CN113564175A - Gene, protein, vector, lentivirus with hexokinase 2 inhibitory activity and application - Google Patents

Gene, protein, vector, lentivirus with hexokinase 2 inhibitory activity and application Download PDF

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CN113564175A
CN113564175A CN202110845528.9A CN202110845528A CN113564175A CN 113564175 A CN113564175 A CN 113564175A CN 202110845528 A CN202110845528 A CN 202110845528A CN 113564175 A CN113564175 A CN 113564175A
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钟加滕
陆枢桠
董鑫
赵铁锁
李永真
杨晓煜
陈志国
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Xinxiang Medical University
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Abstract

The invention relates to the fields of biomedicine and molecular biology, in particular to a gene, a protein, a vector, a lentivirus and application with hexokinase 2 inhibitory activity. The gene is MTSS1 gene, the MTSS1 protein coded by the gene inhibits the activity of HK2 by competitively binding with mitochondrion-bound HK2, and the aerobic glycolysis level of breast cancer cells is regulated down, so that the invasion and migration of the breast cancer cells are inhibited, and a new treatment direction and an application basis are provided for clinically targeting HK2 and inhibiting breast cancer metastasis.

Description

Gene, protein, vector, lentivirus with hexokinase 2 inhibitory activity and application
Technical Field
The invention belongs to the technical field of biological medicine and molecular biology, and particularly relates to a gene, protein, vector, lentivirus and application with hexokinase 2 inhibitory activity.
Background
Breast Cancer (Breast Cancer) is one of the common malignant tumors of women worldwide, the incidence rate of the Breast Cancer is the first of the female Cancer incidence rate, about 167 thousands of new Breast Cancer cases occur every year worldwide, and about 52 thousands of people die of the Cancer. Distant tissue organ metastasis is one of the leading causes of death in breast cancer patients. The breast cancer metastasis is involved in various factors, a dynamic process develops in multiple stages, and how to prevent and reduce the breast cancer metastasis becomes a difficult point and a key point for improving the survival rate of breast cancer patients. In recent years, with the advent of precise medicine and targeted therapy, the search for effective molecular targets and drug combination strategies has become an effective way to treat distant organ metastasis in breast cancer patients.
MTSS1 gene is an actin-binding protein, exerts its regulatory effect by binding to proteins, and is widely expressed in various tissues. However, in the case of metastatic tumors, no significant high expression was observed. The research shows that MTSS1 gene plays an important role in tumor invasion and metastasis. Although MTSS1 is associated with metastasis of various cancers, its regulatory mechanism is not well understood.
Tumor cells do not acquire energy by means of oxidative phosphorylation even when oxygen is sufficient, but undergo energy metabolism by means of glycolysis, a phenomenon known as the "Warburg effect" or aerobic glycolysis. Recent studies have shown that tumors and the metabolic abnormalities in the microenvironment they are located have a close relationship with tumor metastasis. And research shows that aerobic glycolysis of tumor cells plays an important role in tumor invasion and metastasis.
Hexokinase 2(HK2) is the first rate-limiting enzyme in the glycolytic pathway, and in normal cells HK2 exists predominantly in free form, whereas in tumor cells HK2 exists predominantly in bound form. Research shows that the mitochondria-bound HK2 enhances the enzymatic power and simultaneously can reduce the negative feedback inhibition of the metabolite G-6-P, thereby increasing the kinase activity of HK2 and the aerobic glycolysis level.
However, to date, there has been no study on MTSS1 targeting HK2 to regulate aerobic glycolysis to affect breast cancer invasion and migration.
Disclosure of Invention
In view of the deficiencies of the prior art, it is an object of the present invention to provide a gene having hexokinase 2 inhibitory activity, said gene being MTSS1 gene.
It is also an object of the present invention to provide a protein having hexokinase 2 inhibitory activity, which is encoded by the gene.
It is a further object of the present invention to provide an overexpression vector comprising the gene having hexokinase 2 inhibitory activity, the gene sequence being embedded in the vector.
Further, the vector is a lentiviral vector.
