CN112679583B - Specific polypeptide of target oncoprotein BORIS and application and gene thereof - Google Patents
Specific polypeptide of target oncoprotein BORIS and application and gene thereof Download PDFInfo
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- CN112679583B CN112679583B CN202110016541.3A CN202110016541A CN112679583B CN 112679583 B CN112679583 B CN 112679583B CN 202110016541 A CN202110016541 A CN 202110016541A CN 112679583 B CN112679583 B CN 112679583B
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
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Abstract
The invention provides a specific polypeptide of a target oncoprotein BORIS and application and a gene thereof, relating to the technical field of biological medicine, wherein the amino acid sequence of the specific polypeptide is shown as SEQ ID No. 1. The specific polypeptide provided by the invention is used for treating tumors by inhibiting the function of cancer BORIS protein. The specific polypeptide provided by the invention can inhibit non-small cell lung cancer and prostatic cancer and inhibit the development of non-small cell lung cancer subcutaneous tumor.
Description
Technical Field
The invention relates to the technical field of biomedicine, in particular to a specific polypeptide of a target oncoprotein BORIS and application and a gene thereof.
Background
Brother factor of the regulator of imprinted sites (BORIS) is associated with malignancy or tumor resistance, and nearly all types of cancer cells express BORIS, including lung, breast, prostate, leukemia, etc. [1 ]. Pathological information of tumor genomic map (TCGA) collected from human protein map database indicates that high expression of BORIS correlates with low survival of cancer patients to varying degrees among different types of cancer. BORIS is restricted to high expression in testis in healthy humans and very low or no expression of BORIS in other tissues [2-5 ]. Female mice with BORIS gene knockout develop normally [6 ]. The male mice with the BORIS gene knockout only have weakened reproductive capacity, and the bred mice still develop normally. The expression of BORIS in tumors results from either the demethylation of the BORIS gene promoter or the change in the copy number of the BORIS gene [3,7 ]. BORIS is specifically expressed in cancerous tissues but not in corresponding paracancerous normal tissues, which is an advantage of BORIS in clinical diagnosis and therapy [1,5 ]. The expression of BORIS is increased along with the development of drug resistance after ALK targeted therapy in neuroblastoma, which indicates that BORIS neuroblastoma plays an important role after drug resistance, so BORIS has an application prospect in the diagnosis or treatment of drug-resistant patients [8 ]. Immunotherapy targeting cytotoxic T Cells (CTL) of BORIS can significantly inhibit the progression of cervical cancer and the proliferation of lung cancer cells [9-11 ]. The above evidence supports BORIS as a potential target for cancer therapy.
Expression of BORIS is essential for the proliferation of malignant cells such as colorectal cancer cells, lung cancer cells, neuroblastoma, etc. [5,8,12 ]. BORIS maintains the stability of the cancer cell genome [12 ]. In neuroblastoma, the expression of BORIS increases stepwise with the transition from MYCN to BORIS dependent on cancer cells [8 ]. In colorectal cancer cells, BORIS is located in the cytoplasm and nucleus [5 ]. The distribution of BORIS in cancer cells depends on the cell type. BORIS has a dual localization in the nucleus and cytoplasm different from its homologous protein CTCF (CCCTC binding factor) which localizes only in the nucleus [13 ]. Cytoplasmic BORIS inhibits apoptosis [5], suggesting that cytoplasmic BORIS plays a completely different role than CTCF. Although immunotherapy strategies against BORIS have achieved some efficacy against cervical or breast cancer in animal experiments [9,11,14-16], BORIS have not been found on cell membranes. Immunotherapy against intracellular BORIS may not be the best strategy. Inhibitors of BORIS cannot be designed due to lack of understanding of the BORIS ligand and its structure.
Disclosure of Invention
In view of this, the present invention aims to provide a specific polypeptide targeting oncoprotein BORIS and its application and gene, and the use of the specific polypeptide provided by the present invention can inhibit the function of oncoprotein BORIS.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a specific polypeptide of a target oncoprotein BORIS, and the amino acid sequence of the specific polypeptide is shown in SEQ ID No. 1.
