CN117051108A - Application of CDYL gene in preparation of multiple myeloma markers - Google Patents
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
- C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- G01N33/57407—Specifically defined cancers
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- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
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Abstract
The invention belongs to the technical field of biology and new medicines, and particularly discloses application of a chromosome domain Y-like protein (CDYL) of a new diagnosis and treatment marker of multiple myeloma, and targeting CDYL such as pyrroltinib and the like to treatment of multiple myeloma. The invention shows that the high expression of CDYL in a patient with multiple myeloma is obviously related to the disease process and poor prognosis of the patient in a clinical patient database, and experiments show that CDYL promotes the proliferation of multiple myeloma cells, and meanwhile, the application of molecular docking and in-vitro and in-vivo experiments show that the pyrroltinib can induce the multiple myeloma cells to undergo apoptosis. The invention discloses the regulation and control effect of CDYL in the occurrence and development of multiple myeloma for the first time, provides a new action target point for the treatment of multiple myeloma, and simultaneously discovers the application of pyrroltinib in multiple myeloma for the first time, and provides a new strategy for the treatment of multiple myeloma.
Description
Technical Field
The invention relates to the technical field of biology and new medicines, in particular to the discovery of a novel diagnosis and treatment marker CDYL of multiple myeloma and the application of the novel diagnosis and treatment marker CDYL of multiple myeloma to the treatment medicine of targeting CDYL in multiple myeloma, such as pyrroltinib, and the like, which promote the proliferation of multiple myeloma cells and the expression of the multiple myeloma cells in exosomes.
Background
Multiple Myeloma (MM) is a malignant clonal disease of plasma cells, a second tumor of the blood system. The main characteristics are that the tumor plasma cells are excessively proliferated, monoclonal immunoglobulin is abnormally secreted, osteolytic bone is destroyed, and various tissue viscera are damaged caused by anemia, infection, renal failure and pulp cell extramedullary infiltration. With the knowledge of MM molecular biology characteristics and pathogenesis, the treatment with proteasome inhibitors and immunomodulators as basic stones changes the overall treatment mode of the disease, and the survival time is obviously prolonged. Nevertheless, MM is a tumor of immune cells with extremely strong heterogeneity, and multiple mechanisms such as immune escape, clone evolution and the like lead to the fact that the disease is still incurable, drug resistance and recurrence are unavoidable and treatment means are deficient. Therefore, the research on the pathogenic genes and pathogenesis of MM is very important, and the discovery of new diagnosis and treatment targets of MM is explored.
The development and progression of MM is highly dependent on the bone marrow microenvironment, which can be communicated by different factors including extracellular vesicles, which can sustain MM cell growth. This communication has two major effects, namely, the initiation of drug resistance and the promotion of the development of osteolysis. At present, the research on myeloma exosomes is mainly focused on aspects of drug resistance, angiogenesis, promotion of differentiation of osteoclasts and the like, and the research is closely related to tumor microenvironment. Therefore, exosomes play an important role in the development and progression of tumors.
The invention uses MM patient clinical database analysis to screen MM potential high risk factor CDYL as research target, verifies the relation between CDYL and MM occurrence and development through three aspects of clinical database, in vitro cell experiment and in vivo animal experiment, detects CDYL expression in myeloma exosomes, clarifies the role played by CDYL in multiple myeloma occurrence and development, and screens out pyrroltinib as potential MM therapeutic drug based on molecular docking for research. Deep research on a novel diagnosis and treatment target and mechanism of MM provides powerful theoretical basis and scheme guidance for further treatment of the MM, and develops a novel medication indication of marketed medicines to lay a theoretical foundation for application of the MM.
Disclosure of Invention
The invention aims to provide application of chromosome domain Y-like protein (CDYL), CDYL (NM_ 004824.4, Q9Y 232) as a novel diagnosis and treatment marker in multiple myeloma, and elucidate the action mechanism of regulating and controlling the proliferation of multiple myeloma cells.
Use of an inhibitor of a CDYL protein or gene encoding the same in the manufacture of a medicament for the treatment of multiple myeloma.
Preferably, the inhibitor is selected from the group consisting of pharmaceutical compounds targeting CDYL proteins or transcripts thereof and capable of inhibiting CDYL protein expression or gene transcription; or siRNA, shRNA, dsRNA, microRNA, long non-coding RNA, antisense nucleic acid; or a DNA sequence or construct capable of expressing or forming said siRNA, dsRNA, microrna, long non-coding RNA, antisense nucleic acid.
As a particularly preferred embodiment, the pharmaceutical compound is pyrroltinib, flecaitinib or a pharmacologically acceptable salt thereof.
The invention discovers that CDYL promotes MM cell proliferation in vitro and in vivo, and that pyrroltinib has better anti-tumor activity, and verifies the effect of the pyrroltinib in vivo by utilizing various mouse models, thereby providing a new medication thought for clinically treating multiple myeloma.
Drawings
Figure 1 shows that CDYL expression is significantly correlated with disease progression and poor prognosis in MM patients.
FIG. 2 is a graph showing that CDYL promotes multiple myeloma development.
FIG. 3 shows the detection of CDYL expression by MM secretion exosomes.
FIG. 4 shows the application of molecular screening of pyrroltinib in MM.
FIG. 5 shows the results of an intermolecular thermophoresis assay (MST) of proteins of different compounds.
