CN114569725B - Application of YKL-40 in treatment of melanoma - Google Patents
Application of YKL-40 in treatment of melanoma Download PDFInfo
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- CN114569725B CN114569725B CN202210319185.7A CN202210319185A CN114569725B CN 114569725 B CN114569725 B CN 114569725B CN 202210319185 A CN202210319185 A CN 202210319185A CN 114569725 B CN114569725 B CN 114569725B
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Abstract
The invention belongs to the technical fields of biological medicine and molecular biology, and particularly relates to an application of YKL-40 in melanoma treatment. The CHI3L1/YKL-40 gene and the expressed YKL-40 protein are subjected to in-vitro and in-vivo experiments to evaluate the treatment effect of a humanized melanoma model, and researches show that the CHI3L1/YKL-40 gene and the expressed YKL-40 protein have good anti-melanoma effect. The technical scheme lays an experimental foundation for developing high-efficiency medicines related to the treatment of the melanoma and provides a new field of view, so that the method has good practical application value.
Description
Technical Field
The invention belongs to the technical fields of biological medicine and molecular biology, and particularly relates to an application of YKL-40 in melanoma treatment.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
Melanoma is a malignant tumor with strong proliferation capacity and high invasion and metastasis rate, and clinically, lymph node, brain, liver and lung metastasis occur frequently. Melanoma causes 65% -75% of skin cancer deaths, and metastatic melanoma patients have only 5% -10% survival rates for 5 years.
At present, the treatment for melanoma mainly comprises surgical excision, radiation therapy and chemotherapy are used after surgery to prolong the survival time of patients, and immunotherapy and targeted therapy have certain effects in recent years, but for melanoma patients, the risk of cancer recurrence after treatment is very high, and the recurrence risk can be reduced to a certain extent by combining an immune checkpoint inhibitor and a signal transduction inhibitor, so that better treatment targets and targeted drugs are still needed for clinical treatment of melanoma.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides the application of YKL-40 in the treatment of melanoma. According to the invention, the CHI3L1/YKL-40 gene can be used as a target spot for resisting melanoma, and further, the YKL-40 protein expressed by the gene has the effect of inhibiting proliferation, invasion and metastasis of melanoma tumor, and the invention is completed based on the research results.
Specifically, the invention relates to the following technical scheme:
according to the invention, the research shows that YKL-40 can inhibit proliferation and invasion of melanoma cells through MAPK and NF- κB signal paths, and increase immune cell infiltration so as to inhibit proliferation of melanoma cells in vivo and increase sensitivity of the melanoma cells to drugs. Accordingly, in a first aspect of the present invention, there is provided the use of a substance for promoting an increase in the CHI3L1/YKL-40 gene and its expression products and/or activity in at least one of the following a 1) -a 5):
a1 Inhibit tumor cell proliferation or preparing a product that inhibits tumor cell proliferation;
a2 Inhibit tumor cell migration and invasion or prepare a product for inhibiting tumor cell migration and invasion;
a3 Inhibit tumor growth or preparing a product that inhibits tumor growth;
a4 Promoting the sensitivity of the tumor to the therapeutic agent or preparing a product for promoting the sensitivity of the tumor to the therapeutic agent;
a5 Tumor treatment or preparation of a product for tumor treatment.
In a second aspect of the invention, there is provided the use of a substance for inhibiting the reduction of the CHI3L1/YKL-40 gene and its expression products and/or activities in at least one of the following b 1) -b 5):
b1 Promoting tumor cell proliferation or preparing a product for promoting tumor cell proliferation;
b2 Promoting tumor cell migration and invasion or preparing a product for promoting tumor cell migration and invasion;
b3 Promoting tumor growth or preparing a product that promotes tumor growth;
b4 Inhibit the sensitivity of the tumor to the therapeutic agent or preparing a product for inhibiting the sensitivity of the tumor to the therapeutic agent;
b5 A tumor cell or an animal model is constructed.
In a third aspect of the present invention, there is provided a composition comprising, as an active ingredient, at least a substance promoting an increase in the CHI3L1/YKL-40 gene and its expression products and/or activities, and other at least one chemotherapeutic agent.
In a fourth aspect of the invention there is provided the use of the above composition in any one or more of the following:
a1 Inhibit tumor cell proliferation or preparing a product that inhibits tumor cell proliferation;
a2 Inhibit tumor cell migration and invasion or prepare a product for inhibiting tumor cell migration and invasion;
a3 Inhibit tumor growth or preparing a product that inhibits tumor growth;
a4 Promoting the sensitivity of the tumor to the therapeutic agent or preparing a product for promoting the sensitivity of the tumor to the therapeutic agent;
a5 Tumor treatment or preparation of a product for tumor treatment.
