of B-cell terminal differentiation into plasma cells and memory B cells [85,86] It regulates E-cadherin [58] |
| |
miR-30 |
| Regulation of B-cell differentiation by determining the ability of developing B cells to move to the GC [50] |
| |
Let-7 |
| Regulation of B-cell terminal differentiation into plasma cells and memory B cells [85,86] | ||
miR-29 |
| Down-regulates TCL1 and MCL1 expression [48,89] |
|
4.2. miRNA Regulate Mature B-Cell Activation and Functions
5. The Role of miRNAs in T-Cell Maturation
5.1. T-Cell Development in the Absence of Dicer
5.2. Individual MiRNAs Have the Potential to Regulate T-Cell Development and Functions
miRNAs | Target | Function |
---|---|---|
miR-181a | CD69 BCL2 TCR-α (DUSP5, DSP6, SHP2, PTPN22) | Regulation of positive selection by governing the homeostasis of CD4/CD8 lymphocytes and modulation of T-cell sensitivity by increasing TCR signaling to peptide antigens through the down-regulation of multiple phosphatases [19,23,45,104,118,126]. Regulation of iNKT cell development through the modulation of TCR signaling threshold resulting the increase responsiveness of DP thymocytes to TCR signals [116]. |
miR-17-92 | CREB1 PTEN Bim | Regulation of effector and memory CD8+ T-cell differentiation. Temporal expression is critical [129]. |
miR-150 | NOTCH3 | Controls of T-cell differentiation [51]. Regulation of differentiation into the memory or effector phenotypes of T cells [59]. Regulation of the differentiation from DP into CD4+ and CD8+ T-cells [45,120,121,122]. Regulation of the intrathymic pre-T-cell receptor selection of T-cells [121,123] |
miR-155 | SOCS1 | Regulation of differentiation into the memory or effector phenotypes of T cells [59]. Controls of T-cell differentiation: to favour Th1 responses partially by modulating cytokine production [60,61]. Control of proliferation and homeostasis of Treg cells by stabilizing the signal of FOXP3 through the targeting of SOCS1 [124]. |
miR-146 | STAT1 | Regulation of the Treg suppressor function by modulating IFNγ responses through the targeting of STAT1 [45,128]: promotion of differentiation into Th1 cells rather than Th2 cells [45,50] |
6. miRNAs and Lymphoid Malignancies
6.1. miRNAs as Oncomirs in Lymphoid Malignancies
6.2. miRNAs as Dysregulated Tumor Suppressor Genes in Lymphoid Malignancies
Ly Type | miRNA | Status | Func. | Target | BioM | Comment/Reference |
---|---|---|---|---|---|---|
HL | miR-135 | DR | JAK2 | The expression of miR-135a in cHL lymph nodes is down-regulated and correlates with clinical outcome. The miR-135a direct down-regulates the JAK2, thus affecting the expression of the antiapoptotic gene BCL-XL. In accordance with this the increased levels of miR-135a causes apoptosis and decreases cell growth [55] | ||
miR-155 | UP | OG | PU.1 | D | Specific biomarker of HL [43,71,72,143,144,145,146,147] | |
let-7/miR-9 | UP | OG | PRDM1/blimp1 | D | [86,88] | |
miR-17-92 | UP | OG | D | Compared to other B-cell lymphoma cell lines, overexpression of the miR-17-92 cluster members miR-17-5p, miR-19a, miR-19b, miR-20a, and miR-92, is prominent in HL [43] | ||
miR-21 | UP | OG | PTEN | D, P, PR | Plasmatic levels are associated with Hasenclever scores ≥ 3 and returned to normal at remission [42,43]. Involved in expression in cHL pathogenesis and is associated with therapeutic resistance [184] | |
miR-150 | DR | TSG | D | [43] | ||
DBLCL | miR-155 | UP in ABC | OG | PU.1 INPP5D (SHIP1) SMAD5 | D, P | More aggressive subtypes [140] Higher in ABC-DBLCL than in GC-DBLCL; useful for differential diagnosis of ABC-DBLCL and as a P considering the poor prognosis of ABC as compared with GC-DBLCL subtypes [71,72,138]. Evaluation of serum levels: 83% sensitivity, 65% specificity [139]. Inverse correlation between NF-kB/miR-155 and PU.1/CD10 expression [140]. Stimulation by TNF-α increases miR-155 expression that induces aberrantly activation of PI3K/AKT pathway, one the most important unfavourable P, by directly targeting INPP5D [66,67,137,140,141]. By targeting SMAD5, it makes DBLCL cells resistant to the growth-inhibitory effects of both TGF-beta1 and BMP [58,64,65,70,100] |
