Pure curcumin decreases the expression of WT1 by upregulation of miR-15a and miR-16-1 in leukemic cells
- Shen-meng Gao†1,
- Jun-jun Yang†2,
- Chi-qi Chen1,
- Jun-jie Chen1,
- Li-ping Ye1,
- Lu-yao Wang1,
- Jian-bo Wu1,
- Chong-yun Xing3 and
- Kang Yu3Email author
© Gao et al; licensee BioMed Central Ltd. 2012
Received: 10 January 2012
Accepted: 27 March 2012
Published: 27 March 2012
Pure curcumin has been reported to down-regulate the expression of WT1 in leukemic cells. However, the molecular mechanism underlying the down-regulation of WT1 by curcumin is not completely delineated. The purpose of this present study is to identify a new miRNA-mediated mechanism which plays an important role in the anti-proliferation effects of curcumin in leukemic cells.
K562 and HL-60 cells were treated with different concentrations of curcumin for 24 and 48 hours, the level of miR-15a/16-1 and WT1 were detected by qRT-PCR and Western blotting. WT1 expression and cell proliferation were detected by Western blotting and CCK-8, after curcumin treated-K562 and HL-60 cells were transfected with anti-miR-15a/16-1 oligonucleotides.
We found that pure curcumin upregulated the expression of miR-15a/16-1 and downregulated the expression of WT1 in leukemic cells and primary acute myeloid leukemia (AML) cells. Overexpression of miR-15a/16-1 deduced the protein level of WT1 in leukemic cells, but downregulation of WT1 by siRNA-WT1 could not increase the expression of miR-15a/16-1 in leukemic cells. These results reveal that curcumin induced-upregulation of miR-15a/16-1 is an early event upstream to downregulation of WT1. Furthermore, anti-miR-15a/16-1 oligonucleotides (AMO) partly reversed the downregulation of WT1 induced by pure curcumin in leukemic cells and AMO promoted the growth of curcumin treated-K562 and HL-60 cells.
Thus, these data suggest for the first time that pure curcumin downregulated the expression of WT1 partly by upregulating the expression of miR-15a/16-1 in leukemic cells. miR-15a/16-1 mediated WT1 downregulation plays an important role in the anti-proliferation effect of curcumin in leukemic cells.
The Wilms' tumor 1 (WT1) gene, which is located at the short arm of chromosome 11 and contains 10 exons, encodes a DNA-binding transcription factor essential for embryonal development . High level of WT1, which is detected in most cases of acute human leukemia and chronic myelogeous leukemia (CML) in blast crisis, is associated with a worse long-time prognosis . Downregulation of WT1 by special siRNA can inhibit cell proliferation and induce apoptosis in K562 and HL-60 cells . WT1 acts as a potent transcriptional regulation factor involved in cell growth and development due to the presence of zinc fingers . WT1 is firstly thought to function as tumor suppressor, but the following wildly studies support that WT1 acts as oncogene .
Curcumin, a naturally occurring flavinoid and proapoptotic compound derived from the rhizome of Curcuma longa, has strong anti-inflammatory, antioxidant, anticarcinogen, anticancer properties through regulating multiple downstream cancer-related signaling molecules. The molecular targets of curcumin include modulation of NF-kappaB, Jak/STAT, WT1, extracellular signal regulated kinase and other key molecules involved in tumorigenesis [6–8]. The mechanisms underlying the anticancer activity of curcumin have been widely investigated. Bharti et al. showed curcumin decreased NF-kappaB in human multiple myeloid cells, leading to the suppression of proliferation and induction of apoptosis . Recently more and more data have shown that WT1 is a very important target gene by curcumin . However the exact mechanism by which curcumin downregulated the expression of WT1 is still not clear.
MicroRNAs (miRNAs) are non-coding regulatory RNAs of 21 to 25 nucleotides which regulate most of basal progress such as cell proliferation, survival, apoptosis, and differentiation by triggering either translational repression or mRNA degradation . Furthermore, computational prediction demonstrated that each miRNA may target hundreds of genes, and that more than 50% of human protein-coding genes could be modulated by miRNAs . Recently some data have indicated pure curcumin inhibited cancer cell proliferation though miRNAs mediated signal pathway. Michael et al. showed curcumin inhibited the proliferation of pancreatic cancer cells through upregulation of miR-22 and downregulation of miR-199a* . Yang et al. demonstrated that curcumin induced MCF-7 cells apoptosis through miR-15a/16-1 mediated down-regulation of Bcl-2 . These emerging results suggest that specific targeting of miRNAs by natural agents may open new avenues for the complete elucidation of antitumor activity by curcumin.