The fourth purpose of the invention is to provide a lentivirus containing the over-expression vector, which is obtained by cell packaging of the lentivirus vector.
The fifth purpose of the invention is to provide the application of the lentivirus in preparing the medicaments for inhibiting aerobic glycolysis.
The sixth purpose of the invention is to provide the application of the lentivirus in preparing a medicament for relieving or treating breast cancer.
Compared with the prior art, the invention has the following beneficial effects:
1. the invention discovers that HK2 is used as a MTSS1 gene target for the first time, and regulates the aerobic glycolysis of breast cancer cells to inhibit the invasion and metastasis of breast cancer.
2. The invention provides MTSS1 targeted mitochondrion-bound HK2, which reduces the kinase activity of HK2, inhibits aerobic glycolysis and inhibits invasion and migration of breast cancer by competitively binding mitochondrion-bound HK 2.
3. The invention provides a basis for clinically targeting MTSS1 and inhibiting the metastasis of breast cancer by aerobic glycolysis, and also provides a new direction for the clinical application of a combined glycolysis inhibitor.
Drawings
FIG. 1 shows the basal expression levels of MTSS1 protein (A) and HK2 protein (B) in different breast cancer cell lines.
FIG. 2 shows the efficiency verification of high expression of MTSS1(A) and interference with HK2(B) in breast cancer cells.
FIG. 3 shows glucose uptake (A) and lactate production (B), HK2 activity (C), and other glycolytic kinase (D) activities in breast cancer cells highly expressing MTSS 1.
FIG. 4 shows the effect of HK2 shRNA (A) and HK2 inhibitor (B) on glucose uptake and lactate production in breast cancer cells by high expression MTSS1 breast cancer cells.
FIG. 5 shows the effect of glycolytic inhibitor on the invasion and migration of breast cancer cells with MTSS 1-highly expressed.
FIG. 6 shows the effect of HK2 shRNA and HK2 inhibitors on the invasion and migration of breast cancer cells by high expression MTSS1 breast cancer cells.
FIG. 7 shows lung metastasis phenotype (A) and lung metastasis count statistics (B) of a nude mouse breast cancer tail vein metastasis model.
FIG. 8 shows that co-immunoprecipitation detects the binding between MTSS1 and HK2 protein (A) and mitochondrial separation detects the change of HK2 protein in MDA-MB-231 and SKBR3 of breast cancer cells highly expressing MTSS1 (B).
Detailed Description
The invention is described in detail below with reference to the figures and the specific embodiments, but the invention should not be construed as being limited thereto. The technical means used in the following examples are conventional means well known to those skilled in the art, and materials, reagents and the like used in the following examples can be commercially available unless otherwise specified.
Example 1 screening of MTSS1 Low-expression and HK2 high-expression breast cancer cell lines
Will be in logarithmic growthThe breast cancer cell lines MCF-7, MDA-MB-231, BT474, SKBR3 and human normal breast epithelial cells MCF-10A in the stage of 10cm2When the confluence degree in the cell culture dish is about 90%, collecting cells, adding cell lysate for cracking, and collecting protein. Measuring protein concentration by BCA method, detecting absorbance at 570nm with microplate reader, drawing standard protein curve, R2>Protein concentration was determined at 0.999. Calculating the sample volume according to the protein concentration, preparing a kit by SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis), carrying out electrophoresis, transferring a membrane, closing, cutting the membrane according to the size of the required molecular weight, adding a corresponding primary antibody at 4 ℃ overnight, recovering the primary antibody (MTSS1, GAPDH) the next day, washing the membrane, adding a corresponding secondary antibody (rabbit antibody or mouse antibody), sealing the membrane on a shaker for 1 hour, and washing the membrane for exposure.
As shown in FIG. 1, the basal expression rate of MTSS1 and the basal expression rate of HK2 of two strains of breast cancer cells MDA-MB-231 and SKBR3 are low.
Example 2 efficiency verification of breast cancer cells MDA-MB-231 and SKBR3 over-expressing MTSS1 and interfering HK2
1. Construction of MTSS1 overexpression lentivirus: lentiviruses were constructed by Shanghai Jikai Gene Ltd.
(1) Carrier information
Carrier name: GV 358;
the element sequence is as follows: Ubi-MCS-3FLAG-SV 40-EGFP-IRES-puromycin;
(2) information of target gene
