CN113564255A - Application of lncRNA NEAT1_1 - Google Patents
Application of lncRNA NEAT1_1 Download PDFInfo
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- CN113564255A CN113564255A CN202110928943.0A CN202110928943A CN113564255A CN 113564255 A CN113564255 A CN 113564255A CN 202110928943 A CN202110928943 A CN 202110928943A CN 113564255 A CN113564255 A CN 113564255A
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Abstract
The invention provides an application of lncRNA NEAT1_1, wherein lncRNA NEAT1_1 is used for predicting drug resistance of lung adenocarcinoma EGFR-TKI. The lncRNA NEAT1_1 can promote the drug resistance of the lung adenocarcinoma EGFR-TKI, can be used as a treatment target for overcoming the drug resistance of the lung adenocarcinoma EGFR-TKI, can be used for preparing a drug for overcoming the drug resistance of the lung adenocarcinoma EGFR-TKI, and has wide clinical application prospects.
Description
Technical Field
The invention belongs to the technical field of oncology, and particularly relates to application of lncRNA NEAT1_ 1.
Background
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) significantly improve prognosis of lung adenocarcinoma patients carrying EGFR mutations, but drug resistance limits further application of the drug. Screening potential populations for EGFR-TKI resistance is crucial to improving efficacy. The EGFR T790M mutation is one of the more definite factors which are known to cause EGFR-TKI drug resistance at present, but the actual positive rate of the EGFR T790M mutation in China is low, and about 35% of cases can not find the definite drug resistance reason. In recent years, a plurality of researches show that lncRNA plays an important role in drug resistance of EGFR-TKI in lung adenocarcinoma. However, whether lncRNA can be used as a biomarker for predicting drug resistance of lung adenocarcinoma EGFR-TKI remains to be explored.
Disclosure of Invention
The technical problem to be solved by the invention is to provide the application of lncRNA NEAT1_1 aiming at the defects of the prior art, the lncRNA NEAT1_1 can promote the drug resistance of the lung adenocarcinoma EGFR-TKI, can be used as a treatment target for overcoming the drug resistance of the lung adenocarcinoma EGFR-TKI, and has wide clinical application prospect.
In order to solve the technical problems, the invention adopts the technical scheme that: the application of lncrRNA NEAT1_1, wherein the lncrRNA NEAT1_1 is used for predicting drug resistance of EGFR-TKI of lung adenocarcinoma, and the nucleotide sequence of the lncrRNA NEAT1_1 is shown as SEQ ID No. 1.
Preferably, the LncRNA NEAT1_1 is used for preparing a medicament for overcoming the drug resistance of EGFR-TKI of the lung adenocarcinoma.
Compared with the prior art, the invention has the following advantages:
the lncRNA NEAT1_1 can promote the drug resistance of the lung adenocarcinoma EGFR-TKI, can be used as a treatment target for overcoming the drug resistance of the lung adenocarcinoma EGFR-TKI, and has wide clinical application prospect.
The present invention will be described in further detail with reference to the accompanying drawings and examples.
Drawings
FIG. 1 is a graph showing the expression levels of lncRNA NEAT1_1 in EGFR-TKI primary drug resistant patients and susceptible patients according to example 1 of the present invention.
FIG. 2 is a graph showing the cumulative ratio of the progression free survival time to the progression free survival time of lncRNA NEAT1_1 patients with high expression and patients with low expression in example 1 of the present invention.
Figure 3 is a characteristic curve of the working of subjects with a progression free survival time of 24 months in example 1 of the present invention.
Figure 4 is a graph of PC9GR cell activity at different concentrations of gefitinib for in vitro experiment a of example 2 of the present invention.
FIG. 5 is a graph of apoptosis of PC9GR cells from in vitro experiment A of example 2 of the present invention.
Figure 6 is a graph of PC9GR cell activity at different concentrations of gefitinib for in vitro experiment B of example 2 of the present invention.
FIG. 7 is a graph of apoptosis of PC9GR cells from in vitro experiment B of example 2 of the present invention.
FIG. 8 is a graph of the tumor volume of PC9GR cells from in vivo experiment A of example 3 of the present invention.
FIG. 9 is a graph of the tumor volume of PC9GR cells from in vitro experiment B of example 3 of the present invention.
Detailed Description
Example 1
The application of lncRNA NEAT1_1 in the embodiment is that lncRNA NEAT1_1 (long non-coding RNA NEAT1_1) is used for predicting drug resistance of lung adenocarcinoma EGFR-TKI (epidermal growth factor receptor-tyrosine kinase inhibitor), and the nucleotide sequence of lncRNA NEAT1_1 is shown as SEQ ID No. 1.
Biopsy tissue was collected, and sample collection criteria: the method comprises the following steps of (1) pathologically diagnosing lung adenocarcinoma, assessing the existence of distant metastasis or unresectable tumor tissues by imaging, detecting the existence of EGFR mutation (19 or 21 exons) and not combining T790M mutation by gene, and taking oral EGFR-TKI medicines (including gefitinib, erlotinib and erlotinib) as first-line treatment. A total of 74 samples were collected.
