CN107267606A - A kind of lncRNA and its application in lung cancer detection label or prognosis recurrence label is merged as breast cancer - Google Patents

A kind of lncRNA and its application in lung cancer detection label or prognosis recurrence label is merged as breast cancer Download PDF

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CN107267606A
CN107267606A CN201710450952.7A CN201710450952A CN107267606A CN 107267606 A CN107267606 A CN 107267606A CN 201710450952 A CN201710450952 A CN 201710450952A CN 107267606 A CN107267606 A CN 107267606A
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丁先锋
张玉涵
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Zhejiang Sci Tech University ZSTU
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Abstract

A kind of application the invention discloses lncRNA and its in lung cancer detection label or prognosis recurrence label is merged as breast cancer, the lncRNA is at least one of following nucleic acid molecules:(1) nucleic acid molecules of the cDNA sequence as shown in SEQ ID NO.1, SEQ ID NO.2 or SEQ ID NO.3;(2) nucleic acid molecules of the cDNA sequence as shown in SEQ ID NO.1, SEQ ID NO.2 or SEQ ID NO.3 have the nucleic acid molecules of 90% and above homology.The present invention filters out one group of lncRNA and merges the molecular marked compound of lung cancer as breast cancer, and prepared by relevant primer optimization into primed probe chip, sensitivity high the advantages of low with testing cost;The present invention is so that breast cancer merges this compound cancer of lung cancer as an example, the research blank for the domestic compound bio label lncRNA that takes the lead in having filled up.The present invention using one group of lncRNA as compound cancer relevant biomarkers thing, can effectively improve compound cancer clinical diagnosis and prognosis evaluation so as to guiding clinical treatment.

Description

A kind of lncRNA and its multiple merging lung cancer detection label or prognosis as breast cancer Send out the application in label
Technical field
The invention belongs to bio-medical technology field, and in particular to a kind of lncRNA and its be used as breast cancer merge lung cancer Detect the application in label or prognosis recurrence label.
Background technology
Breast cancer is the most common malignancy disease of women, and American Cancer Society's data statistics shows that the incidence of disease accounts for whole body The 29% of various malignant tumours, occupies first of the female malignant incidence of disease.Meanwhile, breast cancer is the multifactor height of a class Heterogeneous tumour, its Histological Study is varied, and the features such as easily shifting makes its prognosis poor.There is breast cancer incidence over year Increase year by year and tend to the trend of rejuvenation, statistics shows that patient with breast cancer's death rate occupies second in all malignant tumours, Breast cancer has turned into the major malignant tumor of serious threat women's health.
Lung cancer morbidity rate and case fatality rate sustainable growth, have become the incidence of disease and case fatality rate highest cancer in worldwide One of disease, because lung cancer early diagnoses difficulty and lacks effective therapeutic scheme, its 5 years survival rates only 15% or so, seriously Compromise the health of the mankind.With the development and the expansion of early screening of oncotherapy, the life cycle recent decades of tumor patient Significantly extend.Along with the generation of the knurl of mainly swelling again of risk of cancer, that is, the compound cancer of compound cancer.Compound cancer is With individual simultaneously or the different time occur two or more primary carcinoma, occur without temporal relation, lung is breast cancer Common metastasis site, patient with breast cancer's prognosis, which is shown, easily occurs Lung metastases.It is right with the research and development of biology and genetics The teiology of compound cancer, pathology, diagnosis and treat also pay attention to day by day how, but how to differentiate compound cancer and metastatic carcinoma often to facing Bed doctor brings certain puzzlement.Therefore, finding a kind of new reliable biomarker is used for the diagnosis that mammary gland merges lung cancer And Index for diagnosis, with potential scientific research value and potential applicability in clinical practice.
Long non-coding RNA (lncRNA) are that a class is located at the similar mRNA of its structure in nucleus or cytoplasm, Transcript length exceedes 200bp non-coding RNA.Originally research thinks that lncRNA is subgenomic transcription " noise ", is RNA The accessory substance of polymerase II transcription, without biological function.Increasing research evidence shows that lncRNAs can be widely Genome regulation is participated in, such as X chromosome silence, genomic imprinting and chromatin modification, transcriptional activation, transcription are disturbed, in core Transport etc., so that wide participation regulation and control individual grows and the vital movement such as Apoptosis, propagation, differentiation.It is substantial amounts of Research report proves that lncRNA plays an important role in the generating process of tumour, and it can both promote swollen as proto-oncogene The growth of knurl, can also suppress the propagation of tumour cell and migrate as tumor suppressor gene.In many development of cancer Along with lncRNA unconventionality expression.Along with the development of cancer gene group, study the molecular mechanism of cancer and explore its life Substance markers thing is one of focus of current cancer research.Current miRNA has obtained relatively broad recognizing as tumor markers Together, although however, lncRNA is still in the starting stage as the research of novel tumor markers, because they have type " more than three " feature more than many, binding mode and more than quantity, makes it show good application prospect in diagnosing tumor.
Substantial amounts of research in recent years has shown that lncRNAs plays an important role in many biological processes, lncRNAs's Unconventionality expression is also closely bound up related to the generation of many diseases.For the description lncRNA of system express spectra, characterization of molecules And more system editor and update these information, some database applications and give birth to.It is existing that LncRNAdb can help us to inquire about Some RNA titles, sequence etc., the database provide comprehensive annotation of the long-chain non-coding RNA of biological function, and with analysis Instrument, can be achieved database retrieval, information and collects and extract customizing messages.LncRNAdisease is lncRNA and disease association Database.Some researchs show the exception of transcription, expression, structure and the regulation and control of LncRNAs and its Binding proteins before this It is probably the major reason of many important diseases occurrence and development such as tumour, senile dementia, self-closing disease, LncRNADisease Detailed annotation has been done to the relation between long non-coding RNA and disease, researcher can have been allowed to be predicted according to bioinformatics tools New mankind's long non-coding RNA and the relation of disease.
