CN107488740A - Detect the LncRNA combinations of stomach cancer prognosis situation and the kit containing the combination - Google Patents
Detect the LncRNA combinations of stomach cancer prognosis situation and the kit containing the combination Download PDFInfo
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Abstract
Kit the invention discloses the LncRNA combinations of detection stomach cancer prognosis situation and containing the combination, the present invention utilizes the change of divergence of specific one group of LncRNA expression quantity in quantitative fluorescent PCR or digital pcr technical appraisement Patients with Gastric Cancer sample (sample can be tissue, blood plasma, serum gastric juice etc.) and corresponding cancer side sample or normal sample, early accurate evaluation recurrence of gastric cancer or the risk of transfer.The kit of the present invention provides the biomarker LncRNA combinations of detection stomach cancer prognosis situation and detects the LncRNA included in the combination primer and related reagent, can effectively improve stomach cancer prognosis recurrence or the detection efficiency and accuracy rate of transfer.The present invention is avoided relatively low as susceptibility caused by tumor markers kit and specificity only with a kind of Testing index lncRNA and is caused the mistake of diagnosing gastric cancer to examine rate and the defects of rate of missed diagnosis greatly increases using the related lncRNA combinations of one group of prognosis transfer.
Description
Technical field
The invention belongs to biomedicine technical field, and in particular to the LncRNA of detection stomach cancer prognosis situation is combined and contained
The kit of the combination.
Background technology
Stomach cancer（GC）It is the malignant tumour that stomach lining glandular epithelium occurs, majority is gland cancer, is a kind of heterogeneous very high
Tumour, its clinical manifestation and Histological Study difference are huge.At present, one of most common malignant tumour is exactly in global range
Stomach cancer.In China, incidence gastric cancer population and dead population exceed 40% death rate in the whole world.Under the conditions of medical means intervention,
The recent and at a specified future date recovery of predictive disease or the degree of progress are extremely important for survival of patients or rehabilitation.Traditional stomach cancer prognosis
Forecasting Methodology is based on clinical case features such as patient age, tumor size, lymph node infiltration and histological grades, also including one
A little genetic marker, Serological markers and cytological markers etc. carry out the assessment of individual relapse and metastasis risk, but because these refer to
Target specificity and sensitiveness are each variant, are badly in need of better method to 5 years relapse and metastasis risks of patients with gastric cancer and auxiliaryization
Treat benefit to be predicted, make part early carcinoma of stomach patient, avoid the chemotherapy of pain.With RNA going out as tumor markers
It is existing, prompt during tumor development, RNA appears earlier than acceptor, albumen etc., and this diagnosis to tumour is particularly
It is important.
Tumor Heterogeneity includes the heterogeneity in time and space：The different zones of same tumour, the different trouble of same tumor
Different biological properties be present in person and the different treatment stages of same patient, tumour.Because malignant tumour heterogeneity is deposited
Make the tumour cell for occurring different subtype inside tumor tissues, cause high complexity of the tumour in evolution process and more
Sample, its difference can be such that patient is had differences to chemicals sensitiveness or to radiation sensitivity；In addition the leaching of tumour can also be made
Had differences in terms of profit and transfer, the speed of growth, invasive ability isophenous.The individual of tumour is often given in the presence of Tumor Heterogeneity
Change diagnosis and treatment brings great difficulty.Though the mechanism of Tumor Heterogeneity does not illustrate completely, genic instability institute
Role is then unquestionable.As study hotspot, it judges in the generation of tumour, development, transfer and prognosis etc. for genetic test
Aspect has certain advantage.Discovered in recent years, in the huge transcript profile of mammalian cell, there is a kind of length to be more than
200 nt, but do not have encoding proteins or the simply gene transcript of the very short polypeptide of coding, i.e. long-chain non-coding RNA
(Long noncoding RNA, LncRNA).Effects of the lncRNA in tumour at present, it is divided into the lncRNA of carcinogenesis
With the lncRNA of cancer suppressing action.They participate in multiple processes such as cycle, apoptosis, transfer and the sensitiveness to chemotherapy of tumour.
LncRNA equally has as the mark of diagnosing tumor and the potentiality of therapy target, for example, lncRNA DD3/PCA by
Prostate cancer nucleic acid amplification biomarker is developed into, it is higher than the specificity of serum PSA.
