CN114807289A - Novel metabolic marker for preparing medicine for treating liver cancer and application thereof - Google Patents
Novel metabolic marker for preparing medicine for treating liver cancer and application thereof Download PDFInfo
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- CN114807289A CN114807289A CN202210235726.8A CN202210235726A CN114807289A CN 114807289 A CN114807289 A CN 114807289A CN 202210235726 A CN202210235726 A CN 202210235726A CN 114807289 A CN114807289 A CN 114807289A
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Abstract
The invention discloses a novel metabolic marker for preparing a medicament for treating liver cancer and application thereof. Through constructing an ALDH6A1 overexpression liver cancer cell line, the detection shows that the level of the methyl citrate in the cell is inversely proportional to the proliferation and migration rate of the liver cancer cell. An AKT/NRAS liver cancer model is constructed in an Aldh6a1 knockout mouse by high-pressure tail vein injection, and the content of the methyl citric acid in serum is found to be inversely proportional to the ALT and AST levels of the mouse serum and inversely proportional to the liver cancer load of the mouse. The metabolite methyl citric acid disclosed by the invention can be used for independently and effectively inhibiting the proliferation of the liver cancer cells and enhancing the inhibition effect of sorafenib on the proliferation of the liver cancer cells. The metabolite can effectively inhibit the formation of tumors, can be used as a metabolic marker for liver cancer detection, and can judge the severity of liver cancer more accurately and efficiently; can also be used as a novel metabolite for treating liver cancer, and can improve the treatment effect of liver cancer.
Description
Technical Field
The invention relates to the field of functions and applications of metabolites, in particular to a novel metabolic marker for preparing a medicament for treating liver cancer and application thereof.
Background
During the development of cancer, the continued growth and proliferation of cancer cells through metabolic reprogramming provides fuel and has become an emerging marker of cancer. Metabolic reprogramming includes aerobic glycolysis "Warburg effect", glutamine catabolism, macromolecule synthesis and redox homeostasis. In liver cancer metabolism, metabolic reprogramming mainly includes glucose metabolism, energy production metabolism and lipid metabolism reprogramming.
Methyl citrate is a citrate synthase that catalyzes the synthesis of propionyl-coa and oxaloacetate. Methyl citrate may be a biomarker of congenital errors in propionic acid metabolism. The methyl citric acid can induce brain ammonium accumulation and apoptosis, and promote brain injury caused by methylmalonic aciduria. In recent years, with intensive research, metabolic reprogramming also becomes one of the novel markers of liver cancer, and methyl citrate may play an important role in liver cancer generation and regulation.
The sorafenib serving as a first-line therapeutic drug for treating advanced hepatocellular carcinoma provides drug selection for improving the survival rate of hepatocellular carcinoma patients, but the sorafenib only prolongs the survival period of the patients by 3 months, and the treatment effect is limited. Heterogeneity exists in the therapeutic effects of sorafenib, and serious side effects including diarrhea, hypertension, anorexia and the like are accompanied.
In the process of cancer occurrence, due to the existence of tumor heterogeneity, understanding of liver cancer metabolic reprogramming, mining of metabolites for early diagnosis and targeted therapy are very important for improving the cure rate and prognosis of cancer. With the advent of the accurate medical age, the treatment effect can be maximized by performing personalized accurate treatment on diseases and specific patients in clinical diagnosis and treatment of cancer. Multigroup techniques and large-scale sequencing provide a powerful support for this. However, metabolic markers associated with accurate diagnosis and treatment of cancer remain to be explored and studied.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a novel metabolic marker for preparing a medicament for treating liver cancer and application thereof. By detecting the metabolic markers in the liver cancer tissue sample, the liver cancer patient can be subjected to personalized accurate treatment according to the metabolite level. According to the invention, experimental researches show that the metabolite level of the methyl citric acid in the liver cancer is inversely proportional to the severity of the liver cancer.
The invention provides a metabolite for preparing a liver cancer marker and application thereof, namely the function and application of methyl citric acid in liver cancer detection and treatment, namely the application of methyl citric acid as a novel medicament in liver cancer treatment. Experimental research shows that the methyl citric acid plays an important role in liver cancer, and can obviously inhibit the proliferation rate of liver cancer cells and the capability of inhibiting the formation of subcutaneous tumors of the liver cancer cells.
In order to achieve the purpose, the invention provides the following technical scheme:
in a first aspect, the present invention provides a novel metabolic marker for preparing a drug for treating liver cancer, wherein the novel metabolic marker is characterized in that: the metabolite is methyl citric acid.
In a second aspect, the use of a novel metabolic marker for the manufacture of a medicament for the treatment of liver cancer, characterized in that: the methyl citric acid is used as a liver cancer metabolic marker and is applied to liver cancer treatment.
