CN113637062B - Polypeptide for treating glioma and application thereof - Google Patents
Polypeptide for treating glioma and application thereof Download PDFInfo
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- CN113637062B CN113637062B CN202110860180.0A CN202110860180A CN113637062B CN 113637062 B CN113637062 B CN 113637062B CN 202110860180 A CN202110860180 A CN 202110860180A CN 113637062 B CN113637062 B CN 113637062B
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Abstract
The invention discloses a polypeptide for treating glioma and application thereof. The amino acid sequence of the polypeptide for treating glioma is shown as SEQ ID NO.1, and the amino acid sequence of the secretory polypeptide is shown as SEQ ID NO. 2. The experimental result shows that the polypeptide can be combined with NGAL, block the activation of NGAL on NGALR, and inhibit the invasion and migration capacity of glioma cells, and the polypeptide has a larger application prospect in the preparation of glioma treatment medicines.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to a polypeptide for treating glioma and application thereof.
Background
Gliomas are the most common refractory tumors of the central nervous system, seriously harming human health. Especially high-grade gliomas, such as glioblastoma multiforme (GBM), have high infiltrates, often penetrate into adjacent normal brain tissue, and are variable in shape without a definite range, and have extremely high lethality; the median survival time of GBM patients is only 12-15 months, the five-year survival rate is less than 5%, and the 1-year survival rate is less than 30%. The invasive growth pattern of gliomas makes the tumor boundaries difficult to define and difficult to clean during surgery, the most important cause of their high recurrence rate and high mortality rate. Chemotherapy dominates in the treatment of malignant glioma for a long time, but traditional chemotherapeutic drugs such as cisplatin, teniposide, carmustine and the like have not ideal treatment effect on glioma, and the clinical actual effective rate is only 20-25%. In recent years, temozolomide (TMZ) is recommended at home and abroad as a first-line chemotherapeutic drug for treating glioma, the effective rate is less than 40%, and the temozolomide has no inhibition effect on the invasion characteristics of glioma cells. Targeting therapy aiming at special molecules of tumor cells is more and more emphasized in tumor therapy, so that key molecules for promoting the invasion characteristics of glioma are searched, effective molecular targeted chemotherapeutic drugs capable of inhibiting invasion are developed, and the targeting chemotherapeutic drugs are important subjects in the fields of clinical treatment and basic research of glioma.
Secreted protein NGAL (official name Lipocalin, LCN 2) is a neutrophil gelatinase-associated Lipocalin, one of the members of the Lipocalin (Lipocalin) family. NGAL has the characteristics of small molecular weight and difficult degradation, and can be secreted to the outside of cells or discharged out of the body along with urine. The physiological role of NGAL may not only induce the growth of innate immunosuppressive bacteria by capturing iron-containing cells, but may also be involved in maintaining cell homeostasis by modulating inflammation. In pathological conditions, the biological effects of NGAL are complex. For example, the detection of NGAL in blood and urine has been reported as an early marker of acute kidney injury and has also been associated with poor prognosis in type II diabetes and myocardial injury. In colon cancer, NGAL is reported to inhibit cell proliferation and epithelial to mesenchymal transition to inhibit tumor progression. However, in cervical cancer, NGAL is ubiquitously expressed and promotes local invasion of tumor cells and lymph node metastasis. In breast cancer, NGAL is knocked out in a mouse body to inhibit breast cancer metastasis, and the NGAL is suggested to have an important tumor metastasis promotion effect. We previously reported that the abnormally elevated expression of NGAL in human glioma tissues, particularly in high-grade gliomas, could serve as an independent factor suggesting a poor prognosis for patients with gliomas, but the biological role and specific mechanism of action of NGAL in pathological conditions, including gliomas, are quite unclear. Currently available studies have shown that NGAL may be involved in regulating ion transport primarily through its receptor protein NGALR (official name of source carrier family 22member 17, slc22a17). However, reports on the role of NGALR in diseases, especially in tumors, are relatively rare. The applicant's group earlier reported that NGALR expression was generally elevated in esophageal squamous carcinoma tissues due to low levels of promoter methylation. Applicants have also previously reported that, like their ligand NGAL, NGALR expression in human glioma tissues, and particularly in high-grade gliomas, is abnormally elevated and may also serve as an independent factor in suggesting a poor prognosis for patients with gliomas. However, the biological role of NGAL/NGALR in pathological states including gliomas is unclear, and NGALR is especially used as a receptor, and downstream effector proteins and signaling pathways for recruitment after activation by NGAL stimulation have not been reported. It is worth mentioning that NGAL is used as a secretory protein, NGALR is used as a cell receptor, and the molecular characteristics of the NGAL and the NGALR have very important research values for being used as a diagnostic marker and a therapeutic target. Chinese patent CN1874783A, CN1924006A, CN101270158A and the like all disclose glioma-resistant polypeptides or proteins, however, glioma-resistant polypeptides for NGAL/NGALR have only been reported.