Tumour is an extremely complex entirety, and its heterogeneity is present to be brought to the Accurate Diagnosis of tumour and accurate treatment
Many problems： 1）According to single tumor specimen biopsy, because it does not represent monoblock tumour, have occurred and that and turn for tumour cell
For the patient of shifting, the tumor tissues at some position are only taken, the overall condition of patient can not be reacted；2）Tumor sample is taken
During material, pathologist often pays close attention to the worst tumor tissue, and then may missing inspection to most progressivity, aggressive region；3）By detecting
Label heterogeneous expression in tumour, judge then more likely to cause to understand disease progression with one or two single check mark things
It is not comprehensive.
The occurrence and development of lncRNA and stomach cancer have close relationship, and can be stabilized and be detected in the tissue
Survey, meet the requirement of clinical marker thing.It is 201610717476.6,201710328860.1 and in existing patent application number
In 201710069879.9, lncRNA as new tumor markers be used for tumour auxiliary diagnosis and Index for diagnosis index
Be reported, but they only with single lncRNA as diagnostic marker；In addition, also patent application
201510569987.3 are chosen serum/plasma lncRNA the mark MALAT1 and HOTAIR related to stomach cancer as diagnosis
Label, with the further investigation to Tumor Heterogeneity, above-mentioned several mistaken diagnosis that Tumor Heterogeneity can not have been avoided to bring,
Influence the judgement to the course of disease.Therefore, the present invention is to specific expressed in patients with gastric cancer cancerous tissue and cancer side or in blood samples of patients
15 LncRNA expression is detected, and establishes the diagnostic kit for distinguishing patients with gastric cancer prognosis mala.Can be from
Gene level is improved to stomach cancer prognosis curative effect and transfer, the degree of accuracy of recurrence prediction comprehensively.
In view of the diagnosis to stomach cancer at present and the incomplete present situation for the treatment of.The present invention detects biological marker on transcriptional level
The expression of thing, increase detection label, the mistaken diagnosis for avoiding Tumor Heterogeneity from bringing, has to stomach cancer Prognosis and treatment
Important Clinical significance of MG.
The content of the invention
It is an object of the invention to overcome above mentioned problem, there is provided one kind increase detection label, improve accuracy in detection, subtract
The LncRNA combinations of the detection stomach cancer prognosis situation of few misdiagnosis rate and the kit containing the combination.
To achieve the above object, the invention provides the LncRNA combinations of detection stomach cancer prognosis situation, including
LINC00261、FENDRR、GAS5、LET、LncRNA-ATB、NEAT1、HOTAIR、ANRIL、CCAT2、LINC00668、PVT1、
One or more in Sox2ot, TUG1, MALAT1, HIF1A-AS2 molecule.
Preferably, the LncRNA combinations：LncRNA-ATB、NEAT1、HOTAIR、ANRIL、CCAT2、LINC00668、
One or more up-regulated expression in PVT1, Sox2ot, TUG1, MALAT1, HIF1A-AS2 molecule, and differential expression is higher than ginseng
Examine scope, prompt lncRNA in stomach cancer in high expression and negatively correlated with the prognosis of patients with gastric cancer, height expression prompting patient's
Life cycle may be shorter, is the hazards of GC prognosis, illustrates patients with gastric cancer prognosis mala, may recurrence or transfer（It is shown in Table 3）.
Preferably, the LncRNA combinations：One or more expression in LINC00261, FENDRR, GAS5, LET molecule
Lower, and differential expression be less than term of reference, prompt lncRNA in stomach cancer in low expression and be in just with the prognosis of patients with gastric cancer
Correlation, the life cycle of low expression prompting patient may be shorter, is the hazards of GC prognosis, illustrates patients with gastric cancer prognosis mala,
May recurrence or transfer（It is shown in Table 3）.
The method for detecting stomach cancer prognosis situation, is comprised the steps of：
1）Determine the lncRNA expressions of unconventionality expression in vitro sample；
2）Compare in measured in vitro sample and whether there is with LncRNA molecules in the normal mucosa tissues of reference sample/pairing
Differential expression, differential expression have correlation with patients with gastric cancer prognosis recurrence or transfer.
Preferably, methods described uses PCR TRAPs.