As one of the preferred embodiments, the methyl citric acid is used as a liver cancer metabolic marker, and the metabolite level of the methyl citric acid is inversely proportional to the severity of liver cancer.
As a second preferred scheme, the methyl citric acid can significantly inhibit liver cancer cell proliferation and subcutaneous neoplasia, and can significantly enhance the inhibition effect of sorafenib on liver cancer cell proliferation.
The methyl citric acid plays an important role in early diagnosis of liver cancer and treatment of liver cancer.
The invention has the following advantages and beneficial effects:
the invention cultures liver cancer cells in vitro, detects the proliferation and migration rate of the liver cancer cells and the level of metabolites in the cells, and finds that the content of the methyl citric acid is inversely proportional to the proliferation and migration rate of the liver cancer cells. The invention constructs a liver cancer model in a mouse body through high-pressure tail vein injection or intraperitoneal injection, detects the metabolite level in the mouse serum and liver cancer tissues, and finds that the content of the methyl citric acid is inversely proportional to the ALT and AST levels of the mouse serum and inversely proportional to the liver cancer load of the mouse. The results show that the content of the methyl citric acid is in negative correlation with the severity of the liver cancer, and the methyl citric acid can be used as a metabolic marker for early diagnosis and severity of the liver cancer.
According to the invention, sodium methyl citrate is added into human liver cancer cells for culture, so that the liver cancer cell proliferation can be obviously inhibited, and the effect of sorafenib on inhibiting the liver cancer cell proliferation is enhanced. The invention also discloses a tumor model constructed by injecting HCCLM9 cells to the subcutaneous part of a BABL/C nude mouse, and the treatment is carried out by injecting sodium methyl citrate into the abdominal cavity, and the result shows that the sodium methyl citrate can obviously inhibit the subcutaneous tumor formation speed. The above results indicate that the methyl citric acid is effective in improving and treating liver cancer.
Drawings
In fig. 1:
a: the level of intracellular methyl citrate;
b: counting the cell proliferation rate;
c: counting the migration rate of the cells;
*,p<0.05；**,p<0.01；***,p<0.001；****,p<0.0001。
in fig. 2:
a: representative liver schematic.
B: detecting the level of the methyl citric acid by serum;
c: counting the number of liver cancer nodules of the mice;
d: serum detection of ALT, AST levels;
*,p<0.05；**,p<0.01；***,p<0.001；****,p<0.0001。
in fig. 3:
a: HCCLM9 cells were treated with sodium methyl citrate (0, 20, 100. mu.M), and cell proliferation was detected by RTCA; sodium methyl citrate significantly inhibited the cell proliferation rate of HCCLM 9.
B: MHCC97L cells were treated with sodium methyl citrate (0, 50, 100. mu.M), and RTCA detected cell proliferation; sodium methyl citrate significantly inhibited the cell proliferation rate of MHCC 97L.
C: huh7 cells were treated with sodium methyl citrate (50. mu.M) and sorafenib (1. mu.M), and cell proliferation was detected by RTCA; the sodium methyl citrate can obviously inhibit the cell proliferation rate of Huh7, and the combined drug with sorafenib can obviously enhance the inhibition effect on cell proliferation.
D: HCCLM9 cells were treated with sodium methyl citrate (10. mu.M) and sorafenib (0.5. mu.M), and RTCA detected cell proliferation; the sodium methyl citrate and sorafenib combined drug can obviously enhance the inhibition effect on cell proliferation.
In fig. 4:
a: subcutaneous tumor pictures, in the Vehicle group, and the sodium methyl citrate group (MCA-Na) at the end of the experiment, the tumor size was significantly lower in the sodium methyl citrate group than in the Vehicle group.
B: statistical map of subcutaneous tumor volumes. The volume of subcutaneous tumors in mice was measured at different time points and the tumor volume in the sodium methyl citrate group was significantly lower than that of the blank group.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the present invention is not limited thereto.
Example 1: in vitro construction of liver cancer cell model
1. Culturing liver cancer cells including HCCLM9 and HEK293T human liver cancer cells at 37 deg.C and 5% CO 2 The culture in the incubator, the cell passage and the operation are all carried out in a biological safety cabinet among sterile cells. The cells were cultured in DMEM medium, 10%
Fetal bovine serum, 1% double antibody.
2. Constructing an ALDH6A1 overexpression stable transfer cell line:
(1) and (3) slow virus packaging: 293T cells were used, the proportion of transfection plasmid was pHAGE-ALDH6A 1: pMD2G: pSPAX2 ═ 2:2: 1. After transfection for 48h, the culture medium supernatant was collected, filtered through a 0.45 μ M filter and stored in a freezer at-80 ℃.
(2) Lentivirus infection of HCCLM9 cells: HCCLM9 cells were seeded one day in advance in 6-well plates and 2ml of virus solution and polybrene (final concentration 10. mu.g/ml) were added. After 10h, the medium was changed to fresh complete medium.
