CN106929577A - A kind of lncRNA biomarker related to adenocarcinoma of lung - Google Patents
A kind of lncRNA biomarker related to adenocarcinoma of lung Download PDFInfo
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Abstract
The invention discloses a kind of lncRNA biomarker related to adenocarcinoma of lung, the mark is LOC105371720, and the present invention detects that checking LOC105371720 expresses downward in pulmonary adenocarcinoma by QPC.Further, the present invention proves that the expression of promotion LOC105371720 genes can promote the apoptosis of lung adenocarcinoma cell by biological experiment, suppresses the migration and invasion and attack of cancer cell.Based on this, LOC105371720 can apply to diagnosis and the targeted therapy of adenocarcinoma of lung as a kind of potential molecule.
Description
Technical field
The invention belongs to biomedicine field, it is related to a kind of lncRNA biomarker related to adenocarcinoma of lung, specifically
The lncRNA biomarkers are LOC105371720.
Background technology
Lung cancer is the first cause of tumour associated death.Lung cancer can be divided into non-small cell lung cancer (non-small cell
Lung cancer, NSCLC) and ED-SCLC (small cell lung cancer, SCLC) two major classes, wherein NSCLC accounts for
The 80-85% of total cases of lung cancer.Most of Patients with Non-small-cell Lung it is medical when to late period, operation is difficult to effect a radical cure, and postoperative
Easily recurrence.Radiation and chemotherapy is frequently as postoperative supplementary means, it is impossible to special killing tumor cell, while also producing larger
Toxic and side effect.Explore Treatment for Non-small Cell Lung new way, especially from gene level illustrate non-small cell lung cancer generation,
Development and Evolution Mechanism, the target spot for finding efficient gene treatment is the focus of Recent study.
The potential the Molecular Biology Mechanism research of non-small cell lung cancer and treatment are achieved compared with much progress, but non-small cell
Lung cancer overall survival phase or limited.Due to lacking sensitive diagnostic means, many patients have been late period when making a definite diagnosis, therefore wrong
Optimal therapic opportunity is crossed.Many Early stage NSCLC patients are after surgery it can also happen that metastases.For lung
The molecular targeted therapy of adenocarcinoma patients can significantly improve the survival rate of Patients with Non-small-cell Lung；However, still there is substantial amounts of trouble
Person is to failing to respond to any medical treatment.Thus, patient of the life cycle more than 5 years is no more than 20%.The relevant potential molecule machine of non-small cell lung cancer
System do not understand completely also, therefore, in order to early diagnose, early treatment so as to obtain more preferable prognosis, to non-small cell lung
Further research is particularly important for the generation development of cancer.
Tumorigenic Study on Molecular Mechanism was concentrated on protein coding gene in the past.As high flux transcript profile is sequenced
The development of technology, the transcript profile in researcher's discovery human genome more than 90% is non-coding RNA microRNAs therein
(miRNAs) it has been considered as being related to multiple bioprocess, including the malignant activity of lung cancer.With the miRNA related to lung cancer
Confirmed, people start to focus on another non-coding RNA i.e. long-chain non-coding RNA (long non-coding
RNAs,lncRNAs).Long-chain non-coding RNA length has no or only limited encoding histone energy more than 200 nucleotide units
Power.Different according to institute position in the cell, long-chain non-coding RNA has the function of adjusting chromatin and Gene regulation.To mesh
Before untill have more than 10000 a plurality of long-chain non-coding RNAs and be found, however, only being annotated less than 1%.Although long-chain is non-
Coding RNA potential function is still mysterious, some research find, they can adjust various cell processes, such as breed, cell growth and
Apoptosis.The unconventionality expression of long-chain non-coding RNA is closely related with the generation of tumour, and increasing evidence shows
LncRNAs participates in the mechanism that non-small cell lung cancer develops.The function of studying lncRNAs is the biology of non-small cell lung cancer
Research opens new approach, and provides new possibility to develop new more effective treatment.
The content of the invention
In order to make up the deficiencies in the prior art, adenocarcinoma of lung diagnosis and treatment are can be used for it is an object of the invention to provide a kind of
LncRNA biomarkers, lncRNA biomarkers provided by the present invention for human lung adenocarcinoma have sensitivity higher and
Specificity, can be used for the detection and treatment of adenocarcinoma of lung as new biomarkers.
To achieve these goals, the present invention is adopted the following technical scheme that：
The invention provides applications of the LOC105371720 in the product for preparing diagnosis adenocarcinoma of lung.
Further, the sequence of the LOC105371720 such as SEQ ID NO.1.
The invention provides applications of the above-mentioned LOC105371720 in the product for preparing diagnosis adenocarcinoma of lung.
