CN110423812A - Skiv2l2(MTR4) purposes of the gene in oncotherapy - Google Patents
Skiv2l2(MTR4) purposes of the gene in oncotherapy Download PDFInfo
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- CN110423812A CN110423812A CN201910593437.3A CN201910593437A CN110423812A CN 110423812 A CN110423812 A CN 110423812A CN 201910593437 A CN201910593437 A CN 201910593437A CN 110423812 A CN110423812 A CN 110423812A
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- mtr4
- skiv2l2
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/65—Tetracyclines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
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- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/178—Oligonucleotides characterized by their use miRNA, siRNA or ncRNA
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Abstract
The present invention relates to a kind of purposes of Skiv2l2 (MTR4) gene in oncotherapy, belong to gene therapy and area of medical diagnostics.Purposes the present invention provides Skiv2l2 (MTR4) gene as target in screening tumor therapeutic agent, the DNA sequence dna of Skiv2l2 (MTR4) gene is as shown in SEQ ID NO:1.The present invention carries out Knockdown using shRNA, reduces Skiv2l2 (MTR4) in the expression of liver cancer cells, effectively inhibits growth, the proliferation, internal one-tenth knurl ability of tumour cell；Skiv2l2 (MTR4) can achieve the effect that treat liver cancer in the treatment of liver cancer as the application of neoplasm targeted therapy by striking its low expression as a result,.
Description
Technical field
The present invention relates to a kind of purposes of Skiv2l2 (MTR4) gene in oncotherapy, belong to gene therapy and medicine
Diagnostic field.
Background technique
The discovery of oncogene and tumor repressive gene has epoch-making meaning in the history of tumor research room, is the mankind in cancer
Recognize on etiological study enrich constantly it is perfect as a result, and people start from molecular level recognize tumour important symbol.
They widely exist in the normal physiology course such as the proliferation for participating in cell into the cell, differentiation and apoptosis and adjust, and are that cell is raw
Indispensable important composition ingredient in life activity.
Oncogene is a kind of base that can cause normal cell turnover in vitro by its expression product, cause carcinoma in vivo
Cause.Oncogene is found to be present in virus, and then there is also and similar to viral oncogene in normal cellular genes group
It is homologous, cancer is active to be known as proto-oncogene to this genoid without promoting, and it is important that expression product participates in cell Proliferation, differentiation etc.
Physiological effect process.When cell is by various biologies, physical and chemical effect, proto-oncogene can be by the recurring structures such as being mutated, recombinating
Or expression is abnormal, becomes the oncogene for promoting cell transformation, finally causes the generation of tumour.Therefore, the research of oncogene
There can be deeper understanding to generation, the development of tumour with let us, to the diagnosis of tumour, parting, the selection of therapeutic scheme, treatment
Have broad application prospects on reaction and Index for diagnosis, provides further strategy for the treatment of clinically tumour.
Summary of the invention
It is an object of the invention to provide a kind of Skiv2l2 (MTR4) gene in place of overcome the deficiencies in the prior art to exist
Purposes in oncotherapy can effectively inhibit tumour by reducing expression of Skiv2l2 (MTR4) gene in tumour cell
Cell growth, proliferation, to achieve the purpose that antitumor.
To achieve the above object, the technical scheme adopted by the invention is as follows:
In a first aspect, the present invention provides Skiv2l2 (MTR4) gene as target screening tumor therapeutic agent in
Purposes, the DNA sequence dna of Skiv2l2 (MTR4) gene is as shown in SEQ ID NO:1.
Studies have shown that Skiv2l2 (MTR4) gene is overexpressed in liver cancer cells, when reduction Skiv2l2 (MTR4) gene
When expression in liver cancer cells, growth, the proliferation of tumour cell can be effectively suppressed, to achieve the purpose that antitumor.As a result,
It can be using Skiv2l2 (MTR4) gene as target for screening tumor therapeutic agent.
Embodiment as a preferred embodiment of the above technical solution, the tumour are liver cancer.
Embodiment as a preferred embodiment of the above technical solution, the tumor therapeutic agent include shRNA, the shRNA's
Base sequence is GGAAGGATTTCCGATGGATTT (as shown in SEQ ID NO:2).ShRNA, that is, short hairpin RNA.ShRNA can
The expression for reducing target gene is interfered to cause phenotypic alternation by RNA.The present invention strikes bottom Skiv2l2 (MTR4) using shRNA
Expression of the gene in liver cancer cells.
Embodiment as a preferred embodiment of the above technical solution, the tumor therapeutic agent also include inducible shRNA in body
The inducer of interior expression.
