CN107937540B - Glioma diagnosis marker circ17:47618350|47619164 and application - Google Patents
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Abstract
The invention belongs to the technical field of biology, and discloses a glioma diagnosis marker circ17:47618350|47619164 and application thereof. In the present invention, the expression level of circ17:47618350|47619164 in the serum exosome of glioma patients is found to be obviously increased compared with that of the control group for the first time (P is 0.0218), and the ROC curve analysis shows that the expression level has higher diagnostic value for glioma (AUC is 0.875, P is 0.001, and the sensitivity and specificity are 96.3% and 72.7% respectively). Therefore, by detecting the expression level of circ17:47618350|47619164 in the serum exosome of the glioma patient, the early and rapid noninvasive diagnosis of the glioma patient can be made.
Description
Technical Field
The invention belongs to the technical field of biology, and relates to a serum circRNA marker circ17:47618350|47619164 for glioma diagnosis, application of a reagent for detecting the marker in preparation of a glioma diagnosis preparation, and a kit.
Background
Brain gliomas originate from brain glial cells, are common intracranial tumors, accounting for about 40% to 50% of tumors in the central nervous system, with malignant gliomas (world health organization classification iii, iv) accounting for about 77.5% of all gliomas. Brain glioma has the characteristics of high three-high one-low, namely high morbidity, high postoperative recurrence, high fatality rate and low cure rate, and the biggest biological characteristic is that tumor cells grow infiltratively and can not be completely removed by operation. Although the treatment method is developed from single operation treatment to the combined treatment of operation, radiotherapy, chemotherapy and the like at present, the prognosis of the patient with the glioma is not obviously improved in the last decades. Therefore, it is important to find the indicators for early diagnosis, treatment effect evaluation and prognosis judgment of brain glioma.
Circular RNA (circular RNA) is an emerging endogenous non-coding RNA (ncRNA), has attracted extensive attention in recent years, and is a hotspot of RNA research at present. The circRNA joins 3 'and 5' ends by exon circularization or intron circularization to form a complete circular structure, and thus is more stable and more conservative than linear RNA, and can be present in many types in organisms. More and more researchers find that circRNA plays an important role in gene expression regulation, which enriches the understanding of people on endogenous non-coding RNA and prompts that circRNA has wide prospects in clinical diagnosis and treatment. In recent years, it has been found that exosomes also contain a large amount of circRNA and may play an important role. At present, as circRNA has the characteristics of richness, stability, high conservation, space-time specificity and the like, the circRNA plays an increasingly large role in the aspect of tumor diagnosis markers.
Disclosure of Invention
The first object of the present invention is: provides a serum exosome circRNA marker for glioma diagnosis.
The main contents comprise: a serum exosome circRNA marker circ17:47618350|47619164 for glioma diagnosis, the sequence of which is shown in SEQ NO 1. The circRNA is located on chromosome 17 of human and has a total length of 264 bp.
The second purpose of the invention is to provide the application of the reagent for detecting the expression quantity of the circRNA marker in a serum exosome in the preparation of a glioma diagnostic preparation.
It is a third object of the present invention to provide a glioma diagnostic kit capable of determining the content of circ17:47618350|47619164 in serum exosomes.
The glioma diagnostic kit contains a PCR primer for detecting the content of circ17:47618350| 47619164. Preferred primers have the sequences shown in SEQ NO 2 and 3.
The glioma diagnosis kit comprises all reagents for extracting exosome from serum, extracting RNA from the exosome and performing reverse transcription and fluorescence quantitative PCR, except a circ17:47618350|47619164 primer.
The method comprises the following steps:
(1) reagents required for extracting serum exosomes: total Exosome Isolation Reagent (fromservum), available from Invitrogen corporation under the trade designation 4478360;
(2) reagents required for the extraction of exosome RNAs: trizol reagent, trichloromethane, isopropanol, 75% ethanol and enzyme-free water;
(3) reagents required for reverse transcription: random Primer (Random Primer), enzyme-free water, 5 × reverse transcription buffer, base triphosphate deoxynucleotide, RNase inhibitor, MMLV reverse transcriptase;
(4) reagents required for fluorescent quantitative PCR: circ17:47618350|47619164 upstream and downstream primers, GAPDH internal reference upstream and downstream primers, SYBR dye, and enzyme-free water.
The invention has the beneficial effects that:
the serum exosomes of glioma patients were found to have a significant upregulation of circ17:47618350|47619164 compared to the normal serum exosome control group for the first time (p ═ 0.0218). ROC curve analysis showed that circ17:47618350|47619164 as a biomarker had higher diagnostic value for glioma (AUC 0.875, sensitivity and specificity 96.3% and 72.7%, respectively). By applying the cyclic RNA in glioma diagnosis and analysis, the glioma can be diagnosed more conveniently and accurately, a foundation is laid for a clinician to quickly and accurately master the state of an illness of a patient, the clinical treatment effect is improved, and help is provided for finding a novel micromolecular drug target with potential treatment value.
Drawings
FIG. 1 is a real-time fluorescent quantitative PCR analysis of the expression difference of circ17:47618350|47619164 in glioma serum and normal serum exosomes;
FIG. 2 is a diagram for analyzing specificity and sensitivity of circ17:47618350|47619164 derived from serum exosome to early diagnosis of glioma by using ROC curve.