The invention also provides a gene for coding the specific polypeptide in the technical scheme, and the nucleotide sequence is shown as SEQ ID No. 2.
The invention also provides application of the specific polypeptide in the technical scheme in preparation of a medicine for inhibiting BORIS anticancer apoptosis.
The invention also provides the application of the specific polypeptide in the technical scheme in the preparation of the medicine for treating tumors.
Preferably, the tumor comprises non-small cell lung cancer and/or prostate cancer.
Preferably, the medicament comprises a specific polypeptide and pharmaceutically acceptable auxiliary materials.
The invention provides a specific polypeptide of a targeted oncoprotein BORIS, application and a gene thereof, wherein the amino acid sequence of the specific polypeptide is shown as SEQ ID No. 1. The specific polypeptide provided by the invention can be used for treating tumors by inhibiting the expression of cancer BORIS protein regulation ERCC1 and cMYC, so that the genome of cancer cells is unstable, and the apoptosis of the cancer cells is induced.
The results of the embodiments of the present invention show that: the specific polypeptide provided by the invention can inhibit non-small cell lung cancer and prostatic cancer and inhibit the development of non-small cell lung cancer subcutaneous tumor.
Drawings
FIG. 1 is the screening process of SEQ ID No.1, wherein A is BORIS antigen BORIS N for screening SEQ ID No.11-258And BORIS del N1-258B is a screening flow chart of SEQ ID No.1, and C is the content statistics of the phage after each screening;
FIG. 2 is a graph showing the binding assay between SEQ ID No.1 and BORIS protein, wherein A is the binding assay between BORIS protein and SEQ ID No.1, and B is the binding assay between SEQ ID No.1 and BORIS protein;
FIG. 3 is a diagram showing the detection of the specific binding effect of SEQ ID No.1 to BORIS in cells, wherein A is the binding force analysis of SEQ ID No.1 binding to BORIS expressed by eukaryotic cells, B is the detection of the interaction of SEQ ID No.1 with BORIS expressed in cells, C is the cell membrane penetration detection of SEQ ID No.1, and D is the detection of the specificity of SEQ ID No.1 recognizing BORIS in cells as compared with the monoclonal antibody of BORIS;
FIG. 4 is a binding site assay of SEQ ID No.1 with BORIS, wherein A is the binding site assay of SEQ ID No.1 with BORIS and B is the detection of the interaction of SEQ ID No.1 with the interaction protein BAT3 of BORIS;
FIG. 5 is an analysis of the inhibitory effect of SEQ ID No.1 on cancer cells, wherein A is the analysis of SEQ ID No.1 for the inhibition of proliferation of non-small cell lung cancer cell H1299, B is the analysis of IC50 value of SEQ ID No.1 for the inhibition of proliferation of non-small cell lung cancer cell H1299, and C is the analysis of SEQ ID No.1 for the inhibition of proliferation of normal cells without BORIS;
FIG. 6 shows that SEQ ID No.1 induces DNA damage and apoptosis in cancer cells, wherein A is SEQ ID No.1 induces DNA damage in cancer cells, B is SEQ ID No.1 induces apoptosis in cancer cells, and C is SEQ ID No.1 inhibits expression of ERCC1 and cMYC genes in cancer cells;
FIG. 7 is a graph of SEQ ID No.1 showing the experimental procedure of SEQ ID No.1 showing the inhibition of the development of non-small cell lung cancer subcutaneous tumors, B showing the inhibition of the development of non-small cell lung cancer subcutaneous tumors by SEQ ID No.1, and C showing the gravimetric analysis of non-small cell lung cancer subcutaneous tumors;
FIG. 8 shows that SEQ ID No.1 induces DNA damage of non-small cell lung cancer subcutaneous tumor, wherein A is SEQ ID No.1 induces DNA damage of non-small cell lung cancer subcutaneous tumor, and B is SEQ ID No.1 induces DNA damage of non-small cell lung cancer subcutaneous tumor without causing hepatotoxicity or hepatotoxicity.