Washing the tissue surface residual blood with precooled PBS, subpackaging on ice, and quickly freezing in liquid nitrogen for 30min in a-80 deg.C ultra-low temperature refrigerator for later use. Tissue RNA extraction and quantitative analysis: shearing the tissue with an enzymic ophthalmological scissors, adding 1000 mul Trizol reagent, cracking the tissue with a tissue crusher, standing for 10 minutes at room temperature, adding 200 mul chloroform, vortexing for 10 seconds, standing for 3 minutes at room temperature, centrifuging at 12000g for 15 minutes at 4 ℃; sucking 400 μ L of supernatant, adding 400 μ L of precooled isopropanol, standing at room temperature for 15 minutes, and centrifuging at 4 ℃ for 10 minutes at 2000 g; washing the precipitate with 1mL of absolute ethanol, and centrifuging at 7500g for 10 minutes at 4 ℃; air dried, and 10. mu.L of DEPC water was added to dissolve the RNA precipitate. Using PrimeScriptTMThe RT kit reverse transcribes the extracted RNA to cDNA, which is diluted to 10 ng/. mu.L with DEPC water after detection of the cDNA concentration.
Using the CFX96 Real-Time PCR detection system, the above cDNA was used as a template, and Real-Time quantitative PCR was performed to detect lncRNA NEAT1_1 according to the instructions of the HieffqPCR SYBR Green Master Mix kit from Shanghai assist, Inc., with the following primers: the nucleotide sequence of the upstream primer is shown as SEQ ID No.2, and the nucleotide sequence of the downstream primer is shown as SEQ ID No. 3. Primers for detecting GAPDH (internal control) were as follows: the nucleotide sequence of the GAPDH upstream primer is shown as SEQ ID No.4, the nucleotide sequence of the GAPDH downstream primer is shown as SEQ ID No.5, and the real-time quantitative PCR reaction system is shown as follows: hieff qPCR SYBR Green Master Mix 25 uL, upstream primer 1 uL, downstream primer 1 u L, cDNA 2 uL, and sterile ultrapure water 11 uL;
amplification was performed on an Applied Biosystems Step One instrument using the following amplification program: pre-denaturation at 95 ℃ for 5 min; denaturation at 95 ℃ for 10s, annealing and extension at 60 ℃ for 30s, and circulation for 40 times.
Patients were first reviewed 4 weeks after oral EGFR-TKI (imaging assessment, RECIST v1.1 criteria was taken) followed by 8 weeks every time the disease progression was considered primary resistance, as shown in figure 1, patients with EGFR-TKI primary resistance (a in figure 1) had significantly higher lncRNA NEAT1_1 expression levels than sensitive patients (B in figure 1).
The time between the patient receiving EGFR-TKI treatment and the disease progression was taken as progression-free survival (PFS). The threshold of lncRNA NEAT1_1 was evaluated using X-tile software based on patient disease progression, Progression Free Survival (PFS) and lncRNA NEAT1_1 expression levels, with the final lncRNA NEAT1_1 expression threshold being 1.83X 10-7. Patients were grouped into high expression groups (47 cases) and low expression groups (27 cases) according to the expression threshold. As shown in fig. 2, lncRNA NEAT1_1 patients in the high expression group (a in fig. 2) had significantly shorter PFS than the low expression group (B in fig. 2).
As shown in fig. 3, 24 months was taken as the cut-off time for observing PFS and the working characteristic curve of the subject was plotted, and the results showed that lncRNA NEAT1_1 as a biomarker predicted EGFR-TKI resistance to have a sensitivity of 82.35% and a specificity of 56.14% (fig. 3, a is the subject curve, B is the diagonal, only as a reference).
Example 2
The LncRNA NEAT1_1 is applied to preparation of a drug for overcoming EGFR-TKI resistance of lung adenocarcinoma, wherein the drug comprises CRISPR technology or interference plasmids with an LncRNA NEAT1_1 sequence as a target; the nucleotide sequence of lncRNA NEAT1_1 is shown in SEQ ID No.1, and the in vitro experiment is performed in the embodiment.
The lncRNA NEAT1_1 can promote the drug resistance of the lung adenocarcinoma EGFR-TKI, can be used as a treatment target for overcoming the drug resistance of the lung adenocarcinoma EGFR-TKI, and can reduce the IC (integrated circuit) of the EGFR-TKI type drugs (gefitinib) in the treatment of PC9GR cells by inhibiting lncRNA NEAT1_150While transfection of lncRNA NEAT1_1 increased IC in PC9 cells treated with gefitinib50Therefore, inhibition of lncRNA NEAT1_1 expression would help overcome EGFR-TKI resistance.
The PC9 cell is a lung adenocarcinoma cell which carries EGFR 19 exon mutation and is sensitive to EGFR-TKI, and the PC9GR cell is a cell which carries EGFR 19 exon mutation, does not have EGFR T790M mutation and is resistant to EGFR-TKI and is formed by culturing a PC9 cell by a drug gradient increasing method.