Disclosure of Invention
The present invention aims to overcome the above-mentioned drawbacks and deficiencies of the prior art and to provide a polypeptide for the treatment of glioma.
The second objective of the invention is to provide a secreted polypeptide for treating glioma.
The third purpose of the invention is to provide the application of the polypeptide in preparing drugs for treating glioma.
The above object of the present invention is achieved by the following technical solutions:
a polypeptide for treating glioma, wherein the amino acid sequence of the polypeptide is shown as SEQ ID NO. 1:
PPLHCHYGAFPPNASGWEQPPNASGVSVASAALAASAASRVATSTDPSCSGFAPPDFNHCLKDWDYNGLPVLTTNAIGQWDLVCDLGWQVILEQILFILGFASGYLFLGY。
a secretory polypeptide for treating glioma, the amino acid sequence of said secretory polypeptide is shown in SEQ ID NO. 2:
MHSFPPLLLLLFWGVVSHSPPLHCHYGAFPPNASGWEQPPNASGVSVASAALAASAASRVATSTDPSCSGFAPPDFNHCLKDWDYNGLPVLTTNAIGQWDLVCDLGWQVILEQILFILGFASGYLFLGY; wherein MHSFPPLLLLLFWGVVSHS is a signal peptide.
The in vitro experiment results show that the polypeptide can be combined with NGAL, the activation of NGAL on NGALR is blocked, the invasion and migration capacity of glioma cells is inhibited, and the polypeptide can be used for preparing glioma treatment medicines.
Therefore, the invention also provides the application of the polypeptide in preparing drugs for treating glioma.
The application of the polypeptide in preparing the medicine for inhibiting glioma migration or invasion.
The invention also provides a preparation method of the secretory polypeptide, which inserts the coding sequence of the secretory polypeptide by selecting a prokaryotic protein expression system to obtain a recombinant plasmid; then introducing the recombinant plasmid into a bacterium for protein expression, screening positive bacteria for amplification culture, inducing expression protein by IPTG, and purifying to obtain the recombinant plasmid.
Preferably, the coding sequence of the secreted polypeptide is as shown in SEQ ID NO. 3.
A drug for treating glioma, which comprises a polypeptide shown in SEQ ID NO.1 or SEQ ID NO.2 or a plasmid or cell line for expressing the polypeptide shown in SEQ ID NO.1 or SEQ ID NO. 2.
Preferably, the medicament further comprises pharmaceutically acceptable auxiliary materials.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a polypeptide for treating glioma, wherein the amino acid sequence of the polypeptide for treating glioma is shown as SEQ ID No.1 or SEQ ID No. 2. The research of the invention shows that the polypeptide can be combined with NGAL, block the activation of NGAL to NGALR, inhibit the invasion and migration capacity of glioma cells, and have a wide application prospect in the preparation of glioma treatment medicines.
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FIG. 1 is the preparation and detection of secreted NGALR peptide fragments. A is a schematic diagram for constructing a secretory NGALR peptide fragment expression plasmid; b, detecting the purification effect of the secretory NGALR peptide fragment; the expression of the secretory NGALR peptide segment linked with the expression tag Flag is shown to be successful.