The tumor may be melanoma.
The product can be a drug or an experimental reagent which can be effectively used for basic research.
In a fifth aspect of the invention, there is provided a method of melanoma treatment comprising administering to a subject a therapeutically effective dose of the above-described substances that promote an increase in the CHI3L1/YKL-40 gene and expression products and/or activity thereof or the above-described composition.
The beneficial technical effects of one or more of the technical schemes are as follows:
according to the technical scheme, the CHI3L1/YKL-40 gene and the YKL-40 protein expressed by the gene are subjected to in-vitro and in-vivo experiments to evaluate the treatment effects of a humanized melanoma cell model and a melanoma animal model, and researches show that the CHI3L1/YKL-40 gene and the YKL-40 protein expressed by the gene in the technical scheme have good anti-melanoma effect; the technical scheme lays an experimental foundation for developing high-efficiency medicines related to the treatment of the melanoma and provides a new field of view, so that the method has good practical application value.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention.
FIG. 1 shows the results of the verification of the expression of proteins in human melanoma cells A375 and murine melanoma cells B16-F10 over-expressing YKL-40 used according to the invention; wherein A is a humanized melanoma cell A375 and B is a murine melanoma cell B16-F10;
FIG. 2 shows the measurement of the proliferation inhibition effect of YKL-40 on melanoma cells A375 and B16-F10 according to the invention by cell proliferation assays (MTS) and cell clone formation assays; wherein A is the experimental statistical result of proliferation of A375 cells, B is the experimental result of cloning A375 cells and B16-F10 cells, C is the experimental statistical result of cloning A375 cells, and D is the experimental statistical result of cloning B16-F10 cells; * *: p <0.01; * **: p <0.001.
FIG. 3 is a graph showing the detection of YKL-40 inhibiting the migration of melanoma cells A375 and B16-F10 by cell scoring experiments according to the invention; wherein a is a375 cell scratch test result, B is a375 cell scratch test statistical result, C is a B16-F10 cell scratch test result, D is a B16-F10 cell scratch test statistical result,: p <0.01; * **: p <0.001.
FIG. 4 is a Transwell invasion assay for detecting that YKL-40 inhibits the invasion of melanoma cells A375 and B16-F10 according to the invention; wherein, a is a375 cell Transwell invasion experimental result, and B is a375 cell Transwell invasion experimental statistical result,: p <0.01.
FIG. 5 is a flow cytometry experiment used in the present invention to detect an increase in sensitivity of YKL-40 to dacarbazine by melanoma cells A375 and B16-F10; wherein, a is the experimental result of apoptosis of a375 and B16-F10 in dacarbazine stimulation by flow cytometry, B is the statistical result of flow cytometry detection of a375, C is the statistical result of flow cytometry detection of B16-F10, x: p <0.01.
FIG. 6 is a graph showing the increase in sensitivity of YKL-40 to melanoma cells A375 and B16-F10 versus miltinib using the cell resistance assay (MTS) of the invention; wherein, A is the statistics of A375 cell MTS experiments, B is the statistics of B16-F10 cell MTS experiments,: p <0.05.
FIG. 7 is a model of the invention for subendothelial tumor-bearing in vivo, demonstrating the ability of YKL-40 to inhibit the tumorigenesis of melanoma cells B16-F10 in C57BL/6 mice; wherein, a is a comparison graph of the results of subcutaneous tumor formed by B16-F10 melanoma cells over-expressing YKL-40 and control cells in mice, B is the change of volume of subcutaneous tumor with time, and C is the tumor tissue weighing result: p <0.05.
FIG. 8 is an in vivo lung metastasis model of the present invention, demonstrating the ability of YKL-40 to inhibit lung metastasis of melanoma cells B16-F10 in C57BL/6 mice; wherein, A is a comparison graph of lung metastasis results of B16-F10 cells which over express YKL-40 and control group cells melanoma, and B is a counting statistical result of lung metastasis node number: p <0.05.
Detailed Description
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the present application. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments in accordance with the present application. As used herein, the singular is also intended to include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that the terms "comprises" and/or "comprising" when used in this specification are taken to specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof. Experimental methods in the following embodiments, unless specific conditions are noted, are generally in accordance with conventional methods and conditions of molecular biology within the skill of the art, and are fully explained in the literature. See, e.g., sambrook et al, molecular cloning: the techniques and conditions described in the handbook, or as recommended by the manufacturer.