Preferably, step 2）Described in differential expression Main Analysis object include Gender, the age, tumor locus,
Diameter of tumor, degree of tissue differentiation, tumor invasive depth, lymphatic metastasis, DISTANT METASTASES IN, TNM stage and 5 annual survival rates etc. face
Bed pathological characters（It is shown in Table 2）.
Preferably, the term of reference of the related lncRNA combinations of the patients with gastric cancer prognosis mala is shown in Table 5.
Preferably, described in vitro sample is stomach organization sample, blood/plasma excretion body, gastric juice etc..
For detecting the kit of stomach cancer prognosis situation, comprising for detecting lncRNA combination in the tissue or blood
The component of liquid/blood plasma excretion body, expression quantity height in gastric juice.
Preferably, the component includes RNA extraction systems, reverse transcription reagents and PCR amplifing reagents.
Preferably, the RNA extraction systems include lysate, RNA adsorption columns and RNA rinsing liquids.
Preferably, the reverse transcription reagents are 5 × iScript Reaction Mix, iScript Reverse
Transcriptase and DEPC water.
Preferably, the kit include specific amplification be used for detect the LINC00261, FENDRR, GAS5, LET,
LncRNA-ATB、NEAT1、HOTAIR、ANRIL、CCAT2、LINC00668、PVT1、Sox2ot、TUG1、MALAT1、HIF1A-
AS2 upstream and downstream primer sequence and internal reference GAPDH upstream and downstream primer sequence.
Preferably, after total serum IgE mixing of the kit also containing 80 stomach organization sample extractions, reverse transcription simultaneously dilutes
CDNA, the positive template as the feasibility for detecting the primer sets.
Preferably, the PCR amplifing reagents are 5 × FastStart Universal SYBR Green Master
And DEPC water (ROX).
The effect of giving warning in advance can be played to tumor recurrence or transfer by the differential expression for detecting lncRNA, clinician can
To judge reaction of the tumour to treatment, tumor recurrence risk is predicted, by monitoring in time, early detection, improves the existence of patient
Rate.
LncRNA combinational expressions change the relation with stomach cancer prognosis situation：
LINC00261 is proportionate in low expression and with the prognosis of Patients with Gastric Cancer in stomach cancer；LINC00261 is in Metastasis of Gastric Cancer disease
Downward rate is 80% in people；LINC00261 low expressions are expressed with tumor invasive depth, neoplasm staging is higher, lymphatic metastasis, TNM
It is by stages closely related, with patient age sex, knub position, tumor size, differentiation, DISTANT METASTASES IN relation unobvious；LncRNA
The life cycle of LINC00261 low expressions prompting patient may be shorter, is a hazards of GC prognosis, or Overall survival may
It is shorter.
GAS5 is proportionate in low expression and with the prognosis of Patients with Gastric Cancer in stomach cancer；GAS5 low expressions and invasive depth,
Lymph Node Metastasis is closely related, DISTANT METASTASES IN, TNM stage, tumor size are related, with patient age sex, knub position, histology
Classification, Lymph Node Metastasis relation unobvious；The life cycle of LncRNA GAS5 low expressions prompting patient may be shorter, is GC prognosis
One hazards.
LET is proportionate in low expression and with the prognosis of Patients with Gastric Cancer in stomach cancer；LET low expressions and invasive depth, leaching
Bar transfer, TNM stage, DISTANT METASTASES IN are significantly correlated, with patient age sex, tumor size, differentiation relation unobvious；LET is low
The life cycle of expression prompting patient may be shorter, is a hazards of GC prognosis.
FENDRR is proportionate in low expression and with the prognosis of Patients with Gastric Cancer in stomach cancer；FENDRR low expressions are deep with infiltration
Degree, Lymph Node Metastasis, TNM stage, regional lymphatics transfer are significantly correlated, with patient age sex, tumor size, knub position, group
Knit histological grading, DISTANT METASTASES IN relation unobvious；The life cycle of FENDRR low expressions prompting patient may be shorter, is the one of GC prognosis
Individual hazards.
LncRNA-ATB is in stomach cancer in high expression and negatively correlated with the prognosis of Patients with Gastric Cancer；The high expression of LncRNA-ATB
With vessel invasion, transfer is related, with patient age sex, tumor size, differentiation, invasive depth, DISTANT METASTASES IN relation unobvious；
The life cycle of the high expression prompting patients of LncRNA-ATB may be shorter, is a hazards of GC prognosis.
