CN113528528B - shRNA for promoting apoptosis of imatinib-resistant chronic myelocytic leukemia cell K562/G01 and application thereof - Google Patents

shRNA for promoting apoptosis of imatinib-resistant chronic myelocytic leukemia cell K562/G01 and application thereof Download PDF

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CN113528528B
CN113528528B CN202110886139.0A CN202110886139A CN113528528B CN 113528528 B CN113528528 B CN 113528528B CN 202110886139 A CN202110886139 A CN 202110886139A CN 113528528 B CN113528528 B CN 113528528B
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黄波
章海斌
王小中
邹叶青
李书琪
刘静
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Abstract

The invention discloses a novel molecular target-DUSP 21 for promoting apoptosis of imatinib-resistant chronic myelocytic leukemia cells (K562/G01), and correspondingly provides a shRNA for inhibiting a target molecule and application thereof. The shRNA is psc60342 or psc60343, is targeted to DUSP21 gene and interferes with DUSP21 expression, can inhibit expression of DUSP21 in K562/G01 and promote apoptosis of K562/G01 cells, can be applied to preparation of medicines for inhibiting proliferation and apoptosis of human imatinib-resistant chronic myelocytic leukemia cells, and provides a new way for development of new medicines for treating imatinib-resistant chronic myelocytic leukemia.

