CN102145181A - siRNA for inhibiting tumor growth and oligomeric nucleic acid combination and application of siRNA - Google Patents
siRNA for inhibiting tumor growth and oligomeric nucleic acid combination and application of siRNA Download PDFInfo
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Abstract
The invention discloses a siRNA for inhibiting tumor growth and oligomeric nucleic acid combination and application of the siRNA. The oligomeric nucleic acid of the invention is double-strand RNA as the following 1) or 2): 1) oligomeric nucleic acid siPTN consisting of sequence 1 and sequence 2 in a sequence table; and 2) double oligomeric nucleic acid consisting of the oligomeric nucleic acid siPTN of 1) and miR-34a, wherein the miR-34a is the oligomeric nucleic acid consisting of sequence 3 and sequence 4 in the sequence table. Tumor cells are inoculated to nude mice, and after tumors are formed, the experiment in which the oligomeric nucleic acid is used for treatment proves that the oligomeric nucleic acid combination can inhibit in-vivo growth of tumors effectively. As a novel small nucleic acid-type antitumor drug, the siRNA chemically synthesized and modified is hardly degraded, has long effect half-life, and can be used for in vitro experiment, even for in vivo treatment.
Description
Technical field
The present invention relates to suppress siRNA and the nucleic acid oligomer combination and the relevant application of tumor growth.
Background technology
Pleiotrophin (PTN) (PTN) is a kind of secreted somatomedin, and it has the pleiotropy function, plays an important role in increment, differentiation and the vascularization of cell.Discover PTN at the cerebral tumor, breast carcinoma, cancer of pancreas, colon cancer, gastric cancer, pulmonary carcinoma, carcinoma of testis, kinds of tumors such as melanoma are organized and high expressed all occurred and seldom expression in normal tissue.Therefore infer and select the specificity of PTN, the characteristics of the universality of tumor are arranged again as the existing tumor of target spot of oncotherapy.Because PTN can stimulating cellular growth, can quicken angiogenesis again,, growth of tumor and transfer may can be suppressed effectively with the expression of the reticent PTN of siRNA.According to the different mechanism of tumor development, PTN-siRNA is formed different prescriptions with other antineoplastic siRNA (siRNA) and small nucleic acid (miRNA), will more can treat neoplastic disease effectively than single PTN-siRNA.
Summary of the invention
The object of the present invention is to provide a kind of nucleic acid oligomer to suppress the reagent or the application in inhibition PTN expresses of tumor growth in preparation; Described nucleic acid oligomer is following 1) or 2) double-stranded RNA:
1) the nucleic acid oligomer siPTN that sequence 1 and sequence 2 are formed in the sequence table;
2) the duoupoly polynucleic acid that nucleic acid oligomer siPTN described 1) and miR-34a form, described miR-34a are the nucleic acid oligomers that sequence 3 and sequence 4 are formed in the sequence table.
Further, above-mentioned 2) nucleic acid oligomer siPTN in the duoupoly polynucleic acid, described 1) and the mass ratio of miR-34a are (0.5-2): (0.5-2), and preferably 1: 1.
In actual applications, above-mentioned nucleic acid oligomer can be through following 1) or 2) modify the nucleic acid oligomer that obtains:
1) phosphodiester bond of the connection nucleotide of described nucleic acid oligomer is modified, preferably the oxygen with described phosphodiester bond replaces with sulfur;
2), preferably described 2 '-OH is replaced with methoxyl group or fluorine or described 2 '-OH is carried out deoxidation modify to the modification of 2 '-OH of the ribose of described nucleic acid oligomer.
In the above-mentioned sequence table sequence 1,3,5 from left to right direction be 5 '-3 ', in the sequence table sequence 2,4,6 from left to right direction be 3 '-5 '.
Above-mentioned tumor can be intestinal cancer, nasopharyngeal carcinoma, cervical cancer, hepatocarcinoma, breast carcinoma or pulmonary carcinoma.
Can comprise at least a and at least a pharmaceutically acceptable carrier in the above-mentioned nucleic acid oligomer molecule in the mentioned reagent." pharmaceutically acceptable carrier " used herein should be compatible with the double stranded rna molecule in the pharmaceutical composition of the present invention.In a preferred embodiment, described " pharmaceutically acceptable carrier " is meant transfection reagent in the body, as polymine (PEI), and jetPEI (linear polyethylene imines), TF-PEI (transferrins polymine) liposome, transferrins, folic acid etc.