Second aspect, the present invention provides the reagents that can reduce Skiv2l2 in tumour cell (MTR4) gene expression to make
Purposes in standby tumor therapeutic agent, the DNA sequence dna of Skiv2l2 (MTR4) gene is as shown in SEQ ID NO:1.It reduces
The reagent of Skiv2l2 (MTR4) gene expression includes but is not limited to that Skiv2l2 (MTR4) gene expression is made to strike bottom in tumour cell
Reagent.
Embodiment as a preferred embodiment of the above technical solution, the tumour are liver cancer.
Embodiment as a preferred embodiment of the above technical solution, it is described to reduce Skiv2l2 in tumour cell (MTR4) gene
The reagent of expression includes shRNA, and the base sequence of the shRNA is GGAAGGATTTCCGATGGATTT (such as SEQ ID NO:2
It is shown).
The third aspect, the present invention also provides a kind of tumor therapeutic agent, the tumor therapeutic agent is swollen comprising that can reduce
The reagent of Skiv2l2 (MTR4) gene expression in oncocyte, the DNA sequence dna such as SEQ ID of Skiv2l2 (MTR4) gene
Shown in NO:1.
Embodiment as a preferred embodiment of the above technical solution, it is described to reduce Skiv2l2 in tumour cell (MTR4) gene
The reagent of expression includes shRNA, and the base sequence of the shRNA is GGAAGGATTTCCGATGGATTT (such as SEQ ID NO:2
It is shown).
Embodiment as a preferred embodiment of the above technical solution, the tumor therapeutic agent also include inducible shRNA in body
The inducer of interior expression；It is highly preferred that the inducer that the inducible shRNA is expressed in vivo is fortimicin
(Doxycycline)。
Compared with prior art, the invention has the benefit that Skiv2l2 (MTR4) is overexpressed in liver cancer cells, this
Invention using shRNA carry out gene strike it is low, reduce Skiv2l2 (MTR4) in the expression of liver cancer cells, effectively inhibit swollen
The growth of oncocyte, proliferation.Skiv2l2 (MTR4) can pass through in oncotherapy as the application of neoplasm targeted therapy as a result,
Its low expression is struck to achieve the effect that treat tumour.
The present invention is sent out also according to character mutation of the low rear observation to tumour is struck to study Skiv2l2 (MTR4) in tumour
It is acted in exhibition, its binding mode and regulatory mechanism to tumour is illustrated with this, established to develop the target spot of clinical cancer therapy
Basis.
Detailed description of the invention
Fig. 1 is 1 conditional knockdown of the embodiment of the present invention (conditionity refers to tetracycline-regulated gene expression system) Skiv2l2
(MTR4) influence of the expression to Tumor formation in human hepatoma cell strain HEPG2 body；
Fig. 2 is 1 conditional knockdown of the embodiment of the present invention (conditionity refers to tetracycline-regulated gene expression system) Skiv2l2
(MTR4) influence of the expression to Tumor formation in human hepatoma cell strain PLC/RPF/5 body；
Fig. 3 is that present invention implementation 2 strikes low Skiv2l2 (hMTR4) expression to human hepatoma cell strain HEPG2 and PLC/RPF/5
In vitro to the influence of tumor proliferation and Colony forming；
Fig. 4 is the influence result figure of MTR4 shRNA and control group to HepG2 cell lines and PLC/RPF/5；Its
In, SC indicates scrambled；KD indicates knockdown.
Specific embodiment
Purposes, technical schemes and advantages in order to better illustrate the present invention, below in conjunction with the drawings and specific embodiments pair
The present invention is described further.
Embodiment 1
A kind of embodiment of purposes of Skiv2l2 (MTR4) gene of the present invention in oncotherapy, the present embodiment use
ShRNA reduces the expression of Skiv2l2 (MTR4) gene in tumour cell, and steps are as follows for the specific experiment of the present embodiment:
A, Animal Model
A, experimental animal
The NOD/SCID mouse of 6~8 week old of animal 10,20~25g of weight are provided by Beijing Experimental Animal Center.
B, divide experimental group and control group
Control group: it is transferred to and strikes low Skiv2l2 (MTR4) containing conditionity (conditionity refers to tetracycline-regulated gene expression system)
(carrier contains ShMTR4 targeting sequence to carrier, and ShMTR4 targets sequence as shown in SEQ ID NO:2, specially
GGAAGGATTTCCGATGGATTT HepG2, PLC/RPF/5 cell strain)；
Experimental group: it is transferred to and strikes low Skiv2l2 (MTR4) containing conditionity (conditionity refers to tetracycline-regulated gene expression system)
(carrier contains ShMTR4 targeting sequence to carrier, and ShMTR4 targets sequence as shown in SEQ ID NO:2, specially
GGAAGGATTTCCGATGGATTT HepG2, PLC/RPF/5 cell strain), drug-induced target gene strike low.