HIF1A-AS2 is in stomach cancer in high expression and negatively correlated with the prognosis of Patients with Gastric Cancer；The high expression of HIF1A-AS2 with
Invasive depth, Lymph Node Metastasis, TNM stage are significantly correlated, fail to understand with patient age, sex, histological grade, knub position relation
It is aobvious；The life cycle of the high expression prompting patients of HIF1A-AS2 may be shorter, is a hazards of GC prognosis.
NEAT1 is in stomach cancer in high expression and negatively correlated with the prognosis of Patients with Gastric Cancer；The high expression of NEAT1 turns with lymph
Move, clinical scale is significantly correlated, DISTANT METASTASES IN, histological grade are related, fail to understand with patient age, sex, invasive depth relation
It is aobvious；The life cycle of the high expression prompting patients of NEAT1 may be shorter, is a hazards of GC prognosis.
HOTAIR is in stomach cancer in high expression and negatively correlated with the prognosis of Patients with Gastric Cancer；The high expression of HOTAIR turns with peritonaeum
Move significantly correlated（Japan）, closed with patient age sex, tumor size, histological grade pathological grading, hepatic metastases, Lymph Node Metastasis
It is unobvious（Japan）；The high expression of HOTAIR and tumor size, differentiation degree are significantly correlated（China's Mainland）；The high expression of HOTAIR
Prompt the life cycle of patient may be shorter, be a hazards of GC prognosis.
ANRIL up-regulation rate ratios in Metastasis of Gastric Cancer patient are 77.5%；ANRIL is in stomach cancer in high expression and gastric cancer
The prognosis of people is negatively correlated；The high expression of ANRIL and tumor size, TNM stage is significantly correlated, with patient age, sex, histology
Classification, invasive depth, Lymph Node Metastasis, DISTANT METASTASES IN, relation unobvious；The life cycle of the high expression prompting patients of ANRIL may be compared with
It is short, it is a hazards of GC prognosis.
CCAT2 is in stomach cancer in high expression and negatively correlated with the prognosis of Patients with Gastric Cancer；The high expression of CCAT2 and Lymph Node Metastasis
Significantly correlated, DISTANT METASTASES IN is related, fails to understand with patient age, sex, tumor size, differentiation, TNM stage, invasive depth relation
It is aobvious；The life cycle of the high expression prompting patients of CCAT2 may be shorter, is a hazards of GC prognosis.
LINC00668 is in stomach cancer in high expression and negatively correlated with the prognosis of Patients with Gastric Cancer；The high expression of LINC00668 with
Invasive depth, TNM stage is significantly correlated, with patient age sex, histological grade, Lymph Node Metastasis relation unobvious；
The life cycle of the high expression prompting patients of LINC00668 may be shorter, is a hazards of GC prognosis.
PVT1 is in stomach cancer in high expression and negatively correlated with the prognosis of Patients with Gastric Cancer；The high expression of PVT1 and invasive depth,
TNM stage is significantly correlated, fails to understand with patient age sex, histological grade, Lymph Node Metastasis, DISTANT METASTASES IN, knub position relation
It is aobvious；The life cycle of the high expression prompting patients of PVT1 may be shorter, is a hazards of GC prognosis.
Sox2ot is in stomach cancer in high expression and negatively correlated with the prognosis of Patients with Gastric Cancer；The high expression of Sox2ot divides with clinical
Phase, Lymph Node Metastasis, DISTANT METASTASES IN, invasive depth are significantly correlated, with patient age, sex, histological grade relation unobvious；
The life cycle of the high expression prompting patients of Sox2ot may be shorter, is a hazards of GC prognosis.
TUG1 is in stomach cancer in high expression and negatively correlated with the prognosis of Patients with Gastric Cancer；TUG1 in Metastasis of Gastric Cancer patient on
Tune rate 85%；The high expression of TUG1 and invasive depth, TNM stage is significantly correlated, with patient age sex, histological grade, lymph
Transfer, DISTANT METASTASES IN, relation unobvious；The life cycle of the high expression prompting patients of TUG1 may be shorter, is a danger of GC prognosis
Dangerous factor.