Real-time fluorescence quantitative PCR reaction (real-time fluorescent quantitative PCR, qPCR) is logical The change for crossing the fluorescence signal intensity of fluorescent dye in PCR courses of reaction carrys out the expression quantity of real-time monitoring gene.Real-time fluorescence is determined It is a kind of quantitative PCR technique with revolutionary significance to measure reverse transcription polymerase chain (RT-qPCR), and it is used for into cancer LncRA quantitative study in disease tissue samples, with higher Sensitivity and Specificity.In the generation of human cancer with developing Cheng Zhong, the amplification of gene is a kind of common phenomenon, understands analysis oncogene amplification situation, contributes to cancer diagnosis, curative effect to see Examine and prognosis evaluation.
The content of the invention
The technical problem to be solved in the present invention is to provide a kind of lncRNA, unconventionality expression and breast cancer and the lung of the lncRNA The compound carcinogenesis of cancer is related, can be used as the compound cancer detection label or the compound cancer prognosis recurrence label.
In order to solve the above-mentioned technical problem, the technical scheme is that:
A kind of lncRNA, is at least one of following nucleic acid molecules:
(1) nucleic acid molecules of the cDNA sequence as shown in SEQ ID NO.1, SEQ ID NO.2 or SEQ ID NO.3;
(2) nucleic acid molecules of the cDNA sequence as shown in SEQ ID NO.1, SEQ ID NO.2 or SEQ ID NO.3 have 90% and the nucleic acid molecules of above homology.
Present invention discover that lncRNA is variant compared with by cancer in mammary gland merges patients with lung cancer breast cancer and cancerous lung tissue, and And comprehensive analysis PVT1 and breast cancer correlated clinical indexes ER, PR, HER2, p53 etc. have certain correlation.Many research cards Bright PVT1 is a kind of oncogene in the cancerous tissues such as breast cancer, lung cancer, but PVT1 goes out in compound cancer milk adenocarcinoma tissue Now substantially lower, therefore PVT1 can be used as important indicator during mammary gland merging lung cancer detection.By with the primary breast of pure Gland cancer and lung cancer are compared, the study find that SHG6 in simple primary lung cancer low expression and in compound breast cancer high table Reach, NEAT1 low expressions in simple primary lung cancer, the high expression in compound lung cancer, thus it is speculated that the mistake regulation and control of both genes The generation that mammary gland merges this disease of lung cancer may be result in.Therefore, these three lncRNA can merge lung cancer as breast cancer Detection label, as important auxiliary detection means.
Meanwhile, these three lncRNA various cancers by stages in there is also differential expression, be presented as PVT1 and SNHG6 I Phase is combined differential expression in breast cancer tissue, illustrates that they take part in the getting up early of breast cancer tissue generation, and PVT1 is multiple in III phase Close same low expression in cancerous tissue, thus it is speculated that PVT1 low expression slow down the deterioration of III primary breast cancer, also improve another original The possibility that hair property cancer occurs.It was I phase that breast cancer, which merges patients with lung cancer lung cancer, in this research, and NEAT1 height shows this Gene may take part in the early formation of lung cancer.Therefore these genes are also used as breast cancer and lung cancer in mammary gland merging lung cancer Clinical stages index, the auxiliary detection means as clinical stages.
Merge the clinical diagnosis of lung cancer as breast cancer present invention also offers above-mentioned lncRNA and the biological for the treatment of is marked Remember the application of thing.
Gene biological label of the present invention is that present invention also offers above-mentioned lncRNA conducts using two kinds of lncRNA chips Breast cancer merges the application in lung cancer for prognosis recurrence label.For example, PVT1 is low in ER+, PR-, p53+, HER2+++ tissues Expression, therefore these lncRNA can be used as the clinical auxiliary detection means for being combined breast cancer detection.
Preferably, the biomarker is respectively acting on breast cancer and cancerous lung tissue using primed probe chip Biomarker.
Present invention also offers a kind of chip for being used to detect above-mentioned lncRNA.
Present invention also offers a kind of kit for being used to detect above-mentioned lncRNA.
Preferably, the kit includes reverse transcription system and amplimer system.
Preferably, the reverse transcription system includes reverse transcriptase, reverse transcription system buffer solution and RNase inhibitor.
Preferably, the amplimer system is included in following (I) class, (II) class and (III) class at least One class, in addition to as (IV) class of reference gene, described (I) class, (II) class, (III) class and (IV) class are selected from Following upstream amplification primer:
(I) upstream amplification primer:SEQ ID NO.4;
(II) upstream amplification primer:SEQ ID NO.5;
(III) upstream amplification primer:SEQ ID NO.6;
(IV) upstream amplification primer:FP:SEQ ID NO.7;
Described (I) class, (II) class, (III) class and (IV) class are selected from following downstream amplification primer:
(I) downstream amplification primer:SEQ ID NO.8;
(II) downstream amplification primer:SEQ ID NO.9;
(III) downstream amplification primer:SEQ ID NO.10;
(IV) downstream amplification primer:RP::SEQ ID NO.11.
The expression of the lncRNA described in test agent and control group is detected using the reagent, and binding analysis is related Clinical indices can merge lung cancer with auxiliary judgment mammary gland and other types are combined whether there is for cancer.If be tested sample SNHG6 and NEAT1 relative comparison sample expression quantity is significantly improved, PVT1 relative reductions, then can tentatively judge to have and suffer from mammary gland merging lung The risk of cancer.
Be available for detection sample can be separation body fluid or corresponding site tissue samples, wherein body fluid can be serum, Blood plasma, tissue fluid saliva of buccal cavity or urine etc..
Present invention also offers the prognosis detecting system that a kind of Diagnosis of Breast cancer merges lung cancer, the detecting system includes above-mentioned Kit.
Present invention also offers the prognosis detecting system that a kind of Diagnosis of Breast cancer merges lung cancer, the detecting system includes above-mentioned Chip.
