CN112816708B - Protein index for predicting sensitivity of esophageal squamous carcinoma patient to chemotherapeutic drugs and application - Google Patents
Protein index for predicting sensitivity of esophageal squamous carcinoma patient to chemotherapeutic drugs and application Download PDFInfo
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- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
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Abstract
The invention belongs to the technical field of biological medicines, and particularly relates to a protein index for predicting sensitivity of an esophageal squamous carcinoma patient to chemotherapeutic drugs and application thereof. The invention discovers that the expression of FBXO31 protein of an esophageal squamous carcinoma patient is up-regulated, so that cofilin-1 phosphorylation level is reduced, and cofilin-1 activity is increased, and further, the drug resistance of the patient to paclitaxel is caused. Therefore, the up-regulation of the expression of FBXO31 protein can indicate that the patient has drug resistance to the chemotherapeutic drug paclitaxel. Before the treatment of patients with esophageal squamous cell carcinoma, the sensitivity of the patients to chemotherapeutic drugs is judged by detecting the FBXO31 protein expression condition in the patients through RT-PCR or immunohistochemistry, a judgment index is provided for doctors in the treatment process, the selection of the esophageal squamous cell carcinoma treatment drugs is guided, the medication scheme can be adjusted in time, and the treatment duration of the patients with esophageal squamous cell carcinoma is shortened to a certain extent.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a protein index for predicting sensitivity of an esophageal squamous carcinoma patient to chemotherapeutic drugs and application thereof.
Background
Esophageal cancer is one of digestive tract malignant tumors seriously threatening human life and health, and about 90 percent of esophageal cancer in China is esophageal squamous cell carcinoma. Chemotherapy is one of the important treatment methods for esophageal cancer, and the use of chemotherapeutic drugs plays an important role in inhibiting the growth, recurrence and metastasis of tumors. However, primary multidrug resistance and secondary resistance are one of the important causes of failure in esophageal cancer treatment and low survival rate. Common anticancer drugs such as alkylating agent, platinum compound and topoisomerase inhibitor (taking DNA as an action target spot and killing tumor cells mainly by damaging cell DNA or inducing apoptosis) and paclitaxel (promoting tubulin polymerization and preventing microtubule depolymerization so as to stabilize microtubules and inhibit cancer cell mitosis and trigger apoptosis), and interference with DNA damage response and inhibition of apoptosis are important mechanisms for generating drug resistance of tumor cells. At present, in-vitro drug sensitivity experiments are clinically carried out on patients aiming at drug resistance of the drugs, but the relevance is not obvious.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a protein index for predicting sensitivity of an esophageal squamous carcinoma patient to a chemotherapeutic drug and application thereof, and aims to solve part of problems in the prior art or at least alleviate part of problems in the prior art.
The protein index for predicting the sensitivity of the esophageal squamous carcinoma patient to the chemotherapeutic drugs is FBXO 31.
The invention also provides application of the FBXO31 protein in preparing a reagent for predicting and/or regulating sensitivity of an esophageal squamous carcinoma patient to chemotherapeutic drugs.
The invention also provides application of the cofilin-1 protein in preparation of a reagent for predicting and/or regulating sensitivity of an esophageal squamous carcinoma patient to chemotherapeutic drugs.
The invention also provides a reagent for predicting the sensitivity of an esophageal squamous carcinoma patient to chemotherapeutic drugs, which comprises an FBXO31 protein expression detection reagent.
The invention also provides a reagent for regulating and controlling the sensitivity of an esophageal squamous carcinoma patient to chemotherapeutic drugs, which comprises an FBXO31 protein expression inhibitor and/or a cofilin-1 activity inhibitor.
Further, the chemotherapeutic drug is paclitaxel.