MALAT1 is in stomach cancer in high expression and negatively correlated with the prognosis of Patients with Gastric Cancer；The high expression of MALAT1 turns with peritonaeum
Move significantly correlated and patient age sex, tumor size, histological grade, Lymph Node Metastasis relation unobvious（Japan）；MALAT1
The life cycle of height expression prompting patient is shorter, is a hazards of GC prognosis.
The beneficial effects of the invention are as follows：
(1) one group screened is verified in stomach organization and the LncRNA of normal mucosa tissues differential expression, sieve by RT-qPCR
The lncRNA combinations selected can assess the propagation and invasive ability of patients with gastric cancer cancer cell, further guiding clinical treatment.
(2) molecular marked compounds of one group of LncRNA as stomach cancer detection prognosis will be filtered out, prepares and determines by using fluorescence
Amount/digital pcr method carrys out the kit or biochip for stomach cancer prognosis detection, and gastric cancer tumor heterogeneity can be avoided to bring
Detection error, improve the accuracy of diagnosis.
(3) label for improving single is difficult to overcome as new stomach cancer prognostic markers thing using one group of LncRNA
Due to low difference caused by Tumor Heterogeneity and low sensitivity, Patients with Gastric Cancer prognosis effect appraisal can be effectively improved so as to refer to
Lead clinical therapeutic guideline.
(4) its detection be a series of stomach cancer mark of correlation things, can with it is single see also to combine see, it will help stomach cancer is pre-
The assessment of risk and the prediction of clinical prognosis recurred and shifted afterwards.
Brief description of the drawings
Fig. 1 is that fluorescence quantitative PCR method detects lncRNA in stomach organization and pairing normal mucosa tissues pair in embodiment 1
Schematic diagram is analyzed according to the different expression between product；
Fig. 2 is that fluorescence quantitative PCR method detects lncRNA in Plasma of Patient With Gastric Cancer and human normal plasma reference substance in embodiment 2
Different expression analyzes schematic diagram.
Embodiment
Acted on to evaluate LncRNA in the detection of stomach cancer prognosis situation, promote applications of the lncRNA in clinic, the present invention
Evidence is collected by the method for evidence-based medicine EBM, by retrieving Pubmed, Embase, Medline, middle National IP Network, Wanfang Database
Deng database, the clinical research that relevant lncRNA is used for the detection of stomach cancer prognosis situation, analysis lncRNA expression and stomach cancer are screened
Relation between prognosis situation.
Document quality assessment is carried out to the research included by nosgen standards.According to including and exclusion standard, from 2013
Year January in September, 2017 shares 15 comparative studies and finally included, and final will include document classified finishing, extract it is original effectively
Collected after data, selected article carries out data extraction（It is shown in Table 1）, including group by the cancer and cancer of 2137 patients with gastric cancer
Knit, evidence-based medicine EBM statistical analysis is carried out using Stata 12.0 to the data of extraction.
Having filtered out can indicate that the lncRNA combinations of stomach cancer prognosis recurrence or transfer include 15 lncRNA molecules at present,
Respectively LINC00261, FENDRR, GAS5, LET, LncRNA-ATB, NEAT1, HOTAIR, ANRIL, CCAT2,
LINC00668, PVT1, Sox2ot, TUG1, MALAT1, HIF1A-AS2 expression have differences.In patient tissue or blood sample
In, 4 lncRNA therein are likely to occur downward expression, are respectively：LINC00261、FENDRR、GAS5、LET；11
LncRNA is likely to occur up-regulated expression, is respectively：LncRNA-ATB、NEAT1、HOTAIR、ANRIL、CCAT2、LINC00668、
PVT1、Sox2ot、TUG1、MALAT1、HIF1A-AS2。
For stomach cancer prognosis situation detection lncRNA combination and kit makings LncRNA kits making with
Operating process is based on lncRNA RT-qPCR methods and RT-dPCR methods.Kit includes lncRNA primers（It is shown in Table 4）, RNA extraction examination
Agent（Tissue, blood/plasma excretion body, gastric juice）, RT reagents, PCR reagent and Healthy People cDNA reference substances.It can be used according to specific
Experimental method combination order and select, reagent is well known to those skilled in the art.This kit passes through qPCR methods and numeral
PCR methods detect lncRNA expression quantity, then by the difference aided assessment recurrence of gastric cancer or the risk of transfer, not only stablize, examine
It is convenient to survey, and quantitative accurate, greatly improves the Sensitivity and Specificity of disease detection, therefore this kit is put into and put into practice, can
To help to instruct clinic accurately to make diagnosis.
