CN107604074B - Glioma prognostic marker circ15:101235082|101235577 and application thereof - Google Patents
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Abstract
The invention belongs to the technical field of biology, and discloses a glioma prognosis marker circ15:101235082|101235577 and application thereof, namely, a reagent for detecting circRNA circ15:101235082|101235577 derived from brain tissues is used for preparing a prognosis preparation for a glioma patient. The research proves that the patient with higher circRNA circ15:101235082|101235577 expression level in glioma has higher postoperative survival rate. The prognosis of glioma patients is judged by detecting the expression level of circRNA circ15:101235082|101235577 in the glioma tissues of glioma patients.
Description
Technical Field
The invention belongs to the technical field of biology, and relates to a serum circRNA marker for glioma prognosis, application of a reagent for detecting the marker in preparation of a glioma prognosis preparation, and a kit.
Background
Brain glioma is the most frequent brain tumor disease of adults, and accounts for 40.49 percent of intracranial tumors. From the time of diagnosis, the average life span of brain glioma patients does not exceed five years. In order to diagnose glioma, a malignant disease with a very high genetic material correlation, the pathogenesis of glioma must be explored at the molecular biological level from the aspect of genetic information expression. At present, the diagnosis and treatment methods of glioma are in the continuous improvement stage, but the survival rate of glioma patients is not obviously improved. Glioma diagnosis is still in an empirical stage based on clinical, pathological and imaging information, and once diagnosed, most of them are in middle and advanced stages, and the survival rate after surgery is not optimistic. Therefore, the search of glioma prognostic markers for carrying out prognostic analysis on patients, the improvement of the postoperative life quality of glioma patients, the corresponding selection of reasonable subsequent treatment schemes and the improvement of survival rate are research tasks to be solved urgently in the field of neuroscience.
The circRNA is a kind of endogenous non-coding RNA molecules which are widely and diversely present in mammalian cells and have the function of regulating gene expression, has a covalently closed ring structure, is widely present in various cells, and is also a latest research hotspot of an RNA family following microRNA (miRNA). In recent years, with the wide application of deep sequencing technology and the rapid development of biophysical and informatics technologies, it has been found that human transcripts of many exons can be non-linearly reverse spliced or rearranged by gene to form circRNA, and that they account for a considerable proportion of all spliced transcripts, have the characteristics of richness, stability, high conservation, space-time specificity and the like, and have potential as molecular markers of many diseases.
Disclosure of Invention
The first object of the present invention is: provides a circRNA marker circ15:101235082|101235577 of brain tissue origin for prognosis of glioma patients, the sequence of which is shown in SEQ NO 1.
The second purpose of the invention is to provide the application of the reagent for detecting the expression quantity of the circRNA marker in brain tissues in preparing a glioma prognosis preparation.
The third purpose of the invention is to provide a glioma prognosis kit, which can determine the content of circ15:101235082|101235577 in brain tissues.
The glioma prognosis kit contains a PCR primer for detecting the content of circ15:101235082| 101235577. Preferred primers have the sequences shown in SEQ NO 2 and 3.
The glioma prognosis kit contains all reagents for extracting RNA from brain tissues and carrying out reverse transcription and fluorescence quantitative PCR besides the primers of circ15:101235082| 101235577. The method comprises the following steps:
(1) extracting total RNA from glioma tissue with reagent comprising RNA stabilizing solution, Trizol reagent, chloroform, isopropanol, and enzyme-free water;
(2) the reagent for reverse transcription of circ15:101235082|101235577 into cDNA by using total RNA as a template comprises a reverse transcription buffer solution, base triphosphate deoxynucleotide, RNase inhibitor, MMLV reverse transcriptase and
random primers used for circ15:101235082| 101235577;
(3) the reagents used for real-time quantitative PCR of cDNA comprise circ15:101235082|101235577 real-time fluorescent quantitative PCR specific primers, GAPDH reference specific PCR primers, real-time fluorescent quantitative SYBR dye and enzyme-free water.
The research of the invention proves that the circRNA circs 15:101235082|101235577 derived from the brain tissue can be used for prognosis analysis of glioma patients, and the expression quantity of the circRNA circs 15:101235082|101235577 derived from the brain tissue has correlation with the postoperative survival rate of the patients. Therefore, the method can be used for the prognostic analysis of glioma patients.
The applicant finds that the circRNAcir 15:101235082|101235577 derived from glioma tissues is related to the survival rate of patients through fluorescent quantitative PCR and survival curve analysis, and the higher the content is, the higher the survival rate is. The method provides powerful technical support for prognosis analysis of glioma, is beneficial to improving the postoperative life quality of glioma patients, making a postoperative treatment scheme, improving survival rate and having profound clinical significance and popularization.
Drawings
FIG. 1 shows real-time fluorescent quantitative PCR analysis of differences in expression of circ15:101235082|101235577 in glioma tissues and normal brain tissues;
FIG. 2 is a survival curve for analyzing the influence of the expression level of circ15:101235082|101235577 derived from glioma tissues on the prognosis of glioma patients.