Further, product recited above can by detect the expression of the LOC105371720 genes in sample come
Whether diagnosis patient suffers from adenocarcinoma of lung, and when the lower timing of LOC105371720 expression in sample, patient suffers from adenocarcinoma of lung or presence
Suffer from the risk of adenocarcinoma of lung.
Further, the product of the diagnosis adenocarcinoma of lung includes chip, preparation or kit.
Wherein, chip includes：Solid phase carrier；And the oligonucleotide probe on the solid phase carrier, institute are fixed in order
The oligonucleotide probe stated specifically corresponds to the part or all of sequence shown in LOC105371720；Kit includes core
Piece or specificity are directed to the primer of LOC105371720.
The invention provides a kind of chip, preparation or kit, it contains above-mentioned LOC105371720.
Further, the chip can be used to detect including the multiple genes including LOC105371720 genes (for example, and lung
The related multiple genes of gland cancer) expression；The kit can be used to detect including including LOC105371720 genes
The expression of multiple genes (for example, multiple genes related to adenocarcinoma of lung).
The answering in the product for preparing diagnosis adenocarcinoma of lung the invention provides chip recited above, preparation or kit
With.
The invention provides purposes of the above-mentioned LOC105371720 in human lung adenocarcinoma diagnosis and treatment medicine is screened.
The invention provides applications of the LOC105371720 in the pharmaceutical composition for preparing prevention or treatment adenocarcinoma of lung.
Further, described pharmaceutical composition includes LOC105371720 genes and/or the accelerator of its expression product.
The invention provides a kind of pharmaceutical composition for preventing or treating adenocarcinoma of lung, described pharmaceutical composition includes controlling
Treat accelerator described above effective dose.
Further, described pharmaceutical composition also includes and other medicine classes of the accelerator compatibility and pharmaceutically acceptable
Carrier and/or auxiliary material.
Medicine of the invention can also with the drug combination of other treatment adenocarcinoma of lung, other therapeutic compound can with it is main
Active component be administered simultaneously, or even be administered simultaneously in same composition.
Other treatments can also be individually given with single composition or the dosage form different from main active component
Property compound.The Fractional of main component can be administered simultaneously with other therapeutic compounds, and other dosage can be independent
Administration.Over the course for the treatment of, can be according to the physiologic response of the order of severity of symptom, the frequency of recurrence and therapeutic scheme, adjustment
The dosage of pharmaceutical composition of the present invention.
The advantages of the present invention：
Present invention firstly discovers that the differential expression of LOC105371720 is to the generation development of adenocarcinoma of lung related, by detection
The expression of LOC105371720 in subject's sample, it can be determined that whether subject suffers from adenocarcinoma of lung or the wind with adenocarcinoma of lung
Danger, so as to instruct clinician to provide prevention scheme or therapeutic scheme to subject.
LncRNA LOC105371720 are provided as potential molecular target, clinical diagnosis and treatment for adenocarcinoma of lung
New possibility.
The study mechanism for being found to be adenocarcinoma of lung of the invention provides theoretical foundation, and the personalization for patients with lung adenocarcinoma is controlled
Treat and provide new way.
Brief description of the drawings
Fig. 1 is the expression figure in pulmonary adenocarcinoma using QPCR detection LOC105371720 genes；
Fig. 2 is the transfected condition figure in lung adenocarcinoma cell using QPCR detections LOC105371720；
Fig. 3 is to detect the influence figure that LOC105371720 gene pairs lung adenocarcinoma cell is bred with CCK-8 methods；
Fig. 4 is with the influence figure of flow cytomery LOC105371720 gene pairs Apoptosis of Lung Adenocarcinoma Cell；
Fig. 5 is to detect the influence figure that LOC105371720 is migrated to lung adenocarcinoma cell；
Fig. 6 is to detect the influence figure that LOC105371720 is attacked to lung adenocarcinoma cell.
Specific embodiment
The present invention, by a large amount of screenings, is found that in adenocarcinoma of lung first by in-depth study extensively
LOC105371720 is presented specific low expression.It is demonstrated experimentally that putting down or expressing by the special expression for improving LOC105371720
The activity of product, can effectively suppress the growth and invasion and attack of lung adenocarcinoma cell, and the effect of adenocarcinoma of lung is suppressed so as to reach
Biomarker
Term " biomarker " is its expression in tissue or cell and normal or healthy cell or tissue
Expression compares any gene for changing.
It would be recognized by those skilled in the art that practicality of the invention is not limited to marker gene of the invention
The gene expression of any specific variants is quantified.Used as nonrestrictive example, marker gene can have SEQ ID NO.1
The nucleotide sequence specified.In some embodiments, it has and the same or analogous cDNA of listed sequence at least 85%
All sequences listed as described above at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% of sequence or at least
99% same or analogous cDNA sequence.
The present invention can determine gene expression using any method known in the art.Those skilled in the art should manage
Solution, the means for determining gene expression are not importances of the invention.The table of biomarker can be detected on transcriptional level
Up to level.