Detailed Description
The invention provides a specific polypeptide of a target oncoprotein BORIS, the amino acid sequence of the specific polypeptide is shown as SEQ ID No.1, and the specific polypeptide is as follows:
VHWDFRQWWQPSGGRKKRRQRRRG。
the invention also provides a gene for coding the specific polypeptide in the technical scheme, wherein the nucleotide sequence of the gene is shown as SEQ ID No.2, and the specific sequence is as follows:
GTGCATTGGGATTTTCGGCAGTGGTGGCAGCCTTCTGGTGGCCGTAAAAAGCGCCGACAACGGAGAAGGGGA。
the invention also provides application of the specific polypeptide in the technical scheme in preparation of a medicine for inhibiting BORIS anticancer apoptosis. In the present invention, the medicament preferably comprises the specific polypeptide and a medically acceptable excipient. In the present invention, the drug has the specific polypeptide as the only active substance. The dosage form and preparation method of the drug are not particularly limited, and a person skilled in the art can routinely select a medically acceptable dosage form and preparation method according to the specific polypeptide.
The invention also provides the application of the specific polypeptide in the technical scheme in the preparation of the medicine for treating tumors. In the present invention, the tumor preferably comprises non-small cell lung cancer and/or prostate cancer. In the present invention, the medicament preferably comprises the specific polypeptide and a medically acceptable excipient. In the present invention, the drug has a specific polypeptide as the only active substance. The dosage form and preparation method of the drug are not particularly limited, and a person skilled in the art can routinely select a medically acceptable dosage form and preparation method according to the specific polypeptide. In the invention, the specific polypeptide treats the tumor by inhibiting oncoprotein BORIS from regulating the expression of ERCC1 and cMYC and inducing cancer cell apoptosis.
In the present invention, the concentration of the polypeptide for treating cells is 5 to 100. mu.M. PBS is used as a solvent for animal experiments, and the concentration of the polypeptide is 16-25 mg/kg of body weight.
In order to further illustrate the present invention, the following detailed description of the invention is given in conjunction with examples, which should not be construed to limit the scope of the invention.
Example 1
Screening and characterization of BORIS binding peptide (SEQ ID No.3 VHWDFRQWQPS)
In this example, a BORIS specific fragment of N-terminal 1-258AA was used to screen for a specific targeting polypeptide of BORIS. The specific operation method comprises the following steps: firstly, 1-258AA (BORIS-N)1-258) The BORIS N-terminal fragment of (A) was constructed into the plasmid of Pfn6k (Promega) and labeled at the N-terminus with HQHQ tag peptide for expression of BORIS-specific protein segments of the selected targeting polypeptide and subsequent purification of the protein. In addition, a BORIS N-terminal deletion (BORIS del N) was constructed on the Pfn6k vector1-258) For expressing and purifying BORIS non-specific protein segmentAimed at clearing away irrelevant peptides that do not target BORIS. The above BORIS delN1-258And BORIS-N1-258Both vectors of (a) were expressed in KRX bacterial protein expression system and purified by Ni-NTA column chromatography (a in fig. 1). BORIS-del N1-258Is first used for ph.d.TM-12 phage display peptide library (purchased from New England Biolabs) that does not bind BORIS-N1-258The pre-clearance of phage of the antigenic protein of (a). Then using BORIS-N1-258Phage clones were further enriched (B in fig. 1). After two rounds of enrichment until there was no change in the eluted phage titer (C in fig. 1), 60 phage clones were randomly selected for sequencing the nucleotide sequence of the displayed polypeptide. The highest frequency of occurrence of the polypeptide having the amino acid sequence VHWDFRQWWQPS (which is a precursor of SEQ ID No. 1) was found after sequencing the clones.