Detailed Description
The following examples are intended to further illustrate the invention without limiting it.
Example 1 preparation of reagent for measuring the expression level of circRNA circ15:101235082|101235577 for the preparation of a kit for prognosis of glioma patients (50 reactions)
50ml RNA stabilizing solution
2. Isopropanol 100ml
3. Chloroform 100ml
4.Trizol 50ml
5. 10ml of enzyme-free water
6.1 μ M random reverse transcription primer 50 μ l
7.5 × reverse transcription buffer 200ml
8.10mM deoxynucleotide triphosphate base 100. mu.l
9.40U/. mu.l RNase inhibitor 500. mu.l
10.200U/. mu.l MMLV reverse transcriptase 50. mu.l
11.Premix Ex Taq 50μl
12.10. mu.M circRNA circ15: 101235082. mu. 101235577 real-time fluorescent quantitative PCR specific primers 30. mu.l
circRNA circ15:101235082|101235577 forward primer: 5'-ACCACGGAAGAAATGGGA-3' the flow of the air in the air conditioner,
circRNA circ15:101235082|101235577 reverse primer: (ii) a 5'-CAGATGTGTCAGAACCCTCA-3'
13.10 μ M GAPDH specific primer 30 μ l
The forward primer was set to 5'-ATCATCAGCAATGCCTCCT-3' (wt.),
the reverse primer was 5'-CATCACGCCACAGTTTCC-3'.
Example 2 detection of the expression level of circRNA circ15:101235082|101235577 in brain tissue samples
1. Collecting glioma or normal brain tissue to be detected, putting the glioma or normal brain tissue into a freezing storage tube containing RNA stable solution, and putting the tube into a refrigerator at minus 80 ℃ for standby.
2. Extraction of RNA from tissues: taking a proper amount of specimen, adding liquid nitrogen into a mortar baked for 6-8h at 180 ℃, grinding the specimen into powder, adding 1ml of Trizol mortar specimen into the mortar, grinding the specimen into liquid, transferring the liquid to a tube, and standing and cracking the liquid on ice for 15 minutes. After cleavage was complete, centrifugation was carried out at 12000rpm for 10min at 4 ℃ and the supernatant was transferred to a new tube. Adding 200 μ l chloroform into Tube, shaking by hand for 15-30s, standing on ice for 5min, centrifuging at 4 deg.C and 12000rpm for 15 min; carefully taking the upper water phase into a new tube, adding 0.5ml of precooled isopropanol, uniformly mixing, standing on ice for 20min, and centrifuging at 12000rpm for 10min at 4 ℃; discarding the supernatant, adding 1-2ml ethanol diluted with 75% DEPC water, mixing, centrifuging at 4 deg.C and 7500rpm for 5min, discarding the supernatant, drying at room temperature for 5-10min, and adding 10-20 μ l DEPC water to dissolve RNA.
3. circRNA circ15:101235082|101235577 reverse transcription: a reverse transcription kit from Thermo was used. The system for 20. mu.l reverse transcription reaction was as follows:
| composition (I) | Dosage/tube |
| Random reverse transcription primer (1. mu.M) | 1μl |
| RNA samples | 2μg |
| Enzyme-free water | To 12μl |
Reverse transcription first step conditions: 5 minutes at 65 DEG C
| Composition (I) | Dosage/tube |
| 5 × reverse transcription buffer solution | 4μl |
| Base triphosphate deoxynucleotide (10mM) | 2μl |
| RNase inhibitor (40U/. mu.l) | 1μl |
| MMLV reverse transcriptase (200U/. mu.l) | 1μl |
| Products of the first PCR | 12μl |
| Total volume | 20μl |
Reverse transcription second step procedure: 5 minutes at 25 ℃, 60 minutes at 42 ℃ and 5 minutes at 70 ℃.
4. Real-time quantitative PCR was performed using circ15:101235082|101235577 specific primers, synthesized by Hantah Biotech Ltd: firstly, the reverse transcription product is diluted by 10 times and mixed evenly. The 20. mu.l reaction was as follows:
specific primers for qRT-PCR:
a forward primer: 5'-ACCACGGAAGAAATGGGA-3' the flow of the air in the air conditioner,
reverse primer: 5'-CAGATGTGTCAGAACCCTCA-3' are provided.
GAPDH internal reference specific PCR primers:
the forward primer was set to 5'-ATCATCAGCAATGCCTCCT-3' (wt.),
the reverse primer was 5'-CATCACGCCACAGTTTCC-3'.
Real-time fluorescent quantitative PCR reaction program: 95 ℃ for 3 minutes, 40 cycles, 95 ℃ for 10 seconds, 60 ℃ for 30 seconds.