The target gene is as follows: MTSS1 Gene (Gene ID: 9788);
(3) the experimental method comprises the following steps:
breast cancer cells MDA-MB-231 and SKBR3 with good growth states are respectively paved in a 6-well plate, lentivirus transfection is carried out when the cells grow to 30-40%, the required virus supernatant volume is calculated according to the MOI value of the target cells, and the required virus supernatant volume is (the cell number multiplied by the MOI value)/the virus titer. For virus transfection, the medium required cannot be supplemented with a double antibody, and 2ml of a mixture of virus and medium per well in a 6-well plate is required. After 24h of transfection, the cells were changed according to their cell status, and stable cell lines were selected by adding puromycin at 2ng/ml for one week.
2. HK2 inhibitor and/or HK2 shRNA action
HK2 interferes with the construction of lentiviruses: lentiviruses were constructed by Shanghai Jikai Gene Ltd.
(1) Carrier information
Carrier name: GV 248;
the element sequence is as follows: hU 6-MCS-Ubiquitin-EGFP-IRES-puromycin;
(2) information of target gene
The target gene is as follows: HK2 Gene (Gene ID: 3099).
(3) sequence information of shRNA: as shown in table 1.
TABLE 1 shRNA sequence information
Figure BDA0003180411570000051
(4) Experimental methods
a. Breast cancer cells MDA-MB-231 and SKBR3 in logarithmic growth phase were plated in 6-well plates, respectively, and a group selected for pre-administration of the HK2 inhibitor 3-bromopyruvate (3-BP, 50. mu.M) for 2 h.
b. Breast cancer cells MDA-MB-231 and SKBR3 in the logarithmic growth phase were plated in 6-well plates, respectively, and lentivirus transfection was performed when the cells grew to 30-40%, and the desired virus supernatant volume, which was (number of cells × MOI)/virus titer, was calculated from the MOI value of the target cells. For virus transfection, the medium required cannot be supplemented with a double antibody, and 2ml of a mixture of virus and medium per well in a 6-well plate is required. After 24h of transfection, the cells were changed according to their cell status, and stable cell lines were selected by adding puromycin at 2ng/ml for one week.
Western blotting verifies the high expression and interference efficiency of the protein.
The results are shown in FIG. 2, the virus has high expression and obvious interference efficiency, and a foundation is provided for subsequent experiments.
Example 3
Effect of high expression MTSS1 Breast cancer cells on glycolysis related kinase Activity
Taking a breast cancer high-expression MTSS1 cell strain in a logarithmic growth phase, uniformly paving an NC group and an overexpression group into a 24-pore plate or a 6-pore plate according to experimental grouping, collecting cell culture supernatant or cell protein after cells are attached to the wall for 24 hours, and adding related reagents to detect the activities of different glycolysis related kinases.
As shown in FIGS. 3 and 4, the activity of hexokinase kinase related to glycolysis of breast cancer cells MDA-MB-231 and SKBR3 was reduced after MTSS1 was highly expressed, and the activity of other kinases was not significantly changed.
Example 4
Effect of glycolytic inhibitors and HK2 inhibition and/or shRNA on invasion and metastasis of high expressing MTSS1 breast cancer cells.
The cells are uniformly paved in a 6-well plate or a Transwell chamber according to the required quantity, and are respectively divided into: control group, MTSS1 group, 2-DG + MTSS1 group, BAY-876+ MTSS1 group; control group, MTSS1 group, shHK2 group, shHK2+ MTSS1 group; ③ control group, MTSS1 group, 3-BP group and 3-BP + MTSS1 group, wherein in each group, the dosage of 2-DG is 2mM, and the dosage of BAY-876 is 1 μ M. Cell scratch and Transwell invasion and migration experiments prove the influence of different treatment groups on invasion and migration capabilities of breast cancer cells MDA-MB-231 and SKBR 3.
The results are shown in fig. 5 and 6, and the glycolytic inhibitor can reduce the inhibition effect of MTSS1 on the invasion and migration of breast cancer cells, and the shRNA of HK2 and/or the HK2 inhibitor can reduce the inhibition effect of MTSS1 on the invasion and migration of breast cancer cells.
Example 5
Construction of nude mouse tail vein transfer model
BALB/c nude mice (females) were randomly divided into 3 groups: MDA-MB-231NC group, MDA-MB-231 MTSS1 high expression group, 3-BP + MDA-MB-231 MTSS1 high expression group, 6 each group, each group is divided according to experiment, the number of cells corresponding to each group of nude mouse tail vein injection is 1 multiplied by 107One month later, the nude mice are dissected, the lung metastasis condition of the nude mice is observed, and the metastasis condition is further observed by HE staining.