FIG. 2 shows the effect of secreted NGALR peptide with NGAL and NGALR. A: the secretory NGALR peptide segment can be combined with NGAL; b: the secretory NGALR peptide segment can inhibit the combination of NGAL and NGALR; c: the secretory NGALR peptide segment can inhibit the activation of NF kappa B; the secretory NGALR peptide segment can be combined with NGAL in vitro, block the combination of NGAL and NGALR, and inhibit NF-kB signal channel at the downstream of NGALR.
Figure 3 is a graph of the ability of secreted NGALR peptide fragments to inhibit invasion of glioma cell lines a172 and U251MG through Matrigel in vitro.
FIG. 4 is the ability of secreted NGALR peptide fragments to inhibit the migration of glioma cell lines A172 and U251MG in vitro.
Detailed Description
The invention is further described with reference to the drawings and the following detailed description, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
Example 1 preparation of secreted NGALR peptide fragments
1. Constructing a secretory NGALR peptide fragment expression plasmid: as shown in figure 1A, a pET prokaryotic protein expression system is selected, a secretory NGALR peptide segment DNA sequence is inserted into an AlwN I enzyme cutting site of a pET-31b (+) vector through homologous recombination, the 3' end of the peptide segment DNA sequence is provided with a Flag label, and a terminator adopts TAA. The DNA sequence of the secretory NGALR peptide fragment is shown in SEQ ID NO. 3.
2. Plasmids were obtained by small extraction, introduced into the protein-expressing bacterium Rosetta (DE 3) (chloramphenicol resistant bacterium), transformed into plates and PCR-identified positive monoclonals.
3. And adding the positive bacteria into 100mL of fresh LB culture medium (added with chloramphenicol and kana antibiotic), and shaking the bacteria for 16h to obtain a small shake bacteria liquid. Further taking 0.2mL of the small shake culture solution, adding the small shake culture solution into 200mL of fresh LB culture medium (added with chloramphenicol and kana antibiotics), and shaking the bacteria for 14h to obtain a large shake culture solution.
Iptg stimulates bacteria to express proteins: the temperature of the shake-up bacteria liquid is reduced to 16 ℃, and 100mM IPTG (final concentration of 1 mM) and MgCl are directly added into 200mL bacteria liquid 2 、ZnCl 2 (final concentration is 50 mu M), shaking the bacteria for 12h, collecting the bacteria block, and carrying out ultrasonic lysis on the bacteria until the bacteria liquid is uniform and has good fluidity.
5. Protein purification: filtering with 0.45mm filter head to obtain protein liquid, and purifying with AKTApurifier 10 high pressure column chromatography system (replacing protein by dialysis method).
6. The purification effect of the secretory NGALR peptide fragment is determined by identifying the expression of the Flag tag through an immunoblotting experiment, and the result is shown in figure 1B, which indicates that the secretory NGALR peptide fragment linked with the expression tag Flag is successfully expressed.
Example 2 secreted NGALR peptide fragments can bind to NGAL and block NGAL from activating NGALR
1.293FT cells were transfected with secretory NGALR peptide fragment expression plasmid and NGAL-HA expression plasmid, and the secretory NGALR peptide fragment was enriched by Flag magnetic beads using co-immunoprecipitation, and found to be capable of binding to NGAL (FIG. 2A).
2.293FT cells are transfected with NGAL-HA plasmids, and the co-immunoprecipitation experiment finds that NGAL can be combined with NGALR, and further the expression plasmid for highly expressing the secretory NGALR peptide fragment can inhibit the combination of NGAL and NGALR (figure 2B).
3. Luciferase report experiments are used for detecting the activity of NF kB signal channels at the downstream of NGALR in glioma cell lines A172 and U251MG, the activity of NF kB luciferase is obviously improved after NGAL is highly expressed, and the activation of NF kB can be inhibited by further treating with secretory NGALR peptide fragments (figure 2C).