In this study, we explored the potential modulation of miR-15a and miR-16-1 by curcumin in leukemic cells. Our study aims to explain a new mechanism by which curcumin downregulates the expression of WT1 via the upregulation of miR-15a/16-1 in leukemic cells.
Material and methods
Cell lines and primary AML cells
The data of acute myeloid leukemia patients
46, XY PML-RARa+
46, XX MYH11-CBFβ+
46, XY PML-RARa+
46, XX AML-ETO+
46, XX MYH11-CBFβ+
46, XX AML-ETO+
pRETROSUPER vector expressing miR-15a/16-1 (pRS-15/16) was constructed as previously described. The same empty plasmid (pRS-E) was served as negative control. K562 and HL-60 cells were transiently transfected with 1 μg/mL (final concentration) pRS-15/16 or pRS-E vector mediated by Lipofectamine™ LTX and PLUS™ Reagents (Invitrogen) according to the manufacturer's instructions.
Total RNA from curcumin-treated or untreated leukemic cells were extracted by TRIzol (Invitrogen) Following the manufacture's protocol. RNA concentration and quality were quantified by measuring the absorbance at 260 nm with Beckman DU6400 spectrophotometer (Beckman, USA) and gel analysis.
qPCR for miRNA and mRNA expression
Quantitative real-time polymerase chain reaction(qRT-PCR) analysis for miR-15a and miR-16-1 was performed in triplicate by the aid of the NCode™ miRNA First-strand cDNA synthesis (Invitrogen) and SYBR® Green PCR Master Mix (Applied Biosystems, Foster City, CA) according to the manufacturer's instructions. U6 snRNA level was used for normalization. The fold change for each miRNA in curcumin-treated leukemic cells relative to untreated cells was calculated using the 2-ΔΔCT method . WT1 transcript was determined by quantitative real-time PCR using specific primer. ABL and GAPDH housekeeping genes were used for normalization [15, 16]. The following primers were used respectively, miR-15a: 5'-TAG CAG CAC ATA ATG GTT TGT G-3', miR-16-1: 5'-TAG CAG CAC GTA AAT ATT GGC G-3', U6: 5'-CGC AAG GAT GAC ACG CAA ATT C-3', WT1: sense strand: 5'-CAG GCT GCA ATA AGA GAT ATT TTA AG CT-3', antisense strand: 5'-GAA GTC ACA CTG GTA TGG TTT CTC A-3', Taqman probe: 5'-Fam-CTT ACA GAT GCA CAG CAG GAA GCA CAC TGA-Tamra-3'), ABL: (sense strand: 5'-GAT GTA GTT GCT TGG GAC CCA-3', antisense strand: 5'-TGG AGA TAA CAC TCT AAG CAT AAC TAA AGG T-3', Taqman probe: 5'-Fam-CCA TTT TTG GTT TGG GCT TCA CAC CAT T-Tamra-3'). GAPDH: (sense strand: 5'-CCA GGT GGT CTC CTC TGA CTT C-3', antisense strand: 5'-GTG GTC GTT GAG GGC AAT G-3', Taqman probe: 5'- Fam-ACA GCG ACA CCC ACT CCT CCA CCT T-Tamra-3').
Cell counting kit-8 (CCK-8) assay
K562 and HL-60 cells were seeded into 96-well plates (6.0 × 103 cells/well). Cell viability was assessed by CCK-8 assay (Dojin Laboratories, Kumamoto, Japan). The absorbance at 450 nm (A450) of each well was read on a spectrophotometer. Three independent experiments were performed in quadruplicate.
Protein extracts from cell lines, patient samples prepared with RIPA lysis buffer (50 mM TrisHCl, 150 mM NaCl, 0.1% SDS, 1% NP-40, 0.5% sodiumdeoxycholate, 1 mM PMSF, 100 mM leupeptin, and 2 mg/mL aprotinin, pH 8.0) were separated on an 8% SDS-polyacrylamide gel and transferred to nitrocellulose membranes. After blocking with 5% nonfat milk, the membranes were incubated with an appropriate dilution (WT1 1:2000) of the primary antibody (Abcom, Cambridge, MA, USA), followed by incubation with the horseradish peroxidase (HRP)-conjugated secondary antibody (Abcom). The signals were detected by chemiluminescence phototope-HRP kit (Cell Signaling, Danvers, MA, USA). Blots were stripped and reprobed with anti-GAPDH antibody (Abcom) as an internal control. All experiments were repeated three times.