Above-mentioned nucleic acid oligomer is chemosynthesis, can carry out 2 ' fluoro (2 '-F), 2 ' methoxyl group (2 '-OMe), sulfo-(PS) and 2 ' deoxidation (2 '-chemical modification such as deoxy).
Experimental result with chemosynthesis and the above-mentioned nucleic acid oligomer molecule transfection human nasopharyngeal epithelioma 1 CNE that modifies, colon-cancer cell strain HCT116, breast carcinoma cell strain MCF7, tumor cells such as cervical cancer cell strain Hela, hepatoma cell strain HepG2 shows described 1) or 2) nucleic acid oligomer can effectively suppress the propagation of above-mentioned tumor cell, specifically as shown in Figure 6, the average tumor heavy and light 38.2% of siPTN individual processing group and matched group (PBS), the heavy PBS of average tumor of mixing treatment group organizes light by 51.89%.
Tumor cell inoculation in nude mice, is formed the described nucleic acid oligomer combination that experimental results show that for the treatment of with described nucleic acid oligomer after the tumor and can effectively suppress growth of tumor in vivo.
As the antitumor drug of novel small nut acids, chemosynthesis and the described nucleic acid oligomer of modifying are difficult for being degraded, and the long effect half-life is arranged, and can be used for experiment in vitro, more can be used for interior therapeutic.
Description of drawings
Fig. 1 detects the bar diagram that siPTN suppresses tumor cell proliferation for mtt assay.
Fig. 2 detects the expression that siPTN suppresses tumor cell PTN for QRT-PCR.
Fig. 3 is that RT-PCR detects the PTN that siPTN suppresses tumor cell and expresses, 2 '-F-siPTN swimming lane 1-4 is respectively transfection siPTN, transfection 2 '-F-siPTN, the cell of untransfected, the negative control of transfection random sequence (NC).
Fig. 4 is 2 '-F-siPTN and 5 later nude mice tumor effect figure of nucleic acid oligomer treatment intestinal cancer transplanted tumor thereof.
Fig. 5 is 2 '-F-siPTN and 6 later tumor volume broken line graphs of nucleic acid oligomer combined therapy intestinal cancer thereof.
Fig. 6 is 2 '-F-siPTN and nucleic acid oligomer combination thereof add 6 heavily bar diagrams of later tumor of treatment intestinal cancer.
Fig. 7 is 2 '-F-siPTN and nucleic acid oligomer combined therapy intestinal cancer thereof 6 times after tumor effect figure.
The specific embodiment
The invention will be further described below in conjunction with specific embodiment, but the present invention is not limited to following examples.
Among the following embodiment, if no special instructions, be conventional method.
The preparation of embodiment 1, nucleic acid oligomer
The PTN-s of nucleic acid oligomer described in the present invention iRNA sequence positive-sense strand is: 5 '-GCCCAAACCUCAAGCAGAATT-3 ' (SEQ ID No.1); Antisense strand is 3 '-TTCGGGUUUGGAGUUCGUCUU-5 ' (SEQ ID No.2); The miR-34a positive-sense strand is 5 '-UGGCAGUGUCUUAGCUGGUUGU-3 ' (SEQ ID No.3) among the present invention; Antisense strand is 3 '-UUACCGUCACAGAAUCGACCAA-5 ' (SEQ ID No.4); Random sequence described in the present invention is as negative control (NC), and the positive-sense strand sequence of NC is: 5 '-UUCUCCGAACGUGUCACGUTT-3 ' (SEQ ID No.5), the antisense strand sequence is: 3 '-TTAAGAGGCUUGCACAGUGCA-5 ' (SEQ ID No.6).A, G, C, U in described nucleic acid oligomer and the NC sequence represents adenine ribonucleotide, guanosint ribotide, cytosine ribonucleotide and uracil ribonucleotide, and T represents thymidylic acid.
Described nucleic acid oligomer and NC entrust Shanghai lucky agate (GenePharma) Pharmaceutical Technology Inc. synthetic and carry out following any one chemical modification: 2 ' methoxyl group (2 '-OMe), 2 ' fluoro (2 '-F), sulfo-and 2 '-deoxidation (2 '-deoxy), handle through lyophilizing then and obtain the nucleic acid oligomer powder, be used for the experiment of embodiment 2-4.