BORIS-N1-258The amino acid sequence of (A) is shown as SEQ ID No.6, and specifically as follows:
MAATEISVLSEQFTKIKELELMPEKGLKEEEKDGVCREKDHRSPSELEAERTSGAFQDSVLEEEVELVLAPSEESEKYILTLQTVHFTSEAVELQDMSLLSIQQQEGVQVVVQQPGPGLLWLEEGPRQSLQQCVAISIQQELYSPQEMEVLQFHALEENVMVASEDSKLAVSLAETTGLIKLEEEQEKNQLLAERTKEQLFFVETMSGDERSDEIVLTVSNSNVEEQEDQPTAGQADAEKAKSTKNQRKTKGAKGTFH。
the polypeptide is synthesized by a chemical synthesis method, and the biological-Layer interference method (BLI technique) is used for testing the polypeptide and BORIS-N1-258The specific operation method is as follows: coupling BORIS-N1-258The protein was bound to biotin and loaded onto the SSA sensor; VHWDFRQWWQPS synthetic peptide was dissolved in buffer (PBS plus 0.02% Tween 20) to a range of concentrations from 29.5. mu.M to 1594. mu.M, and the peptide was analyzed by the ForteBio OctetRed96 system for binding to the target protein BORIS-N1-258Affinity of (c). The analysis result shows that the polypeptide (VHWDFRQWWQPS) and BORIS-N1-258Has a strong binding affinity (Kd) of 86.38. mu.M (A in FIG. 2).
In addition, a reverse experiment was performed using the ForteBio OctetRed96 system, the polypeptide was labeled with biotin, loaded onto the SA sensor, and BORIS-N was applied at a series of concentrations (B in FIG. 2) of 0.25 to 0.625. mu.M1-258Solution (protein in PBS plus 0.02%)Tween 20) was assayed for affinity between the two. The binding Kd value was found to be 5.30nM (FIG. 2B).
Specific polypeptide SEQ ID No.1 of targeting oncoprotein BORIS is specifically combined with BORIS in cells
Since the BORIS antigen for screening the polypeptide is isolated and purified from bacteria, it is shown that the polypeptide binds to BORIS-N expressed in mammalian cells1-258The interaction between the two genes, expression and purification of BORIS-N from HEK293 cells1-258(original HEK293 cells do not express BORIS). The BLI technique is used to show that the polypeptide (VHWDFRQWWQPS) and the mammal BORIS-N1-258Has a Kd value of 6.37nM, which is comparable to the affinity of the previously tested polypeptide for the bacterially expressed BORIS antigen (A in FIG. 3), indicating that the polypeptide obtained from the previous screen can target the BORIS protein expressed by eukaryotic cells. Then, the polypeptide is fused with HIV-TAT peptide (the sequence of the HIV-TAT peptide is SEQ ID No. 4: GGRKKRRQRRRG; the sequence of the nucleotide is shown as SEQ ID No.5, in particular GGTGGCCGTAAAAAGCGCCGACAACGGAGAAGGGGA) and is used for penetrating cell membranes to form polypeptide SEQ ID No.1 which specifically targets BORIS in cancer cells and induces cancer cell apoptosis. In this example, the biotin-labeled tracer of SEQ ID No.1 (hereinafter referred to as SEQ ID No.1-biotin) was used to detect the interaction of SEQ ID No.1 with its target protein BORIS in cells. The Myc-labeled BORIS is over-expressed in HEK293 cells, cell lysates are collected and 25 mu M of SEQ ID No.1-biotin is given for incubation, and the interaction between SEQ ID No.1-biotin and BORIS is detected by co-immunoprecipitation. The result shows that the streptavidin is combined with the magnetic bead (can pull down the protein containing biotin) to pull down the SEQ ID No.1-biotin, and the specific protein segment BORIS-N that the SEQ ID No.1 is combined with BORIS can be detected1-258And full-length protein of BORIS, but not with BORIS-del N1-258Binding (B in