In some embodiments, the expression of biomarker is detected on transcriptional level.Using nucleic acid hybridization skill
Various methods that art carries out specific DNA and RNA measurements are well known by persons skilled in the art.Certain methods are related to electrophoretic separation
(for example, Southern traces and Northern traces for detecting RNA for detecting DNA), but can also be unfavorable
With the measurement (for example, by Dot blot) that DNA and RNA is carried out in the case of electrophoretic separation.Genomic DNA is (for example, come from
People) Southern traces can be used to screen RFLP (RFLP), to detect influence polypeptide of the present invention
The presence of inherited disorder.The RNA of form of ownership can be detected.
Chip
Described lncRNA chips of the invention include：Solid phase carrier；And be fixed in order on the solid phase carrier
Oligonucleotide probe, described oligonucleotide probe specifically corresponds to the part or all of sequence shown in LOC105371720
Row.
Specifically, suitable probe can be designed according to lncRNA of the present invention, is fixed on solid phase carrier, shape
Into " oligonucleotide arrays ".Described " oligonucleotide arrays " refer to (addressable i.e. with distinctive with addressable point
The position that address is characterized) array, a coupled characteristic oligonucleotides is contained in each addressable point.According to
Need, oligonucleotide arrays can be divided into multiple Asia battle arrays.
In the present invention, the solid phase carrier is including plastic products, microparticle, membrane carrier etc..The plastic products can lead to
Cross non-covalent or physical absorption mechanism to be combined with antibody or proteantigen, the most frequently used plastic products are made for polystyrene
Small test tube, globule and micro-reaction plate；The microparticle is the microballoon or particle aggregated into by high polymer monomer, and its diameter is generally
Micron, due to the functional group that can be combined with protein, easily forming chemical coupling with antibody (antigen), binding capacity is big；Institute
Stating membrane carrier includes nitrocellulose filter, glass fibre element film and miillpore filter etc. nylon membrane.
Term " probe " refers to the molecule that can be combined with the particular sequence of another molecule or subsequence or other parts.Unless another
Point out, term " probe " is often referred to be matched and another polynucleotides (often referred to as " target polynucleotide ") by complementary base
With reference to polynucleotide probes.Lack sufficient sequence complementarity according to the stringency of hybridization conditions, probe energy and with the probe
Target polynucleotide is combined.Probe can make direct or indirect mark, and its scope includes primer.Crossing system, including, but do not limit
In：Solution, solid phase, mixed phase or in situ hybridization determination method.
Term " complementation " or " complementarity " are used to refer to polynucleotides (that is, the nucleosides for passing through basepairing rule correlation
The sequence of acid).For example, sequence " 5'-A-G-T-3' " is complementary with sequence " 3'-T-C-A-5' ".Complementarity can be " part ",
The base of only few of which nucleic acid is matched according to basepairing rule.Or, can also exist between nucleic acid " complete " or
It is " total " complementary.Complementarity between nucleic acid chains has significant impact for the hybridization efficiency and intensity between nucleic acid chains.
It is even more important in the detection method of this combination between amplified reaction and dependence nucleic acid.
Term " stringency " is used to refer to the condition carried out residing for nucleic acid hybridization：Temperature, ionic strength and other compounds
The presence of (such as organic solvent).Under " low stringency condition ", nucleotide sequence of interest will with its exact complementary sequence, have
The sequence of single base mispairing, closely related sequence (for example, the sequence with 90% or more high homology) and only portion
Divide sequence (for example, the sequence with the 50-90% homologys) hybridization of homology.It is of interest under " medium stringent conditions "
Nucleotide sequence by only with its exact complementary sequence, the sequence with single base mispairing and closely related sequence (for example,
90% or more high homology) hybridization.Under " stringency high ", nucleotide sequence of interest will only and its exact complementary sequence
(depending on the condition of such as temperature) has the sequence hybridization of single base mispairing.In other words, under stringency high,
High-temperature can be risen to exclude and the sequence hybridization with single base mispairing.
Oligonucleotide probe in the present invention for LOC105371720 genes can be that DNA, RNA, DNA-RNA are fitted together to
Body, PNA or other derivatives.The length of the probe is not limited, as long as completing specific hybrid and purpose nucleotide sequence
Specific binding, any length can.The length of the probe can be as short as 25,20,15,13 or 10 bases longs.Equally,
The length of the probe can be grown to 60,80,100,150,300 base-pairs or longer, or even whole gene.Due to different spies
Pin length has different influences to hybridization efficiency, signal specificity, and the length of the probe is typically at least 14 base-pairs, most
Length is usually no more than 30 base-pairs, and complementary length is optimal with 15-25 base-pair with purpose nucleotide sequence.The probe
Self-complementary sequences are most preferably less than 4 base-pairs, in order to avoid influence hybridization efficiency.