Wherein: miR-34a after 2 ' fluoro is modified called after 2 '-F-miR-34a; PTN-siRNA after 2 ' methoxyl group is modified called after 2 '-F-siPTN; NC after 2 ' fluoro is modified called after 2 '-F-NC.
Above-mentioned synthetic method be derived from one piece nineteen ninety-five disclosed document: Wincott F, DiRenzo A, Shaffer C, GrimmS, Tracz D, Workman C, Sweedler D, Gonzalez C, Scaringe S and Usman N.Synthesis, deprotection, analysis and purification of RNA and ribozymes.Nucleic Acids Res.1995,23:2677-84.Whole chemosynthesis can roughly be divided into four process (1) oligomerization ribonucleic acid synthetic; (2) deprotection; (3) purifies and separates; (4) the desalination aseptic sterilization of annealing.
(1) the oligomerization ribonucleotide is synthetic
In that automated DNA/the RNA synthesizer (for example, Applied Biosystems EXPEDITE8909) goes up the RNA that sets synthetic 1 mM, setting each circulation coupling time simultaneously is 10-15 minute, starting material is that 5 '-O-of connecting of solid phase is to dimethoxy-thymidine holder, first circulates in and connects a base on the solid support, then in the n time (19 〉=n 〉=2) circulation, on the base that the n-1 time circulation connected, connect a base, repeat this circulation until finishing the synthetic of whole nucleotide sequences.
(2) deprotection
The solid support that is connected with RNA is joined in the test tube, and in this test tube, add ethanol/ethamine (volume ratio is 1: 3) of 1 milliliter, sealing then, place 55-70 ℃ of incubator, hatched 2-30 hour, taking-up is connected with the solid support of siRNA and with distilled water drip washing 2 times (each 1 milliliter), collects eluent, and at room temperature dry 30 minutes.Then, add the tetrahydrofuran solution (1M) of 1 milliliter of tetrabutyl ammonium fluoride, room temperature was placed 4-12 hour, added 2 milliliters of ethanol again, and collecting precipitation promptly obtains the crude product of little RNA.
(3) purifies and separates
It is in 1 mole/milliliter the ammonium acetate solution that the crude product of the RNA that obtains is dissolved in 2 ml concns, separates by the C18 high pressure liquid chromatography then, obtains the purified RNA product.
(4) desalination annealing
With concentration is ethanol water washing purified RNA product 2-4 time (each 2 milliliters) of 75 weight %, removing salt, and drying under the room temperature.Then with oligomerization ribonucleic acid mixed dissolution (10mM Tris in the buffer of 1-2 milliliter of positive-sense strand and antisense strand, pH=7.5-8.0,50mM NaCl), this solution is heated to 95 ℃, slowly this solution is cooled to room temperature then, and kept room temperature 16-22 hour, obtain containing the solution of double-stranded Microrna.
Experimental procedure is: with embodiment 1 obtain 2 '-F-siPTN (being called for short siPTN among the figure) and negative control 2 '-F-NC (being called for short NC among the figure) powder is dissolved in respectively in the sterilized water of no RNA enzyme, the nucleic acid oligomer solution that to be made into 2 kinds of final concentrations be 20pmol/L.Collect logarithmic (log) phase intestinal cancer HCT116 cell (available from Beijing consonance cell bank, for 2 '-F-siPTN and 2 '-F-NC transfection), adjust concentration of cell suspension, divide kind in 96 orifice plates, every hole 150 μ l totally 5000 cells; Place 37 ℃, contain 5%CO
2Incubator in make cell attachment, cultivated 6-24 hour.During transfection, respectively with 0.25 μ l 2 '-F nucleic acid oligomer solution (above-mentioned 2 '-F nucleic acid oligomer or 2 '-F nucleic acid oligomer negative control) and the lipofectamine 2000 (Invitrogen) of 0.25 μ l be diluted in respectively in the 25 μ l serum-free culture culture fluid (Opti-MEM), and at room temperature hatched 5 minutes, then above-mentioned nucleic acid oligomer solution is mixed with lipofectamine2000 solution, complex is after room temperature leaves standstill 20 minutes, nucleic acid oligomer-liposome complex of 50 μ l is added to (cell growth fusion rate is 50-70%) in the Tissue Culture Plate, for making cell synchronous, in transfection,, continue to cultivate 72 hours with being changed to the 2.5%FBS-DMEM culture medium more afterwards with cell serum starvation 12 hours; The careful suction removed supernatant 120ul, makes that the fertility culture fluid is 80 μ l in the hole, adds 20 μ lMTT (5mg/ml) again, and promptly 0.5% MTT continues to cultivate 4 hours; Suction goes supernatant to add the dimethyl sulfoxide DMSO of 100 μ l, measures the light absorption value in each hole at enzyme-linked immunosorbent assay instrument 492nm place; Be provided with simultaneously and transfer 0 hole (culture medium, MTT, dimethyl sulfoxide), every group is provided with 3 multiple holes; The result as shown in Figure 1, with transfection 2 '-F-NC relatively, transfection 2 '-the obviously reduction of cell 0D value of F-siPTN (Fig. 1), illustrate 2 '-F-siPTN can obviously suppress the propagation of tumor cell.