Description

shRNA for promoting apoptosis of imatinib-resistant chronic myelocytic leukemia cell K562/G01 and application thereof
Technical Field
The invention relates to a novel molecular target-DUSP 21 for promoting imatinib-resistant chronic myelocytic leukemia cell apoptosis, and correspondingly provides a shRNA for inhibiting a target molecule and application thereof. Can be applied to the preparation of the medicines for inhibiting the proliferation and the apoptosis of the human imatinib-resistant chronic myelocytic leukemia cells and provides a new way for the development of new medicines for treating the imatinib-resistant chronic myelocytic leukemia.
Background
Chronic Myelogenous Leukemia (CML) is a common hematologic malignancy, with cytogenetic markers t (9; 22) (q 34; q11) forming Philadelphia chromosome (Ph), resulting in a fused BCR/ABL and BCR-ABL1, which encodes an oncoprotein with strong tyrosine kinase activity. Imatinib (IM) serving as a Tyrosine Kinase Inhibitor (TKI) can effectively reduce the level of BCR-ABL1 and improve the survival rate of patients, and is recommended to be a first-line clinical medicine. However, imatinib resistance occurs in approximately 15% to 20% of patients during clinical use and results in serious adverse consequences.
The mechanism of CML resistance to IM is currently classified into BCR-ABL1 dependent or non-BCR-ABL 1 dependent according to whether BCR-ABL1 is dependent or not. The former includes BCR-ABL1 kinase domain mutation such as T315I mutation, BCR-ABL1 kinase domain mutation such as SH2, SH3 domain mutation, DNA repair mechanism defect and over-expression of BCR-ABL 1; while the resistance mechanisms that BCR-ABL1 are not dependent on involve signaling pathways, drug transporters and plasma binding proteins, clonal evolution and epigenetic modifications, leukemic stem cells, bone marrow microenvironment, apoptotic defects, autophagy, and mitochondrial metabolism. Aiming at a drug resistance mechanism depended by BCR-ABL1, the current second-generation TKIs Dasatinib (Dasatinib, DA), Nilotinib (Nilotinib, NI), Bosutinib (BO) and third-generation TKI pinatinib (Ponatiniib, PO) enter the clinic, and the treatment effect of part of patients with IM drug resistance is effectively improved. However, the existing second-generation TKIs have no effect on the most frequently occurring T315I mutation of BCR-ABL 1; third-generation TKIs, although effective against all mutations, are at risk for abdominal pain, thrombocytopenia, severe arterial thrombosis, and heart failure. Aiming at a drug resistance mechanism which is not dependent on BCR-ABL1, researchers also carry out a large number of researches in multiple aspects such as targeting signal paths, targeting bone marrow microenvironment, targeting mRNA transcription and the like, unfortunately, all the strategies do not completely solve the problem of IM drug resistance, so that the research on a new IM drug resistance mechanism and the search of a new therapeutic target become a research hotspot of the current imatinib-resistant CML therapy.
The DUSP21 gene is located on the short arm of the X chromosome and comprises a 570 nucleotide sequence, only contains one exon, and the encoded protein is a member of the 190 amino acid family of human low molecular weight dual specificity phosphatase (DUSP). The physiological state DUSP21 is specifically expressed in testis, can be localized in cytoplasm and nucleus in cells, and has the function of clearing phosphate groups in phosphotyrosine and phosphothreonine residues. In 2002, Hood KL et al identified DUSP21 protein for the first time, and subsequently Rardin MJ et al found that DUSP21 was localized in the stroma of the inner and outer membranes in the mitochondria, while DUSP18, which corresponded to it, was localized in the membrane space of the inner and outer membranes. The clinical utility value of DUSP21, a newly identified molecule, has also been of increasing interest in recent years. In 2014, the Deng Q team discovered that 9 CT genes, including DUSP21, were required to maintain the survival of Focus nuclear PLC/PRF/5 cells when screening hepatocellular carcinoma for a new CT antigen (CT). Further research finds that DUSP21 is silenced to remarkably inhibit cell proliferation and clonogenic formation, so DUSP21 is proposed to be a potential target for hepatocellular carcinoma treatment. In addition to therapeutic potential, the Aziz team compared gene expression profiles of patients with colorectal cancer Dukes 'B and Dukes' C found that analysis of 19 genes including DUSP21 could provide a more accurate prediction of colorectal cancer patient survival. However, the therapeutic value of DUSP21 for imatinib resistant CML is currently unknown.
Disclosure of Invention
One of the technical problems to be solved by the invention is to provide DUSP21, a target molecule for targeted inhibition of imatinib-resistant chronic myelocytic leukemia cells.
The second technical problem to be solved by the invention is to provide an application of shRNA for targeted inhibition of DUSP21 gene expression in preparation of drugs for inhibiting proliferation and promoting apoptosis of imatinib-resistant CML cells.
In order to solve the problems, the invention provides shRNA for inhibiting the expression of a DUSP21 gene which is a chronic myelocytic leukemia cell target molecule resistant to imatinib, which is characterized in that: the shRNA is psc60342 or psc60343, wherein the psc60342 comprises a sense strand as shown in SEQ ID No.1 of the sequence table and an antisense strand as shown in SEQ ID No.2 of the sequence table; the psc60343 comprises a sense strand as shown in SEQ ID No.3 of the sequence Listing and an antisense strand as shown in SEQ ID No.4 of the sequence Listing.
The invention provides application of shRNA for targeted inhibition of DUSP21 gene expression in preparation of a medicament for treating chronic myelocytic leukemia.
The invention provides application of shRNA for targeted inhibition of DUSP21 gene expression in preparation of a drug for treating imatinib-resistant chronic myelocytic leukemia.
The invention provides application of shRNA for targeted inhibition of DUSP21 gene expression in preparation of a drug for inhibiting proliferation of imatinib-resistant chronic myeloid leukemia cells.
The invention provides application of shRNA for targeted inhibition of DUSP21 gene expression in preparation of a drug for promoting apoptosis of imatinib-resistant chronic myelocytic leukemia cells.
Preferably, in the application of the shRNA for targeted inhibition of the gene expression of the imatinib-resistant chronic myelocytic leukemia cell target molecule DUSP21, the shRNA is two shRNA of psc60342 and psc 60343.
The invention has the beneficial effects that:
the shRNA for targeted inhibition of human DUSP21 gene expression can inhibit expression of DUSP21 in imatinib-resistant CML cells, inhibit proliferation of target cells and promote apoptosis of the target cells. Therefore, the shRNA can be applied to preparation of medicines for treating CML, especially to treatment of imatinib-resistant CML, and can obviously inhibit proliferation and promote apoptosis of imatinib-resistant CML cells.