The invention will be further illustrated with reference to specific examples, which are given for the purpose of illustration only and are not to be construed as limiting the invention. If experimental details are not specified in the examples, it is usually the case that the conditions are conventional or recommended by the sales company; reagents, consumables, cells, laboratory animals, etc. used in the examples are commercially available unless otherwise specified.
As previously mentioned, there remains a need for better therapeutic targets and targeted drugs for clinical treatment of melanoma.
In view of the above, the present invention has found through research that YKL-40 may inhibit proliferation and invasion of melanoma cells through MAPK and NF- κB signaling pathways, increase infiltration of immune cells to inhibit proliferation in melanoma cells, and increase sensitivity of melanoma cells to drugs.
In an exemplary embodiment of the present invention, there is provided the use of a substance for promoting an increase in the CHI3L1/YKL-40 gene and its expression products and/or activity in at least one of the following a 1) -a 5):
a1 Inhibit tumor cell proliferation or preparing a product that inhibits tumor cell proliferation;
a2 Inhibit tumor cell migration and invasion or prepare a product for inhibiting tumor cell migration and invasion;
a3 Inhibit tumor growth or preparing a product that inhibits tumor growth;
a4 Promoting the sensitivity of the tumor to the therapeutic agent or preparing a product for promoting the sensitivity of the tumor to the therapeutic agent;
a5 Tumor treatment or preparation of a product for tumor treatment.
In yet another embodiment of the present invention, the substances that promote an increase in the CHI3L1/YKL-40 gene and its expression products and/or activity include, but are not limited to, substances that up-regulate the CHI3L1/YKL-40 expression and/or promote its activity using gene specific Mimics based techniques; such as short hairpin RNA (shRNA) of artificially synthesized CHI3L1/YKL-40 or a promoter or lentivirus for up-regulating CHI3L1/YKL-40 expression; also comprises a compound accelerant; the compound promoter can be used for activating the expression of YKL-40 protein.
In still another specific embodiment of the present invention, the CHI3L1/YKL-40 gene sequence is shown in SEQ ID NO. 1; the expressed product of the CHI3L1/YKL-40 gene can be YKL-40 protein, and the amino acid sequence of the protein is shown as SEQ ID NO. 2.
In yet another embodiment of the present invention, the tumor may be melanoma.
The product can be a drug or an experimental reagent which can be effectively used for basic research.
In yet another embodiment of the present invention, there is provided the use of a substance for inhibiting the reduction of the CHI3L1/YKL-40 gene and its expression products and/or activity in at least one of the following b 1) -b 5):
b1 Promoting tumor cell proliferation or preparing a product for promoting tumor cell proliferation;
b2 Promoting tumor cell migration and invasion or preparing a product for promoting tumor cell migration and invasion;
b3 Promoting tumor growth or preparing a product that promotes tumor growth;
b4 Inhibit the sensitivity of the tumor to the therapeutic agent or preparing a product for inhibiting the sensitivity of the tumor to the therapeutic agent;
b5 A tumor cell or an animal model is constructed.
In yet another embodiment of the present invention, the substances that inhibit the reduction of the CHI3L1/YKL-40 gene and its expression products and/or activity include, but are not limited to, RNA interfering molecules or antisense oligonucleotides directed against CHI3L1/YKL-40, small molecule inhibitors, shRNAs (small hairpin RNAs), small interfering RNAs, substances that effect lentiviral infection or gene knockout, and specific antibodies directed against YKL-40 itself or its upstream and downstream molecules, such as anti-YKL-40 antibodies.
In still another specific embodiment of the present invention, the CHI3L1/YKL-40 gene sequence is shown in SEQ ID NO. 1; the expressed product of the CHI3L1/YKL-40 gene can be YKL-40 protein, and the amino acid sequence of the protein is shown as SEQ ID NO. 2.
In yet another embodiment of the present invention, the tumor may be melanoma.
In yet another embodiment of the present invention, a composition is provided, the active ingredient of which comprises at least a substance promoting an increase in the CHI3L1/YKL-40 gene and its expression products and/or activity, and other at least one chemotherapeutic drug.