Heretofore described solid phase carrier can be using the various common used materials in genetic chip field, such as but not limited to nylon
Film, the slide modified through active group (such as aldehyde radical, amino) or silicon chip, unmodified slide, plastic sheet etc..
Preparing for described LOC105371720 chips can be using the common manufacturing method of biochip known in the art.
For example, if solid phase carrier uses modification slide or silicon chip, 5 ' ends of probe are gone here and there containing amido modified poly- dT, can be by widow
Nucleotide probe is configured to solution, then uses point sample instrument by its point on modification slide or silicon chip, is arranged in predetermined sequence
Or array, then fixed by standing overnight, so that it may obtain lncRNA chips of the invention.
Kit
The invention provides a kind of kit, the kit can be used to detect the expression of LOC105371720.
Preferably, also containing the label for labeled RNA sample in described preparation or kit, and with the mark
The corresponding substrate of note thing.Additionally, be may also include in described kit required for extracting RNA, PCR, hybridization, colour developing etc.
Various reagents, including but not limited to：Extract, amplification liquid, hybridization solution, enzyme, comparison liquid, nitrite ion, washing lotion etc..Additionally, described
Kit in also include operation instructions and/or chip image analysis software.
Drug screening
The invention provides purposes of the LOC105371720 in human lung adenocarcinoma diagnosis and treatment medicine is screened.I.e.：Use candidate substances
The system for the treatment of expression LOC105371720；With the expression or activity for detecting LOC105371720 in the system；If the time
Selecting material can promote expression or the activity of LOC105371720, then show that the candidate substances are the potential materials for suppressing adenocarcinoma of lung.
The system of described expression LOC105371720 for example can be cell (or cell culture) system, and described cell can be
The cell of endogenous expression LOC105371720；Or can be the cell for recombinantly expressing LOC105371720.Described expression
The system of LOC105371720 can also be subcellular fraction system, solution system, organizational framework, organ systems or animal system (such as
The animal model of animal model, preferably non-human mammal, such as mouse, rabbit, sheep, monkey) etc..
The accelerator of LOC105371720 and pharmaceutical composition
Based on discovery of the invention, the invention provides a kind of pharmaceutical composition, described pharmaceutical composition is included
The accelerator of LOC105371720.
The accelerator of described LOC105371720 refers to any to improve LOC105371720 genes or expression product is steady
Expression that is qualitative, raising LOC105371720, the effective acting time for increasing lncRNA LOC105371720 or promotion
The material of the transcription of LOC105371720 genes, these materials are used equally to the present invention, used as raising LOC105371720
The useful material of expression of gene, so as to can be used for preventing or treat adenocarcinoma of lung.
Used as a kind of preferred embodiment of the invention, the accelerator of described LOC105371720 is that one kind contains
The expression vector of LOC105371720.Described expression vector generally also contains promoter, replication orgin and/or marker gene
Deng.
The expression vector that method well-known to those having ordinary skill in the art can be used for needed for building the present invention.These methods include
Recombinant DNA technology in vi, DNA synthetic technologys, In vivo recombination technology etc..Described expression vector preferably includes one or more
Selected marker, to provide the phenotypic character of the host cell for selecting conversion, such as kalamycin, gentamicin, tide
Mycin, amicillin resistance.
In the present invention, be various carriers known in the art, such as commercially available carrier, including plasmid, clay, bacteriophage,
Virus etc..Expression vector can be gathered to the importing in host cell using electroporation, calcium phosphate method, liposome method, DEAE Portugals
The known methods such as the combination of sugared method, microinjection, virus infection, liposome transfection and cell-membrane permeable peptide.
Term " host cell " includes prokaryotic and eukaryotic.The example of conventional prokaryotic host cell includes large intestine
Bacillus, hay bacillus etc..Conventional eukaryotic host cell includes yeast cells, insect cell and mammalian cell.It is preferred that
The host cell is eukaryotic, such as Chinese hamster ovary celI, COS cells.
Pharmaceutical composition
Pharmaceutical composition in the present invention include the accelerator of LOC105371720, and/or with the accelerator compatibility
Other medicine classes and pharmaceutically acceptable carrier and/or auxiliary material.