We found by mass spectrometry that FBXO31 is another substrate protein, Cofilin-1, an actin-related protein that plays an important role in maintaining rapid cycling of globular actin (G-actin) monomers by depolymerizing and cleaving filamentous actin. Various regulatory kinases and phosphatases regulate cofilin activity through phosphorylation/dephosphorylation processes. Paclitaxel can make tubulin and tubulin dimer composing microtubule lose dynamic balance, induce and promote tubulin polymerization, microtubule assembly, prevent depolymerization, thus make microtubule stable and inhibit cancer cell mitosis and trigger apoptosis, and then effectively prevent cancer cell proliferation, playing the role of anticancer; we find that the expression of FBXO31 protein of esophageal squamous carcinoma patients is up-regulated, so that cofilin-1 phosphorylation level is reduced, and cofilin-1 activity is increased, and the patients generate drug resistance to paclitaxel. Therefore, the up-regulation of the expression of FBXO31 protein can indicate that the patient has drug resistance to the chemotherapeutic drug paclitaxel.
In summary, the advantages and positive effects of the invention are:
before the treatment of the esophageal squamous carcinoma patient, the FBXO31 protein expression condition in the patient body is detected through RT-PCR or immunohistochemistry to judge the sensitivity of the patient to the chemotherapeutic drugs, so that a judgment index is provided for a doctor in the treatment process, the selection of the esophageal squamous carcinoma treatment drugs is guided, the medication scheme can be adjusted in time, and the treatment duration of the esophageal squamous carcinoma patient is shortened to a certain extent.
Drawings
FIG. 1 is a graph of apoptosis analyzed by flow cytometry in example 1;
FIG. 2 shows the result of detecting apoptosis by TUNEL method in example 1;
FIG. 3 shows the results of apoptosis in Colony survival experiment in example 1;
FIG. 4 is the result of mass spectrometry in example 2;
FIG. 5 is the experimental results of example 3;
FIG. 6 is the experimental results of example 4;
FIG. 7 is the experimental result of example 5;
FIG. 8 shows the results of the experiment in example 6.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail below with reference to examples, and the equipment and reagents used in the examples and test examples are commercially available without specific reference. The specific embodiments described herein are merely illustrative of the invention and are not intended to be limiting.
Various modifications to the precise description of the invention will be readily apparent to those skilled in the art from the information contained herein without departing from the spirit and scope of the appended claims. It is to be understood that the scope of the invention is not limited to the procedures, properties, or components defined, as these embodiments, as well as others described, are intended to be merely illustrative of particular aspects of the invention. Indeed, various modifications of the embodiments of the invention which are obvious to those skilled in the art or related fields are intended to be covered by the scope of the appended claims.
For a better understanding of the invention, and not as a limitation on the scope thereof, all numbers expressing quantities, percentages, and other numerical values used in this application are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated otherwise, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. As used herein, "about" means within 10%, preferably within 5%, of a given value or range.
The normal temperature in the following embodiments of the present invention refers to a natural room temperature condition in four seasons, and is not subjected to additional cooling or heating treatment, and is generally controlled at 10 to 30 ℃, preferably 15 to 25 ℃.
The invention discloses a protein index for predicting sensitivity of an esophageal squamous carcinoma patient to chemotherapeutic drugs and application thereof.
The technical method or technical thought of the invention comprises the steps of carrying out RT-PCR or immunohistochemistry on pathological tissue biopsy of an esophageal squamous carcinoma patient and detecting the expression condition of FBXO31 protein. The method mainly comprises the following steps:
the method comprises the following steps: collecting pathological tissue biopsy and para-carcinoma tissue biopsy of esophageal squamous carcinoma patients.
Step two: the expression of FBXO31 protein in the patient is detected by RT-PCR or immunohistochemistry, and one of the two ways is selected.
【1】 RT-PCR technique
Extracting total RNA from pathological tissues and tissues beside cancer, taking mRNA in the total RNA as a template, and performing reverse transcription to obtain cDNA by using oligo (dT) or random primers by using reverse transcriptase. And then carrying out PCR amplification by taking the cDNA as a template so as to detect gene expression, and the method comprises the following specific steps:
1. extraction of tissue Total RNA
(1) Grinding the tissue in liquid nitrogen, adding 1ml of TRIzol into every 50-100 mg of tissue, and homogenizing by using a homogenizer. Sample volume should not exceed TRIzol volume 10%.