In yet another embodiment of the invention, substances that promote an increase in the CHI3L1/YKL-40 gene and its expression products and/or activity include, but are not limited to, substances that up-regulate the CHI3L1/YKL-40 expression and/or promote its activity using techniques based on gene-specific chemistry; such as short hairpin RNA (shRNA) of artificially synthesized CHI3L1/YKL-40 or a promoter or lentivirus for up-regulating CHI3L1/YKL-40 expression; also comprises a compound accelerant; the compound promoter can be used for activating the expression of YKL-40 protein.
In still another embodiment of the present invention, the chemotherapeutic agent is not specifically limited, and in one embodiment of the present invention, the chemotherapeutic agent may be one or more of BRAF inhibitors such as bimatinib and one or more of common chemotherapeutic agents such as dacarbazine.
In yet another embodiment of the present invention, there is provided the use of the above composition in any one or more of the following:
a1 Inhibit tumor cell proliferation or preparing a product that inhibits tumor cell proliferation;
a2 Inhibit tumor cell migration and invasion or prepare a product for inhibiting tumor cell migration and invasion;
a3 Inhibit tumor growth or preparing a product that inhibits tumor growth;
a4 Promoting the sensitivity of the tumor to the therapeutic agent or preparing a product for promoting the sensitivity of the tumor to the therapeutic agent;
a5 Tumor treatment or preparation of a product for tumor treatment.
In yet another embodiment of the present invention, the tumor may be melanoma.
In yet another embodiment of the invention, the product may be a pharmaceutical or experimental agent that is effective for use in basic research.
According to the invention, when the product is a medicament, the medicament further comprises at least one pharmaceutically inactive ingredient.
The pharmaceutically inactive ingredients may be carriers, excipients, diluents and the like which are generally used in pharmacy. Further, the composition can be formulated into various dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, sprays, etc., for oral administration, external use, suppositories, and sterile injectable solutions according to a usual method.
The non-pharmaceutically active ingredients, such as carriers, excipients and diluents, which may be included, are well known in the art and can be determined by one of ordinary skill in the art to meet clinical criteria.
In yet another embodiment of the present invention, the carriers, excipients and diluents include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil and the like.
In yet another embodiment of the invention, the medicament of the invention may be administered to the body in a known manner. For example, by intravenous systemic delivery or local injection into the tissue of interest. Alternatively via intravenous, transdermal, intranasal, mucosal or other delivery methods. Such administration may be via single or multiple doses. It will be appreciated by those skilled in the art that the actual dosage to be administered in the present invention may vary greatly depending on a variety of factors, such as the target cell, the type of organism or tissue thereof, the general condition of the subject to be treated, the route of administration, the mode of administration, and the like.
In yet another embodiment of the invention, the subject to be administered can be human or non-human mammals, such as mice, rats, guinea pigs, rabbits, dogs, monkeys, gorillas, etc.
In yet another embodiment of the invention, a method of treating melanoma is provided, comprising administering to a subject a therapeutically effective dose of the above-described substances that promote an increase in CHI3L1/YKL-40 gene and expression products and/or activity thereof or the above-described composition.
In yet another embodiment of the present invention, the melanoma treatment may be any one or more of immunotherapy, gene therapy, and inhibitory antibody therapy.
In yet another embodiment of the invention, the subject is an animal, preferably a mammal, most preferably a human, who has been the subject of treatment, observation or experiment. By "therapeutically effective amount" is meant that amount of active compound or pharmaceutical agent, including a compound of the present invention, which causes a biological or medical response in a tissue system, animal or human that is sought by a researcher, veterinarian, medical doctor or other medical personnel, which includes alleviation or partial alleviation of the symptoms of the disease, syndrome, condition or disorder being treated. It must be recognized that the optimal dosage and spacing of the active ingredients of the present invention is determined by its nature and external conditions such as the form, route and site of administration and the particular mammal being treated, and that such optimal dosage may be determined by conventional techniques. It must also be appreciated that the optimal course of treatment, i.e. the daily dosage of the simultaneous compounds over the nominal time period, can be determined by methods well known in the art.
The invention is further illustrated by the following examples, which are not to be construed as limiting the invention. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention.
EXAMPLE 1 establishment of cell lines stably overexpressing YKL-40 protein
A375 cells and B16-F10 cells were cultured in DMEM complete medium containing 10% fetal calf serum and 1% green-streptomycin, placed in a constant temperature incubator at 37℃with 5% CO2 and saturated humidity, after the monolayer cells were grown, digested with 0.25% trypsin (EDTA) 1mL until the cell connection was broken into circles, the complete medium was added to terminate the digestion, and the cells were resuspended for passage at a ratio of 1:3 to continue culturing.