(3) And (3) resistance screening: and adding corresponding resistance screening for 48h, and verifying and expressing the survival cells to obtain the constructed stable transgenic cell line over-expressed by ALDH6A 1.
3. Intracellular metabolite detection: get 10 7 The cells were washed three times with PBS, centrifuged at 3000 rpm for 1min, and the supernatant removed. The level of methyl citrate metabolites was determined by liquid chromatography-mass spectrometry (HPLC-MC).
4. RTCA detection of cell proliferation: xCELLigence Cell function analyzer (DP System) is used to detect Cell proliferation. Adherent cells were trypsinized and resuspended in complete DMEM medium at a density of about 4.0X 10 4 and/mL. The E-Plate View 16 was then filled with 50. mu.L of complete DMEM medium to perform a baseline examination (cell index should be less than 0.063). Thereafter, 100. mu.L of cell suspension was added to each well, and then different drug treatments were added to each well, and real-time detection was started for about 96 hours.
5. RTCA detects cell migration: xCELLigence Cell function analyzer (DP System) is used to detect Cell migration. The adherent cells are trypsinized and then resuspended in serum-free DMEM medium with the density of about 4.0X 10 5 and/mL. The CIM-Plate lower chamber was filled with 165. mu.L of complete medium, the upper chamber was mounted on the lower chamber, and 30. mu.L of serum-free DMEM medium was added to the upper chamber. Assembled CIM-Plate at 37 ℃ with 5% CO 2 The incubator was equilibrated for 1h to perform a baseline check (cell index should be less than 0.063). Thereafter, 100. mu.L of cell suspension was added to each well and real-time detection was started for about 96 hours.
According to the invention, HCCLM9 human liver cancer cells are used for constructing ALDH6A1 overexpression and constructing a liver cancer cell model, and the result shows that after ALDH6A1 overexpression, cell proliferation and migration rate are inhibited, and the level of intracellular methyl citric acid is increased. The results show that the methyl citric acid can be used as a metabolic marker of the severity of the liver cancer.
Example 2: construction of liver cancer model in vivo by high-pressure tail vein injection in mice
1. Experimental animals and breeding: species, sex, week age and source of experimental animals: c57BL/6(WT) mice and C57BL/6 background Aldh6a1 knockout (Aldh6a 1) -/- ) Mouse, male, 8 weeks old.
2. Animal feeding and environmental conditions: all experimental mice were housed in the SPF class animal house, the institute of Life sciences, Wuhan university. The lighting is alternated every 12 hours, the temperature is 24 +/-2 ℃, the humidity is 40-70%, and the mice eat water freely.
3. Constructing a Sleep beauty high-pressure tail vein mouse liver cancer model:
selection of WT Male mice and Aldh6a1 -/- Male mice, 8 weeks old. PT3-myr-AKT-HA, pCMV (CAT) T7-SB100 and pT/Caggs-NRASV12 were placed in physiological saline and injected into the mouse tail vein at high pressure. AKT and NRAS entering the liver can be integrated into a mouse genome under the action of transposase and stably expressed, and finally liver canceration is induced. The injection needs to be completed in 5-7 seconds. After injection, mouse status and body weight changes were recorded weekly. The material is taken 6-8 weeks after injection. The whole blood is placed at 4 ℃ overnight at 2500 rpm for 4 ℃, centrifuged for 3min, the supernatant is serum, and the serum is quickly frozen by liquid nitrogen. Taking out the liver of the mouse, taking a picture, separating the liver cancer and tissues beside the cancer of the mouse, and quickly freezing by liquid nitrogen.
4. Serum metabolite level detection: the whole blood is placed at 4 ℃ overnight at 2500 rpm for 4 ℃, centrifuged for 3min, the supernatant is serum, and 50 mu L of liquid nitrogen is taken for quick freezing. The level of methyl citrate metabolites was determined by liquid chromatography-mass spectrometry (HPLC-MC).
5. ALT assay (NJJC, C009-2-1) adding 20. mu.L of alanine aminotransferase substrate solution preheated at 37 ℃ to each of the assay and control wells, adding 5. mu.L of the sample to be tested to each of the assay wells, pipetting, mixing, and placing in a 37 ℃ water bath for 30 minutes. Then 20. mu.L of 2, 4-dinitrophenylhydrazine liquid was added to each measurement well and control well, and 5. mu.L of sample was added to the control well. The mixture was pipetted and mixed and placed in a 37 ℃ water bath for 20 minutes. Finally 200. mu.L of 400mM NaOH was added to each well. After gentle shaking and standing for 15 minutes, the absorbance at 510nm was measured.
