CN115232199B - Method for screening endogenous polypeptide and application of screened polypeptide - Google Patents
Method for screening endogenous polypeptide and application of screened polypeptide Download PDFInfo
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- CN115232199B CN115232199B CN202211165451.1A CN202211165451A CN115232199B CN 115232199 B CN115232199 B CN 115232199B CN 202211165451 A CN202211165451 A CN 202211165451A CN 115232199 B CN115232199 B CN 115232199B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6875—Nucleoproteins
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
- G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/70—Mechanisms involved in disease identification
- G01N2800/7023—(Hyper)proliferation
- G01N2800/7028—Cancer
Abstract
The invention belongs to the field of small molecular polypeptides, and particularly relates to a method for screening endogenous polypeptides and application of the screened polypeptides. The invention screens whether the separated and purified endogenous polypeptide has the biological activity function at a position which is preferably investigated, and screens the polypeptide of which the precursor protein expression level is closely related to the clinical prognosis of the patient with endometrial cancer by adopting a bioinformatics analysis tool. An endogenous polypeptide PDAEP-1 derived from endometrial cancer tissues is obtained by screening and is released into a focal microenvironment in a paracrine manner. PDAEP-1 polypeptide is taken as a target spot, which can be a specific target spot for treating endometrial cancer, particularly for patients with invasive metastasis, and is applied to the research and development of preparing novel biological targeted drugs for treating endometrial cancer; especially, the method has important scientific research value for developing new biological medicines for endometrial cancer patients who have invasion and metastasis.
Description
Technical Field
The invention belongs to the field of small molecular polypeptides, and particularly relates to a method for screening endogenous polypeptides and application of screened polypeptides.
Background
Endometrial Cancer (EC), which accounts for about 7% of the total number of cancers in women, is one of the three malignancies in the female reproductive tract. In recent years, the incidence of endometrial cancer in China tends to rise year by year and to be younger. As nearly 30% of patients with endometrial cancer are in malignant progress and are found to be in middle and late stages, even though the existing comprehensive treatment means are exhausted, the survival rate is not obviously improved, and the chemoradiotherapy supplemented after the operation also has certain toxic and side effects. Based on this, there is an urgent clinical need for new targets for the treatment of endometrial cancer to prepare natural low-toxicity bio-targeted drugs. Currently, the mechanisms of malignant progression associated with the onset, invasion and metastasis of endometrial cancer are still poorly understood. Further analyzing the pathogenesis of the gynecological tumor, searching for a new target and developing a new biological treatment medicament become difficult points in the current research field of gynecological tumor prevention and treatment.
Polypeptides (peptides) are a class of compounds formed by the linkage of alpha-amino acids by peptide bonds and have been previously considered to be merely degradation products of macromolecular proteins. In recent years, with the development of proteomics, researchers have come to recognize the functional diversity of small polypeptides. Based on the small molecular weight of the polypeptide, the polypeptide has the advantages of easy synthesis, low toxicity, high efficiency, strong targeting property, easy blood brain barrier penetration and the like, and has natural advantages in screening and preparing novel anti-tumor biological medicines from the perspective of the polypeptide. The polypeptide is very likely to become a new biological target for treating gynecological malignant tumors, particularly endometrial cancer.
Endogenous polypeptides are mainly derived from enzymolysis of endogenous proteins or are coded by non-coding RNA, and the rapid development of mass spectrum technology is benefited, and especially the possibility is provided for the mining of endogenous polypeptides with potential biological activity by human tissue peptide fragment analysis based on liquid chromatography-tandem mass spectrum technology (LC-MS/MS). The application of LC-MS/MS-based proteomics analysis in endometrial cancer tissues is continuously tried and perfected, the expression characteristics of endogenous polypeptide molecules secreted by the endometrial cancer tissues are deeply excavated, important potential scientific research values are undoubtedly provided for clarifying the occurrence and malignant progress of the endometrial cancer, and the possibility is expected to be provided for preparing endometrial cancer biological target drugs.
Disclosure of Invention
In view of the above, the present invention provides a method for screening endogenous polypeptides and applications of the screened polypeptides. The invention screens out a polypeptide which plays an important role in the malignant progression mechanism of endometrial cancer, and provides a new choice for preparing a medicament for treating endometrial cancer by the screened polypeptide.