let-7f | UP | OG | D | [58] | ||
let-7b | UP in ABC | OG | PRDM1/blimp1 | D | [88] | |
miR-9 | UP in ABC | OG | PRDM1/blimp1 | D | [58,102] | |
miR-15a | DR | TSG | BCL2 | D | [2] | |
miR-17-92 (miR-17-5b, miR- 9b) | UP in GC | OG | BIM/PTEN | P | Consistent with more aggressive phenotype [31,40,41,87] MiR-19b promotes cell proliferation and angiogenesis, represses apoptosis | |
miR-21 | UP in ABC | OG | BCL2 | D, P | Elevated levels (in serum or biopsy) are associated with a better RFS in de novo DBLCL [138] More highly expressed in the poor risk ABC than in the GC-DBLCL subtype and higher in disease stages III-IV compared to stages I-II [138,153,154]. Conversely in B-CLL [46,156,158] | |
miR-30 | DR | TSG | BCL6 PRDM1 | [50,85] | ||
miR-34a | DR | OG | ||||
miR-150 | DR | TSG | c-Myb | [18,41] | ||
MCL | miR-17-92 | UP | OG | E2F1 (c-MYC) PHLPP2 PTEN BIM | D, PR | Enhances resistance to chemo- [37] and radiotherapy via PI3K/AKT by targeting PTEN and PHLPP2 [152] [27,31,34,35,37,152] |
miR-16-1 | 1. BS-del 2. DR | TSG | CCDN1 | P | 1. Truncation in CCDN1 mRNA alters its ability to be down-regulated by miR-16-1, resulting in MCL development and correlating with poor prognosis [174] 2. Myc represses miR-15/16-1 expression through recruitment of HDAC3 [175]. | |
miR-181c | UP | [57,58] | ||||
miR-155 | UP | OG | [185] | |||
FL | miR-9 | UP | PRDM1/blimp1 | D | MiR-9 (-5p, -3p) is significantly upregulated; Activated by MYC. It regulates NF-kB and down-regulates PRMD1/BLIMP1 [41,58] | |
let-7 | UP | TSG | PRDM1/blimp1 | D | Reduced PRDM1 levels are important in FL characterized by the tightly regulated expression of BCL6 and PRDM1 [86,87]. | |
miR-155 | UP | [41] | ||||
BL | let-7a, let-7c, let-7e, let-7-f | DR | PRDM1/blimp1 | Loss of the let-7 (a; c) participates to the genesis and maintenance of the lymphoma phenotype through c-MYC regulation [186] | ||
miR-9 | UP | OG | ||||
miR-17-92 | UP | miR-17-3p, miR-18a, miR-19a, miR-19b, miR-92 up-regulated in BL vs. NHL [58] | ||||
miR-29 | DR/lost | TSG | TP53 TCL1 | D | MiR-29 family regulates TP53 [27,58] MiR-29b, regulates TCL-1 expression, whereby the aberrantly expression of TCL1 in BL has been proposed as a diagnostic marker [48,58] MiR-29 is negatively correlated with MCL-1. | |
miR-34b | DR | Targeted by TP53 | ||||
miR-150 | DR | TSG | [18,58] | |||
miR-155 | DR/lost | MiR-155 is the most significantly lost miRNA in BL [72] followed by miR-29b and miR-146a [58], this making it one of the most suitable markers for differential diagnosis between BL vs. DBLCL [44,75]. | ||||
miR-15a/miR-16-1 | DR/del. | TSG | BCL2 TP53 | D, P | Deleted (region 13q) or down-regulated in ≈ 68% of B-CLLs [133]. | |
miR-15a/miR-16-1 | DR/del. | TSG | BCL2 TP53 | D, P | It is associated with pathogenesis and outcome of B-CLLs: monoallelic deletion slower growth kinetic than biallelic [164] due to the directly targeting of TP53 [166] and consistent with indolent B-CLL and more favourable prognosis than 17p13 or 11q23 deletions [90]. In addition targets BCL2, MCL1 and CDK6 [165] | |
miR-17-92 | UP | OG | D | Specifically: miR-19a, miR-20a, miR-92 [43] | ||
BL | miR-21 | UP | OG | ANP32A SMAR-CA4 PTEN | P | Dramatically overexpression without genomic loci amplification: dysregulation at post- or transcriptional level [137] High expression is a significantly unfavourable P independent of other clinic-pathological factors in B-CLL patients [156] Can trigger B-lymphomagenesis by targeting ANP32A, SMAR-CA4 and PTEN [157,158] |
miR-29 | DR | TSG | TCL1 | P | Expression of members of miR-29 family could discriminate between good and bad prognosis CLL samples as results of TCL1 targeting. MiR-29b is down-regulated in aggressive and poor prognosis B-CLLs which are characterized by high levels of TCL1 [48,90]. MiR-29c is associated with TSF and OS [187]. | |