C, subcutaneous tumor formation
Take 10 mouse (20~25g/ only), by be transferred to containing conditionity Skiv2l2 (MTR4) strike low carrier HepG2,
PLC/RPF/5 cell is collected, and is resuspended with cold 150ulPBS, is inoculated under the lower limb skin of left and right respectively.
Grows transplantable tumor for 2-3 weeks or so after transplanting, when transplantable tumor grows to 5mm3When left and right, it is divided into two groups, one group is given
Doxycycline (fortimicin) induces the internal expression of shRNA, and one group is not given Doxycycline (fortimicin), continuously
Administration 12 days takes pictures after dissection and peels subcutaneous knurl, claims knurl weight, take pictures.
Experimental result
Influence of low Skiv2l2 (MTR4) expression to Tumor formation in human hepatoma cell strain HEPG2 body is struck as shown in Figure 1, striking
Influence of low Skiv2l2 (MTR4) expression to Tumor formation in human hepatoma cell strain PLC/RPF/5 body is as shown in Figure 2.By Fig. 1 and figure
2 as it can be seen that plus inducer Doxycycline, induction Skiv2l2 (MTR4) express reduction group, its size and weight of transplantable tumor compare
Low and light according to organizing, growth is also relatively slow.
Conclusion:
It is above-mentioned the results showed that using Knockdown technology, reduce the expression quantity of Skiv2l2 (MTR4) gene, can have
Effect ground inhibits the growth of tumour cell, proliferation.The method that this experiment uses inside and outside to combine, it is real from cell in vitro and internal mouse
It tests to verify, Skiv2l2 (MTR4) can be used as the target of oncotherapy and diagnosis.
Embodiment 2
A kind of embodiment of purposes of Skiv2l2 (MTR4) gene of the present invention in oncotherapy, the present embodiment are investigated
The influence of MTR4 shRNA gene pairs HepG2 cell lines, PLC/RPF/5 proliferation, specific step is as follows for the present embodiment:
By MTR4 shRNA (experimental group, sequence is as shown in SEQ ID NO:2, specially GGAAGGATTTCCGATGGATTT) with compare
Group (Scramble, sequence CCTAAGGTTAAGTCGCCCTCG) is transferred to respectively in human liver cancer cell HepG2, PLC/RPF/5,
It establishes and surely turns cell line.The influence of measurement experiment group and control group to liver cancer cells, as a result as shown in Figure 4.
A. experimental material
A. cell strain is to HepG2 cell lines, PLC/RPF/5
B. reagent and instrument
Fetal calf serum (Gemini Bio company), DMEM culture medium (Gibco company), trypsase (Gibco company),
PBS (Gibco company), Cell Counting Kit-8 (DOJINDO company), violet staining liquid (Beyontime company),
BioTek ELx800 microplate reader (BioTek company, the U.S.), the desk-top autobalance centrifuge (Eppendorf 5702) of low speed, blood
Ball count plate (Shanghai City refinement biochemical reagents Instrument Ltd.), inverted fluorescence microscope (NIKON-Ti-U).
B. experimental method
A. control group and when experimental group HepG2, PLC/RPF/5 cell culture growth to exponential phase of growth, i.e., with 0.25%
Trypsin digestion, 1000 × g are centrifuged 5min, and cell precipitation is resuspended with the DMEM culture medium of 10%FBS, with blood counting chamber meter
Number, the every hole of 96 orifice plates is inoculated with 5000 cells, the cell hole of inoculation 4 days, while 6 orifice plates are inoculated with 500 cells, are placed in 37 DEG C,
It is cultivated under the conditions of 5%CO2 and saturated humidity.
B, divide experimental group and control group
Control group: HepG2, PLC/RPF/5 cell strain containing Control shRNA carrier are transferred to；Control shRNA
Targeting sequence is CCTAAGGTTAAGTCGCCCTCG.
Experimental group: it is transferred to containing HepG2, PLC/RPF/5 cell strain for striking low Skiv2l2 (MTR4) shRNA carrier；
It is GGAAGGATTTCCGATGGATTT that ShMTR4, which targets sequence,.
C. experimental group and control histone are collected respectively, detect the expression of Skiv2l2 (MTR4) at two groups.