In the present embodiment, siPTN through 2 ' methoxyl group (2 '-OMe), sulfo-(PS) and 2 ' deoxidation modify the back to the influence of tumor cell proliferation with through 2 ' fluoro (2 '-F) the effect there was no significant difference after the modification.
The QRT-PCR that embodiment 3, nucleic acid oligomer suppress its expression of target gene detects PTN and the test detection of effect half-life
Use the lipofectamine of Invitrogen
TM2000 liposomees carry out transfection, the rule of operation that all operations all provides by Invitrogen.With intestinal cancer HCT116 cell inoculation (5X10 in 6 orifice plates
5Individual cells/well), supports liquid (available from GIBCO) cultivation after 16-24 hour, cell culture fluid is changed into the IMDM culture fluid that contains antibiotic-free with the DMEM that contains 5% hyclone.With the nucleic acid oligomer powder (2 '-F-siPTN and 2 '-F-NC) be dissolved in respectively in the sterilized water of no RNA enzyme, being made into final concentration is the nucleic acid oligomer solution of 20pmol/L.
During transfection, getting the above-mentioned oligonucleotide solution of 10 μ l and the lipofectamine 2000 of 5 μ l respectively is diluted in respectively in the 250 μ l serum-free culture culture fluid (Opti-MEM), and at room temperature hatched 5 minutes, then above-mentioned nucleic acid oligomer solution is mixed with lipofectamine 2000 solution, complex is after room temperature leaves standstill 20 minutes, nucleic acid oligomer-liposome complex of 500 μ l with after 1.5ml serum-free DMEM culture fluid mixes, be added in the Tissue Culture Plate, be changed to the 10%FBS-DMEM culture medium after 6 hours, respectively at 24,48,72 hours collecting cells carry out QRT-PCR and detect.
The step that QRT-PCR detects is: use the HCT116 cell of 1ml TRIzol (invitrogen) described nucleic acid oligomer of cracking transfection or nucleic acid oligomer negative control, and extract total RNA by the rule of operation of the TRIzol description of product.Because the RNA effects of jamming may be by potential a spot of genomic DNA influence, experiment adopts DNase I (RNase-free) (TaKaRa) further to digest residual DNA among total RNA that degrades.With 37 ℃ of digestion of DNase I after 30 minutes, according to purify again total RNA and RNA carried out quantitatively and Quality Identification of the DNase I description of product.Reverse transcription reaction is to use the M-MLV reverse transcriptase system of TaKaRa company, and total RNA of 1ug is mixed with the Oligo dT of 0.5ug, heats 5 minutes, is cooled to 0 ℃ rapidly.Press the description of product and add buffer, hatched 1 hour for 42 ℃.CDNA behind the reverse transcription reaction is as the template detection target gene of QRT-PCR reaction.Transfection 2 '-the pattern detection PTN of F-siPTN expresses, and forward primer is 5 '-CACGGGAGGGCACTCGGACT-3 ', and downstream primer is 5 '-GTCTTCTGGCATTCGGCATTG-3 '.The PCR reaction condition is 95 degree 5 seconds, 60 degree 30 seconds, totally 40 circulations.QRT-PCR result is directly carried out relative expression's analysis with software.
The result as shown in Figure 2, with the negative control group of transfection nucleic acid oligomer (2 '-F-NC, be called for short NC among the figure) relatively, transfection 2 '-PTN that F-siPTN obviously suppresses tumor cell expresses (Fig. 2).Fig. 2 is the rectangular histogram of relative expression quantity.