Pharmaceutically acceptable carrier can be that one kind can also be various, and the carrier includes but is not limited to diluent such as
Lactose, sodium chloride, glucose, urea, starch, water etc.；Adhesive such as starch, pregelatinized starch, dextrin, maltodextrin, sugarcane
Sugar, Arabic gum, gelatin, methylcellulose, carboxymethylcellulose calcium, ethyl cellulose, polyvinyl alcohol, polyethylene glycol, polyethylene
Than pyrrolidone, alginic acid and alginate, xanthans, hydroxypropyl cellulose and hydroxypropyl methyl cellulose etc.；Surfactant
Such as polyoxyethylene sorbitan fatty acid ester, lauryl sodium sulfate, glyceryl monostearate, hexadecanol；Humectant
Such as glycerine, starch；Absorption carrier such as starch, lactose, bentonite, silica gel, kaolin and soap clay etc.；Lubricant such as stearic acid
Zinc, glycerin monostearate, polyethylene glycol, talcum powder, calcium stearate and magnesium, polyethylene glycol, boric acid powder, hydrogenated vegetable oil,
Sodium stearyl fumarate, polyoxyl 40 stearate, single bay sucrose acid ester, sldium lauryl sulfate, magnesium laurylsulfate, 12
Alkylsurfuric acid magnesium etc.；Filler such as mannitol (granular or powdery), xylitol, sorbierite, maltose, erythrose, microcrystalline cellulose
Element, polymerization sugar, coupling sugar, glucose, lactose, sucrose, dextrin, starch, sodium alginate, laminarin powder, agar powder, carbon
Sour calcium and sodium acid carbonate etc.；Disintegrant such as cross-linked ethylene pyrrolidones, sodium carboxymethyl starch, low-substituted hydroxypropyl ylmethyl, crosslinking
Sodium carboxymethylcellulose, soybean polyoses etc..
Pharmaceutical composition in the present invention can also include stabilizer, bactericide, buffer, isotonic agent, chelating agent, pH controls
The additive such as preparation and surfactant.
Term " effective dose " can produce function or activity to people and/or animal and can be connect by people and/or animal
The amount received." pharmaceutically acceptable carrier " refers to the carrier for Therapeutic Administration, including various excipient and diluent.The art
Language refers to such some medicament carriers：Themselves it is not necessary active component, and does not have undue toxicity after administration.Properly
Carrier be well known to those of ordinary skill in the art.Pharmaceutically acceptable carrier can contain liquid in the composition, such as
Water, salt solution, buffer solution.In addition, there is likely to be complementary material in these carriers, such as filler, lubricant, glidant,
Wetting agent or emulsifying agent, pH buffer substance etc..Lipofectamine can also be contained in described carrier.
In the present invention, can using various methods well known in the art by described accelerator or its open gene or
Its pharmaceutical composition delivers medicine to mammal.Including but not limited to：Hypodermic injection, intramuscular injection, for percutaneous administration of, administer locally to,
Implantation, sustained release give；Preferably, the administering mode is that non-bowel gives.
Preferably, can be carried out using the means of gene therapy.Such as, directly the accelerator of LOC105371720 can be passed through
The methods such as injection deliver medicine to subject；Or, the promotion that can will carry LOC105371720 by certain approach is adjusted
Ceneme (such as expression vector or virus etc.) be delivered on target spot, concrete condition need to regard the type of described accelerator and
Fixed, these are well-known to those skilled in the art.
The effective dose of the accelerator of LOC105371720 of the present invention can be with the pattern and disease to be treated of administration
The order of severity etc. and change.The selection of preferred effective dose can come true by those of ordinary skill in the art according to various factors
Determine (such as by clinical test).Described factor is included but is not limited to：The medicine generation of the accelerator of described LOC105371720
Kinetic parameter such as bioavailability, metabolism, half-life period etc.；The order of severity of the disease to be treated of patient, the body of patient
Weight, the immune state of patient, approach of administration etc..For example, by an urgent demand for the treatment of situation, can daily give and separate several times
Dosage, or dosage is reduced pari passu.
Term " sample " is used with its broadest sense.In a kind of implication, it is intended that including originating what is obtained from any
Sample or culture, and biological and environmental samples.Biological specimen is available from animal (including people) and covers liquid, solid, group
Knit and gas.Biological specimen includes blood product, blood plasma, serum etc..However, such sample should not be construed as limitation being applicable
In sample type of the invention.
The present invention is further detailed explanation with reference to the accompanying drawings and examples.Following examples are merely to illustrate this
Invention rather than limitation the scope of the present invention.The experimental technique of unreceipted actual conditions in embodiment, generally according to conventional strip
Part, such as Sambrook et al., molecular cloning：Laboratory manual (New York:Cold Spring HarborLaboratory
Press, 1989) described in condition, or according to the condition proposed by manufacturer.
Embodiment 1 screens the gene marker related to adenocarcinoma of lung
1st, sample collection
It is each to collect 8 adenocarcinoma of lung cancer beside organisms and pulmonary adenocarcinoma sample.Adenocarcinoma of lung tumor tissues specimen sampling position is
Vital tumor areas, positioned at tumor mass China and foreign countries 1/3 and normal structure junction, exclude tumor center substantially necrosis, calcification portion
Divide and tumour periphery normal lung tissue；Ai Pang normal lung tissues sample takes from the position of more than borderline tumor 5cm, visually observes
Without significant change.The acquirement of above-mentioned all samples is by the agreement of the committee of organizational ethics.