(2) For example, the sample contains more protein, fat, polysaccharide or extracellular substances. Centrifuging at 2-8 deg.C 10000 Xg for 10min, and collecting supernatant. The pellet obtained by centrifugation contains cell envelope, polysaccharide, high molecular weight DNA, and supernatant contains RNA. When adipose tissues are treated, a large amount of oil should be removed from the upper layer. The clear homogenate was taken for further processing.
(3) 0.2ml of chloroform was added to 1ml of TRIzol, and the mixture was vigorously shaken for 15 seconds and left at room temperature for 5 min.
(4) Centrifuging at 10000 Xg for 15min at the temperature of 2-8 ℃. The sample was divided into three layers. RNA is predominantly in the aqueous phase, with a volume of approximately 60% of the TRIzol reagent used.
(5) The aqueous phase was transferred to a new EP tube to which an equal volume of isopropanol was added and left at room temperature for 10 min.
(6) Centrifuging at 2-8 ℃ and 10000 Xg for 10min, wherein RNA precipitate cannot be seen before centrifuging, and colloidal white precipitate appears on the tube side and the tube bottom after centrifuging. The supernatant was discarded and the next step was performed.
(7) The RNA pellet was washed with 75% ice-cold ethanol. At least 1ml 75% ethanol per 1ml TRIzol used. Centrifuging at 2-8 ℃ and no more than 7500 Xg for 5min, and discarding the supernatant.
(8) And (4) drying the air in the super clean bench for about 5-10 min. Not too dry, which would result in a significant decrease in the solubility of the RNA. The RNA was dissolved by adding 25 to 200. mu.l of RNase-free water.
2. Reverse transcription
(1) A reaction solution was prepared with the following composition:
negative control RNA template was replaced with DEPC-treated water and the remaining components were the same. The reaction components were added to a 0.5ml EP tube, mixed well and centrifuged briefly.
(2) Placing each reaction tube on a PCR amplification instrument, and performing denaturation at 37 ℃ for 60min and 70 ℃ for 15 min. The reverse transcription product was stored at 4 ℃ until use.
PCR amplification
(1) A reaction solution was prepared with the following composition:
the reverse transcription negative control was used to replace the cDNA template as the PCR negative control, and the above reaction components were added to a 0.2ml PCR tube, centrifuged briefly, and mixed well.
(2) Placing each PCR reaction tube into a DNA amplifier, carrying out thermal cycling at 94 ℃ for 5min, and then carrying out thermal cycling according to the following conditions: circulating 30 times at 94 deg.C for 45s, 56 deg.C for 30s, and 72 deg.C for 30s, and finally extending at 72 deg.C for 10 min.
【2】 Immunohistochemistry
(1) Making pathological tissue sections;
(2) baking the paraffin section in an oven at 75 ℃ for 2 h;
(3) dewaxing and rehydration: xylene 10min, 100% ethanol 5min, 95% ethanol 5min, 90% ethanol 5min, 85% ethanol 5min, 80% ethanol 5min, 75% ethanol 5min, 60% ethanol 5min, 50% ethanol 5min, 30% ethanol 5min, and tap water 1 min;
(4) dripping 3% H2O2 (as prepared) to cover the whole tissue, washing with distilled water for 3 times (3 min each time) at room temperature for 10 min;
(5) microwave repair: the sections were immersed in an autoclave containing 1 liter of EDTA and aerated for 6-7min for antigen retrieval.
(6) Naturally cooling the slices to room temperature, washing with PBS for 3 times, 5min each time;
(7) blocking, 5% BSA, room temperature 20min, and throwing off the redundant liquid;
(8) dripping primary antibody at 37 ℃ for 1h or at 4 ℃ overnight;
(9) PBS wash 3 times, each time 3 min;
(10) adding secondary antibody dropwise at 37 deg.C for 15-30 min;
(11) PBS wash 3 times, each time 3 min;
(12) dripping DAB color developing agent on the section for dyeing, and detecting the reaction time (about 5min) under a mirror at room temperature;
(13) washing with tap water, and passing through distilled water;
(14) counterstaining with hematoxylin for 1-2min, and washing with tap water;
(15) and (3) dehydrating: 30% ethanol for 3min, 50% ethanol for 3min, 70% ethanol for 3min, 80% ethanol for 3min, 90% ethanol for 3min, 95% ethanol for 3min, 100% ethanol for 3min, and xylene for 20 min;
(16) the slices were put in a fume hood for air drying, sealed with gum, and examined under a microscope.