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FIG. 1 is a graph showing the results of the difference in gene expression between imatinib-resistant K562/G01 cells and imatinib-sensitive K562 cells;
FIG. 2 is a graph demonstrating the results of QPCR-verified expression of DUSP21 in different cell lines;
FIG. 3 is a graph showing the effect of Western Blot on DUSP21 protein expression by each shRNA;
FIG. 4 is a graph showing the effect of CCK-8 in identifying the inhibition effect of each shRNA on K562/G01 cell proliferation;
FIG. 5 is a graph showing the effect of Caspase3/7 and Annexin V-APC in identifying the promotion of apoptosis in K562/G01 by each shRNA.
Detailed Description
The following examples are intended to illustrate the invention only and are not intended to limit the scope of the invention. The experimental methods in the examples, in which specific conditions are not specified, are generally performed under conventional conditions.
Example 1
Analysis of gene expression difference of imatinib sensitive and drug resistant cells and verification of target gene
Respectively extracting total RNA of K562 cells sensitive to imatinib and K562/G01 cells resistant to imatinib, analyzing the gene expression conditions of the two cells by an Affymetrix gene expression profiling chip (shown in figure 1), and verifying the expression of a target gene DUSP21 in different cells by RT-PCR (shown in figure 2).
Sequence information of di and shRNA
According to the design principle of an RNA interference sequence, a DUSP21 gene is used as a template to design a 19-21nt RNA interference target sequence, an shRNA interference sequence is designed aiming at the target sequence, and suitable restriction enzyme cutting sites are added at two ends.
TABLE 1 shRNA sequence information
Figure BDA0003194258840000041
The AgeI enzyme cutting site is ACCGGT; EcoRI cleavage site GAATTC
Third, construction of vector and lentivirus packaging
Single-stranded DNA oligos having hairpin structures were synthesized by Shanghai Czeri according to different shRNAs in Table 1.
Restriction enzyme sites AgeI and EcoRI are selected as insertion sites of DNA fragments, DNA fragments corresponding to different shRNAs are used for GV115 vector construction, and the constructed vector with the target fragment and a no-load GV115 vector are used for packaging lentivirus. The method comprises the following specific steps:
1) the synthesized single-stranded DNA oligo dry powder was dissolved in annealing buffer (final concentration 20. mu.M), water-bathed at 90 ℃ for 15min, and naturally cooled to room temperature to form a double strand with a sticky end.
2) And (3) vector linearization: mu.l of GV115 Vector (1. mu.g/. mu.l), 5. mu.l of CutSmart Buffer, 1. mu.l of AgeI (10U/. mu.l)EcoRI (10U/. mu.l) 1. mu.l, plus H2The GV115 vector was linearized by reacting O to 50. mu.l at 37 ℃ for 1 h.
3) Connecting: take 1. mu.l of linearized Vector (100 ng/. mu.l), 1. mu.l of Insert (100 ng/. mu.l), 2. mu.l of 10 XT 4 DNA ligase Buffer, 1. mu.l of T4 DNA ligase, add H2And reacting the mixture O to 20 mu l at 16 ℃ for 1-3 h, and naming the ligation product as psc60342 and psc 60343.
4) And (3) transformation: adding 10 μ l of the ligation products psc60342 and psc60343 into 100 μ l of Escherichia coli competent cells, ice-bathing for 30min, heat-shocking for 90s at 42 ℃, ice-bathing for 2min, adding 500 μ l of LB culture medium without antibiotics, shaking and culturing at 2000rpm and 37 ℃ for 1 h; 150 μ l of the bacterial solution was applied to LB solid medium containing Amp and cultured overnight at 37 ℃.
5) Plasmid extraction and identification: and (3) extracting plasmids according to the instruction and carrying out enzyme digestion identification, carrying out enzyme digestion on the positive clone, then carrying out the size of a segment connected with psc60342 to be 379bp and the size of a segment connected with psc60343 to be 380bp, and finally verifying that the insertion sequence of the positive clone is completely correct through sequencing.
6) And (3) slow virus packaging: and (3) transfecting 293T cells by using PSC60342 and PSC60343 plasmids as an experimental group and using an unloaded plasmid GV115 as a control group, harvesting lentiviruses after 48h of transfection, respectively naming shDUSP21-PSC60342, shDUSP21-PSC60343 and shCtrl, and using the lentiviruses for subsequent experiments after quality detection is qualified.
Interference effect analysis of four and shRNA
Infecting K562/G01 cells with lentiviruses shDUSP21-PSC60342, shDUSP21-PSC60343 and shCtrl, and detecting the expression quantity and apoptosis condition of DUSP21 proteins of the K562/G01 cells, wherein the specific steps are as follows:
1) lentivirus infection of K562/G01 cells: infecting K562/G01 cells with lentivirus under the condition that MOI is 10-20, collecting the cells after 8-12 h, and replacing a normal culture medium for culture.
2) Expression of DUSP21 protein in K562/G01 cells: total protein of K562/G01 cells after virus infection was extracted, and DUSP21 expression was analyzed by Western Blot (see FIG. 3).
3) K562/G01 cell proliferation assay: CCK-8 measures proliferation of K562/G01 cells after viral infection (see FIG. 4).
4) Apoptosis assay of K562/G01: caspase3/7 and Annexin V-APC were tested for apoptosis in K562/G01 cells after viral infection (see FIG. 5).
As shown in FIG. 3, the shRNA (psc60342 and psc60343) of the present invention significantly inhibited the expression of human DUSP21 in K562/G01 cells.
As can be seen from FIGS. 4-5, after the shRNA (psc60342 and psc60343) of the invention inhibits the expression of DUSP21, the proliferation of K562/G01 is obviously lower than that of a control group, and the apoptosis is obviously higher than that of the control group, which indicates that the down-regulation of the expression of human DUSP21 gene can achieve the effects of inhibiting the cell proliferation and promoting the cell apoptosis on K562/G01.
Therefore, the shRNA (psc60342 and psc60343) can be applied to preparation of a preparation for inhibiting the cell proliferation of K562/G01 and promoting the apoptosis of K562/G01, and provides a new way for treating imatinib-resistant chronic myelocytic leukemia.
Sequence listing
<110> second subsidiary Hospital of Nanchang university
<120> shRNA for promoting apoptosis of imatinib-resistant chronic myelocytic leukemia cell K562/G01 and application thereof
<160> 4
<170> SIPOSequenceListing 1.0
<210> 1
<211> 40
<212> RNA
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> misc_RNA
<223> shRNA
<400> 1
ccgggacaca gagaaggacc accgagaggc cccaagagcg 40
<210> 2
<211> 43
<212> RNA
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> misc_RNA
<223> shRNA
<400> 2
aacaaaaaga cacagagaag gaccaccgag aggccccaag agc 43
<210> 3
<211> 40
<212> RNA
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> misc_RNA
<223> shRNA
<400> 3
ccggcagaca aaagggccgc cgagaacagg caccagacgg 40
<210> 4
<211> 43
<212> RNA
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> misc_RNA
<223> shRNA
<400> 4
aacaaaaaca gacaaaaggg ccgccgagaa caggcaccag acg 43