siRNA, mimics, and anti-miR-15a/16-1 oligonucleotide (AMO) transfection
SiRNA sequences targeting WT1: ccauaccagugugacuuca corresponds to positions 9-27 of exon 7 within the WT1 coding sequence. SiRNA-WT1 and unspecific control siRNA (N.C) were synthesized from Invitrogen. 50 nM SiRNA-WT1 or N.C were transfected into K562 and HL-60 cells using Hiperfect transfection reagent (Qiagen, Valencia, USA) according to manufacturer's instructions. miR-15a or miR-16-1 mimics was synthesized from Gene Pharma (Shanghai, China). 40 uM miR-15a or miR-16-1 mimics were transfected into K562 using Hiperfect transfection reagent (Qiagen). The sequences of AMO were designed according to the principle of sequences complementary to mature miRNA-15a/16-1. AMO and scramble (SCR) were chemically synthesized by Qiagen. AMO and SCR (final concentration of 50 nM) were transfected into K562 and HL-60 cells using the Hiperfect transfection reagent (Qiagen). All transfections were performed in triplicate for each time point.
The significance of the difference between groups was determined by Student's t-test. A P value of less than .05 was considered statistically significant. All Statistical analyses were performed with SPSS software (version 13).
Pure curcumin downregulated the expression of WT1 and effectively inhibited cell proliferation in leukemic cells
Pure curcumin upregulated the expression of miR-15a/16-1 in leukemic cells and primary AML blasts
Overexpression of miR-15a/16-1 could deduce WT1 expression but downregulation of WT1 by siRNA could not increase the expression of miR-15a/16-1 in leukemic cells
Anti-miR-15a/16-1 oligonucleotides (AMO) partly reversed the down-regulation of WT1 induced by curcumin in leukemic cells
WT1 is considered to play an important role in leukemogenesis because the expression of WT1 increases 1000-10000 fold in primary leukemic cells than normal cells . Glienke and Bergmann showed that siRNA-reduced WT1 mRNA expression was associated with a decreased cell proliferation in K562 and HL-60 cells after transfection for 24 and 48 h . Several studies indicated that pure curcumin downregulated the expression of WT1 in leukemic cell lines . Moreover, combined treatment with curcumin and siRNA targeting WT1 resulted in a significant inhibition of cell proliferation compared to curcumin-treated cells alone in pancreatic cancer cells. All these data suggest that WT1 plays an important role in the anti-proliferative effects of curcumin. However, the mechanism by which pure curcumin downregulates WT1 expression is still unknown. Our data show for the first time that pure curcumin downregulates WT1 expression via miRNAs pathway.
The gene expression is regulated via a complicated network. Semsri et al. reported that pure curcumin decreased the mRNA and protein levels of WT1 through attenuating WT1 auto-regulatory function and inhibiting PKCalpha signaling in K562 cells . Our data showed that curcumin downregulated the expression of WT1 via miRNAs mediated pathway. However, whether other regulating factors are involved in the regulation is still not completely delineated. Therefore it is difficult to accurately calculated how much of the down-regulation of WT1 in the curcumin- treated cells is attributable to the action of the miRNAs. Our previous data had showed overexpression of miR-15a/16-1 downregulated the protein level of WT1 but not mRNA level . However, in this report curcumin decreased the mRNA and protein levels of WT1 in leukemic cells. Therefore, it is obvious that additional mechanisms  other than the induction of miR-15a/16-1 expression contribute to curcumin-induced WT1 downregulation. Taken together, as Additional file 1: Figure S2 indicated pure curcumin inhibited the cell growth partly through miR-15a/16-1 mediated downregulation of WT1.
Each miRNA typically targets mRNAs of hundreds of distinct genes by pairing to the mRNAs of protein-coding genes. Previous data had reported that Bcl-2 , WT1 , caprin-1  and HMGA1  were the target genes by miR-15a/16-1. WT1 and Bcl-2 are highly expressed in leukemic cells and function as oncogenes. The use of SiRNAs against WT1 and Bcl-2 in leukemic cells could effectively inhibit leukemic cells growth . Overexpression of miR-15a/16-1 in leukemic cells suppressed cell growth probably through targeting WT1 and Bcl-2. However it is difficult to estimate how much of the inhibition of cell growth in leukemic cells is attributable to the downregulation of WT1 or Bcl-2.