miR-34 | DR | P | Aggressive B-CLL: in 11q deleted CLL with high levels of ZAP-70 [166]. | |||
miR-181b | DR | TSG | TCL1 | P | Aggressive B-CLL. DR in poor prognosis.Down-regulation of TCL1 results the activation mTOR, NF- kB, Mdm2 and CyclinD1 pathways [178]. So its expression correlates with disease aggressiveness: high expression in aggressive B-CLL, and lower in indolent disease [48] | |
miR-181a | DR | TSG | BCL2 | [45] | ||
miR-150 | UP | TSG | c-MYB | [18,58] | ||
miR-155 | UP | OG | P | Aggressive B-CLL. Increased expression for dysregulation at post- or transcriptional level. [71,90,137] | ||
MZL | miR-9 | UP | OG | NF-κB | [41,44] | |
miR-155 | UP | OG | [41,71] | |||
miR-200a, miR-200b, miR-200c | UP | ZEB1 ZEB2 | miR-200 family inhibits the initiating step of metastasis, the EMT, by maintaining the epithelial phenotype through directly targeting the transcriptional repressors of E-cadherin, ZEB1 and ZEB2 [58] | |||
miR-126 | DR | [58] | ||||
NK/T Ly | miR-21 | UP | OG | PDCD4 PTEN | Overexpression may contribute to the typical aggressiveness of NK/T cell lymphoma by the strong repression of PDCD4 and PI3K/PTEN/AKT [159,160,161,162] | |
miR-34a | DR | TSG | Hypermethylated in a tumor specific manner [55] | |||
miR-150 | DR | TSG | DKC1 AKT2 | Potential causative event for the onset and progression of NK/T cell lymphoma since the transduction of miR-150 decreases cell proliferation and induces apoptosis into NK/T cell lymphoma lines [56] | ||
ALCL | miR-29a | TSG | miR-29a targets MCL-1 that could promote tumor cell survival by inhibiting apoptosis. This down-modulation requires an active NPM-ALK Kinase since the absence of kinase results an increase of miR-29a expression. In ALCL cell lines and in a xenografted model the increased expression of miR-29a modulated apoptosis through inhibition of MCL-1 expression, with a concomitant tumor growth reduction suggesting a potential new tool to affect tumorigenesis in these lymphomas [89]. | |||
ALCL | miR-16 | VEGF HIF-1a | Down-regulation of miR-16 increases both angiogenesis and tumor growth by up-regulating VEGF translation via the hypoxia-miR-16 pathway [176] | |||
let-7 | UP | OG | PRDM1/blimp1 | [56] | ||
B-NHLs | miR-15a/16-1 | DR/ | TSG | c-MYC-induced miR-15a/16-1 repression by HDAC may be a mechanism for malignant transformation in aggressive B-cell lymphoma [175]. Deletion in indolent disease. | ||
miR-21 | UP | OG | ANP32A SMAR-CA4 PTEN | D, P | Key role in B lymphomagenesis [157,158] | |
miR-17-92 | UP | OG | BIM PTEN E2F1 PHLPP2 | D, P, PR | Located in 13q31-q32 region frequently (65%) amplified in lymphomas, especially in aggressive B-NHLs.Oncogenic effects depend on the Bim, PTEN and E2F1 targeting [30,34]. | |
miR-34a | UP | OG | SIRT1 | Confers drug resistance in B cells that overexpress MYC [79,81] | ||
miR-155 | UP | OG | Distinguishes ABC-DLBCL from GC-DLBCL [71,138]. In more aggressive B-NHLs aberrant activation of NF-kB increases expression of miR-155, which then down-regulates PU.1, and consequently leads to reduced CD10 expression [140] |
6.3. miRNAs as Diagnostic or Prognostic Tool in Lymphoid Malignancies
Lymphomas | Signatures | St. | Comments/Ref. |
---|---|---|---|
DBLCL | miR-210, miR-155, miR-106a, miR-17-5p | UP | Significantly higher expression in DBLCL than RLN [41] |
miR-150, miR-145, miR-328, miR-139, miR-95, miR-99a, miR-10a, miR-149, miR-320, miR-151, let-7e (miR-17-3, miR-595, miR-663) | DR/lost | Significantly lower expression in DBLCL than RLN [41] miR-17-3, miR-595, miR-663 most significantly lost in DBLCL [58] | |
FL | miR-9, miR-301, miR-213, miR-9*, miR-330, miR-106a, miR-338, miR-155, miR-210 | UP | Significantly higher expression in FL than RLN [41] |
miR-320, miR-149, miR-139 | DR | Significantly lower expression in FL than RLN [41] | |