With reference to specific embodiment and accompanying drawing, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate
The present invention rather than limitation the scope of the present invention.The experimental method of unreceipted actual conditions in the following example, generally according to
Normal condition, or according to the condition proposed by manufacturer.DNA nucleic acid oligomers used in the present invention are synthesized by Shanghai life work,
Used RNA nucleic acid oligomers are synthesized by Shanghai Ji Ma bio tech ltd.
Embodiment 1.
With difference of the RT-qPCR technology for detection lncRNA combinations in the cancerous tissue of stomach cancer and the normal mucosa tissues of pairing
Expression：1. nucleic acid purification post extracts stomach organization and corresponding cancer beside organism total serum IgE
Pretreatment：The clear area of less RNase interference (all apparatus are wiped with 1 ‰ DEPC water), mortar needs 200 DEG C
Sterilizing 5h simultaneously cools down 4h.
2. Tissue Lysis：
1) in vitro stomach cancer cancerous tissue and cancer beside organism's sample about 20mg is weighed respectively to having had in the mortar of Liquid nitrogen precooler,
It is ground to powdered (yield for the RNA that grinding can then not have a strong impact on thoroughly) with grinding rod；2) 700 μ l are added
QIAzol lysates continue to be ground to the uniform liquid without obvious tissue block into mortar, are then transferred to no RNA enzymes
In 1.5ml eppendorf pipes；3) 4 DEG C of refrigerated centrifuge, 12000 rpm, centrifugation 10min are uncracked in solution to remove
Complete organization and cell fragment；4) the careful supernatant drawn after centrifugation, another new eppendorf pipes is moved to, are sure not to inhale
Remove confluent monolayer cells fragment residue precipitation；5) 140 μ l chloroforms are added, are turned upside down, acutely stand 2min after vibration；6) it is cold
Freeze the centrifugation of 4 DEG C of centrifuge, 12000rpm, 15min, and it is new without in RNase eppendorf pipes that supernatant liquor is transferred into one；
7) 1.5 times of absolute ethyl alcohols are added, is vortexed and mixes；3. RNA is adsorbed：1) all liq is fully transferred to adsorption column
In, and adsorption column is placed in 2ml collecting pipe, 8000 rpm centrifugation 15s, the filtrate abandoned in collecting pipe；2) take 700 μ l's
RWT solution 8000 rpm centrifugation 15s, abandons filtrate into adsorption column；4.RNA is washed and elution
1) take 500 μ l buffer RPE to be washed into adsorption column, 8000 rpm centrifugation 15s, abandon filtrate；
2) adsorption column is washed with 500 μ l buffer RPE again, 8000 rpm centrifugation 2min, abandons filtrate and underlying collection
Sleeve pipe；3) adsorption column is transferred in a new 2ml collecting pipe, centrifuges 1min at full speed；
4) underlying collection pipe is abandoned, adsorption column is moved into new 1.5ml eppendorf pipes, adds 45 μ lRNase-free
Water elutes adsorbed film, stands 1min, 8000 rpm centrifugations 1min；5) 1min is centrifuged at full speed again.5. total serum IgE
Quantitative and quality testing
1) content of stomach organization RNA samples is detected using Nanodrop 2000, is quantitative determined through OD values, to calculate
The volume of required RNA solution during LncRNA reverse transcriptions；
2) degraded through the qualitative detection exclusion and more serious RNA samples of DNA pollution, to ensure the specificity of subsequent experimental；
3) specific detection method is as follows：
Total serum IgE quantifies：260nm and 280nm OD values are determined on ultraviolet specrophotometer, and draw A260/A280, when it
Numerical value illustrates that the purity of total serum IgE is preferable between 1.8~2.0；When the salt ion and small molecule that have remnants less than 2.0 explanations
The pollution of magazine, when the degraded of more than the 2.0 possible total serum IgEs of explanation.The integrity detection of total serum IgE：1% denaturing formaldehyde fine jade
RRNA (rRNA) in sepharose electrophoretic separation total serum IgE, the brightness of two maximum band 28s RNA and 18s RNA
Substantially than for 2:When 1, illustrate that RNA integrality is preferable, do not occur signs of degradation.