2nd, the preparation of RNA sample (is utilizedMiRNA kit are operated)
Liquid nitrogen is imported in mortar, the tissue for taking above-mentioned acquisition is put into mortar, is shredded in liquid nitrogen and grind into powder,
Put into after shredding in liquid nitrogen and be ground to it is powdered, in then continuing at glass homogenizer；Tissue homogenate adds in glass homogenizer
Enter Trizol reagents, in tissue abrasion on ice.Tissue homogenate after homogenate is transferred in the EP pipes without RNase, is stood at room temperature
5min.Extracted according to the specification in kit and separate RNA.It is specific as follows：
1) separation of RNA：
0.2m1 chloroforms are added in EP pipes, EP lids are covered tightly, 15s is acutely vibrated manually, it is fully mixed.At room temperature
Hatching 5min.Then 15min is centrifuged with 14000g at 4 DEG C.Sample is divided into three layers after centrifugation, and RNA is present in upper strata aqueous phase.
2) RNA precipitate
The water that will be separate is mutually taken during 450 μ l move to the new EP pipes without RNase, according to 1:1 ratio adds 450 μ l different
Propyl alcohol, hatches 10min at room temperature after mixing of turning upside down, 4 DEG C of 14000g are centrifuged 10min.
3) RNA wash-outs
It is careful after centrifugation to remove supernatant, add the ethanol of 1ml 75% (destroy the enzyme treatment, matching while using and in precooling on ice) punching
RNA is washed, subsequent 4 DEG C of 7500g are centrifuged 5min.
4) RNA is redissolved
The careful supernatant removed after washing, opens EP pipe lids in superclean bench, and RNA samples are placed at room temperature
5-10min, dries.Add without RNase treatment water 20-50 μ l, water-bath 10min in 55-60 DEG C of water bath.
5) quality analysis of RNA sample
Spectrophotometer is detected：
NanoDrop1000 spectrophotometers detect RNA sample, the sample requirement of RNA-seq sequencings：OD260/OD280 is
1.8-2.2。
Agarose gel electrophoresis is detected：
The RNA of said extracted is entered into row agarose gel electrophoresis, Agilent Technologies
2100Bioanalyzer detects RNA sample quality, and observation 28S rRNA and 18S rRNA master tapes are obvious, complete without degraded, RNA
Sex index is qualified, concentration reaches requirement, can be used for the lncRNA express spectras of chip and screening experiment.
3rd, reverse transcription and mark
With Low RNA Input Linear Amplification Kit by mRNA reverse transcriptions into cDNA, while using Cy3
Difference labelling experiment group and control group.
4th, hybridize
Genetic chip uses Kang Cheng biology-Human lncRNA Array, carries out the step of by chip operation instructions miscellaneous
Hand over.
5th, data analysis
Chip results are analyzed using Agilent GeneSpring softwares, screening expression quantity has significant difference
(standard is that the lncRNA differs more than 2 times, and p with the expression quantity by cancer in cancer<0.05) lncRNA.
6th, result
Result shows that expression quantity of the LOC105371720 in pulmonary adenocarcinoma is substantially less than the expression in cancer beside organism
Amount.
The differential expression of the QPCR sequence verification LOC105371720 genes of embodiment 2
1st, large sample QPCR checkings are carried out to LOC105371720 gene differential expressions.Received according to the sample in embodiment 1
Mode set selects adenocarcinoma of lung cancer beside organism and each 50 of pulmonary adenocarcinoma.
2nd, RNA extraction steps are as described in Example 1.
3rd, reverse transcription
1) reaction system：
The μ l of RNA templates 1, the μ l of random primer 1, distilled water adds to 12 μ l, mixes, slow-speed of revolution centrifugation, 65 DEG C of 5min, Ran Houfang
In cooled on ice.
Continuation adds following ingredients in 12 μ l reaction solutions：
The μ l of 5 × reaction buffer 4, μ l, the AMV reverse transcriptions of 1 μ l, 10mM dNTP mixed liquors of RNase inhibitor (20U/ μ l) 2
The μ l of enzyme (200U/ μ l) 1；Fully mix and carry out centrifugal treating；
2) reverse transcription reaction condition
25 DEG C of 5min, 42 DEG C of 60min, 70 DEG C of 5min.
3) polymerase chain reaction
Design of primers：
According to LOC105371720 genes in Genebank and the sequences Design QPCR amplimers of GAPDH genes, by winning
Mai De biotech firms synthesize.Specific primer sequence is as follows：
LOC105371720 genes：
Forward primer is 5 '-ACGATAGGAAGTAGAAGAC-3 ' (SEQ ID NO.2)；
Reverse primer is 5 '-AGTTCCTCCAAGTACAAG-3 ' (SEQ ID NO.3).