10ulCCK-8 solution is added for 24 hours, after 48h, 72h, 96h to every hole in cell culture, cultivates 1h in the incubator, uses
Microplate reader measurement is the absorbance value (OD) at 450nm in wavelength.
After cell culture 2 weeks, the fixed 15min of 2ml methanol is added in every hole, then uses violet staining 30min, PBS washing
Several times, 6 orifice plates are dried, are taken pictures.
C. experimental result
As a result as shown in figure 3, as seen from Figure 3: knock out the proliferation that can inhibit tumour cell after Skiv2l2 (MTR4) gene and
Cell viability.
Finally, it should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention rather than protects to the present invention
The limitation of range is protected, although the invention is described in detail with reference to the preferred embodiments, those skilled in the art should
Understand, it can be with modification or equivalent replacement of the technical solution of the present invention are made, without departing from the essence of technical solution of the present invention
And range.
SEQUENCE LISTING
<110>Nanfang Medical Univ
<120>Skiv2l2(MTR4) purposes of the gene in oncotherapy
<160> 2
<170> PatentIn version 3.3
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<211> 4222
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aaaagtcagg ggaacatttt tgtcggctgc gcgactcgac tacttttgtc tcctgcgggc 180
cactgttgag ccttcacgag acgtcactgt cttcggtcgc ggggcatcgt gggtaggagg 240
gagatttgct ctcactgctc ccaaaaatgg cggacgcatt cggagatgag ctgttcagcg 300
tgttcgaggg cgactcgacc actgcggcgg gaaccaaaaa agacaaggaa aaggacaagg 360
ggaaatggaa ggggcctcca gggtctgcag acaaggcagg gaaacgtttt gatggtaaat 420
tacaatcaga atcaactaat aatggaaaaa ataagagaga tgtagatttc gaaggtacag 480
atgaacccat ttttggaaag aagcccagga tagaagagtc aataactgaa gacttaagtt 540
tggcagacct gatgcccaga gtcaaggtac aatcagttga aactgttgaa gggtgtacac 600
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ctgctaagga atacccgttc attcttgatg cttttcaaag agaggccatt cagtgtgttg 720
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aggctctgag taaccaaaaa taccgtgaaa tgtatgaaga atttcaagat gttggtttga 900
tgactggtga tgttactatt aatcctacgg catcttgtct tgttatgacc acagagattt 960
tgagaagtat gctttacaga ggttccgaag ttatgagaga agttgcttgg gttatatttg 1020
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tgcttcctga taacgtccac tatgtctttc tttcggctac tattccaaat gcccgacagt 1140
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ggcccactcc attgcaacac tacatttttc cagcaggggg agatggcctg catcttgtgg 1260
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atgcaggtga tttggccaaa ggagaccaga aagggcggaa aggaggaaca aaaggaccat 1380
caaatgtttt caaaattgtg aagatgatta tggaaagaaa tttccaacct gtgattattt 1440
tcagttttag taagaaagat tgtgaagcct atgcacttca aatgaccaaa ttagatttca 1500
acacagatga agaaaagaag atggttgaag aagtattcag taatgcaatt gattgcttat 1560
ccgatgaaga taaaaaactc cctcaggtag aacatgtact tcctcttttg aagaggggaa 1620
ttggtattca ccatggtggt ttacttccta ttttgaaaga aactatagaa attctctttt 1680
ctgaaggatt gataaaggcc ttatttgcca cggagacctt tgctatggga attaacatgc 1740
cagctagaac tgttttattt acaaatgccc gcaaatttga tgggaaggat ttccgatgga 1800
tttcttctgg tgaatacatt cagatgtctg gtcgtgctgg aaggagagga atggatgata 1860
gaggaattgt aattcttatg gtagatgaaa agatgagccc aacaattgga aaacaattac 1920
ttaagggctc cgctgatcct ctaaatagtg ctttccattt gacctacaac atggttttga 1980
acttactacg tgtagaagaa attaatcctg agtacatgtt ggaaaaatcc ttctaccagt 2040
ttcagcatta tagagcaatt ccaggagtag tagagaaggt aaagaattca gaagaacagt 2100
ataataaaat agtaattccc aatgaagaaa gtgtggttat ctattataag attagacagc 2160
agcttgccaa attgggtaaa gaaattgaag aatatattca caaaccaaaa tactgcttac 2220
cttttctaca accaggtcgt ttggtaaagg taaagaatga aggagatgac tttggctggg 2280
gagtagtggt gaatttctca aaaaagtcaa atgttaagcc taactctggt gaactggatc 2340