Step three: comparing the expression of FBXO31 protein in the pathological tissue biopsy and the tissue biopsy beside cancer, if the expression of FBXO31 protein in the pathological tissue biopsy is higher than that of the tissue beside cancer, the patient is supposed to generate drug resistance to the chemotherapeutic drug paclitaxel, and a doctor can consider an immunotherapy, targeted drug therapy or combined therapy scheme to avoid the paclitaxel from being used independently; if the expression level of FBXO31 protein in pathological tissues and tissues beside cancer is not obviously different, the conventional chemotherapeutic drugs can be used for treatment.
Example 1 in vitro cell assay study to modulate the effects of FBXO31 on the sensitivity of esophageal squamous cell carcinoma cells to paclitaxel drugs
Paclitaxel, which is commonly used in clinical practice, is used as a drug, and a stable FBXO31 silencing and control cell line (refer to Liu, J., L.Han, B.Li, J.Yang, M.S.Huen, X.Pan, S.W.Tsao and A.L.Cheng (2014). "F-box only protein 31(FBXO31) novel regulation p38 mitogen-activated protein kinase (MAPK) signalling by mediated hydrolysis and degradation of mitogen-activated protein kinase kinase 6(MKK 6)"J Biol Chem289(31) 21508-.
Two cells in logarithmic growth phase (FBXO31 silenced cell line and control cell line) were seeded in 6-well plates at a density of 0.5-1X 104Cell apoptosis was detected 48h after each well of DMSO and paclitaxel (4 mg/ml).
The apoptosis detection means includes:
flow cytometry for detecting apoptosis
1. Collecting cells: combining the supernatant and the digested cells;
2. and (3) cleaning cells: washing 2 times with pre-cooled PBS;
3. dyeing: diluting 4 × binding buffer to 1 × buffer solution with PBS, sucking up the residual PBS in the centrifuge tube, adding 100 μ L of 1 × binding buffer in each tube, blowing and beating cells with a pipetting gun to fully resuspend the cells, adding 5 μ L of dye PI in a dark condition, and gently mixing with the pipetting gun;
5. and (3) computer detection: after incubation for 15 minutes in the dark at room temperature, 300. mu.L of binding buffer (1X) was added and mixed well, and the cell suspension was transferred to a 5mL flow tube in the dark for 1h on-machine detection on a flow cytometer.
The results show FIG. 1: by comparing the percentage of cells in the sub-G1 phase, the increase in the percentage of apoptosis after treatment with paclitaxel was observed, and the percentage of apoptosis in the silenced FBXO31 cells was higher than that in the control group.
② TUNEL method for detecting cell apoptosis
PBS or HBSS wash once.
2. If the cells are not firmly attached, the sample can be dried to make the cells more firmly attached.
3. Cells were fixed with 4% paraformaldehyde or immunostaining fixative (P0098) for 30-60 min.
4. Washed once with PBS or HBSS.
5. PBS containing 0.1% Triton X-100 was added and incubated for 2 minutes in an ice bath.
6. Wash 2 times with PBS or HBSS.
7. Mu.l of TUNEL assay was added to the samples and incubated for 60min at 37 ℃ in the absence of light. Note that: care should be taken during incubation to keep the surroundings wet with soaked paper or cotton wool or the like to minimize evaporation of the TUNEL detection solution.
PBS or HBSS washes 3 times.
9. And (4) sealing the plate by using an anti-fluorescence quenching sealing liquid and observing under a fluorescence microscope. The excitation wavelength range of 450-500nm and the emission wavelength range of 515-565nm (green fluorescence) can be used.
The results show FIG. 2: the figures show that the percentage of apoptosis in the silenced FBXO31 cells is higher than that in the control.