In order to achieve the above purpose, the invention provides the following technical scheme:
in one aspect, the invention provides a method for screening for an endogenous polypeptide,
the endogenous polypeptide is PDAEP-1, and the amino acid sequence of the endogenous polypeptide is IQGITKPAIR.
On the other hand, the invention also provides application of the endogenous polypeptide in preparing a specific target medicament of endometrial cancer.
On the other hand, the invention also provides application of the endogenous polypeptide in preparing a medicament for preventing or treating endometrial cancer. Preferably, the endometrial cancer is metastatic endometrial cancer.
In another aspect, the present invention provides a method for screening for an endogenous polypeptide, comprising the steps of:
(1) Extracting polypeptide from a cancer tissue specimen of an endometrial cancer patient who has undergone local invasion and metastasis, and further separating and purifying by using an ultrafiltration tube to obtain a detection sample;
(2) Detecting the expression profile of endogenous polypeptides in a sample by using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology to obtain polypeptides differentially expressed in endometrial cancer tissues;
(3) Obtaining endogenous polypeptide with potential biological activity specific to endometrial cancer by means of a bioinformatics prediction method.
Preferably, the molecular weight of the ultrafiltration tube in the step (1) is less than or equal to 3kDa.
The differentially expressed p described in step (2) is <0.05.
The bioinformatics prediction in step (3) is to evaluate the correlation of the differential prepro-polypeptide protein with the clinical prognosis of the patient.
The endogenous polypeptide in the step (3) is derived from a precursor protein Histone H4.
Compared with the prior art, the invention has the beneficial effects that:
the invention obtains an endogenous polypeptide from endometrial cancer tissues through screening, and the endogenous polypeptide is released into a focus microenvironment in a paracrine mode. The invention screens whether the separated and purified endogenous polypeptide has the biological activity function at a position which is preferably investigated, and screens the polypeptide of which the precursor protein expression level is closely related to the clinical prognosis of the patient with endometrial cancer by adopting a bioinformatics analysis tool. Through verification, the PDAEP-1 polypeptide obtained by screening plays an important role in the malignant progression mechanism of the endometrial cancer and can be used as a target index for endometrial cancer treatment. PDAEP-1 polypeptide is taken as a target spot, which can be a specific target spot for treating endometrial cancer, particularly for patients with invasive metastasis, and is applied to the research and development of preparing novel biological targeted drugs for treating endometrial cancer; especially has important scientific research value for the development of new biological medicines for endometrial cancer patients with invasion and metastasis.
Drawings
FIG. 1 is a graph of the effect of various concentrations of PDAEP-1 polypeptide on proliferation of endometrial cancer cells HEC-1-A;
FIG. 2 is a graph of the effect of PDAEP-1 polypeptide on the invasion of endometrial cancer cells HEC-1-A; in the figure, A is a typical diagram of Transwell of PDAEP-1 inhibiting HEC-1-A invasion, and B is a quantitative comparison diagram of the Transwell experiment;
FIG. 3 is a graph of the effect of PDAEP-1 polypeptide on the migration of HEC-1-A in endometrial cancer cells; in the figure, A is a typical scratch experiment graph of PDAEP-1 inhibiting HEC-1-A migration, and B is a quantitative comparison graph of the scratch experiment;
FIG. 4 is a graph of the effect of PDAEP-1 polypeptide on the invasion and metastasis of endometrial cancer cells HEC-1-A in vivo.
Detailed Description
In order to make the technical solutions of the present application better understood by those skilled in the art, the technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application, and it is obvious that the described embodiments are only some embodiments of the present application, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present application.
It should be noted that the present application describes generally and/or specifically the materials used in the tests and the test methods. The following examples are examples of experimental methods in which specific conditions are not specified, and the detection is usually carried out according to conventional conditions or according to conditions recommended by the manufacturers. Reagents, biomaterials, etc. used in the following examples are commercially available unless otherwise specified.
Example 1
The clinical sample is from the maternal and child health care institute in Nanjing; mainly comes from female patients who receive operation treatment, do not receive any treatment including radiotherapy and chemotherapy before operation and do not contain any other malignant tumor history, and are all clearly pathologically diagnosed after the operation. Endometrial cancer tissues of endometrial cancer patients who have locally invasive metastasis (age =57 ± 5.5 years, experimental group) and endometrium samples of healthy women matched with the same age are collected as control samples (age =55 ± 4.4 years, control group) respectively for 3 cases, and the ages of the patients in the two groups are not statistically different (p > 0.05). Endogenous polypeptides were extracted for subsequent studies.