Recent studies have shown that natural agents, including curcumin, isoflavone, and EGCG, can regulate the expression of many miRNAs which increase the sensitivity of cancer cells to conventional agents and thereby suppress tumor cell proliferation [23, 24]. Zhang et al. reported that pure curcumin downregulated the expression of miR-186* in A549/DDP cells. Moreover, overexpression of miR-186* significantly inhibited curcumin-induced apoptosis in A549/DDP cells and transfection of cells with a miR-186* inhibitor promoted A549/DDP apoptosis . Mudduluru et al. demonstrated that in Rko and HCT116 cells curcumin reduced the expression of miR-21 in a dose-dependent manner by inhibiting AP-1 binding to the promoter of miR-21, and induced the expression of the tumour suppressor programmed cell death protein 4, which is a target of miR-21 . These data showed curcumin suppress tumor cell growth through downregulating a panel of onco-miRNAs. Saini et al. showed curcumin increased the expression of miR-203 via inducing the hypomethylation of the miR-203 promotes. This led to downregulation of miR-203 target genes Akt2 and Src resulting in decreased proliferation and increased apoptosis in bladder cancer cells . Bao et al. demonstrated that a novel curcumin analog CDF inhibited pancreatic tumor growth and aggressiveness through upregulating a panel of tumor suppressive miRNAs let-7, miR-26a, miR-101 and attenuating EZH2 expression . In a word curcumin suppress tumor cell growth through downregulating a panel of onco-miRNAs or upregulating a panel of tumor suppressive miRNAs. However, very little data reported that miRNAs besides miR-15a/16-1 could regulate the expression of WT1. More study were required to prove whether other miRNAs which target WT1 were regulated by curcumin.
Recently it has been reported that curcumin is an epigenetic agent. Curcumin inhibits the activity of DNA methyltransferase I (DNMT1) through covalently blocking the catalytic thiolate of C1226 of DNMT1. Global DNA methylation levels were decreased by approximately 20% in a leukemic cell line which is treated with 30 uM curcumin compared with untreated basal methylation levels . Curcumin can also modulates histone acetyltransferases (HAT) and histone deacetylases (HDACs) . Previous data had indicated that curcumin upregulated the levels of miR-15a and miR-16-1 in MCF-7 and other cells . Since curcumin is a DNA hypomethylation agent, epigenetic modulation of microRNA expression may be an important mechanism underlying biological effects of curcumin. Curcumin probably regulates the expression of miR-15a/16-1 through epigenetic modulation.
Overexpression of miR-15a and 16-1 downregulated the expression of WT1. Calin et al. showed that WT1 was a target gene of miR-15a/16-1 in MEG-01 cells by microarray and proteomics analysis . However, whether WT1 was directly targeted by miR-15a and miR-16-1 in leukemic cells was not verified in lab. Our previous data showed that overexpression of miR-15a and miR-16-1 in K562 and HL-60 cells significantly downregulated the protein level of WT1. However the mechanism of miR-15a/16-1 downregulating WT1 protein level is not through targeting mRNAs according to the degree of complementarity with their 3'untranlation region. In conclusion, miR-15a and miR-16-1 probably regulated WT1 expression through an indirect effect on WT1 .
Anti-miR-15a/16-1 has the ability to efficiently and specifically silence endogenous miR-15a and miR-16-1. Our data showed anti-miR-15a/16-1 could partly reverse the expression of WT1 in curcumin-treated K562 and HL-60 cells. These results suggest that the decrease of WT1 expression is partly attributable to the increased expression of miR-15a and miR-16-1 in curcumin-treated leukemic cells. Thus our data suggest that one of the important anti-proliferation effects of curcumin on leukemic cells is via miRNAs pathway. Given that many miRNAs are regulated by pure curcumin, many further experiments will be required to define other miRNAs besides miR-15a/16-1 are regulated by curcumin and play an important role in anti-tumor effects of curcumin.
Therefore, we conclude that pure curcumin can decrease WT1 expression partly through upregulating the expression of miR-15a and miR-16-1. Our data show for the first time that miRNAs pathway plays an important role in the function of anti-proliferation by pure curcumin in leukemic cells.
Conflict of interests
The authors declare that they have no competing interests.
The project supported by National Natural Science Foundation of China (81172613), Zhejiang Provincial Natural Science Foundation of China (Y2101069, Y206383, Y12H080019), Scientifical Research Foundation (Y201119952) of Zhejiang Provincial Education Department.
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