As a result, as shown in FIG. 7, each of the NC groups had lung metastasis, only lung metastasis occurred in MTSS1 group 1, and only lung metastasis occurred in MTSS1 in combination with 3-BP group 5. Significant metastasis of breast cancer cells occurs in the lung. Compared with the group with high expression MTSS1 alone, the HE result shows that the group combined with glycolysis inhibitor 3-BP can obviously reduce the inhibition effect of metastasis caused by high expression MTSS 1.
Example 6
Co-immunoprecipitation detection of binding between MTSS1 and HK2 protein and mitochondrial separation detection of changes of HK2 protein in high-expression MTSS1 breast cancer cells MDA-MB-231 and SKBR3
The 293T cells were spread evenly to 10cm2In a cell culture dish, HA-MTSS1 and FLAG-HK2 plasmids (purchased from Shanghai Jikai gene Co., Ltd.) are transfected when the confluence is 70% -80%, the plasmids are divided into HA-MTSS1 group, FLAG-HK2 group and HA-MTSS1+ FLAG-HK2 group, cells are collected after transfection for 48-96h, lysate is added, and 1mg of protein is added into different labeled beads for immune co-precipitation.
Taking high-expression MTSS1 breast cancer cell stable strains MDA-MB-231 and SKBR3 in logarithmic growth phase, and paving the stable strains on two 15 cm-long sections2In the cell culture dish, the cells are grown to 4X 107Meanwhile, cell precipitates are collected, a mitochondria extraction reagent is added, mitochondria and cytoplasmic proteins of breast cancer cells MDA-MB-231 and SKBR3 are separated, and Western blotting detects the change of HK2 protein.
The results are shown in fig. 8, MTSS1 can be combined with HK2 protein, and high-expression MTSS1 breast cancer cells can be competitively combined with mitochondria-bound HK2, HK2 mitochondrial protein is obviously reduced, and cytoplasmic protein is obviously increased.
In normal cells, HK2 was present predominantly in free form, whereas HK2 was present predominantly in bound form in tumor cells. HK2 binds mainly to mitochondrial membrane VDACs (voltage dependent anion channel proteins). Mitochondrial-bound HK2 is a switch in the occurrence of glycolysis and oxidative phosphorylation, and increases the level of aerobic glycolysis in cells when the level of mitochondrially targeted HK2 is increased, which is responsible for the increased expression level of mitochondrial-bound HK2 in tumor cells. Research shows that the mitochondria-bound HK2 enhances the enzymatic power and simultaneously can reduce the negative feedback inhibition of the metabolite G-6-P, thereby increasing the kinase activity of HK2 and the aerobic glycolysis level. In combination with the mechanism of protein regulation by MTSS1, we found that MTSS1 and HK2 proteins can be combined by co-immunoprecipitation, and further isolate mitochondrial proteins, and found that high-expression MTSS1 can reduce mitochondrially targeted HK2, which is required in aerobic glycolysis process of HK 2. This result suggests that MTSS1 may inhibit aerobic glycolysis by reducing levels of mitochondrial-binding HK 2.
While preferred embodiments of the present invention have been described, additional variations and modifications in those embodiments may occur to those skilled in the art once they learn of the basic inventive concepts. Therefore, it is intended that the appended claims be interpreted as including preferred embodiments and all such alterations and modifications as fall within the scope of the invention.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.

Claims (7)

1. A gene having hexokinase 2 inhibitory activity, wherein said gene is MTSS1 gene.
2. A protein having hexokinase 2 inhibitory activity, wherein said protein is encoded by the gene of claim 1.
3. An overexpression vector comprising a gene with hexokinase 2 inhibitory activity according to claim 1, wherein the gene sequence is embedded in the vector.
4. The overexpression vector according to claim 3, wherein said vector is a lentiviral vector.
5. A lentivirus comprising the overexpression vector of claim 4, wherein the lentiviral vector of claim 4 is cell-packaged.
6. Use of a lentivirus of claim 5 in the manufacture of a medicament for inhibiting aerobic glycolysis.
7. Use of a lentivirus of claim 5 in the manufacture of a medicament for the alleviation or treatment of breast cancer.
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