Further separating and purifying the polypeptide from the endogenous polypeptide obtained by extraction by using an ultrafiltration tube with the molecular weight of 3kDa. And (4) separating and purifying the obtained polypeptide, and detecting the polypeptide component by using an LC-MS/MS method. The results showed that a total of 383 polypeptides were expressed from 153 precursor proteins; wherein 12 polypeptides are differentially expressed. The quantity of the obtained polypeptides is obviously less than that of the differential polypeptides obtained in the previous research report, so that the working intensity of later-stage screening is greatly simplified; and are all located in the functional domain of their precursor proteins (fold change >1.5 or <1/1.5, p < 0.05). Table 1 is information on differentially expressed polypeptides.
TABLE 1 differentially expressed polypeptide information
The results in table 1 and above show that there is significant difference and specificity in the polypeptide secreted from cancer tissue compared to the control.
In previous researches, the method considers the physicochemical properties of lipophilicity, isoelectric point, instability and the like, and synthesizes the differential polypeptide in batches to perform biological function detection so as to screen and obtain the differential polypeptide possibly having the biological activity function. Based on the existing development level of polypeptide modification, the physicochemical properties of the polypeptide may be modified to some extent at a later stage by means including chemical methods. Therefore, whether the polypeptide has the biological activity function or not is firstly screened at a position which is preferentially investigated, and in order to screen the target differential polypeptide which has the potential biological activity function, a bioinformatics analysis tool (the Human Protein Atlas web server, https:// www.proteinatlas. Org) is adopted to screen the polypeptide of which the expression level of the precursor Protein is closely related to the clinical prognosis of the patient with the endometrial cancer so as to carry out the next biological activity function verification research. Since the biologically active function of endogenous polypeptide is often similar to or opposite to that of its precursor protein, the polypeptide satisfying the above requirement is defined as being derived from precursor protein Histone H4 (https:// www. Proteinatlas. Org/ENSG00000278637-H4C 1/pathology/endometeral + cancer, 5-year survival rate of high-expression patients is significantly higher than that of low-expression patients, p < 0.05), and an endogenous polypeptide is obtained after screening and named as PDAEP-1 (protein derived anti-EC peptide 1). The amino acid sequence is IQGITKPAIR. The following functional verification was performed on this sequence.
Example 2: cell viability assay (CCK-8 assay)
Inoculating 4000 HEC-1-A cells in logarithmic growth phase per well into 96-well plates, setting to 37 ℃ 5% CO 2 The cells were cultured overnight in a cell culture chamber, the medium was aspirated, 100. Mu.L of a medium (1% FBS) containing PDAEP-1 polypeptide at different concentrations (0. Mu.M, 12.5. Mu.M, 25. Mu.M, 50. Mu.M, 100. Mu.M, 200. Mu.M, 400. Mu.M) was added thereto, the medium was discarded after culturing for 48 hours, fresh medium containing 10. Mu.L of a detection solution of LCCK-8 was added to each well, and the wells were incubated at 37 ℃ for 1 to 4 hours, and the absorbance of each well was measured at a wavelength of 450nm using a microplate reader.
FIG. 1 is a graph of the effect of various concentrations of PDAEP-1 polypeptide on proliferation of endometrial cancer cells HEC-1-A; as shown in FIG. 1, PDAEP-1 showed significant proliferation inhibition effect on EC cell HEC-1-A in the concentration range of 400 μ M or less (P <0.05, compared with 0 μ M concentration group), and had certain concentration dependence.