GAPDH genes：
Forward primer is 5 '-AATCCCATCACCATCTTCCAG-3 ' (SEQ ID NO.4)；
Reverse primer is 5 '-GAGCCCCAGCCTTCTCCAT-3 ' (SEQ ID NO.5).
Prepare PCR reaction systems：
The μ l of 2 × qPCR mixed liquors 12.5, the μ l of gene primer 2.0, reverse transcription product 2.5 μ l, ddH2O 8.0μl。
PCR reaction conditions：95 DEG C of 10min, (95 DEG C of 15s, 60 DEG C of 60s) × 40 circulations, 60 DEG C of 5min extensions.75
DEG C to 95 DEG C, heated up 1 DEG C per 20s, draw solubility curve.Using SYBR Green as fluorescent marker, in Light Cycler
The enterprising performing PCR reaction of quantitative real time PCR Instrument, is analyzed by melt curve analysis and electrophoresis determines purpose band, and Δ Δ CT methods carry out phase
To quantitative.
5th, statistical method
Experiment is all completed according to being repeated 3 times, and result data is represented in the way of mean+SD,
Statistical analysis is carried out using SPSS18.0 statistical softwares, cancer is checked with the paired comparisons of cancer beside organism using t, it is believed that work as P<
There is statistical significance when 0.05.
6th, result
Result is as shown in figure 1, compared with adenocarcinoma of lung cancer beside organism, LOC105371720 is under expression in pulmonary adenocarcinoma
Adjust, difference has statistical significance (P<0.05) it is, consistent with chip detection result.
The LOC105371720 overexpression of embodiment 3
1st, cell culture
Human A459 lung cancer cell line, with the RPMI1640 culture mediums containing 10% hyclone and 1%P/S 37 DEG C, 5%
CO2, cultivate in the incubator that relative humidity is 90%.Change within 2-3 days liquid 1 time, use the 0.25% trypsase routine containing EDTA
Had digestive transfer culture.
Cell in blake bottle is digested and be seeded in 6 orifice plates with pancreatin, it is ensured that cell number is 2-8 × 105Individual/
Hole, adds cell culture medium.Overnight, second day observation of cell density, cell density can be transfected for more than 70%.
2nd, the structure of gene overexpression carrier
CDNA sequence (XR_947271.2.1, as shown in SEQ ID NO.1) synthesis according to LOC105371720 is special
Pcr amplification primer thing, two restriction enzyme sites of HindIII and XhoI are added in 5 ' end primers and 3 ' end primers respectively.With lung
, used as amplification template, above-mentioned cDNA sequence is through restriction enzyme for the cDNA that adenocarcinoma patients' blood is extracted and reverse transcription is obtained
It is inserted into after HindIII and XhoI double digestions in the eukaryotic expression vector pcDNA3.1 through HindIII and XhoI double digestions,
Connecting the recombinant vector pcDNA3.1-1 for obtaining is used for subsequent experimental.
3rd, transfect
Lung adenocarcinoma cell is divided into 3 groups, respectively control group (A549), blank control group (transfection pcDNA3.1-NC), reality
Test group (transfection pcDNA3.1-1).The transfection of carrier, specific transfection method finger to specifications are carried out using liposome 2000
Showing is carried out.The transfection concentrations of pcDNA3.1 empty carriers and pcDNA3.1-1 are 0.5 μ g/ml.
4th, QPCR detects the transcriptional level of LOC105371720 genes
The extraction of 4.1 cell total rnas
1) cell culture fluid in 6 orifice plates is outwelled, is rinsed twice with PBS, each hole adds 1ml Trizol reagents, room temperature
Place 5min.
2) 0.2m1 chloroforms are added, 15s, 4 DEG C, 12000g centrifugations 15min is acutely shaken.
3) water is mutually transferred in new pipe, adds 4.5m1 isopropanols, and room temperature places 10min；4 DEG C, 10000g centrifugations 10min.
4) liquid is outwelled, EP tube walls is washed with 75% ethanol of lml.4 DEG C, 7500g is centrifuged 5min.
5) 75% ethanol after cleaning is outwelled, room temperature hangs 5-10min.
6) DEPC water of the 25 μ l without RNase, -70 DEG C of preservations are added.
4.2 reverse transcription steps are with embodiment 2.
4.3QPCR amplification steps are with embodiment 2.
5th, statistical method
Experiment is all completed according to being repeated 3 times, and result data is represented in the way of mean+SD,
Statistical analysis, the difference between LOC105371720 gene overexpressions group and control group are carried out using SPSS18.0 statistical softwares
Different use t inspections, it is believed that work as P<There is statistical significance when 0.05.
6th, result
Result such as Fig. 2 shows, with non-transfection group compared with empty plasmid group is transfected, table is crossed in transfection LOC105371720 groups
Up to LOC105371720, difference has statistical significance (P<0.05).