Claims (6)

1. The application of shRNA in preparing a medicament for treating chronic myelocytic leukemia is characterized in that: the shRNA is psc60342 or psc60343, wherein the psc60342 comprises a sense strand
5'-CCGGGACATCTATGAGAAGGACCTACTCGAGTAGGTCCTTCTCATAGATGTCTTTTTG-3' and antisense strand
5’-AATTCAAAAAGACATCTATGAGAAGGACCTACTCGAGTAGGTCCTTCTCATAGATGTC-3’；
The psc60343 comprises a sense strand
5’-CCGGCAGTACATAAAGGTGCCTGTTCTCGAGAACAGGCACCTTTATGTACTGTTTTTG-3’
And antisense strand
5’-AATTCAAAAACAGTACATAAAGGTGCCTGTTCTCGAGAACAGGCACCTTTATGTACTG-3’。
2. The application of shRNA (short hairpin ribonucleic acid) as claimed in claim 1 in preparing a medicament for inhibiting the expression of imatinib-resistant chronic myelocytic leukemia cell DUSP21 gene.
3. The use of an shRNA according to claim 1 for the preparation of a medicament for the treatment of imatinib-resistant chronic myeloid leukemia.
4. The use of the shRNA according to claim 1 in the preparation of a medicament for inhibiting imatinib-resistant chronic myeloid leukemia cell proliferation.
5. The use of the shRNA according to claim 1 in the preparation of a medicament for promoting apoptosis of imatinib-resistant chronic myeloid leukemia cells.
6. The application of shRNA in preparing a medicament for treating chronic myelocytic leukemia is characterized in that: the shRNA is two shRNA of psc60342 and psc60343, wherein the psc60342 and psc60343 are as in claim 1.
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