Example 3 secreted NGALR peptide fragments can inhibit invasion and migration of glioma cells
1. Invasion test: 50uL of matrigel was previously spread evenly in a transwell chamber, after digestion counting the differently treated glioma cells A172 and U251MG, resuspended in basal medium and added to the upper chamber layer and the lower chamber layer to complete medium containing 10% FBS. After 36h of cell incubator culture, the cells were fixed and stained with crystal violet for 15min, and the cells were observed under a microscope to cross the chamber. Experiments found that after treatment with the secreted NGALR peptide fragment, the invasion capacity of glioma cells a172 and U251MG was significantly reduced (fig. 3).
2. Migration experiment: the upper layer of the transwell chamber was prepared without matrigel, with differently treated cell suspensions of glioma cells A172 and U251MG prepared in basal medium and added to the upper chamber layer, and the lower chamber layer was added with complete medium containing 10% FBS. After 36h of cell incubator culture, the cells were fixed and stained with crystal violet for 15min, and the cells were observed under a microscope to cross the chamber. It was found that the migratory capacity of glioma cells a172 and U251MG was significantly reduced after treatment with the secreted NGALR peptide fragment (fig. 4).
The results show that the secretory NGALR peptide segment can inhibit the invasion and migration capacity of glioma cells, and has a wide application prospect in preparing glioma treatment medicines.
Sequence listing
<110> Shantou city central hospital
<120> polypeptide for treating glioma and application thereof
<141> 2021-07-27
<160> 3
<170> SIPOSequenceListing 1.0
<210> 1
<211> 110
<212> PRT
<213> Artificial sequences (Synthetic sequences)
<400> 1
Pro Pro Leu His Cys His Tyr Gly Ala Phe Pro Pro Asn Ala Ser Gly
1 5 10 15
Trp Glu Gln Pro Pro Asn Ala Ser Gly Val Ser Val Ala Ser Ala Ala
20 25 30
Leu Ala Ala Ser Ala Ala Ser Arg Val Ala Thr Ser Thr Asp Pro Ser
35 40 45
Cys Ser Gly Phe Ala Pro Pro Asp Phe Asn His Cys Leu Lys Asp Trp
50 55 60
Asp Tyr Asn Gly Leu Pro Val Leu Thr Thr Asn Ala Ile Gly Gln Trp
65 70 75 80
Asp Leu Val Cys Asp Leu Gly Trp Gln Val Ile Leu Glu Gln Ile Leu
85 90 95
Phe Ile Leu Gly Phe Ala Ser Gly Tyr Leu Phe Leu Gly Tyr
100 105 110
<210> 2
<211> 129
<212> PRT
<213> Artificial sequences (Synthetic sequences)
<400> 2
Met His Ser Phe Pro Pro Leu Leu Leu Leu Leu Phe Trp Gly Val Val
1 5 10 15
Ser His Ser Pro Pro Leu His Cys His Tyr Gly Ala Phe Pro Pro Asn
20 25 30
Ala Ser Gly Trp Glu Gln Pro Pro Asn Ala Ser Gly Val Ser Val Ala
35 40 45
Ser Ala Ala Leu Ala Ala Ser Ala Ala Ser Arg Val Ala Thr Ser Thr
50 55 60
Asp Pro Ser Cys Ser Gly Phe Ala Pro Pro Asp Phe Asn His Cys Leu
65 70 75 80
Lys Asp Trp Asp Tyr Asn Gly Leu Pro Val Leu Thr Thr Asn Ala Ile
85 90 95
Gly Gln Trp Asp Leu Val Cys Asp Leu Gly Trp Gln Val Ile Leu Glu
100 105 110
Gln Ile Leu Phe Ile Leu Gly Phe Ala Ser Gly Tyr Leu Phe Leu Gly
115 120 125
Tyr
<210> 3
<211> 387
<212> DNA
<213> Artificial sequences (Synthetic sequences)
<400> 3
atgcactcat tcccaccact actactacta ctattctggg gagtagtatc acactcacca 60
cctctgcact gccactacgg tgcattcccg ccgaacgcat caggctggga acaaccnccg 120
aacgcttcag gcgtgtccgt cgcatcagca gccctcgcag cttctgctgc atcacgcgtc 180
gctacctcaa ccgacccttc atgctcaggc ttcgctccac ccgacttcaa ccactgcctg 240
aaagactggg actacaacgg actgccagtc ctcacgacga acgcaatagg ccaatgggac 300
ctcgtctgcg acctcggatg gcaagtcata ctggaacaaa tactcttcat actcggattc 360
gcatctggat acctcttcct cggatac 387
Claims (8)
1. A polypeptide for treating glioma, wherein the amino acid sequence of the polypeptide is shown as SEQ ID NO. 1.
2. A secretory polypeptide for treating glioma, wherein the amino acid sequence of the secretory polypeptide is shown as SEQ ID NO. 2.