FIG. 3), indicating that the peptide of SEQ ID No.1 specifically binds to BORIS expressed in eukaryotic cells and binds in the 1-258 amino acid segment of BORIS. In addition, since BORIS is expressed in the cells of cancer cells rather than on the outer membrane of cells, to verify whether SEQ ID No.1 can cross the cell membrane into the cells, this example adds SEQ ID No.1-biotin into the cellsThe culture medium was incubated for 4 hours, and the efficiency of the polypeptide crossing the cell membrane was measured by FITC-conjugated anti-biotin secondary antibody binding immunofluorescence, as compared to VHWDFRQWWQPS-biotin. This example found that SEQ ID No.1-biotin is able to penetrate the cell membrane into the cell, whereas VHWDFRQWWQPS-biotin without the transmembrane peptide is unable to enter the cell (C in FIG. 3). Indicating that SEQ ID No.1 is able to enter the cell and VHWDFRQWWQPS is not. In addition, in order to verify that SEQ ID No.1 specifically recognizes BORIS in cells, this example detects the change in expression of BORIS using SEQ ID No.1-biotin after knocking down the expression level of BORIS in HCT116 cells using siRNA (small interfering RNA), and compared with the monoclonal antibody of BORIS from Santa Cruz Biotechnology, USA, having a product code of sc-377085, it was found that SEQ ID No.1 indicates the phenomenon that the expression level of BORIS in cells is reduced as well (D in FIG. 3), indicating that SEQ ID No.1 specifically binds to BORIS in cells. The above evidence indicates that SEQ ID No.1 is capable of crossing cell membrane into cell and binding specifically to BORIS.
Specific polypeptide SEQ ID No.1 of targeted oncoprotein BORIS specifically binds to 52AA-172AA protein segment of BORIS protein
To determine the binding site of SEQ ID No.1 on BORIS, this example shows the binding site in the BORIS-specific protein segment BORIS-N1-258On the basis of the expression vector, 5 deletion mutants are constructed, and the deletion regions of the 5 deletion mutants are respectively delta 1: 2-51AA,. DELTA.2: 52-102AA, Δ 3: 103-171AA, Δ 4: 172-217AA, Δ 5: 215 and 258AA (a in fig. 4). Five BORIS expression vectors of delta 1-delta 5 are transfected into HEK293 cells respectively, and then 5 cell lysates containing the BORIS proteins of delta 1-delta 5 are taken. 25 mu.M of SEQ ID No.1-biotin was incubated with the 5 cell lysates at 4 ℃ for 12 hours, and then the 5 Δ 1- Δ 5BORIS and the SEQ ID No.1-biotin interaction were detected by incubating at room temperature for 2 hours using streptavidin-conjugated magnetic beads (which can pull down the biotin-labeled SEQ ID No. 1-biotin). The results show that SEQ ID No.1-biotin binds to Δ 1, Δ 4, Δ 5, but not to Δ 2 and Δ 3. The 52-102AA Δ 2 deletion and the 103-171AA segment Δ 3 deletion, thus causing SEQ ID No.1 not to bind Δ 2 and Δ 3, are due to SEQ ID No.1 binding to the 52AA-172AA sites on BORIS (A in FIG. 4).
To verify the reliability of the results of this example, it was examined whether SEQ ID No.1 could interact with BAT3 by binding to the 52AA-172AA of BORIS using the reported information BAT3 binding to the 1AA-50AA of BORIS [17 ]. The results indicate that BORIS Δ 1/2/3, i.e., SEQ ID No.1, failed to interact with BAT3 when BORIS lacked 1-172AA (B in FIG. 4). This result demonstrates that SEQ ID No.1-biotin binds to BORIS 52AA-172AA and can indirectly interact with BAT3 by binding to BORIS.