5、2-ΔΔCTOf indexesAnd (3) determination: the experimental data adopts a relatively quantitative analysis method, GAPDH is used as an internal reference gene, the difference between the circRNA circ15:101235082|101235577CT value measured by qRT-PCR and the GAPDH CT value from the same tissue source is obtained to obtain delta CT, and the delta CT are usedControlThe difference is made to obtain delta CT (the average value of the delta CT of the normal samples is taken as delta CTControl) Data were analyzed by Welch assay using the software GraphPad Prism. Analysis shows that the expression quantity of the circRNA circs 15:101235082|101235577 in glioma tissues and the circRNA circs 15:101235082|101235577 in normal brain tissues is different (see figure 1), and the difference is significant (P is P<0.0001)。
6. Through the follow-up statistical data of 30 glioma patients adopted in the experiment, 10 patients are not connected due to the halt of a mobile phone or the change of numbers or other reasons during follow-up, and the number of the glioma patients or family members which can be finally connected is 20, and the 20 patients or family members receive the follow-up analysis. We asked the time of first onset, treatment, recurrence and death of these patients or families in detail, with follow-up period of 1-42 months. In selected glioma patients, the expression value of fluorescent quantitative PCR analysis is selected as a reference standard, the obtained results are high-expressed in a circ15:101235082|101235577 which is higher than the median after descending order arrangement, and the other results are low-expressed in a circ15:101235082|101235577 which are 10 cases in total. Through Kaplan-Meier survival analysis, the survival time of the circ15:101235082|101235577 high-expression patient is longer than that of the circ15:101235082|101235577 low-expression patient, and the survival time is better. The difference was statistically significant (P ═ 0.05). The research shows that circ15:101235082|101235577 can be used as a specific molecular marker for prognosis of glioma patients.
Sequence listing
<110> Hunan ya Hospital of Zhongnan university
<120> glioma prognostic marker circ15:101235082|101235577 and application
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<211>496
<212>RNA
<213> Intelligent (Homo sapiens)
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aucuguacca auuccaguag ugccacuacg ggguguggac gacuccuacc cgccccagaa 120
gaaguccuuc augaugcuca aguacaugca cgaccacuac uuggacaagu augaaugguu 180
uaugagagca gaugaugacg uguacaucaa aggagaccgu cuggagaacu uccugaggag 240
uuugaacagc agcgagcccc ucuuucuugg gcagacaggc cugggcacca cggaagaaau 300
gggaaaacug gcccuggagc cuggugagaa cuucugcaug ggggggccug gcgugaucau 360
gagccgggag gugcuucgga gaauggugcc gcacauuggc aagugucucc gggagaugua 420
caccacccau gaggacgugg aggugggaag guguguccgg agguuugcag gggugcagug 480
ugucuggucu uaugag 496
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<213> Unknown (Unknown)
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accacggaag aaatggga 18
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<213> Unknown (Unknown)
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cagatgtgtc agaaccctca 20
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<213> Unknown (Unknown)
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atcatcagca atgcctcct 19
<210>5
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<213> Unknown (Unknown)
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catcacgcca cagtttcc 18
Claims (4)
1. The application of the reagent for detecting the up-regulation of the expression quantity of circ15:101235082|101235577 in brain tissues in the preparation of a preparation with good prognosis for glioma patients is disclosed, wherein the sequence of the circ15:101235082|101235577 is shown as SEQ NO 1.
2. The use of claim 1, wherein the reagent for detecting the up-regulation of the expression level of circ15:101235082|101235577 in brain tissue contains a primer for detecting the content of circ15:101235082| 101235577.
3. The use of claim 2, wherein the primer has the sequence shown in SEQ ID Nos. 2 and 3.
4. The use according to claim 2 or 3, characterized in that it contains, in addition to the primers for detecting circ15:101235082|101235577, all the reagents for extracting RNA from brain tissue and performing reverse transcription and fluorescence quantitative PCR.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2667193A1 (en) * | 2012-05-23 | 2013-11-27 | Université d'Aix-Marseille | MMP2 as a predictive biomarker of response to antiangiogenic therapy and survival after therapy in cancer patients |
| CN103981271A (en) * | 2014-05-26 | 2014-08-13 | 中南大学 | Application method of serum Exosomes derived long no-coding RNA LINC00470 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2667193A1 (en) * | 2012-05-23 | 2013-11-27 | Université d'Aix-Marseille | MMP2 as a predictive biomarker of response to antiangiogenic therapy and survival after therapy in cancer patients |
| CN103981271A (en) * | 2014-05-26 | 2014-08-13 | 中南大学 | Application method of serum Exosomes derived long no-coding RNA LINC00470 |
Non-Patent Citations (3)
| Title |
|---|
| Circular RNAs are abundant, conserved, and associated with ALU repeats;Jeck WR 等;《RNA》;20121218;第19卷(第2期);第141-157页 * |
| Jeck WR 等.Circular RNAs are abundant, conserved, and associated with ALU repeats.《RNA》.2012,第19卷(第2期), * |
| Loss of brain-enriched miR-124 enhances the stem-like traits and invasiveness of glioma cells;Hongping Xia 等;《J Biol Chem》;20120117;第1-19页以补充数据 * |
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