③Colony survival
The FBXO 31-silenced cells and the control cell line were seeded in six-well plates at a density of 0.5-1X 104And (4) carrying out treatment on each hole, namely not carrying out medicament treatment and carrying out treatment on the cells by using paclitaxel (4mg/ml) respectively on the next day, changing the culture solution after 48 hours, culturing the cells in a culture dish at 37 ℃ for about 2 weeks by using 5% CO2, and timely replacing the fresh culture solution according to the pH change of the culture solution. When macroscopic colonies appeared in the petri dish, the culture was terminated, the culture solution was discarded, carefully washed with PBS solution 2 times, and air-dried. Methanol was fixed for 15 minutes, and air-dried after discarding methanol. Dyeing with Giemsa dye liquor for 10 minutes, slowly washing off the dye liquor with running water, and air drying. And observing the apoptosis condition.
The results show FIG. 3: apoptosis was significantly higher in the group treated with paclitaxel than in the control group, and knockdown of FBXO31 increased apoptosis.
Example 2 molecular biological mechanisms for modulating FBXO31
1. Sample preparation
(1) Materials and reagents
(2) Enzymolysis in glue
The gel strips were minced and the gel pieces were destained using 50% acetonitrile (acetonitrile) containing 50mM ammonium bicarbonate (NH4HCO 3). After dehydrating the gel masses by incubation with 100% acetonitrile for 5 minutes, the liquid phase was removed from the system, and a solution of dithiothreitol (dithiothreitol) was added to the system to a final concentration of 10mM, followed by incubation at 37 ℃ for 60 minutes. The dehydration was again incubated with 100% acetonitrile, the liquid phase removed and iodoacetamide (iodoacetamide) added to a final concentration of 55mM and incubated at room temperature in the dark for 45 minutes. After which a wash with ammonium bicarbonate at a final concentration of 50mM was used and the dehydration was incubated again with 100% acetonitrile. Finally the gel pellet was resuspended in 50mM ammonium bicarbonate containing 10 ng/. mu.l trypsin (trypsin) and incubated on ice for 1 hour. After removing excess solution from the sample, the gel pieces were enzymatically digested at 37 ℃ overnight. Extracting the peptide fragment after enzymolysis into a gel block by using 50% acetonitrile/5% formic acid and 100% acetonitrile in sequence, and freezing and spin-drying the peptide fragment solution for later use.
2. Liquid chromatography-mass spectrometry
(1) Materials and reagents
Mass spectrometer Thermo scientific Q Interactive Plus
(2) Mass spectrometry parameter settings
After the peptide fragment is dissolved by the mobile phase A, the peptide fragment is separated by an EASY-nLC 1000 ultra-performance liquid phase system. Mobile phase a was an aqueous solution containing 0.1% formic acid and 2% acetonitrile, and mobile phase B was an aqueous solution containing 0.1% formic acid and 98% acetonitrile. Setting a liquid phase gradient: 4% -35% of phase B in 0-22 min; 35% -80% of phase B in 22-27 min; 80% of phase B in 27-30 min, and the flow rate is maintained at 400 nL/min.
The peptide fragments are separated by an ultra-high performance liquid phase system, injected into an NSI ion source for ionization and then analyzed by Thermo scientific Q ExactivtM Plus mass spectrum. The ion source voltage was set at 2.0kV and both the peptide fragment parent ion and its secondary fragment were detected and analyzed using the high resolution Orbitrap. The scanning range of the primary mass spectrum is set to be 350-1800m/z, and the scanning resolution is set to be 70,000; the Orbitrap scan resolution was set to 17,500. The data acquisition mode uses a data-dependent scanning (DDA) program, namely, after the primary scanning, the first 20 peptide parent ions with the highest signal intensity are selected to sequentially enter an HCD collision cell for fragmentation by using 28% of fragmentation energy, and the secondary mass spectrometry is also sequentially performed. To improve the effective utilization of the mass spectra, the Automatic Gain Control (AGC) was set to 5E4, the signal threshold was set to 5000ions/s, the maximum injection time was set to 200ms, and the dynamic exclusion time of the tandem mass spectrometry scan was set to 15 seconds to reduce the number of repeated scans of parent ions.