6. the first chain cDNA synthesis：Reverse transcription reaction system is shown in Table 6.Sample after fully mixing it is short centrifugation make liquid extremely
First step reaction is carried out in ttom of pipe, PCR instrument, 65 DEG C of 5 min, 4 DEG C cool, 42 DEG C of 60 min, 70 DEG C of 15 min, 4 DEG C
Preserve.After first chain cDNA of synthesis takes out, -20 DEG C save backup for a long time.The synthesis of the chains of CDNA first：Without RNase
Following components is sequentially added in PCR pipe：
7.Q-PCR analyzes related LncRNA expression quantity
CDNA is detected：GAPDH genes do internal reference, enter performing PCR augmentation detection template quality, and reaction system is shown in Table 7.Q-PCR reacts
Detector is the CFX96 systems of Bio-Rad companies, and reaction condition is：94 DEG C of min of pre-degeneration 5,94 DEG C of 15 s of denaturation, 55 DEG C are moved back
30 s of fire, 72 DEG C of 30 s of extension, totally 40 circulations, solubility curve is between 65 ~ 95 DEG C.Q-PCR uses relative quantification method, gene
Expression analysis software is Bio-Rad CFX manager 2.0, and each sample in triplicate, utilizes 2−△△CtMethod is analyzed,
Reaction system is shown in Table 8.
8. testing result and conclusion
Testing result is shown in Table 8 and Fig. 1, compared with cancer beside organism, has LncRNA molecules differential expression occur in measured sample：
LncRNA-ATB, NEAT1, HOTAIR, ANRIL, CCAT2, LINC00668, PVT1, Sox2ot, TUG1, MALAT1 are upper mileometer adjustment
Reach, wherein LncRNA-ATB, HOTAIR, ANRIL, PVT1, Sox2ot, MALAT1 differential expression are higher than term of reference；
LINC00261, GAS5, LET express to lower, and wherein LINC00261, GAS5 differential expression are less than term of reference, this explanation
Patient's stomach cancer prognosis mala, it is understood that there may be recurrence or transfer.The result simultaneously prompt patients with gastric cancer progression free survival phase or
Overall survival may be shorter.
Embodiment 2. combines the difference table in the cleer and peaceful normal healthy controls of blood in patients with gastric carcinoma with RT-qPCR technology for detection lncRNA
Reach：
1. the serum RNA extractions present invention is comprised the following steps that using the kit extraction of centrifugation column type RNA rapid extractions：
1) 0.25ml serum is taken, 0.75ml lysate RLS is added, homogenised sample is acutely shaken to mixing, in 15-30 DEG C of condition
It is lower to be incubated 5 minutes so that proteosome decomposes completely；
2) 4 DEG C, 10min is centrifuged under conditions of 12000rpm, carefully takes supernatant to be transferred to new RNase free centrifugation
Guan Zhong；
3) 0.15ml chloroforms are added, cover tightly sample tube cover, 15s is acutely vibrated and it is incubated 3min at room temperature；
4) 10min is centrifuged under 4 DEG C, 12000rpm, sample can be divided into three layers：Lower floor is organic phase, and intermediate layer and upper strata are nothing
The aqueous phase of color, RNA are present in aqueous phase, and the capacity of aqueous layer is about the 60% of added lysate RLS volumes, and aqueous phase is shifted
Into new pipe, next step operation is carried out；
5) 1 times of ethanol of volume 70% of addition, overturn and mix (now it is possible that precipitation), obtained solution precipitates with possible
It is transferred to together in adsorption column RA (adsorption column is enclosed in collecting pipe)；
6) 10000 rpm centrifuge 45s, discard waste liquid, adsorption column is recovered into collecting pipe again；
7) add 500 μ l protein liquid removals RE, 12000rpm centrifugation 45s, discard waste liquid；
8) 700 μ l rinsing liquids RW, 12000rpm centrifugation 60s are added, discard waste liquid；
9) 500 μ l rinsing liquids RW, 12000rpm centrifugation 60s are added, discard waste liquid；
10) adsorption column RA is put back in sky collecting pipe, 12000rpm centrifugation 2min, removes rinsing liquid as far as possible, in order to avoid in rinsing liquid
Residual ethanol suppresses downstream reaction；
11) adsorption column RA is taken out, is put into a RNase free centrifuge tube, the middle part of adsorbed film adds 40 μ l RNase
Free water (are heated) in 65-70 DEG C of water-bath in advance, and room temperature places 2min, then centrifuges 1min under 12000rpm；
12) obtained solution is rejoined in centrifugal adsorbing column, centrifuges 1min, obtained RNA solution, which is placed in -80 DEG C, to be protected
Deposit standby.