In vitro experiment a:
the lncRNA NEAT1_1 of PC9GR cells was knocked down using shRNA, treated with EGFR-TKI class drug gefitinib (5. mu.M, 10. mu.M, 15. mu.M, 20. mu.M, 25. mu.M, 30. mu.M, 35. mu.M, 40. mu.M, 45. mu.M, 50. mu.M) at various concentrations for 48 hours, the survival status of PC9GR cells was examined using CCK 8-method and IC of gefitinib was calculated50As shown in FIG. 4, the results indicate IC of gefitinib-treated PC9GR cells (FIG. 4A) that knockdown lncRNA NEAT1_1 compared to the control (FIG. 4B)50The value decreases significantly.
The PC9GR cells knocked down by lncRNA NEAT1_1 and the control PC9GR cells not interfered with were interfered with 30nM gefitinib, and the apoptosis rate was measured by flow cytometry, as shown in fig. 5, and the apoptosis rate of the PC9GR cells knocked down by lncRNA NEAT1_1 (fig. 5A) was significantly increased (the number of Annexin V-FITC/PI positive cells was increased) compared to the control (fig. 5B).
In vitro experiment B:
overexpression of lncRNA NEAT1_1 in PC9 cells by lentivirus transfection, treatment with EGFR-TKI class drug gefitinib (5. mu.M, 10. mu.M, 15. mu.M, 20. mu.M, 25. mu.M, 30. mu.M, 35. mu.M, 40. mu.M, 45. mu.M, 50. mu.M) at various concentrations for 48 hours, detection of survival status of PC9 cells by CCK 8-method and calculation of IC of gefitinib50The results show that gefitinib treated PC9 cells overexpressing lncRNA NEAT1_1 (figure 6B) compared to control (figure 6B)6A) Time of day IC50The value is significantly improved.
PC9 cells overexpressing incrna NEAT1_1 and PC9 cells not intervened (control) were intervened with 30 μ M gefitinib and the apoptosis rate was measured using flow cytometry, as shown in fig. 7, with PC9 cells overexpressing incrna NEAT1_1 (fig. 7A) having significantly reduced apoptosis rate (reduced number of Annexin V-FITC/PI positive cells) compared to the control (fig. 7B).
Example 3
The LncRNA NEAT1_1 is applied to preparation of a drug for overcoming EGFR-TKI resistance of lung adenocarcinoma, wherein the drug comprises CRISPR technology or interference plasmids with an LncRNA NEAT1_1 sequence as a target; the nucleotide sequence of the lncRNA NEAT1_1 is shown in SEQ ID No.1, and the in vivo experiment is performed in the embodiment.
In vivo experiment a:
respectively adopting 4X 106A tumor-bearing mouse model was established by subcutaneous injection of PC9GR cells knocked down for lncRNA NEAT1_1 and uninhibited PC9GR cells (control group) using BALB/c nude mice. Tumor size was measured every 3 days and tumor volume was calculated according to the formula (calculation formula: tumor volume ═ 0.5 × length × width 2). The volume of the tumor to be treated is about 100mm3In this case, mice were fed with the EGFR-TKI class drug gefitinib daily (dose: 50mg/kg mouse body weight). Mice were sacrificed after 6 weeks and tumor tissue was excised. As shown in fig. 8, PC9GR cells that knockdown lncRNA NEAT1_1 grew more slowly compared to the control group, indicating that they were more sensitive to gefitinib.
In vivo experiment B:
respectively adopting 4X 106A tumor-bearing mouse model was established by subcutaneous injection of PC9 cells overexpressing lncRNA NEAT1_1 and uninhibited PC9 cells (control group) using BALB/c nude mice. Tumor size was measured every 3 days and tumor volume was calculated according to the formula (calculation formula: tumor volume ═ 0.5 × length × width 2). The volume of the tumor to be treated is about 100mm3In time, the mice were fed with gefitinib daily (dose: 50mg/kg mouse body weight). Mice were sacrificed after 6 weeks and tumor tissue was excised. As shown in FIG. 9, PC9 cells overexpressing lncRNA NEAT1_1 compared to control groupThe tumor grew more rapidly, indicating that it developed resistance to gefitinib.
The above description is only for the preferred embodiment of the present invention, and is not intended to limit the present invention in any way. Any simple modification, change and equivalent changes of the above embodiments according to the technical essence of the invention are still within the protection scope of the technical solution of the invention.
Sequence listing
<110> Hospital of Hebei medical university
<120> application of lncRNA NEAT1_1
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Claims (2)
1. The application of lncrRNA NEAT1_1, wherein the lncrRNA NEAT1_1 is used for predicting drug resistance of EGFR-TKI of lung adenocarcinoma, and the nucleotide sequence of the lncrRNA NEAT1_1 is shown as SEQ ID No. 1.
2. The use of lncRNA NEAT1_1 according to claim 1, wherein the lncRNA NEAT1_1 is used for preparing a medicament for overcoming EGFR-TKI resistance in lung adenocarcinoma.
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