Detailed Description
Embodiments of the present invention are described in further detail below with reference to the accompanying drawings and examples. The following examples are illustrative of the invention but are not intended to limit the scope of the invention.
Example 1, CDYL expression is significantly correlated with disease progression and poor prognosis in MM patients
The invention first analyzes the expression of CDYL in MM by querying the GEPIA database, then analyzing the expression of CDYL in the gene expression profile GSE5900, and further carrying out correlation analysis on the expression of CDYL and survival curves in 2 independent MM patient prognosis databases (TT 2, APEX). Simultaneously, 20 clinical patient samples are embedded by paraffin and then subjected to immunohistochemistry, and CDYL and tumor proliferation marker Ki67 expression are detected by using 3, 3-Diaminobiphenyl (DAB) chromogenic assay. As can be seen from fig. 1, the results show that CDYL has high expression in various tumors, which suggests that CDYL can be used as a therapeutic target of related tumors, and that CDYL expression levels are significantly inversely related to overall survival in TT2 and APEX 2 databases, which suggests that CDYL gene high expression is related to MM prognosis. Furthermore, immunohistochemical experiments were performed on tissues of normal and clinical patients, and the results showed that CDYL was expressed in MM patients in high amounts and correlated positively with Ki67 expression.
Example 2 promotion of multiple myeloma development by CDYL
According to CDYL CDS region design and synthesis of CDYL plasmid, HEK293 cells are adopted to carry out slow virus packaging, virus supernatant is collected to infect MM cells, puromycin gradient screening is utilized to successfully construct CDYL over-expression stable transgenic cell lines (ARP 1 and KMS28 PE), siRNA technology is utilized to design and synthesize CDYL small interfering RNA, and electroporation experiment is utilized to knock down CDYL expression. The CCK-8 experiment is adopted to detect the proliferation condition of cells, the soft agar cloning experiment is further adopted to detect the long-term proliferation condition, and meanwhile, the flow cytometry is utilized to detect the cycle and the apoptosis condition, as shown by the result of the figure 2, the overexpression of CDYL can promote the proliferation of MM cells, the knocking down of CDYL can inhibit the proliferation of MM cells and promote the apoptosis of cells.
Example 3 detection of CDYL expression by MM secretion exosomes
Collecting exosomes by using a gradient centrifugation method (300 g,10min;2000g,10min;10000g,30min;100000g,70 min), and detecting exosome markers Alix and CD9, negative markers calnexin and CDYL protein expression by using WB after extracting proteins by using RIPA lysate to lyse exosomes. As the results in fig. 3 show, WB detection results indicate the presence of CDYL expression in MM exosomes.
Example 4 application of molecular Screen pyrroltinib in MM
Screening CDYL-targeted medicines through a medicine molecular data molecular library, screening out the pyrroltinib from 12 medicines of protrelin acetate, flavin Mononucleotide (FMN), etidrone hydrochloride, benzyl butanone, oseltamivir, chloramphenicol, nitrofurantoin, abacavir, nicorandil, benseradipine dopa, lika tinib and pyrroltinib through molecular docking, docking scoring, key action, manual selection and comprehensive evaluation of a combined protein intermolecular thermophoresis experiment (MST), and detecting that compounds inhibit MM cells to screen out the pyrroltinib, wherein the pyrroltinib has significant binding with the CDYL as shown in figures 4 and 5, and the cell experiment results show that the pyrroltinib can significantly inhibit proliferation of MM cells and promote apoptosis of the MM cells.
In mice, the clinical dose of the pyrroltinib is converted into the mice, the administration is carried out twice a week according to 30mg/kg by adopting a gastric lavage mode, NOD/SCID mice xenograft tumor results show that the pyrroltinib inhibits MM cell proliferation in vivo, and 5TMM3VT mice model results show that the pyrroltinib prolongs the survival period of the mice.
The embodiments of the present invention have been presented for purposes of illustration and description, but are not intended to be exhaustive or limited to the invention in the form disclosed, and although the invention has been described in detail with reference to the embodiments, it will be apparent to those skilled in the art that modifications may be made to the technical solutions described in the foregoing embodiments, or equivalents may be substituted for some of the technical features thereof.
Claims (6)
- Application of CDYL gene in preparing multiple myeloma markers.
- Use of an inhibitor of a cdyl protein or gene encoding the same in the manufacture of a medicament for the treatment of multiple myeloma.
- 3. The use according to claim 2, wherein the inhibitor is selected from the group consisting of pharmaceutical compounds targeting CDYL protein or transcripts thereof and capable of inhibiting CDYL protein expression or gene transcription; or siRNA, shRNA, dsRNA, microRNA, long non-coding RNA, antisense nucleic acid; or a DNA sequence or construct capable of expressing or forming said siRNA, dsRNA, microrna, long non-coding RNA, antisense nucleic acid.
- 4. The use according to claim 3, wherein the medicament is pyrroltinib, flecaitinib or a pharmacologically acceptable salt thereof.
- CDYL genes are expressed in exosomes.
- 6. A kit for multiple myeloma comprising a CDYL protein or gene encoding the same.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202311142444.4A CN117051108A (en) | 2023-09-06 | 2023-09-06 | Application of CDYL gene in preparation of multiple myeloma markers |
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| CN202311142444.4A CN117051108A (en) | 2023-09-06 | 2023-09-06 | Application of CDYL gene in preparation of multiple myeloma markers |
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2023
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