Compared with prior art, beneficial effects of the present invention are embodied in:
(1) present invention filters out one group of long non-coding RNA, and the RNA can merge the such compound cancer of lung cancer as breast cancer The biomarker that clinical diagnosis and outcome judge;
(2) present invention carries out screening breast cancer, lung cancer using bioinformatic database with the qRT-PCR methods being combined The lncRNAs of middle differential expression, operates more simple, more time saving, laborsaving, economy compared with high throughput sequencing technologies;Meanwhile, number It is bigger according to storehouse information content, it is more convenient the relation between cancer research person's exploration gene alteration and clinic, it is often more important that these numbers Patterned result can be provided according to storehouse, the cancer gene group data of complexity is more readily understood and is received, can allow researcher More fully directly obtain information;
(3) present invention filters out the molecular marked compound that one group of lncRNA merges lung cancer as breast cancer, and by relevant primer Optimization prepares primed probe chip, sensitivity high the advantages of low with testing cost;
(4) with the research and development of biology and genetics, to being combined the diagnosis of cancer and treating also pay attention to day by day, how area Not Fu He cancer and metastatic carcinoma very big puzzlement is also brought to clinician.The present invention using breast cancer merge this compound cancer of lung cancer as Example, the research blank for the domestic compound bio label lncRNA that takes the lead in having filled up.The present invention is using one group of lncRNA as compound Cancer relevant biomarkers thing, can effectively improve compound cancer clinical diagnosis and prognosis evaluation so as to guiding clinical treatment.
Brief description of the drawings
Figure 1A in the present invention in TCGA databases in breast cancer differential expression lncRNA;
Figure 1B in the present invention in TCGA databases in lung cancer differential expression lncRNA;
Expression feelings of the Fig. 2 for three lncRNA in the present invention in breast cancer merges lung cancer and simple primary breast cancer Condition;
Fig. 3 merges the differential expression in patients with lung cancer on different pathological index level for lncRNA in the present invention in breast cancer Analysis;
Fig. 4 is expression and the correlation of patient age of the lncRNA in breast cancer merges cancerous lung tissue in the present invention.
Embodiment
Embodiment 1 (lncRNAs of differential expression screening in breast cancer and lung cancer)
For the gene biological mark of the fully open present invention, gene biological mark of the invention described below is obtained The process of obtaining.
First, difference is carried out with the qRT-PCR technological means being combined by TCGA, lncRNAdb, lncRNAdisease The lncRNAs of expression screening.
(1) TCGA database websites (http://www.cbioportal.org/), breast cancer, cancerous lung tissue are selected Gene expression profile type mRNA Expression z-Scores (RNA Seq V2RSEM), generation result is ranked up, point Not Xuan Ze 4 higher lncRNAs PVT1 of science of heredity rate of change (mutation, copy number change and rna expression change) in mammary gland, Linc00467, SNHG6, linc0657, Expressions in Lung Cancer change four higher EXOC3-AS1, PVT1, linc00467, HCG18, respectively such as Figure 1A and Figure 1B.Screen poor in breast cancer and cancerous lung tissue respectively according to two, laboratory primed probe chip The lncRNA of different expression.
In its chips plate1 lncRNA screened from database lncRNAdb (http://www.lncrnadb.org),
Plate2 screened from lncRNAdisease (http://www.cuilab.cn/lncrnadisease)。
Above-mentioned two chips filter out the lncRNA AFAP1-AS1, aHIF, BDNF- of differential expression in breast cancer respectively The gene BANCR, kucg1, MALAT1, NEAT1 of differential expression in AS, HYMAI, UCA1, Kucg1, MALAT1, lung cancer.
(2) the paraffin sample tissue that the present invention is used is derived from Zhejiang Prov. Tumor Hospital receiving between 2010~2016 years The breast cancer tissue and corresponding cancer beside organism of 11 compound cancer patients for the treatment of, cancerous lung tissue and corresponding cancer beside organism, 7 Simple primary lung cancer and corresponding cancer beside organism, 7 simple primary breast cancers and corresponding cancer beside organism, and owned The extraction of paraffin sample total serum IgE, extraction step is with reference to life company AM1975 paraffin sample rna extracts kits RecoverAllTM Total Nucleic Acid isolation。
Secondly, the quantitative and quality testing of total serum IgE:
RNA content is detected using Nanodrop 2000, is quantitative determined through OD values, to calculate target gene reverse transcription When required RNA solution volume;The degraded and more serious RNA samples of DNA pollution are excluded through qualitative detection, to ensure The specificity of subsequent experimental.Specific detection method is as follows:
(a) total serum IgE is quantitative:260nm and 280nm OD values are determined on ultraviolet specrophotometer, and draw A260/ A280, when its numerical value illustrates that the purity of total serum IgE is preferable between 1.8~2.0;When less than 2.0 explanation have remnants salt ion and The pollution of small molecular weight impurity, when the degraded of more than the 2.0 possible total serum IgEs of explanation:
(b) integrity detection of total serum IgE:RRNA in 1% denaturing formaldehyde agarose gel electrophoresis separation total serum IgE (rRNA), the brightness of two maximum band 28s RNA and 18s RNA is substantially than for 2:When 1, illustrate that RNA integrality is preferable, Do not occur signs of degradation.
LncRNA profiler screen the lncRNA of breast cancer cancerous lung tissue differential expression respectively
Select respectively by 4 compound carninomatosis human breast carcinomas and cancer, the mixing of lung cancer and cancer beside organism's progress total serum IgE is carried out Plate1 and the ripe primer chips of plate2 two qRT-PCR screening verifications.The place of CT values is included according to the every result of experiment Reason, the integrated information such as 3D data and picture filters out the lncRNA of differential expression in 7 breast cancer:AFAP1-AS1, aHIF, The lncRNA of differential expression in BDNF-AS, HYMAI, UCA1, kucg1, MALAT1,4 lung cancer:BANCR, Kucg1, MALAT1, NEAT1.Specific method is as follows:
(a) synthesis of first chain of cDNA
Total serum IgE carries out reverse transcription reaction synthesis cDNA as template using in tissue respectively, is specifically reversed according to Nanjing Vazyme Record kit specification is operated.