2. the first chain cDNA synthesis：As described in Example 1.
3. Q-PCR analyzes related LncRNA differential expression：As described in Example 1.
4. testing result and conclusion
Testing result is shown in Table 9 and Fig. 2, compared with human normal plasma reference substance, has LncRNA molecules table occur in measured sample
Up to difference：NEAT1, HOTAIR, ANRIL, CCAT2, PVT1, Sox2ot, TUG1, MALAT1, HIF1A-AS2 are up-regulated expression,
Wherein NEAT1, HOTAIR, CCAT2, Sox2ot, MALAT1, HIF1A-AS2 differential expression are higher than term of reference；GAS5,
LET expresses to lower, and wherein GAS5 differential expression is less than term of reference, as a result illustrates patient's stomach cancer prognosis mala, may
Prompt the progression free survival phase of patients with gastric cancer or Overall survival may be shorter simultaneously in the presence of recurrence or transfer, the result.Remarks：Can
Can due to tumour-specific, be not detected by patients blood plasma's sample LINC00261, LncRNA-ATB, LINC00261,
FENDRR, LINC00668 are expressed.
Claims (10)
1. detect the LncRNA combinations of stomach cancer prognosis situation, it is characterised in that LncRNA combination include LINC00261,
FENDRR、GAS5、LET、LncRNA-ATB、NEAT1、HOTAIR、ANRIL、CCAT2、LINC00668、PVT1、Sox2ot、
One or more in TUG1, MALAT1, HIF1A-AS2 molecule.
2. the LncRNA combinations of stomach cancer prognosis situation are detected according to claim 1, it is characterised in that the LncRNA groups
Conjunction include LncRNA-ATB, NEAT1, HOTAIR, ANRIL, CCAT2, LINC00668, PVT1, Sox2ot, TUG1, MALAT1,
One or more in HIF1A-AS2 molecules.
3. the LncRNA combinations of stomach cancer prognosis situation are detected according to claim 1, it is characterised in that the LncRNA groups
Conjunction includes one or more in LINC00261, FENDRR, GAS5, LET molecule.
4. the kit for detecting stomach cancer prognosis situation, it is characterised in that the kit, which includes, is used for test right requirement 1
The component of expression quantity height of the lncRNA combinations in the tissue or in blood/plasma excretion body, gastric juice.
5. it is used for the kit for detecting stomach cancer prognosis situation according to claim 4, it is characterised in that the component includes
RNA extraction systems, reverse transcription reagents and PCR amplifing reagents.
6. it is used for the kit for detecting stomach cancer prognosis situation according to claim 5, it is characterised in that the RNA extractions system
System includes lysate, RNA adsorption columns and RNA rinsing liquids.
7. it is used for the kit for detecting stomach cancer prognosis situation according to claim 5, it is characterised in that the reverse transcription reagents
For 5 × iScript Reaction Mix, iScript Reverse Transcriptase and DEPC water.
8. it is used for the kit for detecting stomach cancer prognosis situation according to claim 4, it is characterised in that the kit includes
Specific amplification be used for test right require the 1 LINC00261, FENDRR, GAS5, LET, LncRNA-ATB, NEAT1,
HOTAIR, ANRIL, CCAT2, LINC00668, PVT1, Sox2ot, TUG1, MALAT1, HIF1A-AS2 upstream and downstream primer sequence
The upstream and downstream primer sequence of row and internal reference GAPDH.
9. it is used for the kit for detecting stomach cancer prognosis situation according to claim 4, it is characterised in that also containing 80 stomach cancers
After the total serum IgE mixing of tissue samples extraction, reverse transcription and the cDNA diluted, as the primer sequence described in test right requirement 8
The positive template of the feasibility of row.
10. it is used for the kit for detecting stomach cancer prognosis situation according to claim 5, it is characterised in that the PCR amplifications examination
Agent is 5 × FastStart Universal SYBR Green Master (ROX) and DEPC water.
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