(3) Data search library
Secondary mass spectral data were retrieved using a Proteome scanner 1.3. The search parameter settings are as follows: the database was set to swissprot Human (20203 sequences); the enzyme cutting mode is set as Trypsin/P; the missed cut site was set to 2; the primary parent ion mass error tolerance is set to be 10 ppm; the mass error tolerance of the secondary fragment ions is set to be 0.02 Da; the fixed modification is set as cysteine alkylation; the variable modification is oxidation of methionine and acetylation of the N end of the protein; the ion score of the peptide fragment is required to be higher than 20, and the peptide confidence is set to be High as the identification result.
The results show FIG. 4: cofilin-1, a substrate protein of FBXO31 protein, was found.
Example 3 modulation of Cofilin-1 Activity by FBXO31 protein
On the first day, stable FBXO31 silent cells and a control cell strain are inoculated in a six-well plate, on the second day, protein is extracted after 48 hours of treatment with paclitaxel drugs, and the expression levels of p-cofilin, cofilin and actin are detected by WB.
The results show FIG. 5: knockdown of FBXO31 protein increased the level of cofilin-1 phosphorylation, suggesting a decrease in cofilin-1 activity.
Example 4 knock-down of cofilin-1 regulates the sensitivity of FBXO31 to paclitaxel drugs
On the first day, stable FBXO 31-silenced cells were seeded in six-well plates, and on the next day, si-control and si-cofilin-1 were transfected into two groups of cells, respectively, and after 24h, they were treated with DMSO and paclitaxel (4mg/ml) for 48h, and then apoptosis was detected by flow cytometry (experimental procedure same as in example 1 (r)).
The results show FIG. 6: by comparing the subfin 1 phase in the figure, decreased apoptosis was observed after knocking down Cofilin-1, i.e., knocking down Cofilin-1 reversed apoptosis.
Example 5 in vivo animal experiments study of FBXO31 Effect on sensitivity of esophageal squamous carcinoma cells to paclitaxel drug
Stably expressing FBXO31-sh (right) and a control cell line (scarmble-sh) (left) are inoculated subcutaneously, and are administrated intraperitoneally (DMSO or paclitaxel is 2mg/kg, injection is performed at intervals of 3 days, and injection is performed continuously for 4 weeks), and the inhibition effect of paclitaxel on the tumor formation of different cell lines is observed.
The results show FIG. 7: the tumor size of mice treated by FBXO31 is obviously smaller than that of a control group (DMSO) after being knocked down by paclitaxel drugs
Example 6 study of the expression and drug sensitivity of FBXO31 in esophageal cancer clinical specimens
All clinically relevant experiments were performed under the provisions of the ethical committee of the xiang ya two hospital, central and south university, with ethical approval number: 2005, loun examination No. (research 006). Patient inclusion criteria: the diagnosis is confirmed to be esophageal squamous carcinoma, and the treatment scheme is patients who undergo separate operation and postoperative adjuvant chemotherapy. The expression of FBXO31 in tumor tissues and in paraneoplastic tissues was examined by immunohistochemical methods, using a group of patients resistant to chemotherapeutic drugs and a group of patients sensitive to chemotherapeutic drugs.
The results are shown in FIG. 8: FBXO31 expression in tumor tissue in representative chemotherapeutic drug resistant esophageal squamous carcinoma specimens was higher than in paraneoplastic tissue (IHC). FBXO31 is localized in cytoplasm, FBXO31 is highly expressed in basal layer cells (the layer cells are actively differentiated and proliferated) in normal paracancer tissues, and FBXO31 is more expressed in tumor tissues than in paracancer tissues in 18/40 clinical samples which are resistant to chemotherapeutic drugs; in the other 22 clinical samples sensitive to chemotherapeutic drugs, FBXO31 expression in tumor tissues and tissues adjacent to the cancer tissues has no obvious difference.
The above description is intended to be illustrative of the preferred embodiment of the present invention and should not be taken as limiting the invention, but rather, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention.
Sequence listing
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<120> protein index for predicting sensitivity of esophageal squamous carcinoma patient to chemotherapeutic drugs and application
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Claims (1)
- Application of FBXO31 protein in preparation of reagent for predicting and/or regulating sensitivity of esophageal squamous carcinoma patient to chemotherapeutic drug paclitaxel.
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