(b) qPCR reacts
Use the special premixed liquid ChamQ of Vazyme dye methodTMSYBRqPCR Master Mix(High ROX Premixed the detection of expression quantity) is carried out to mixing breast cancer and cancerous lung tissue sample.To specifications, step is such as specific method Under:1 μ l reverse transcription products are taken, primer 1 μ l, RNase-free H in 5 μ l SYBR, plate1 or plate2 is added2The μ l of O 3, are mixed Vertical centrifugation, qPCR reactions are carried out in StepOne Plus after even, and reaction condition is:
Stage 1:Pre-degeneration, Reps:1,95 DEG C, 30s;
Stage 2:Circular response, Reps:40:95 DEG C, 10s;60 DEG C, 30s;
Stage 3:Melting curve, Reps:1:95 DEG C, 15s;60 DEG C, 60s;95 DEG C, 15s;
(c) processing and analysis of data
When quantitative fluorescent PCR quantitatively detects relative expression's variable quantity of gene, primed probe chip plate1 and plate2 In respectively have 6 reference genes that target gene is normalized, the expression quantity of six reference genes of parallel determination is helped In reducing quantitative error, six genes are respectively 5SRNA, ACTB, B2M, PGK1, GAPDH, HPRT1.Computational methods use ability The conventional RQ=2 in domain-△△Ct,
Δ Δ CT=Δs CT (cancer)-Δ CT (by cancer)
Δ CT (by cancer or cancer)=CT (gene)-CT (internal reference)
Embodiment 2 (lncRNA is in compound expression otherness between cancer and cancer beside organism)
This experiment carries out qRT-PCR in 11 compound cancer patient breast cancer and cancer beside organism, lung cancer and cancer beside organism, and Experimental data is analyzed, the relative change multiple of breast cancer tissue or cancerous lung tissue and sample by cancer is drawn, recycled SPSS statistics softwares carry out independent samples t test to all samples, and the lncRNA for analyzing above-mentioned screening suffers from 11 compound cancers Expression in each correspondence tissue of person.Analysis experimental data draws AFAP1-AS1, PVT1, and HYMAI is in compound cancer milk adenocarcinoma tissue Lower, MALAT1, SNHG6, UCA1 is raised in compound cancer milk adenocarcinoma tissue.The gene expressions such as BDNF-AS, linc00467 become Gesture is obvious or basic indifference;The PVT1 in compound cancer cancerous lung tissue, HCG18, EXOC3-AS1, NEAT1 up-regulated expressions are shown in Fig. 2.Concrete operation step is as follows:
(1) RNA reverse transcriptions:It is identical when agents useful for same is with lncRNA cDNA microarrays.The total serum IgE sample for taking 1 μ g to extract, plus Enter 1 μ l gene-specific primers (gene specific primers) (2 μM), 2 μ 5 × RT of l buffer solutions (Buffer), 0.5 μ l DNTP mixtures (10mM/ μ l), 0.5 μ l RNase inhibitor (40U/ μ l), 0.5 μ l M-MLV (H-) reverse transcriptase (200U/ μ L), DEPC water complements to 20 μ l, 42 DEG C of reactions 45min, 70 DEG C of reaction 15min after mixing.
(2) system that uses when qPCR is with above-mentioned lncRNA cDNA microarrays.Analysis result is also same as above.
GAPDH is selected to be reference gene when in the present invention to the checking of all samples of lncRNA progress of differential expression, it is fixed Three repetitions are set to test in amount, each sample is repeated 3 times in quantitative sample.The data that fluorescent quantitation is drawn carry out statistics credit Analysis, using SPSS17.0 statistical analysis softwares.Relative expression quantity analysis of the target gene in two samples uses levene ' S Chi-square Tests and independent-sample t are examined, as P value < 0.05, it is believed that result statistically has notable Sex differernce.As P value < 0.01, it is believed that result statistically has pole significant difference.Target gene is in different tumours The performance directly perceived that different expression is analyzed in patient tissue is realized by drawing the block diagram containing error line, using GraphPad Prism5 mapping softwares.
Embodiment 3 (mammary gland merges the screening and determination of lncRNA biomarkers in lung cancer)
This research filters out the lncRNA of differential expression in breast cancer and cancerous lung tissue respectively, and is verified.Candidate If lncRNA expression is different from simple primary breast cancer and lung cancer, it tentatively can merge the biological of lung cancer as breast cancer and mark Remember thing.Control finds SNHG6 height expression (RQ=2.2) in compound cancer milk gland cancer of low expression in the primary breast cancer of pure, The NEAT1 of low expression is high in compound cancer lung cancer in simple primary lung cancer expresses (see Fig. 2).Substantial amounts of research has shown that carcinogenophore Because of PVT1, the gene chip results of 2509 patient with breast cancers show in high expression, TCGA databases in breast cancer and cancerous lung tissue Show that gene magnification trend is presented in PVT1 in about 22% patient, and carcinogenesis is played in the generation evolution of breast cancer.Multiple Close PVT1 in cancer milk adenocarcinoma tissue and show obvious down regulation trend (RQ=0.4751, P=0.06).Illustrate in compound cancer milk gland cancer PVT1 low expression have impact on the deterioration of tumour in tissue, extend patient survival, occur newly primary while also increasing The probability of cancer.According to the compound cancer of the expression of these three genes diagnosis, clinically with potential application value.
Embodiment 4 (is used to analyze different expressions of the lncRNA in different clinicopathological parameters)
Table 1 is the pathological information that breast cancer merges cancerous lung tissue patient
Difference analysis masters of the lncRNA that the present invention is screened in breast cancer and cancer beside organism, lung cancer and cancer beside organism To be realized by following factor:
(1) different expression analyses of the lncRNA in compound breast cancer on hormone expression includes ERs sun Property (ER+) and estrogen receptor negative (ER-), the progesterone receptor positive (PR+) and progesterone receptor are negative (PR-);
(2) lncRNA is by HER2 positive (+++) and the compound mammary gland patient of HER2 feminine genders (HER2 ±) are relative to cancer Different expression;
(3) expressions of the lncRNA in p53 positive (p53+) and p53 negative (p53-) patient with breast cancer;
(4) different expressions of the lncRNA in compound breast cancer in different clinical pathology classifications;
(5) lncRNA is in the compound breast cancer and compound lung cancer of different ill age groups (≤median and > medians) Tumor tissues and the different expression of corresponding cancer beside organism.