ctttgtatgt agtagaagta cttctgcgct gtagcaaaga gagcttgaaa aattcagcta 2400
cagaagctgc aaaaccagct aaacctgatg agaaaggaga gatgcaggtt gtcccagttt 2460
tggtgcatct cctgtctgct atcagcagtg ttaggcttta cattcctaaa gaccttcggc 2520
cggtggacaa tagacagagt gttttaaaat caatacagga agttcagaaa cgttttcctg 2580
acggcatccc cttattagac cctattgatg atatgggcat tcaagatcaa gggctgaaaa 2640
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ttaaatctgc aaagcgagaa ctgaagaaag caagaacagt cctacaaatg gatgaactca 2820
aatgtcgcaa acgtgtttta agaaggttgg gatttgctac ttcttctgat gtaatagaga 2880
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tgtttaatgg ccttttcaat gacctttctg cagaacaggc aacagcatta ttaagctgct 3000
ttgtgtttca agagaattct agtgagatgc ccaaattaac agaacaatta gcaggaccac 3060
ttcgtcaaat gcaggaatgt gctaaaagaa ttgcaaaagt ttcagcagaa gccaaattgg 3120
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cctgggcaac tggagctaca tttgcccata tctgcaaaat gacagatgtc tttgaaggca 3240
gcataattcg ttgtatgagg cgcctggaag aattgcttcg acaaatgtgt caagcagcaa 3300
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taaattattg accacctgtt tgattacagt tgactacaaa tgcctgcaag tgtggatttg 3480
gttctcccat acattttaat atgtattata tttaaatcaa acatcattca tagaaagcat 3540
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gcactgtttt ggtggaaggc ttggagtttt tttaatgagt ttagagctat tagataacca 3660
ctgagttaaa ggtaactatg tacacacaaa gtgtgcatcc aagaggcata gcagcagcag 3720
aagtctttaa aggcttgtac accaggaaga aagatgcatc ctcttgcctt gtggcaatca 3780
ttttccttta gaaaacaggc cagcttcacc tgggcaccct gctgcctttc aaggctggtg 3840
attgctcgga tagtgattcc cagttgttgg tgtttcatgc agagttgtat gagagtcctc 3900
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atcaacagca tcctaagata aatataaaca aaaggatata ctttgaggtg tacagattaa 4080
gcatataaaa aattagagac taactgggat tttttaaaga ttattccaaa ttaagagttg 4140
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ggaaggattt ccgatggatt t 21
Claims (10)
- Purposes of 1.Skiv2l2 (MTR4) gene as target in screening tumor therapeutic agent, Skiv2l2 (MTR4) base The DNA sequence dna of cause is as shown in SEQ ID NO:1.
- 2. purposes as described in claim 1, which is characterized in that the tumour is liver cancer.
- 3. purposes as described in claim 1, which is characterized in that the tumor therapeutic agent includes shRNA, the shRNA's Base sequence is GGAAGGATTTCCGATGGATTT.
- 4. purposes as claimed in claim 3, which is characterized in that the tumor therapeutic agent also includes inducible shRNA in body The inducer of interior expression.
- 5. purposes of the reagent of Skiv2l2 in tumour cell (MTR4) gene expression in preparation tumor therapeutic agent can be reduced, The DNA sequence dna of Skiv2l2 (MTR4) gene is as shown in SEQ ID NO:1.
- 6. purposes as claimed in claim 5, which is characterized in that the tumour is liver cancer.
- 7. purposes as claimed in claim 5, which is characterized in that described to reduce Skiv2l2 in tumour cell (MTR4) gene The reagent of expression includes shRNA, and the base sequence of the shRNA is GGAAGGATTTCCGATGGATTT.
- 8. a kind of tumor therapeutic agent, which is characterized in that the tumor therapeutic agent includes that can reduce Skiv2l2 in tumour cell (MTR4) reagent of gene expression, the DNA sequence dna of Skiv2l2 (MTR4) gene is as shown in SEQ ID NO:1.
- 9. tumor therapeutic agent as claimed in claim 8, which is characterized in that described to reduce Skiv2l2 in tumour cell (MTR4) reagent of gene expression includes shRNA, and the base sequence of the shRNA is GGAAGGATTTCCGATGGATTT.
- 10. tumor therapeutic agent as claimed in claim 9, which is characterized in that the tumor therapeutic agent also includes inducible The inducer that shRNA is expressed in vivo；Preferably, the inducer that the inducible shRNA is expressed in vivo is fortimicin.
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