Example 3: cell migration invasion assay
Transwell experiment
Placing the chamber into a 24-well plate, and adding 600 mu L of complete culture medium into the lower chamber; after HEC-1-A cells were digested and counted, 200. Mu.L of a cell suspension (1-10X 10) prepared in a minimal medium (containing 100. Mu.M PDAEP-1 polypeptide) was added to the upper chamber 4 Individual cells/well). Putting the 24-well plate into an incubator for culturing for 48h, taking out, removing the culture medium, and adding 1mL of 4% paraformaldehyde into each well to fix the cells at 4 ℃ for 30min. And adding 50 mu L of crystal violet dye into the upper rear chamber, adding 300 mu L of crystal violet dye into the lower rear chamber, dyeing for 30min, wiping off cells on the upper layer of the porous membrane by using a cotton swab, washing by using PBS, shooting cells on the bottom layer of the membrane, and measuring and calculating the cell amount. (100x, 4-6 fields; 40x full panel). FIG. 2 is a graph of the effect of PDAEP-1 polypeptide on the invasion of endometrial cancer cells HEC-1-A; in the figure, A is a typical diagram of Transwell of PDAEP-1 inhibiting HEC-1-A invasion, and B is a diagram of Transwell experiment quantitative comparison; the Control group means a Control group without PDAEP-1 polypeptide, and the Peptide group is an experimental group with 100 μ M PDAEP-1; as shown in FIG. 2, PDAEP-1 can significantly inhibit the invasive metastatic potential of HEC-1-A cells.
2. Scratch test
Inoculating HEC-1-A cells into a 6-well plate, culturing the cells to be completely attached to the wall and fully spread by about 70-80%, uniformly and straightly scratching about 1mm fine marks at the bottom of each well plate by using a 10 mu L gun head, rinsing the cells for 2-3 times by using PBS (phosphate buffer solution) to wash off the scratched and shed cells, treating the inoculated cells by using PDAEP-1 polypeptide with the final concentration of 100 mu M, observing the scratch healing condition of each group of cells after 0h and 48h of scratch under a microscope, photographing and recording, and analyzing the cell migration condition. FIG. 3 is a graph of the effect of PDAEP-1 polypeptide on the migration of HEC-1-A in endometrial cancer cells; in the figure, A is a typical figure of a scratch experiment for inhibiting HEC-1-A migration by PDAEP-1, and B is a quantitative comparison figure of the scratch experiment; the Control group means a Control group without PDAEP-1 polypeptide, and the Peptide group is an experimental group with 100 μ M PDAEP-1; as shown in FIG. 3, PDAEP-1 can significantly inhibit the migratory capacity of HEC-1-A cells. Therefore, the PDAEP-1 has obvious influence on the invasion and migration of the endometrial cancer and is expected to become a novel target medicine for treating the metastatic endometrial cancer.
The experimental data were calculated by GraphPad Prism software, and are all expressed as mean. + -. Standard deviation of three (or more) experiments, and the difference between groups was tested by Student's t-test (p <0.05 has significant difference; p > 0.05 has no statistical difference).
Example 4: animal experiments
Experiment following ethical requirements of experimental animals of Nanjing university of medical science, 100 μ L HEC-1-A cells (density 5 × 10) resuspended in culture solution were inoculated via tail vein 7 /ml) in female BALB/c nude mice (housed in SPF animal house). After 2 weeks PDAEP-1 (20 mmo L/L/kg) or an equal volume of physiological saline was intraperitoneally injected weekly for 6 consecutive weeks. The mice were sacrificed, lung tissues of nude mice were completely dissociated, specimens were embedded in paraffin, and HE stained after sectioning, and the number of pulmonary metastases foci was counted. FIG. 4 is a graph of the effect of PDAEP-1 polypeptide on the invasion and metastasis of endometrial cancer cells HEC-1-A in vivo; as shown in figure 4, PDAEP-1 can remarkably inhibit the metastasis of endometrial cancer cells HEC-1-A in visceral organs (lungs).
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Claims (5)
1. The application of an endogenous polypeptide in preparing a medicament for preventing or treating endometrial cancer is characterized in that the endogenous polypeptide is PDAEP-1, and the amino acid sequence of the endogenous polypeptide is IQGITKPAIR.
2. The use of claim 1, wherein the drug is a specific target drug.
3. The use of claim 1, wherein said endogenous polypeptide is derived from the precursor protein Histone H4.
4. The use of claim 1, wherein the endometrial cancer is metastatic endometrial cancer.
5. A targeted drug for treating endometrial cancer, which is characterized by comprising an endogenous polypeptide with an amino acid sequence of IQGITKPAIR and further comprising any one or a combination of at least two of a pharmaceutically acceptable carrier, an excipient or a diluent.
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