As shown in figure 3, according to above evaluation index present invention discover that PVT1 is in ER+, PR+, p53+, HER2+++ tissues Low expression, SNHG6 illustrates that SNHG6 take part in the early stage generation of compound cancer milk gland cancer in the interim high expression of breast cancer I.Carcinogenophore Because of PVT1 in I phase, III primary breast cancer equal low expression, illustrate that early stage of breast cancer occurs PVT1 and late period deteriorates and has one Fixed inhibitory action, also patient survival extension, the major reason of how primary compound carcinogenesis.Therefore these are judged LncRNA can be used as the clinical auxiliary detection means for being combined breast cancer detection.
The ill age in patients with lung cancer sample information is merged according to breast cancer respectively, it is 56 to draw patient with breast cancer's median Year, patients with lung cancer median age is 57 years old, and table is being carried out more than median and less than or equal between two age groups of median Up to variance analysis.Present invention discover that some difference expression genes such as BDNF-AS, AFAP1-AS1, the kucg1 that are verified in breast cancer, PVT1, linc00467, SNHG6, HYMAI, which are more than in compound breast cancer in the difference in 56 years old patient with conspicuousness, lung cancer, to be selected The lncRNA gone out expression does not have correlation with the age, sees Fig. 4.
Embodiment 5 (is used for the real time fluorescent quantitative kit for detecting compound cancer lncRNA expression)
For detecting that breast cancer merges lung cancer biomarkers thing PVT1, SNHG6, NEAT1 qRT-PCR Kit components such as Under:
(1) the reverse transcription system of cDNA synthesis:Reaction system as above, including M-MLV (H-) reverse transcriptase (200U/ μ l) with And reverse transcription system buffer solution 5 × RT buffer solutions, dNTP mixtures (10nm each), gene specific Primers (2 μ M), RNase inhibitor (40U/ μ l).Gene-specific primer used is PVT1 wherein in process of reverse-transcription, SNHG6, NEAT1 this The reverse primer of three genes, i.e. downstream amplification primer.
(2) quantitative fluorescent PCR of the kit that the present embodiment is provided based on DNA dye methods, is built upon in embodiment 5 (1) the qPCR amplifications on the basis completed.
The amplimer system includes PVT1, SNHG6, at least one of NEAT1 amplimer and as interior Join the GAPDH of gene amplimer;Wherein foregoing amplimer accordingly includes as follows:
Upstream amplification primer:
PVT1:SEQ ID NO.4
SNHG6:SEQ ID NO.5
NEAT1:SEQ ID NO.6
GAPDH:FP:SEQ ID NO.7
Downstream amplification primer:
PVT1:SEQ ID NO.8
SNHG6:SEQ ID NO.9
NEAT1:SEQ ID NO.10
GAPDH:RP:SEQ ID NO.11
The method that compound cancer is detected using above-mentioned real time fluorescent quantitative kit:
The kit provided using the present embodiment, the application method of the fluorescence quantitative PCR detection based on DNA dye methods is such as Under:
Following sample is sequentially added in the new connecting legs of 0.2ml light reactions PCR eight without RNase,
Table 2
Brief centrifugation after mixing, is operated the computer, and response parameter is set to:
1) stage 1:95 DEG C, 5min;
2) stage 2:40 circular responses:95 DEG C, 10s, 60 DEG C, 30s;
3) stage 3:95 DEG C, 15s, 60 DEG C, 1min, 95 DEG C, 15s;
The value of this kit is the tumor tissues RNA sample by patient, and breast is detected using simple DNA dye methods The expression of gland cancer or lung cancer related gene, then various clinicopathological parameters are combined by the difference degree of the expression, Prognosis and risk of recurrence can be better understood by.Therefore the kit puts into production practice, to distinguish breast cancer merging lung cancer and Clinic auxiliary detection has important effect, if compound cancer can be diagnosed to be in time, patient just has the chance cured early stage, It is also the breakthrough of revolution for clinically.
Finally it should also be noted that the present invention provides new thinking for the research of long non-coding RNA in compound cancer and regarded Open country, case provided above be only the present invention several specific embodiments.Breast cancer merges lung cancer and belongs to the one of compound cancer Class, present invention is equally suited for other how primary compound cancers, also belongs to protection scope of the present invention.
SEQUENCE LISTING
<110>Institutes Of Technology Of Zhejiang
<120>A kind of lncRNA
And its application in lung cancer detection label or prognosis recurrence label is merged as breast cancer