The step that RT-PCR detects is: use the cDNA of above-mentioned steps to be template, above-mentioned PTN primer carries out the PCR reaction.Reaction system is 94 degree 5 minutes, 94 degree 1 minute, 54 degree 30 seconds, 72 degree 20 seconds, totally 28 circulations.The PCR product is carried out agarose gel electrophoresis.
The result as shown in Figure 3, with the negative control group of transfection nucleic acid oligomer (2 '-F-NC, be called for short NC among the figure) relatively, transfection siPTN, 2 '-PTN that F-siPTN obviously suppresses tumor cell expresses.And transfection 2 '-F-siPTN than transfection siPTN arranged the longer effect half-life.
In the present embodiment, siPTN through 2 ' methoxyl group (2 '-OMe), sulfo-(PS) and 2 ' deoxidation modify the back to the influence of the half-life test result of tumor cells expression siPTN and present embodiment in through 2 ' fluoro (2 '-F) influence there was no significant difference after the modification.
Cultivate intestinal cancer HCT116 cell strain with the IMDM culture fluid that contains 5% hyclone, the cell of the trophophase of taking the logarithm is made single cell suspension, regulates cell concentration 1.5 * 10
7Individual cell/ml.At the dorsal part alar part subcutaneous injection 0.1ml tumor cell suspension of male BALB/C nude mice in 5 ages in week, make it form transplanted tumor.Nude mice is divided into 5 groups, be respectively 2 '-F-NC (being called for short the NC group), 2 '-F-miR-34a adds 2 '-F-siPTN (being called for short the miR-34a+siPTN group), 2 '-F-siPTN (being called for short the siPTN group), 2 '-F-miR-34a (being called for short the miR-34a group), after model saline group (being called for short the PBS group) the inoculated tumour cell, carry out tail vein injection earlier 2 times.Reach 50mm to gross tumor volume
3After change intratumor injection into.
The nucleic acid oligomer preparing preparation that the tail vein injection of each group is used is: single nucleic acid oligomer group (NC group, miR-34a group and siPTN group) is to dissolve every group of corresponding nucleic acid oligomer of 100 μ g respectively with the sterilized water 165 μ l that do not contain the RNA enzyme; Duoupoly polynucleic acid group (miR-34a+siPTN group) is to mix (total measurement (volume) 165ul) behind two kind of 50 μ g nucleic acid oligomer in dissolving every group respectively with two parts of sterilized water 87.5 μ l that do not contain the RNA enzyme.Each group adds transfection agents JET-PEI 10 μ l (available from Polyplus company) more then, and incubated at room mixed with equal-volume 10% glucose solution after 15 minutes, and cumulative volume 350ul is in incubated at room laggard end of line intravenous injection in 15 minutes.The oligonucleotide consumption of a shot is 100 μ g/.
The nucleic acid oligomer preparing preparation that intratumor injection is used is to dissolve 2 of 20 μ g '-F-nucleic acid oligomer with the sterilized water 11.3 μ l that do not contain the RNA enzyme.Single nucleic acid oligomer group is got the nucleic acid oligomer that sterilized water that 11.3 μ l do not contain the RNA enzyme dissolves 20 μ g, mixing (total measurement (volume) 11.3ul) behind two kind of 10 μ g nucleic acid oligomer in duoupoly polynucleic acid group is dissolved every group respectively with two parts of sterilized water 5.65 μ l that do not contain the RNA enzyme.The consumption of transfection reagent is 1.2 μ l, adds equal-volume 10% glucose solution and mixes cumulative volume 25ul intratumor injection.The oligonucleotide consumption of a shot is 20 μ g/ points.Every injection in 2 days once, intratumor injection totally 4 times.Inoculate back 3 days and use every three days major diameter (L) of vernier caliper measurement tumor and transverse diameter (S), calculate the approximate volumes of tumor.Computing formula is: V (mm
3)=0.5 * L * S
2Finish experiment behind the intratumor injection 4 times, put to death nude mice, take out tumor and weigh.
Fig. 4 is after the oncotherapy, the oncotherapy design sketch of processed group and matched group.
Fig. 5 is the treatment group of the different nucleic acid oligomer combinations in treatment back and the correlated broken line graph of gross tumor volume of matched group, and the increase of treatment group gross tumor volume is obviously little than matched group, and the matched group gross tumor volume is obvious ascendant trend.The tumor killing effect of nucleic acid oligomer combination miR-34a+siPTN is best.