Constructing a DNA fragment of a YKL-40 gene sequence (the nucleotide sequence is shown as SEQ ID NO.1, the amino acid sequence is shown as SEQ ID NO. 2), carrying out BamHI and EcoRI double digestion on a vector pBABE and a target fragment, connecting an enzyme digestion product to a p-BABE recombinant plasmid through T4 ligase, transforming DH-5 alpha competent cells by the connection product, coating the competent cells on an ampicillin screening plate, incubating the competent cells for 14 hours at 37 ℃, picking positive clones, and extracting plasmids according to a method described in a plasmid extraction kit. After the plasmid extraction is successful, the Lipofectamine2000 liposome transfection method is used for transfecting 293T cells, virus liquid is collected at 72 hours, supernatant is taken after centrifugation, and the supernatant and DMEM complete culture medium are added into the attached cells according to the ratio of 3:4, after 24 hours, the cells are changed into culture medium containing Puromycin of 0.5ug/ml for screening, and finally the obtained cells continue subculture. Western blot verifies that YKL-40 is stably overexpressed, and the result is shown in figure 1.
EXAMPLE 2 inhibition of proliferation of YKL-40 on melanoma cell model
(1) Cell proliferation assay
The growth log phase of the cells of A375 overexpressing YKL-40 and the control cells were treated according to 1X 10 4 Inoculating each hole into a 96-well plate, culturing in a constant temperature incubator at 37 ℃ for 24 hours, adding medicine, continuously culturing for 72 hours, discarding culture medium in the holes, mixing PMS, MTS and DMEM colorless culture medium according to the ratio of 1:20:100 to prepare MTS working solution, adding 100 mu LMTS working solution into each hole, incubating at 37 ℃ for 10 minutes, and measuring OD (optical density) by using an enzyme-labeling instrument after uniform mixing 490nm Absorbance (a) values.
As shown in FIG. 2 (A), the proliferation capacity of A375 cells over-expressing YKL-40 was significantly lower than that of control cells.
(2) Cell clone formation assay
Cells A375 cells and B16-F10 cells which over express YKL-40 and control cells are respectively inoculated in a cell culture dish, 200 cells/dish are replaced every three days, the cells are cultured for two weeks, the culture medium is sucked, the cells are washed twice by PBS, the PFA is fixed for 15min, the cells are washed twice by PBS, the cells are stained for 15min by 0.1% crystal violet, the cells are washed to have no background color, and the average area of the clone formation is calculated by photographing.
As a result, as shown in FIG. 2 (B.C), the average clone area formed by A375 cells and B16-F10 cells that overexpressed YKL-40 was significantly reduced compared to the control group (P < 0.01). YKL-40 inhibited the clonal formation of A375 cells and B16-F10 cells.
EXAMPLE 3 inhibition of YKL-40 on migration and invasion of melanoma cell models
(1) Cell scratch assay
Seeding cells in six well cell culture plates 3×10 6 And (3) dividing each hole into two parallel straight lines by using a 200ul pipette tip, washing cell fragments by using PBS, adding the culture medium of 1% serum, photographing at fixed time points, and recording scratch healing conditions.
As a result, as shown in FIG. 3, the scratch healing rate of A375 cells (P < 0.001) and B16-F10 cells (P < 0.01) overexpressing YKL-40 was significantly slowed. YKL-40 inhibited migration of A375 and B16-F10 cells.
(2) Transwell cell migration experiments
Taking B16-F10 cells in logarithmic growth phase at 1×10 6 Density of the cells/well was added to an atrigel Matrigel coated Transwell chamber (upper chamber), then each set of upper chambers was placed into a cell culture plate well (lower chamber) containing DMEM broth, after 36h incubation the upper chambers were removed, matrigel and membrane surface cells were gently rubbed off with a wet cotton swab, fixed with paraformaldehyde, 0.2% Triton membrane rupture, DAPI staining, PBS wash, and 5 fields were counted under a fluorescent microscope.
As a result, as shown in FIG. 4, the number of B16-F10 cells overexpressing YKL-40 invasively transferred cells was significantly reduced (P < 0.01). YKL-40 inhibited B16 cell invasion.
Example 4YKL-40 increases the sensitivity of melanoma cells to drugs
(1) Apoptosis experiments
Taking cells in logarithmic growth phase at 3×10 5 Density of the individual wells/wells were seeded in six well cell culture plates and after 24h of 150uM Dacarbazine treatment, harvestedAfter cell collection and PBS washing twice, cells were resuspended, 5. Mu.L of Annexin V-FITC and 10. Mu.L of PI were added, incubated for 15min in the dark, and the apoptosis rate of each group of cells was detected using a flow cytometer.