3. Use of the polypeptide of claim 1 or 2 for the manufacture of a medicament for the treatment of glioma.
4. Use of a polypeptide according to claim 1 or 2 for the manufacture of a medicament for inhibiting glioma migration or invasion.
5. The method for preparing the secretory polypeptide of claim 2, wherein a prokaryotic protein expression system is selected and inserted into the coding sequence of the secretory polypeptide to obtain a recombinant plasmid; then introducing the recombinant plasmid into a bacterium for protein expression, screening positive bacteria for amplification culture, inducing expression protein by IPTG, and purifying to obtain the recombinant plasmid.
6. The method of claim 5, wherein the coding sequence of the secreted polypeptide is as shown in SEQ ID No. 3.
7. A drug for treating glioma is characterized in that the drug contains polypeptide shown in SEQ ID NO.1 or SEQ ID NO.2 or plasmid or cell line for expressing the polypeptide shown in SEQ ID NO.1 or SEQ ID NO. 2.
8. The therapeutic agent of claim 7, further comprising a pharmaceutically acceptable excipient.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1313865A (en) * | 1998-07-02 | 2001-09-19 | 大正制药株式会社 | Saccharide transporter |
| WO2005052125A2 (en) * | 2003-11-21 | 2005-06-09 | University Of Massachusetts | 24p3 receptors and uses thereof |
| WO2006078717A2 (en) * | 2005-01-19 | 2006-07-27 | Beth Israel Deaconess Medical Center | Lipocalin 2 for the treatment, prevention, and management of cancer metastasis, angiogenesis, and fibrosis |
| WO2019158579A1 (en) * | 2018-02-13 | 2019-08-22 | Vib Vzw | Targeting minimal residual disease in cancer with rxr antagonists |
-
2021
- 2021-07-28 CN CN202110860180.0A patent/CN113637062B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1313865A (en) * | 1998-07-02 | 2001-09-19 | 大正制药株式会社 | Saccharide transporter |
| WO2005052125A2 (en) * | 2003-11-21 | 2005-06-09 | University Of Massachusetts | 24p3 receptors and uses thereof |
| WO2006078717A2 (en) * | 2005-01-19 | 2006-07-27 | Beth Israel Deaconess Medical Center | Lipocalin 2 for the treatment, prevention, and management of cancer metastasis, angiogenesis, and fibrosis |
| WO2019158579A1 (en) * | 2018-02-13 | 2019-08-22 | Vib Vzw | Targeting minimal residual disease in cancer with rxr antagonists |
Non-Patent Citations (4)
| Title |
|---|
| Biochemical and Structural Characterization of the Interaction between the Siderocalin NGAL/LCN2 (Neutrophil Gelatinase-associated Lipocalin/Lipocalin 2) and the N-terminal Domain of Its Endocytic Receptor SLC22A17;Ana-Isabel Cabedo Martinez;《THE JOURNAL OF BIOLOGICAL CHEMISTRY》;20160205;第291卷(第6期);全文 * |
| NGAL及NGALR在肾脏纤维化进程中的作用;王瑞芳等;《中国实验诊断学》;20180225(第02期);全文 * |
| Overexpression of Lipocalin-2 Inhibits Proliferation and Invasiveness of Human Glioblastoma Multiforme Cells by Activating ERK Targeting Cathepsin D Expression;Yi-Hsien Hsieh;《Biology》;20210501;全文 * |
| 中性粒细胞明胶酶相关脂质运载蛋白在肿瘤生物学行为中的研究进展;苏泽鑫等;《医学综述》;20190604(第11期);全文 * |
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