Fig. 6 is the comparison diagram that described treatment finishes tumor weight between back miR-34a+siPTN mixed processing group and matched group.Similar to the comparison diagram of gross tumor volume, enter fast growing period after, the average tumor heavy and light 38.2% of siPTN individual processing group and matched group (PBS), the average tumor of mixing treatment group is heavy organize than PBS light by 51.89%.
Fig. 7 is after the oncotherapy, the oncotherapy design sketch of miR-34a+siPTN mixed processing group and model group and siPTN processed group.The tumor of mixed processing group is significantly less than other group.
In the present embodiment, siPTN through 2 ' methoxyl group (2 '-OMe), sulfo-(PS) and 2 ' deoxidation modify the back to the influence of the half-life test result of tumor cells expression siPTN with through 2 ' fluoro (2 '-F) influence there was no significant difference after the modification.
Claims (4)
1. nucleic acid oligomer suppresses the reagent or the application in the reagent that inhibition PTN expresses of tumor growth in preparation; Described nucleic acid oligomer is following 1) or 2) double-stranded RNA:
1) nucleic acid oligomer that sequence 1 and sequence 2 are formed in the sequence table;
2) the duoupoly polynucleic acid that nucleic acid oligomer described 1) and miR-34a form, described miR-34a are the nucleic acid oligomers that sequence 3 and sequence 4 are formed in the sequence table.
2. application as claimed in claim 1 is characterized in that: nucleic acid oligomer in the duoupoly polynucleic acid described 2), described 1) and the mass ratio of miR-34a are (0.5-2): (0.5-2), and preferably 1: 1.
3. application as claimed in claim 1 or 2 is characterized in that: described 1) and 2) described nucleic acid oligomer be all pass through following a) or b) modify the nucleic acid oligomer obtain:
A) phosphodiester bond of the connection nucleotide of described nucleic acid oligomer is modified, preferably the oxygen with described phosphodiester bond replaces with sulfur;
B), preferably described 2 '-OH is replaced with methoxyl group or fluorine or described 2 '-OH is carried out deoxidation modify to the modification of 2 '-OH of the ribose of described nucleic acid oligomer.
4. as arbitrary described application among the claim 1-3, it is characterized in that: described tumor is intestinal cancer, nasopharyngeal carcinoma, cervical cancer, hepatocarcinoma, breast carcinoma or pulmonary carcinoma.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106591306A (en) * | 2016-11-08 | 2017-04-26 | 中国人民解放军第三军医大学第附属医院 | Application of small interfering RNA for targeted interference of tumor PTN-PTPRZ1 pathway in tumor immunotherapy |
| CN106668861A (en) * | 2016-10-28 | 2017-05-17 | 清华大学深圳研究生院 | Method for enhancing anti-cervical cancer activity of glutaminase enzyme inhibitor by taking TIGA1 (Transcript Induced by Growth Arrest 1) as target spot |
| CN116474100A (en) * | 2023-04-26 | 2023-07-25 | 深圳市人民医院 | Biological target PTN related to liver cirrhosis or liver fibrosis progress to liver cancer of hepatitis B virus and application thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106668861A (en) * | 2016-10-28 | 2017-05-17 | 清华大学深圳研究生院 | Method for enhancing anti-cervical cancer activity of glutaminase enzyme inhibitor by taking TIGA1 (Transcript Induced by Growth Arrest 1) as target spot |
| CN106668861B (en) * | 2016-10-28 | 2019-07-09 | 清华大学深圳研究生院 | It is a kind of that TIGA1 is enhanced into the active method of glutamine enzyme inhibitor anti-cervical cancer as target spot |
| CN106591306A (en) * | 2016-11-08 | 2017-04-26 | 中国人民解放军第三军医大学第附属医院 | Application of small interfering RNA for targeted interference of tumor PTN-PTPRZ1 pathway in tumor immunotherapy |
| CN106591306B (en) * | 2016-11-08 | 2019-03-08 | 中国人民解放军陆军军医大学第一附属医院 | Application of the siRNA of targeting interference tumour PTN-PTPRZ1 access in immunotherapy of tumors |
| CN116474100A (en) * | 2023-04-26 | 2023-07-25 | 深圳市人民医院 | Biological target PTN related to liver cirrhosis or liver fibrosis progress to liver cancer of hepatitis B virus and application thereof |
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