DBLCL vs. FL | miR-150, miR-17-5p, miR-145, miR-328 vs. miR-9/9*, miR-301, miR-338 and miR-213 | Differentially expressed miRNAs in DBLCL and FL identify signatures respectively in DBLCL and FL [41] | |
DBLCL/FL/RNL | mir-330, mir-17-5p, mir-106a and mir-210 | Correctly identifies 98% of DLBCL, FL and RLN [41] | |
ABC-DBLCL vs. GC-DBLCL | miR-155, miR-21 and miR-221 | UP | More highly expressed in ABC- than GC-subtypes, distinguish between ABC- and GC-DBLCL cases (p < 0.05). MiR-21 expression is an independent prognostic indicator in de novo DLBCL (p < 0.05) [138] |
DBLCL-dn vs. DBLCL-t | miR-27a, miR-19b, miR-25, miR-18a, miR-636, miR-92, miR-621, miR-526c, miR-766, miR-299-5p, miR-380-3p, miR-129, miR-588 | UP | More highly expressed (p < 0.05) in DLBCL de novo than DLBCL-t cases, correctly predict transformation >85% [87] |
FL-t vs. FL-nt | miR-223, miR-217, miR-222, miR-221, let-7i, miR-7b | UP | Differentially expressed (p < 0.05) between FL-t and FL-nt, accurately (89%) predict transformation of FL cases [87] |
DBLCL prognosis | miR-637, miR-608 and miR-302 | Poor prognosis [87] | |
miR-330, miR-30e, miR-425, miR-27a, miR-24, miR-23a, miR-199b, miR-199a* and miR-100 | Better outcome [87] | ||
miR-21, miR-127, miR-34a, miR-195, let-7g, miR-19a, miR-27a | Correlate with EFS and OS [41] | ||
DBLCL drug sensitivity | miR-181a, miR-22 and miR-18a | Independent prognostic indicators of survival in R-CHOP treated DBLCL [190] | |
B-CLL poor prognosis | miR-29 | ||
miR-15a, miR-195, miR-221, miR-23b, miR-155, miR-24-1, miR-146, miR-16-1, miR-16-2 | UP | Significant relationship between the expression of 9 miRNAs and the time from diagnosis to beginning of chemotherapy [90] | |
CLL vs. B-NHL | miR-182, miR-199a*(5p), let-7 family, miR-424, miR-10a, miR-7, mir-126, miR-218, MiR-197, miR-595 , miR-483 | DR/UP | MiR-197 the most highly expressed miRNA, miR-595 and miR-483 also upregulated [58] |
BL vs. B-NHL | miR-17-3p, miR-18a, miR-19a, miR-19b, miR-92 | UP | Up/Down-regulated in BL vs. NHL [58] |
let-7 family, miR-29 (a, b, c), miR-155, miR-146a | DR | ||
HL | miR-17-92 cluster members, miR-16, miR-21, miR-24, and miR-155.miR-150 | UP DR | The HL-specific miRNAs up-regulated [43]. Only miR-150 is significantly down-regulated in HL compared with NHL [43]. |
cHL vs. HL EBV+ | miR-96, miR-128a, miR-128b | DR | Selectively down-regulated in HL lymph nodes of EBV+ HL patients [42] |
cHL prognosis | miR-135a | Expression of miR-135a in HL lymph nodes correlates with clinical outcome. Patients with low miR-135a expression had a higher probability of relapse and a shorter disease- free survival. [55] | |
miR-21, miR-30e, miR-30d and miR-92b | To identify two different risk groups for 5-year FFS [184]. |
7. Novel Therapeutic Strategies by Modulation of miRNAs
- Inhibition of tumor-inducing miRNAs: miRNAs as therapeutic targets;
- MiRNA replacement by re-introducing miRNAs with tumor suppressor functions: miRNAs as therapeutic agents.
8. Conclusions
Acknowledgments
Conflicts of Interest
References
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De Tullio, G.; De Fazio, V.; Sgherza, N.; Minoia, C.; Serratì, S.; Merchionne, F.; Loseto, G.; Iacobazzi, A.; Rana, A.; Petrillo, P.; et al. Challenges and Opportunities of MicroRNAs in Lymphomas. Molecules 2014, 19, 14723-14781. https://doi.org/10.3390/molecules190914723
De Tullio G, De Fazio V, Sgherza N, Minoia C, Serratì S, Merchionne F, Loseto G, Iacobazzi A, Rana A, Petrillo P, et al. Challenges and Opportunities of MicroRNAs in Lymphomas. Molecules. 2014; 19(9):14723-14781. https://doi.org/10.3390/molecules190914723
Chicago/Turabian StyleDe Tullio, Giacoma, Vincenza De Fazio, Nicola Sgherza, Carla Minoia, Simona Serratì, Francesca Merchionne, Giacomo Loseto, Angela Iacobazzi, Antonello Rana, Patrizia Petrillo, and et al. 2014. "Challenges and Opportunities of MicroRNAs in Lymphomas" Molecules 19, no. 9: 14723-14781. https://doi.org/10.3390/molecules190914723