6. And (3) detecting AST (NJJC, C010-2-1), adding 20 mu L of aspartate aminotransferase substrate solution preheated at 37 ℃ into a measurement hole and a control hole respectively, adding 5 mu L of samples to be detected, uniformly mixing the samples by a pipette, and placing the samples in a water bath at 37 ℃ for 30 minutes. Then 20. mu.L of 2, 4-dinitrophenylhydrazine liquid was added to each measurement well and control well, and 5. mu.L of sample was added to the control well. The mixture was pipetted and mixed and placed in a 37 ℃ water bath for 20 minutes. Finally, 200. mu.L of 400mM NaOH was added to each well. After gentle shaking and standing for 15 minutes, the absorbance at 510nm was measured.
The invention uses Sleep beauty high pressure tail vein, WT and Aldh6a1 -/- An AKT/NRAS liver cancer model is constructed in a male mouse, and the result shows that after ALDH6A1 is knocked out, the liver cancer load is enhanced, the number of tumor nodules, the ALT level in blood and the AST level in blood are increased, and the level of methyl citric acid in the serum of the mouse is obviously reduced and is inversely proportional to the liver cancer load. The results show that the methyl citric acid can be used as a metabolic marker of the severity of the liver cancer.
Example 3: culture test of adding sodium methyl citrate and sorafenib into human hepatoma cells
1. Culturing liver cancer cells including HCCLM9, MHCC97L, Huh7, etc. at 37 deg.C and 5% CO 2 The culture in the incubator, the cell passage and the operation are all carried out in a biological safety cabinet among sterile cells. The cells were cultured in DMEM medium, 10% fetal bovine serum, 1% double antibody.
2. RTCA detection of cell proliferation: xCELLigence Cell function analyzer (DP System) is used to detect Cell proliferation. Adherent cells were trypsinized and resuspended in complete DMEM medium at a density of about 4.0X 10 4 The volume is/mL. The E-Plate View 16 was then filled with 50. mu.L of complete DMEM medium to perform a baseline examination (cell index should be less than 0.063). Thereafter, 100. mu.L of cell suspension was added to each well, and then different drug treatments were added to each well, and real-time detection was started for about 96 hours.
According to the invention, human hepatoma cells such as HCCLM9, MHCC97L and Huh7 are used, and sodium methyl citrate (MCA-Na), Sorafenib (Sorafenib), sodium methyl citrate and Sorafenib are jointly used and added into a cell culture medium to construct a hepatoma cell model, and the results show that the sodium methyl citrate can remarkably inhibit the cell proliferation rate, and the sodium methyl citrate can remarkably enhance the inhibition effect of Sorafenib on hepatoma cell proliferation when being used together with Sorafenib. The results show that the sodium methyl citrate can effectively improve and treat liver cancer.
Example 4: mouse subcutaneous tumor model constructed by intraperitoneal injection of sodium methyl citrate
1. Subcutaneous tumorigenesis of BALLC-nude mice: BALB/c-nude mice, 4 weeks old, were housed in SPF grade animal houses. Dividing nude mice into four groups, taking HCCLM9 cells in logarithmic growth phase, and resuspending the cells to 7 × 10 with PBS 7 And/ml. Adding the matrigel unfrozen at 4 ℃ into the cell suspension according to the volume of 1:1, and uniformly mixing. 200ul of cell suspension was inoculated subcutaneously into nude mice in a clean bench, and the tumor size at the inoculation site was measured periodically. After 7 days of subcutaneous injection, saline-blank (Vehicle), sodium methyl citrate (MCA-Na) was intraperitoneally injected once every other day. After about 14 days, the tumors in the Vehicle group grew to about 1000mm 3 The nude mice were sacrificed by cervical dislocation, and the tumor mass was taken out and photographed.
The invention discloses a method for constructing a mouse model by injecting HCCLM9 cells to a BABL/C nude mouse subcutaneously and injecting sodium methyl citrate to an abdominal cavity, and the result shows that the sodium methyl citrate can obviously inhibit the formation of subcutaneous tumors. The results show that the sodium methyl citrate can effectively improve and treat liver cancer.
Claims (4)
1. A novel metabolic marker for preparing a medicament for treating liver cancer is characterized in that: the metabolite is methyl citric acid.
2. The application of a novel metabolic marker for preparing a medicine for treating liver cancer is characterized in that: the methyl citric acid is used as a liver cancer metabolic marker and is applied to liver cancer treatment.
3. Use of the novel metabolic markers for the preparation of a medicament for the treatment of liver cancer according to claim 2, characterized in that: the methyl citric acid is used as a liver cancer metabolic marker, and the metabolite level of the methyl citric acid is inversely proportional to the severity of liver cancer.
4. Use of the novel metabolic markers for the preparation of a medicament for the treatment of liver cancer according to claim 2, characterized in that: the methyl citric acid can obviously inhibit liver cancer cell proliferation and subcutaneous tumor formation, and can enhance the inhibition effect of sorafenib on liver cancer cell proliferation.
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