As shown in FIG. 5, the apoptosis of cells over-expressing YKL-40 was more pronounced upon dacarbazine stimulation. YKL-40 increased the sensitivity of melanoma cells to dacarbazine.
(2) Cell resistance test (MTS)
Taking cells in logarithmic growth phase at 1×10 4 Density of cells/well was seeded in 96-well cell culture plates at binimeinib concentration of 0.3125 μm, control group with equal amount of DMSO, blank group without cells and drug wells, 3 duplicate wells per group. After 72h incubation, the medium was discarded, 100. Mu.L MTS working solution was added to each well and incubated at 37℃for 10min, and the optical density (D) at 490nm was measured using a microplate reader.
Cell activity (%) = (experimental group D value-blank group D value)/(control group D value-blank group D value) ×100%
The results are shown in FIG. 6, in which the cells overexpressing YKL-40 were significantly decreased in cell viability (P < 0.05) upon bimetanib stimulation. YKL-40 increased the sensitivity of melanoma cells to bimetanib.
EXAMPLE 5YKL-40 inhibits melanoma cell formation and metastasis in animal models
(1) Melanoma subcutaneous tumor-bearing mouse model establishment
Taking B16-F10 cells over expressing YKL-40 in logarithmic growth phase and B16-F10 cells of control group, preparing into 5×10 concentration in cold physiological saline 5 Cell suspension per mL. Injections were made outside the hind limbs of six week old wild type C57BL/6 male mice, each injected with 0.2mL of cell suspension. Tumor volumes were measured every other day from day 13, and tumor weights were sacrificed at day 19.
As shown in FIG. 7, the B16-F10 cell over-expressing YKL-40 has obvious difference of the tumor formation speed and volume in mice compared with the control group, and the YKL-40 can inhibit the tumor formation capacity of melanoma cells in mice.
(2) Melanoma lung metastasis mouse model establishment
Taking B16-F10 cells over expressing YKL-40 in logarithmic growth phase and B16-F10 cells of control group, preparing into 4×10 concentration in cold physiological saline 5 Cell suspension per mL. Six week old wild type C57BL/6 female mice were injected tail vein, each with 0.5mL of cell suspension. The lungs were sacrificed at day 15 and the lung melanoma nodules were counted.
As shown in FIG. 8, the number of tumors formed by the transfer of the B16-F10 cells which over-express the YKL-40 to the lung in the mice is obviously reduced compared with the cells of the control group, and the YKL-40 can inhibit the transfer capacity of melanoma cells in the mice.
Finally, it should be noted that: the foregoing description is only a preferred embodiment of the present invention, and the present invention is not limited thereto, but it is to be understood that modifications and equivalents of some of the technical features described in the foregoing embodiments may be made by those skilled in the art, although the present invention has been described in detail with reference to the foregoing embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
SEQUENCE LISTING
<110> Weifang medical college
<120> use of YKL-40 in the treatment of melanoma
<130>
<160> 2
<170> PatentIn version 3.3
<210> 1
<211> 1747
<212> DNA
<213> CHI3L1/YKL-40 DNA sequence
<400> 1
gaggccctgt ctaggtagct ggcaccagga gccgtgggca agggaagagg ccacaccctg 60
ccctgctctg ctgcagccag aatgggtgtg aaggcgtctc aaacaggctt tgtggtcctg 120
gtgctgctcc agtgctgctc tgcatacaaa ctggtctgct actacaccag ctggtcccag 180
taccgggaag gcgatgggag ctgcttccca gatgcccttg accgcttcct ctgtacccac 240