<130>
<160> 11
<170> PatentIn version 3.3
<210> 1
<211> 1957
<212> DNA
<213>The mankind
<400> 1
ctccgggcag agcgcgtgtg gcggccgagc acatgggccc gcgggccggg cgggctcggg 60
gcggccggga cgaggagggg cgacgacgag ctgcgagcaa agatgtgccc cgggaccccc 120
ggcaccttcc agtggatttc cttgcggaaa ggatgttggc ggtccctgtg acctgtggag 180
acacggccag atctgccctc cagcctgatc ttttggccag aaggagatta aaaagatgcc 240
cctcaagatg gctgtgcctg tcagctgcat ggagcttcgt tcaagtattt tctgagcctg 300
atggatttac agtgatcttc agtggtctgg ggaataacgc tggtggaacc atgcactgga 360
atgacacacg cccggcacat ttcaggatac taaaagtggt tttaagggag gctgtggctg 420
aatgcctcat ggattcttac agcttggatg tccatggggg acgaaggact gcagctggct 480
gagagggttg agatctctgt ttacttagat ctctgccaac ttcctttggg tctccctatg 540
gaatgtaaga ccccgactct tcctggtgaa gcatctgatg cacgttccat ccggcgctca 600
gctgggcttg agctgaccat actccctgga gccttctccc gaggtgcgcg ggtgaccttg 660
gcacatacag ccatcatgat ggtactttaa gtggaggctg aatcatctcc cctttgagct 720
gcttggcacg tggctccctt ggtgttcccc ttttactgcc aggacactga gatttggaga 780
gagtctcact ctgtggtcca ggctgaagta cagtggcatg atcccaggtc actgcaaccc 840
ccacctcccg ggttcaagtg atcctcctgc ctcagcctcc cgagtagctg gtattacagg 900
cgtgtgccac aaagcctggc taagttttgt atttttagta gagacggggt ttcaccatgt 960
tggccaggtt ggtctcgaac tcctgacctc aagtgatcca ctcactttgg cctttcaacg 1020
tgctgggatt acaggcgaga gtcaccgcac ccggacgact ctgacatttt tgaagagtcc 1080
agaatcctgt tacacctggg atttaggcac tttcaatctg aaaaaataca tatcctttca 1140
gcactctgga cggacttgag aactgtcctt acgtgaccta aagctggagt attttgagat 1200
tggagaatta agagccagtc ttggtgctct gtgttcacct ggttcatctg aggagctgca 1260
tctaccctgc ccatgccata gatcctgccc tgtttgcttc tcctgttgct gctagtggac 1320
atgagaagga cagaataacg ggctcccaga ttcacaagcc ccaccaagag gatcacccca 1380
ggaacgcttg gaggctgagg agttcactga ggctactgca tcttgagact caggatgaag 1440
acccagcttg gggctgtcaa agaggcctga agaggcagaa caccccagag gagcctgggg 1500
ccaccaccca gcatcactgt gggaaaacgg cagcaggaaa tgtcctctcg cctgcgtgct 1560
ccacctcggt ccacgccttc cctccttctg gaagccttgc ctgaccactg gcctgcccct 1620
tctatgggaa tcactactga ccttgcagct tattatagac ttatatgttt tttgcatgtc 1680
tgacacccat gactccacct ggaccttatg gctccaccca gaagcaattc agcccaacag 1740
gaggacagct tcaacccatt acgatttcat ctctgcccca accactcagc agcaagcacc 1800
tgttacctgt ccacccccac cccttccccc aaactgcctt tgaaaaatcc ctaacctatg 1860
agctttgaat aagatgagta cgaacttcat cgcccacgtg gcgtggccgg cctcgtgtct 1920
attaaattct ttttctacta aaaaaaaaaa aaaaaaa 1957
<210> 2
<211> 472
<212> DNA
<213>The mankind
<400> 2
cctttcccgc gcgaccggcg agggaggaag aagcgcgaag agccgttagt catgccggtg 60
tggtggcggc ggcggagact gcgggcccgt agctgggctc tgcgaggtgc aagaaagcct 120
ttgaggtgaa ggtgtatgaa agtcatcata acagatgttt tccaaaaact tgtagaaggt 180
tgtgaaaaaa ctactaggat cacgcggcat gtattgagca tataggttgc tgtagatgaa 240
tgttcttagc tgtcatgttt aaaaatactt ctgcttcgtt acctcaagtg tggcatgcag 300
cattttggaa ggaaaattga agacgtgttc aagaaaacat gaacagaagc aaatgatgaa 360
aatgagcatt ttacttgatg ttgataacat cacaataaat tatggagaaa aatacatatt 420
tggctaactt ttaattgctg aacaataaag tgttttcttt taaatcaact ct 472
<210> 3
<211> 3756
<212> DNA
<213>The mankind
<400> 3
ggagttagcg acagggaggg atgcgcgcct gggtgtagtt gtgggggagg aagtggctag 60
ctcagggctt caggggacag acagggagag atgactgagt tagatgagac gagggggcgg 120
gctgggggtg cgagaaggaa gcttggcaag gagactaggt ctagggggac cacagtgggg 180
caggctgcat ggaaaatatc cgcagggtcc cccaggcaga acagccacgc tccaggccag 240
gctgtcccta ctgcctggtg gagggggaac ttgacctctg ggagggcgcc gctcttgcat 300
agctgagcga gcccgggtgc gctggtctgt gtggaaggag gaaggcaggg agaggtagaa 360
ggggtggagg agtcaggagg aataggccgc agcagccctg gaaatgatca ggaaggcagg 420
cagtgggtgc agggctgcag gagggccggg agggctaatc ttcaacttgt ccatgccagc 480
agcccctttt tttccagacc aagggctgtg aacccgcctg gggatgaggc ctggtcttgt 540
ggaactgaac ttagctcgac ggggctgacc gctctggccc agggtggtat gtaattttcg 600
ctcggcctgg gacggggccc aggccgggcc cagcctggtg gagcgtccag gtctgggtgc 660
gaagccaggc ccctgggcgg aggtgagggg tggtctgagg agtgatgtgg agttaaggcg 720
ccatcctcac cggtgactgg tgcggcacct agcatgtttg acaggcgggg actgcgaggc 780
acgctgctcg ggtgttgggg acaacattga ccaacgcttt attttccagg tggcagtgct 840
ccttttggac ttttctctag gtttggcgct aaactcttct tgtgagctca ctccacccct 900
tcttcctccc tttaacttat ccattcactt aaaacattac ctggtcatct ggtaagcccg 960
ggacagtaag ccgagtggct gttggagtcg gtattgttgg taatggtgga ggaagagagg 1020
ccttcccgct gaggctgggg tggggcggat cggtgttgct tgcctgcaga gagggtgggg 1080
agtgaatgtg cacccttggg tgggcctgca gccatccagc tgaaagttac aaaaatgctt 1140
catggaccgt ggtttgttac tatagtgttc ctcatggcga gcagatggaa ccgggagaca 1200
tggagtccct ggccagtgtg agtcctagca ttgcaggagg ggagaccctg gaggagagag 1260
cccgcctcaa ttgatgcctg cagattgaat ttccagaggc ttaggaggag gaagttctcc 1320
aatgttctgt ttccaggcct tgctcaggaa gccctgtatt caggaggcta ccatttaaag 1380