Example 2
Polypeptide of SEQ ID No.1 induces tumor cell apoptosis and inhibits tumor cell proliferation
As the SEQ ID No.1 is combined with BORIS which has important effect on tumor, the effect of the targeting peptide on cancer cells is detected through cell proliferation and apoptosis. The non-small cell lung cancer cell H1299 is treated by adding 25-100 μ M of SEQ ID No.1 into the cell culture solution and detected by MTT method and cell counting method. Compared with a control group treated by His-TAT negative control peptide (consisting of 12 tandem repeats of histidine and HIV-TAT transmembrane peptides, the amino acid sequence of which is (SEQ ID No.7) HHHHHHHHHHHHGGRKKRRQRRRG, and the nucleotide sequence of which is (SEQ ID No.8) CATCATCACCATCACCATCATCATCACCATCACCATGGTGGCCGTAAAAAGCGCCGACAACGGAGAAGGGGA), SEQ ID No.1 inhibits H1299 cell proliferation under the condition of 25-100 mu M treatment for 3 days, the number of cancer cells and the inhibition rate of activity of 25 mu M polypeptide are 27.8% and 16.4%, respectively, the number of cancer cells and the inhibition rate of activity of 50 mu M polypeptide are 54.2% and 66%, respectively, and the number of cancer cells and the inhibition rate of activity of 100 mu M polypeptide are 83.1% and 93.5%, respectively (A in FIG. 5). The half inhibitory concentration (IC50) of H1299 cells by treatment with SEQ ID No.1 was 63.12. mu.M (B in FIG. 5). SEQ ID No.1 inhibited proliferation of H1299 lung carcinoma and LNCaP prostate cancer cells, but did not affect proliferation of normal HEK293 cells that do not express BORIS (C in fig. 5). VHWDFRQWWQPS did not penetrate the cell membrane and could not enter the cell, and thus did not have the effect of inhibiting the proliferation of cancer cells (C in fig. 5). Apoptosis by TUNEL analysis showed that SEQ ID No.1 induced DNA damage and increased caspase3/7 activity (A-B in FIG. 6). The prior art reports that BORIS can prevent cancer cell apoptosis and maintain the stability of cancer cell genome, and the treatment of SEQ ID No.1 weakens the protective effect of BORIS on cancer cell genome. This example found that treatment with SEQ ID No.1 suppressed the expression of the DNA repair and cancer cell proliferation associated genes ERCC1 and cMYC in H1299 cells, which are the DNA excision repair gene and the proto-oncogene (C in FIG. 6). The results of the present example prove that SEQ ID No.1 binds to 52AA-172AA of the oncoprotein BORIS, inhibits the effect of regulating the expression of ERCC1 and cMYC, and further leads to the instability of cancer cell genome and the apoptosis of cancer cells.
Example 3
SEQ ID No.1 inhibits the progression of non-small cell lung carcinoma subcutaneous transplantable tumors
To test the cancer suppressing effect of SEQ ID No.1 in animals, H1299 cells were subcutaneously inoculated in a highly immunodeficient nodltsz-scidii 2rg (nsg) mouse to construct a xenograft model (A in FIG. 7). By 1X 106Cells/injection to construct H1299 subcutaneous tumors, mice inoculated with subcutaneous tumors were divided into 2 groups 1 week after tumor cell inoculation, and mice in each group were intraperitoneally injected with 16mg/kg of SEQ ID No.1 (treatment group) or His-TAT (control peptide) every other day, and tumor volumes were measured every other day after polypeptide intraperitoneal injection for 3 weeks (B in fig. 7). After the experiment was completed, the animals were euthanized and tumors were taken and tumor weights were measured. The tumors progressed slowly in the group treated with SEQ ID No.1 compared to the group treated with His-TAT negative peptide (B in FIG. 7 and C in 7). The removed tumor sections were examined for apoptosis by TUNEL method. It was found that three weeks of treatment with SEQ ID No.1 significantly induced apoptosis in subcutaneous tumor cells (a in fig. 8). Meanwhile, the treatment of SEQ ID No.1 did not cause liver and kidney toxicity (B in FIG. 8).
The foregoing is merely a preferred embodiment of the invention and is not intended to limit the invention in any manner. It should be noted that, for those skilled in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be construed as the protection scope of the present invention.