Detailed Description
The following is intended to further illustrate the invention in connection with the embodiments, and not to limit the invention.
First, research object
Serum samples from 27 patients with glioma were provided by Xiangya Hospital, and 11 normal serum samples were healthy individuals who were contemporaneously community disease screened. Samples for research are collected at the same period, and sampling, subpackaging and storing conditions are consistent.
Second, research method
1. Extraction of RNA from glioma/Normal serum exosomes
200. mu.l of serum was centrifuged at 2000g for 30 minutes at room temperature, the supernatant was removed by a micropipette to a new 600. mu.l centrifuge tube, 40. mu.l of an Exosome-extracting Reagent (Total Exosome Isolation Reagent (from serum), cat. No. 4478360, Invitrogen) was added thereto and shaken gently upside down, and the mixture was incubated at 4 ℃ for 45 minutes. And after incubation, centrifuging at room temperature for 10 minutes at 10000g, and removing supernatant to obtain precipitate, namely the exosome in the serum. The pellet was resuspended by adding 200. mu.l Trizol (MRC Co.), and the suspension was transferred to a new 1.5ml tube and supplemented with Trizol to 1 ml. The cells were lysed on ice for 15min, centrifuged at 12000rpm for 10min 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 more than 20min, and centrifuging at 12000rpm for 10min at 4 ℃; discarding the supernatant, adding 1ml 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 μ l DEPC water to dissolve RNA. Stored at-80 ℃ and refrigerator temperatures were recorded daily by the laboratory.
Preparation of cDNA
Reverse transcription was performed according to the instructions of the reverse transcription kit (Thermo Co.). The Reaction total volume was 20. mu.l (10. mu.l total RNA, 1. mu.l Random primer, 1. mu.l enzyme-free water, 4. mu.l 5 × Reaction Buffer, 1. mu.l RI, 1. mu.l RT and 2. mu.l 10mM dNTP).
| Composition (I) | Dosage/tube |
| Random reverse transcription primer (1. mu.M) | 1μl |
| RNA samples | 10μl |
| Enzyme-free water | To 12μl |
Reverse transcription first step conditions: 5 minutes at 65 DEG C
Reverse transcription second step procedure: 5 minutes at 25 ℃, 60 minutes at 42 ℃ and 5 minutes at 70 ℃.
3. Real-time fluorescent quantitative PCR
The real-time quantitative PCR is carried out by adopting specific primers (the primer sequences are shown in SEQ NO:2 and 3) synthesized by Hanhengzheng biotechnology (Shanghai) Limited company: firstly, the reverse transcription product is diluted by 10 times and mixed evenly. The 20. mu.l reaction was as follows:
real-time fluorescent quantitative PCR reaction program: 95 ℃ for 3 minutes, 40 cycles, 95 ℃ for 10 seconds, 60 ℃ for 30 seconds.
4. And (3) data analysis: by using 2-ΔΔCTCirc17:47618350|47619164, representing glioma serum exosomes, expressed fold relative to normal serum exosomes, where △ CT ═ CTSample(s)–CTInternal reference，ΔΔCT＝ΔCTGlioma–ΔCTIs normal. The experimental data was analyzed by a relatively quantitative analysis method using GAPDH as an internal reference gene (primer sequences shown in SEQ NO: 4 and 5) and using software GraphPad Prism and SPSS 17.0.
Third, research results
Serum exosomes of glioma patients had circ17:47618350|47619164 significantly upregulated compared to normal serum exosome controls (p ═ 0.0218). The specific data are shown in fig. 1. ROC curve analysis showed that circ17:47618350|47619164 as biomarker had higher diagnostic value for glioma (AUC 0.875, p <0.001, sensitivity and specificity 96.3% and 72.7%, respectively), and the detailed results are shown in fig. 2.
Sequence listing
<110> Hunan ya Hospital of Zhongnan university
<120> glioma diagnosis marker circ17:47618350|47619164 and application
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Claims (4)
1. The application of the reagent for detecting the expression quantity of circ17:47618350|47619164 in a serum exosome in the preparation of a glioma diagnostic preparation, wherein the sequence of the circ17:47618350|47619164 is shown as SEQ NO: 1.
2. The use of claim 1, wherein the reagent for detecting the expression level of circ17:47618350|47619164 in the serum exosome comprises PCR primers for detecting the content of circ17:47618350| 47619164.
3. The use of claim 2, wherein the primer has the sequence shown in SEQ ID Nos. 2 and 3. .
4. The use of claim 1, 2 or 3, wherein the reagent for detecting the expression level of circ17:47618350|47619164 in the serum exosomes further comprises all reagents for extracting exosomes from serum, extracting RNA from exosomes and performing reverse transcription and fluorescence quantitative PCR.
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Non-Patent Citations (3)
| Title |
|---|
| Cell-type specific features of circular RNA expression;Julia Salzman et al.;《PLoS Genet》;20130905;第9卷(第9期);e1003777第1-15页 * |
| Genome-wide high-density SNP linkage search for glioma susceptibility loci:results from the gliogene consortium;Sanjay Shete et al.;《Cancer Research》;20111028;第71卷(第24期);第7572页左栏第3段-右栏第1段 * |
| Julia Salzman et al..Cell-type specific features of circular RNA expression.《PLoS Genet》.2013,第9卷(第9期),e1003777第1-15页. * |
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