tttgcagatg agcttatggg gggcaatctt aaaaagtcca cagcagatgc atccggctcg 1440
aggggccatc agctttgaat aaatgcttgt tccagagccc atgaatgcca gcaggcaccc 1500
ctcctttcct ggggtaaagg ttttcagatg ctgcatcttc taaattgagc ctccggtcat 1560
actagttttg tgcttggaac cttgcttcaa gaagatccct aagctgtaga acattttaac 1620
gttgatgcca caacgcagat tgatgccttg tagatggagc ttgcagatgg agccccgtga 1680
cctctcacct acccacctgt ttgcctgcct tcttgtgcgt ttctcggaga agttcttagc 1740
ctgatgaaat aacttggggc gttgaagagc tgtttaattt taaatgcctt agactgggga 1800
tatattagag gaagcagatt gtcaaattaa gggtgtcatt gtgttgtgct aaacgctggg 1860
agggtacaag ttggtcattc ctaaatctgt gtgtgagaaa tggcaggtct agtttgggca 1920
ttgtgattgc attgcagatt actaggagaa gggaatggtg ggtacaccgg tagtgctctt 1980
ttgttcttgc ttcgtttttt taaacttgaa ctttacttcg ttagatttca taatactttc 2040
ttggcattct agtaagagga ccctgaggtg ggagttgtgg gggacgggga gaaggggaca 2100
gcttggcacc ggtcccgtgg gcgttgcagt gtgggggatg ggggtatgca gcttggcact 2160
ggtactggga gggatgaggg tgaagaaggg gagagggttg gttagagata cagtgtgggt 2220
ggtgggggtg gtaggaaatg caggttgaag ggaattctct ggggctttgg ggaatttagt 2280
gcgtgggtga gccaagaaaa tactaattaa taatagtaag ttgttagtgt tggttaagtt 2340
gttgcttgga agtgagaagt tgcttagaaa ctttccaaag tgcttagaac tttaagtgca 2400
aacagacaaa ctaacaaaca aaaattgttt tgctttgcta caaggtgggg aagactgaag 2460
aagtgttaac tgaaaacagg tgacacagag tcaccagttt tccgagaacc aaagggaggg 2520
gtgtgtgatg ccatctcaca ggcaggggaa atgtctttac cagcttcctc ctggtggcca 2580
agacagcctg tttcagaggg ttgttttgtt tggggtgtgg gtgttatcaa gtgaattagt 2640
cacttgaaag atgggcgtca gacttgcata cgcagcagat cagcatcctt cgctgcccct 2700
tagcaactta ggtggttgat ttgaaactgt gaaggtgtga ttttttcagg agctggaagt 2760
cttagaaaag ccttgtaaat gcctatattg tgggctttta acgtatttaa gggaccactt 2820
aagacgagat tagatgggct cttctggatt tgttcctcat ttgtcacagg tgtcttgtga 2880
ttgaaaatca tgagcgaagt gaaattgcat tgaatttcaa gggaatttag tatgtaaatc 2940
gtgccttaga aacacatctg ttgtcttttc tgtgtttggt cgatattaat aatggcaaaa 3000
tttttgccta tctagtatct tcaaattgta gtctttgtaa caaccaaata accttttgtg 3060
gtcactgtaa aattaatatt tggtagacag aatccatgta cctttgctaa ggttagaatg 3120
aataatttat tgtattttta atttgaatgt ttgtgctttt taaatgagcc aagactagag 3180
gggaaactat cacctaaaat cagtttggaa aacaagacct aaaaagggaa ggggatgggg 3240
attgtgggga gagagtgggc gaggtgcctt tactacatgt gtgatctgaa aaccctgctt 3300
ggttctgagc tgcgtctatt gaattggtaa agtaatacca atggcttttt atcatttcct 3360
tcttcccttt aagtttcact tgaaatttta aaaatcatgg ttatttttat cgttgggatc 3420
tttctgtctt ctgggttcca ttttttaaat gtttaaaaat atgttgacat ggtagttcag 3480
ttcttaacca atgacttggg gatgatgcaa acaattactg tcgttgggat ttagagtgta 3540
ttagtcacgc atgtatgggg aagtagtctc gggtatgctg ttgtgaaatt gaaactgtaa 3600
aagtagatgg ttgaaagtac tggtatgttg ctctgtatgg taagaactaa ttctgttacg 3660
tcatgtacat aattactaat cacttttctt cccctttaca gcacaaataa agtttgagtt 3720
ctaaactcat tagaaaaaaa aaaaaaaaaa aaaaaa 3756
<210> 4
<211> 20
<212> DNA
<213>It is artificial synthesized
<400> 4
tagatcctgc cctgtttgct 20
<210> 5
<211> 20
<212> DNA
<213>It is artificial synthesized
<400> 5
aggtgcaaga aagcctttga 20
<210> 6
<211> 20
<212> DNA
<213>It is artificial synthesized
<400> 6
tctgtgtgtc aaagcaaggc 20
<210> 7
<211> 19
<212> DNA
<213>It is artificial synthesized
<400> 7
aacggatttg gtcgtattg 19
<210> 8
<211> 20
<212> DNA
<213>It is artificial synthesized
<400> 8
cttcaggcct ctttgacagc 20
<210> 9
<211> 20
<212> DNA
<213>It is artificial synthesized
<400> 9
gcatgccaca cttgaggtaa 20
<210> 10
<211> 20
<212> DNA
<213>It is artificial synthesized
<400> 10
agatgccact gaatcaccca 20
<210> 11
<211> 19
<212> DNA
<213>It is artificial synthesized
<400> 11
ggaagatggt gatgggatt 19

Claims (10)

1. a kind of lncRNA, it is characterised in that at least one of following nucleic acid molecules:
(1) nucleic acid molecules of the cDNA sequence as shown in SEQ ID NO.1, SEQ ID NO.2 or SEQ ID NO.3;
(2) nucleic acid molecules of the cDNA sequence as shown in SEQ ID NO.1, SEQ ID NO.2 or SEQ ID NO.3 have 90% and The nucleic acid molecules of above homology.
2. lncRNA as claimed in claim 1 merges the biomarker of clinical diagnosis and the treatment of lung cancer as breast cancer Using.
3. lncRNA as claimed in claim 1 merges the application in lung cancer for prognosis recurrence label as breast cancer.
4. a kind of chip for being used to detect lncRNA as claimed in claim 1.
5. a kind of kit for being used to detect lncRNA as claimed in claim 1.
6. lncRNA as claimed in claim 5 kit, it is characterised in that the kit includes reverse transcription system and expansion Increase primer system.
7. lncRNA as claimed in claim 6 kit, it is characterised in that the reverse transcription system include reverse transcriptase, Reverse transcription system buffer solution and RNase inhibitor.