Reference documents:
[1]Martin-Kleiner,I.BORIS in human cancers--a review.Europeanjournal of cancer.2012,48,929-35.
[2]Hoivik,E.A.,Kusonmano,K.,Halle,M.K.,Berg,A.,Wik,E.,Werner,H.M.,et al.Hypomethylation of the CTCFL/BORIS promoter and aberrant expression during endometrial cancer progression suggests a role as an Epi-driver gene.Oncotarget.2014,5,1052-61.
[3]Renaud,S.,Pugacheva,E.M.,Delgado,M.D.,Braunschweig,R.,Abdullaev,Z.,Loukinov,D.,et al.Expression of the CTCF-paralogous cancer-testis gene,brother of the regulator of imprinted sites(BORIS),is regulated by three alternative promoters modulated by CpG methylation and by CTCF and p53 transcription factors.Nucleic acids research.2007,35,7372-88.
[4]Sleutels,F.,Soochit,W.,Bartkuhn,M.,Heath,H.,Dienstbach,S.,Bergmaier,P.,et al.The male germ cell gene regulator CTCFL is functionally different from CTCF and binds CTCF-like consensus sites in a nucleosome composition-dependent manner.Epigenetics&chromatin.2012,5,8.
[5]Zhang,Y.,Fang,M.,Song,Y.,Ren,J.,Fang,J.,Wang,X.Brother of Regulator of Imprinted Sites(BORIS)suppresses apoptosis in colorectal cancer.Scientific reports.2017,7,40786.
[6]Loukinov,D.I.,Pugacheva,E.,Vatolin,S.,Pack,S.D.,Moon,H.,Chernukhin,I.,et al.BORIS,a novel male germ-line-specific protein associated with epigenetic reprogramming events,shares the same 11-zinc-finger domain with CTCF,the insulator protein involved in reading imprinting marks in the soma.Proceedings of the National Academy of Sciences of the United States of America.2002,99,6806-11.
[7]Woloszynska-Read,A.,James,S.R.,Link,P.A.,Yu,J.,Odunsi,K.,Karpf,A.R.DNA methylation-dependent regulation of BORIS/CTCFL expression in ovarian cancer.Cancer immunity.2007,7,21.
[8]Debruyne,D.N.,Dries,R.,Sengupta,S.,Seruggia,D.,Gao,Y.,Sharma,B.,et al.BORIS promotes chromatin regulatory interactions in treatment-resistant cancer cells.Nature.2019,572,676-80.
[9]Asano,T.,Hirohashi,Y.,Torigoe,T.,Mariya,T.,Horibe,R.,Kuroda,T.,et al.Brother of the regulator of the imprinted site(BORIS)variant subfamily 6is involved in cervical cancer stemness and can be a target of immunotherapy.Oncotarget.2016,7,11223-37.
[10]Horibe,R.,Hirohashi,Y.,Asano,T.,Mariya,T.,Suzuki,T.,Takaya,A.,et al.Brother of the regulator of the imprinted site(BORIS)variant subfamily 6is anovel target of lung cancer stem-like cell immunotherapy.PloS one.2017,12,e0171460.
[11]Loukinov,D.Targeting CTCFL/BORIS for the immunotherapy of cancer.Cancer immunology,immunotherapy:CII.2018,67,1955-65.
[12]Zhang,Y.,Song,Y.,Li,C.,Ren,J.,Fang,M.,Fang,J.,et al.Brother of regulator of imprinted sites inhibits cisplatin-induced DNA damage in non-small cell lung cancer.Oncology letters.2020,20,251.
[13]Rosa-Garrido,M.,Ceballos,L.,Alonso-Lecue,P.,Abraira,C.,Delgado,M.D.,Gandarillas,A.A cell cycle role for the epigenetic factor CTCF-L/BORIS.PloS one.2012,7,e39371.