atcatctaca gctttgccaa tataagcaac gatcacatcg acacctggga gtggaatgat 300
gtgacgctct acggcatgct caacacactc aagaacagga accccaacct gaagactctc 360
ttgtctgtcg gaggatggaa ctttgggtct caaagatttt ccaagatagc ctccaacacc 420
cagagtcgcc ggactttcat caagtcagta ccgccatttc tgcgcaccca tggctttgat 480
gggctggacc ttgcctggct ctaccctgga cggagagaca aacagcattt taccacccta 540
atcaaggaaa tgaaggccga atttataaag gaagcccagc cagggaaaaa gcagctcctg 600
ctcagcgcag cactgtctgc ggggaaggtc accattgaca gcagctatga cattgccaag 660
atatcccaac acctggattt cattagcatc atgacctacg attttcatgg agcctggcgt 720
gggaccacag gccatcacag tcccctgttc cgaggtcagg aggatgcaag tcctgacaga 780
ttcagcaaca ctgactatgc tgtggggtac atgttgaggc tgggggctcc tgccagtaag 840
ctggtgatgg gcatccccac cttcgggagg agcttcactc tggcttcttc tgagactggt 900
gttggagccc caatctcagg accgggaatt ccaggccggt tcaccaagga ggcagggacc 960
cttgcctact atgagatctg tgacttcctc cgcggagcca cagtccatag aatcctcggc 1020
cagcaggtcc cctatgccac caagggcaac cagtgggtag gatacgacga ccaggaaagc 1080
gtcaaaagca aggtgcagta cctgaaggac aggcagctgg cgggcgccat ggtatgggcc 1140
ctggacctgg atgacttcca gggctccttc tgtggccagg atctgcgctt ccctctcacc 1200
aatgccatca aggatgcact cgctgcaacg tagccctctg ttctgcacac agcacggggg 1260
ccaaggatgc cccgtccccc tctggctcca gctggccggg agcctgatca cctgccctgc 1320
tgagtcccag gctgagcctc agtctccctc ccttggggcc tatgcagagg tccacaacac 1380
acagatttga gctcagccct ggtgggcaga gaggtaggga tggggctgtg gggatagtga 1440
ggcatcgcaa tgtaagactc gggattagta cacacttgtt gattaatgga aatgtttaca 1500
gatccccaag cctggcaagg gaatttcttc aactccctgc cccccagccc tccttatcaa 1560
aggacaccat tttggcaagc tctatcacca aggagccaaa catcctacaa gacacagtga 1620
ccatactaat tataccccct gcaaagccca gcttgaaacc ttcacttagg aacgtaatcg 1680
tgtcccctat cctacttccc cttcctaatt ccacagctgc tcaataaagt acaagagctt 1740
aacagtg 1747
<210> 2
<211> 383
<212> PRT
<213> YKL-40 protein sequence
<400> 2
Met Gly Val Lys Ala Ser Gln Thr Gly Phe Val Val Leu Val Leu Leu
1 5 10 15
Gln Cys Cys Ser Ala Tyr Lys Leu Val Cys Tyr Tyr Thr Ser Trp Ser
20 25 30
Gln Tyr Arg Glu Gly Asp Gly Ser Cys Phe Pro Asp Ala Leu Asp Arg
35 40 45
Phe Leu Cys Thr His Ile Ile Tyr Ser Phe Ala Asn Ile Ser Asn Asp
50 55 60
His Ile Asp Thr Trp Glu Trp Asn Asp Val Thr Leu Tyr Gly Met Leu
65 70 75 80
Asn Thr Leu Lys Asn Arg Asn Pro Asn Leu Lys Thr Leu Leu Ser Val
85 90 95
Gly Gly Trp Asn Phe Gly Ser Gln Arg Phe Ser Lys Ile Ala Ser Asn
100 105 110
Thr Gln Ser Arg Arg Thr Phe Ile Lys Ser Val Pro Pro Phe Leu Arg
115 120 125
Thr His Gly Phe Asp Gly Leu Asp Leu Ala Trp Leu Tyr Pro Gly Arg
130 135 140
Arg Asp Lys Gln His Phe Thr Thr Leu Ile Lys Glu Met Lys Ala Glu
145 150 155 160
Phe Ile Lys Glu Ala Gln Pro Gly Lys Lys Gln Leu Leu Leu Ser Ala
165 170 175
Ala Leu Ser Ala Gly Lys Val Thr Ile Asp Ser Ser Tyr Asp Ile Ala
180 185 190
Lys Ile Ser Gln His Leu Asp Phe Ile Ser Ile Met Thr Tyr Asp Phe
195 200 205
His Gly Ala Trp Arg Gly Thr Thr Gly His His Ser Pro Leu Phe Arg
210 215 220
Gly Gln Glu Asp Ala Ser Pro Asp Arg Phe Ser Asn Thr Asp Tyr Ala
225 230 235 240
Val Gly Tyr Met Leu Arg Leu Gly Ala Pro Ala Ser Lys Leu Val Met
245 250 255
Gly Ile Pro Thr Phe Gly Arg Ser Phe Thr Leu Ala Ser Ser Glu Thr
260 265 270
Gly Val Gly Ala Pro Ile Ser Gly Pro Gly Ile Pro Gly Arg Phe Thr
275 280 285
Lys Glu Ala Gly Thr Leu Ala Tyr Tyr Glu Ile Cys Asp Phe Leu Arg
290 295 300
Gly Ala Thr Val His Arg Ile Leu Gly Gln Gln Val Pro Tyr Ala Thr
305 310 315 320
Lys Gly Asn Gln Trp Val Gly Tyr Asp Asp Gln Glu Ser Val Lys Ser
325 330 335
Lys Val Gln Tyr Leu Lys Asp Arg Gln Leu Ala Gly Ala Met Val Trp
340 345 350
Ala Leu Asp Leu Asp Asp Phe Gln Gly Ser Phe Cys Gly Gln Asp Leu
355 360 365