8. lncRNA as claimed in claim 6 kit, it is characterised in that the amplimer system includes following the (I) at least class in class, (II) class and (III) class, in addition to be used as (IV) class of reference gene, described (I) Class, (II) class, (III) class and (IV) class are selected from following upstream amplification primer:
(I) upstream amplification primer:SEQ ID NO.4;
(II) upstream amplification primer:SEQ ID NO.5;;
(III) upstream amplification primer:SEQ ID NO.6;
(IV) upstream amplification primer:FP:SEQ ID NO.7;
Described (I) class, (II) class, (III) class and (IV) class are selected from following downstream amplification primer:
(I) downstream amplification primer:SEQ ID NO.8;
(II) downstream amplification primer:SEQ ID NO.9;
(III) downstream amplification primer:SEQ ID NO.10;
(IV) downstream amplification primer:RP:SEQ ID NO.11.
9. a kind of Diagnosis of Breast cancer merges the prognosis detecting system of lung cancer, it is characterised in that the detecting system includes right such as will Seek the chip described in 4.
10. a kind of Diagnosis of Breast cancer merges the prognosis detecting system of lung cancer, it is characterised in that the detecting system includes right such as will Seek 5~8 any described chips.
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CN108034725A (en) * 2018-01-08 2018-05-15 北京泱深生物信息技术有限公司 Applications of the LINC02185 in breast cancer diagnosis and treatment
CN108949988A (en) * 2018-08-03 2018-12-07 武汉大学 A kind of application of long-chain non-coding RNA SNHG6 in breast cancer diagnosis or treatment
CN109371130A (en) * 2018-11-19 2019-02-22 北京大学深圳医院(北京大学深圳临床医学院) RIPOR3 is in preparation for the application in the biological products of breast cancer detection and treatment
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CN111139298A (en) * 2018-11-05 2020-05-12 王辉云 Application of 4-LncRNA molecular label in lung cancer prognosis evaluation
CN111378662A (en) * 2020-03-11 2020-07-07 潍坊医学院 Gene for inhibiting proliferation, invasion and transfer of breast cancer cells, expression vector and application
CN111424082A (en) * 2019-01-09 2020-07-17 上海中医药大学附属龙华医院 Application of lncRNA-SNHG6 gene in preparation of medicine for treating osteosarcoma
CN112725444A (en) * 2020-12-30 2021-04-30 杭州联川基因诊断技术有限公司 Primer, probe, kit and detection method for detecting PGR gene expression
CN113201534A (en) * 2020-05-29 2021-08-03 中山大学孙逸仙纪念医院 Long non-coding RNA BDNF-AS and application thereof AS marker and treatment target
CN113999846A (en) * 2019-02-28 2022-02-01 中山大学孙逸仙纪念医院 Interfering RNA for inhibiting AFAP1-AS1 expression and application of interfering RNA in increasing breast cancer radiotherapy sensitivity
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CN107746888B (en) * 2017-11-17 2019-01-08 青岛瑞思德生物科技有限公司 A kind of gene diagnosis kit shifted for diagnosing indication Her-2 overexpression type Bone of Breast Cancer
CN107746888A (en) * 2017-11-17 2018-03-02 李宜健 LncRNA compositions and the purposes for preparing the diagnosis indication overexpression type Bone of Breast Cancer transfering reagent boxes of Her 2
CN108034725A (en) * 2018-01-08 2018-05-15 北京泱深生物信息技术有限公司 Applications of the LINC02185 in breast cancer diagnosis and treatment
CN108949988A (en) * 2018-08-03 2018-12-07 武汉大学 A kind of application of long-chain non-coding RNA SNHG6 in breast cancer diagnosis or treatment
CN111139298A (en) * 2018-11-05 2020-05-12 王辉云 Application of 4-LncRNA molecular label in lung cancer prognosis evaluation
CN111139298B (en) * 2018-11-05 2023-04-11 中山大学肿瘤防治中心(中山大学附属肿瘤医院、中山大学肿瘤研究所) Application of 4-LncRNA molecular label in lung cancer prognosis evaluation
CN109371130B (en) * 2018-11-19 2021-08-13 北京大学深圳医院(北京大学深圳临床医学院) Application of RIPOR3 in preparation of biological products for breast cancer detection and treatment
CN109371130A (en) * 2018-11-19 2019-02-22 北京大学深圳医院(北京大学深圳临床医学院) RIPOR3 is in preparation for the application in the biological products of breast cancer detection and treatment
CN111424082A (en) * 2019-01-09 2020-07-17 上海中医药大学附属龙华医院 Application of lncRNA-SNHG6 gene in preparation of medicine for treating osteosarcoma
CN113999846A (en) * 2019-02-28 2022-02-01 中山大学孙逸仙纪念医院 Interfering RNA for inhibiting AFAP1-AS1 expression and application of interfering RNA in increasing breast cancer radiotherapy sensitivity
CN113999846B (en) * 2019-02-28 2023-06-09 中山大学孙逸仙纪念医院 Interference RNA for inhibiting AFAP1-AS1 expression and application thereof in increasing breast cancer radiotherapy sensitivity
CN110628913A (en) * 2019-04-15 2019-12-31 德阳市人民医院 lncRNA marker related to breast cancer
CN110592218A (en) * 2019-10-22 2019-12-20 德阳市人民医院 Biomarker for diagnosing and treating breast cancer
CN111378662A (en) * 2020-03-11 2020-07-07 潍坊医学院 Gene for inhibiting proliferation, invasion and transfer of breast cancer cells, expression vector and application
CN111378662B (en) * 2020-03-11 2022-04-01 潍坊医学院 Gene for inhibiting proliferation, invasion and transfer of breast cancer cells, expression vector and application
CN113201534A (en) * 2020-05-29 2021-08-03 中山大学孙逸仙纪念医院 Long non-coding RNA BDNF-AS and application thereof AS marker and treatment target
CN112725444A (en) * 2020-12-30 2021-04-30 杭州联川基因诊断技术有限公司 Primer, probe, kit and detection method for detecting PGR gene expression
CN116287277A (en) * 2023-04-24 2023-06-23 上海生物制品研究所有限责任公司 Biomarker of cytidine deaminase activity and application thereof

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