[14]Dougherty,C.J.,Ichim,T.E.,Liu,L.,Reznik,G.,Min,W.P.,Ghochikyan,A.,et al.Selective apoptosis of breast cancer cells by siRNA targeting of BORIS.Biochemical and biophysical research communications.2008,370,109-12.
[15]Mkrtichyan,M.,Ghochikyan,A.,Loukinov,D.,Davtyan,H.,Ichim,T.E.,Cribbs,D.H.,et al.DNA,but not protein vaccine based on mutated BORIS antigen significantly inhibits tumor growth and prolongs the survival of mice.Gene therapy.2008,15,61-4.
[16]Mkrtichyan,M.,Ghochikyan,A.,Davtyan,H.,Movsesyan,N.,Loukinov,D.,Lobanenkov,V.,et al.Cancer-testis antigen,BORIS based vaccine delivered by dendritic cells is extremely effective against a very aggressive and highly metastatic mouse mammary carcinoma.Cellular immunology.2011,270,188-97.
[17]Nguyen,P.,Bar-Sela,G.,Sun,L.,Bisht,K.S.,Cui,H.,Kohn,E.,et al.BAT3 and SET1A form a complex with CTCFL/BORIS to modulate H3K4 histone dimethylation and gene expression.Molecular and cellular biology.2008,28,6720-9.
sequence listing
<110> Hangzhou college of medicine
<120> specific polypeptide of targeting oncoprotein BORIS and application and gene thereof
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Val His Trp Asp Phe Arg Gln Trp Trp Gln Pro Ser Gly Gly Arg Lys
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Lys Arg Arg Gln Arg Arg Arg Gly
20
<210> 2
<211> 72
<212> DNA
<213> Artificial Sequence (Artificial Sequence)
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<213> Artificial Sequence (Artificial Sequence)
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Val His Trp Asp Phe Arg Gln Trp Trp Gln Pro Ser
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<213> Artificial Sequence (Artificial Sequence)
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Gly Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Gly
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<213> Artificial Sequence (Artificial Sequence)
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ggtggccgta aaaagcgccg acaacggaga agggga 36
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Met Ala Ala Thr Glu Ile Ser Val Leu Ser Glu Gln Phe Thr Lys Ile
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Claims (4)
1. A specific polypeptide of a target oncoprotein BORIS is characterized in that the amino acid sequence of the specific polypeptide is shown as SEQ ID No. 1.
2. A gene encoding the specific polypeptide of claim 1, wherein the nucleotide sequence of the gene is as shown in SEQ ID No. 2.
3. Use of a specific polypeptide according to claim 1 for the preparation of a medicament for the treatment of a tumor;
the tumor is non-small cell lung cancer and/or prostate cancer.
4. The use according to claim 3, wherein the medicament consists of the specific polypeptide and a pharmaceutically acceptable excipient.
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| NL2028912A NL2028912B1 (en) | 2021-01-07 | 2021-08-03 | Specific peptide targeting oncoprotein boris and use and encoding gene thereof |
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| US8974774B2 (en) * | 2004-03-03 | 2015-03-10 | Revance Therapeutics, Inc. | Compositions and methods for topical diagnostic and therapeutic transport |
| EP2188396A4 (en) * | 2007-08-10 | 2011-09-28 | Vendevia Group Llc | Gene silencing of the brother of the regulator of imprinted sites (boris) |
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| CN106061981A (en) * | 2013-11-06 | 2016-10-26 | 索尔斯蒂斯生物有限公司 | Polynucleotide constructs having disulfide groups |
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| CN112679583A (en) | 2021-04-20 |
| NL2028912A (en) | 2022-07-22 |
| NL2028912B1 (en) | 2022-10-10 |
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Effective date of registration: 20231018 Address after: No. 8-1 Jingangshan Road, Liuting Street, Chengyang District, Qingdao City, Shandong Province, 266000 Patentee after: Shandong Meiserde Biotechnology Co.,Ltd. Address before: 310012 No. 182 Tianmu Mountain Road, Zhejiang, Hangzhou Patentee before: HANGZHOU MEDICAL College |