Arg Phe Pro Leu Thr Asn Ala Ile Lys Asp Ala Leu Ala Ala Thr
370 375 380
Claims (6)
1. Use of a substance for promoting an increase in CHI3L1/YKL-40 gene and expression products and/or activity thereof in at least one of the following a 1) -a 5):
a1 Preparing a product for inhibiting proliferation of tumor cells;
a2 Preparing a product for inhibiting tumor cell migration and invasion;
a3 Preparing a product for inhibiting tumor growth;
a4 Preparing a product that promotes the sensitivity of the tumor to the therapeutic agent;
a5 Preparing a product for tumor treatment;
the tumor is melanoma;
the substances for promoting the CHI3L1/YKL-40 gene and the expression products and/or the activity of the genes are substances for up-regulating the CHI3L1/YKL-40 expression and/or promoting the activity of the genes by adopting a gene-specific hybrid technology;
the CHI3L1/YKL-40 gene sequence is shown as SEQ ID NO. 1; the expressed product of the CHI3L1/YKL-40 gene is YKL-40 protein, and the amino acid sequence of the protein is shown as SEQ ID NO. 2;
the therapeutic drug is bimetanib or dacarbazine.
2. The use according to claim 1, wherein,
the product is a drug or an experimental reagent, and the experimental reagent is used for basic research.
3. A composition, characterized in that the composition comprises at least a substance promoting an increase in CHI3L1/YKL-40 gene and its expression products and/or activity, and at least one other chemotherapeutic agent as an active ingredient;
the substances for promoting the CHI3L1/YKL-40 gene and the expression products and/or the activity of the genes are substances for up-regulating the CHI3L1/YKL-40 expression and/or promoting the activity of the genes by adopting a gene-specific hybrid technology;
the CHI3L1/YKL-40 gene sequence is shown as SEQ ID NO. 1; the expressed product of the CHI3L1/YKL-40 gene is YKL-40 protein, and the amino acid sequence of the protein is shown as SEQ ID NO. 2;
the chemotherapeutic drug is bimetanib or dacarbazine.
4. Use of a composition according to claim 3 in any one or more of the following:
a1 Preparing a product for inhibiting proliferation of tumor cells;
a2 Preparing a product for inhibiting tumor cell migration and invasion;
a3 Preparing a product for inhibiting tumor growth;
a4 Preparing a product that promotes the sensitivity of the tumor to the therapeutic agent;
a5 Preparing a product for tumor treatment;
wherein the tumor is melanoma;
the therapeutic drug is bimetanib or dacarbazine.
5. The use according to claim 4, wherein the product is a pharmaceutical or experimental agent for use in basic research.
6. The use according to claim 5, wherein when the product is a medicament, the medicament further comprises at least one pharmaceutically inactive ingredient.
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| US7229770B1 (en) * | 1998-10-01 | 2007-06-12 | The Regents Of The University Of California | YKL-40 as a marker and prognostic indicator for cancers |
| AU2015309684A1 (en) * | 2014-08-25 | 2017-03-23 | The Council Of The Queensland Institute Of Medical Research | Treatment and detection of melanoma |
| CN106520800A (en) * | 2016-11-25 | 2017-03-22 | 南京医科大学第二附属医院 | Codon-optimized Chi3L1 gene and application thereof |
| CA3076241A1 (en) * | 2017-09-21 | 2019-03-28 | Yale University | Anti-ykl40 antibodies and methods of use |
| KR102083478B1 (en) * | 2017-12-28 | 2020-04-28 | 한양대학교 산학협력단 | Pharmaceutical compositions for preventing and treating of metastatic cancer comprising CHI3L1 inhibitor |
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