The influence of the LOC105371720 gene pairs lung adenocarcinoma cell of embodiment 4 propagation
Influenceed using CCK-8 experiment detection LOC105371720 gene pairs lung adenocarcinoma cells multiplication capacities.
1st, cell culture and transfection procedure are with embodiment 3.
2nd, cell was taken out in second day, basis of microscopic observation cell growth status, 1ml/ holes add the pancreatin containing EDTA, enter
Row cell dissociation, removes pancreatin after the completion of waiting to digest, adding cell culture medium to mix makes cell suspend, and then carries out cytometer
Number.
3rd, concentration of cell suspension is diluted to 15000/ml, afterwards toward being inoculated with 96 orifice plates, cell is added per hole
The μ l of suspension 200, cell is controlled at 3000 or so, is inoculated with 8 multiple holes.PcDNA3.1-1 experimental groups and pcDNA3.1-NC are set
Control group.4 piece of 96 orifice plate is spread altogether is respectively used to 24h, 48h, 72h, 96h4 detection time point.
4th, after 24h, first piece of 96 orifice plate is taken out, adds the CCK-8 of 10 μ l to detect liquid in every hole, 96 orifice plates are continued to put
Enter and 4h or so is incubated in cell culture incubator, absorbance and record data of each hole at 450nm wavelength are detected with ELIASA.
5th, the operation in 4 is respectively repeated steps after 48h, 72h, 96h, the absorbance at each time point is finally counted,
Make growth curve chart.
6th, statistical analysis
Experiment is all completed according to being repeated 3 times, and statistical analysis is carried out using SPSS18.0 statistical softwares, both it
Between difference using t check, it is believed that work as P<There is statistical significance when 0.05.
7th, result
Result is as shown in figure 3, compared with the control, after pcDNA3.1-1 is transfected, the propagation of cell is substantially subject to experimental group
Suppress, difference has a statistical significance (P<0.05) explanation LOC105371720 has the effect for suppressing cell propagation.
The influence of the LOC105371720 gene pairs Apoptosis of Lung Adenocarcinoma Cell of embodiment 5
Use the influence of flow cytomery LOC105371720 gene pairs Apoptosis.
1st, cell culture step is with embodiment 3.
2nd, cell transfecting step is with embodiment 3.
3rd, step
1) by 10 × sample-loading buffers of 3m1 27m1 distilled water dilutings.
2) collection of cellular samples and with the PBS of precooling.
3) 1 × sample-loading buffers of lml, 300g centrifugation 10min is added to suction out buffer solution in cell.
4) 1 × sample-loading buffers of lml are added again, and cell concentration in cell suspension is adjusted to 1 × 106Individual/ml.
5) cell suspension is taken out into 100 μ l, in addition EP pipes.
6) by the Annexin V FITC addition EP pipes of 5 μ l, the liquid in EP pipes is mixed, lucifuge is incubated at room temperature
10min。
7) to 5 μ l PI dye liquors are added in EP pipes, lucifuge 5min at room temperature.
8) PBS solution of 500 μ l is added in EP pipes, is gently mixed, flow cytometer is detected in 1h.
3rd, statistical method
Experiment is all completed according to being repeated 3 times, and result data is represented in the way of mean+SD,
Statistical analysis is carried out using SPSS13.0 statistical softwares, the t inspections of difference use between the two, it is believed that work as P<When 0.05
With statistical significance.
4th, result：
As shown in figure 4, experimental group is compared with control group, apoptosis rate has significant change (P to result<0.05), should
Result illustrates that LOC105371720 has obvious influence on the apoptosis of lung adenocarcinoma cell.
The cell migration of embodiment 6 and Matrigel
1st, prepared by Transwell cells
Matrigel is ice bath melted under aseptic condition, and 20 times of dilutions are carried out with PBS, is layered on the volume in 50 μ l/ holes
On the polycarbonate membrane of Transwell cells.37 DEG C of placement 4h, take out after Matrigel glue aggregates into gel, gently suction out
Upper strata separates out liquid.The serum-free medium containing BSA of 50 μ l is added in per hole carries out hydration process, 37 DEG C of placements to basilar memebrane
30min。
2nd, cell suspension is configured
Cell removes serum starvation treatment 12-24h, and digestion process is carried out to cell, is centrifuged after terminating digestion, in removal
Layer nutrient solution.Sedimentation cell is cleaned with PBS, adds the serum free medium containing BSA to carry out it resuspended.Adjustment is thin
The density of born of the same parents is to 5 × l05Individual/ml.
3rd, cell inoculation
The μ l of obtained cell suspension 200 (migration experiment is 100 μ l, and Matrigel is 200 μ l) are added to Transwell cells
In.Room adds 1640 culture mediums of the 500 μ l containing FBS under 24 orifice plates.Cell is put into cell culture incubator and cultivates 24h.
4th, dye
Cell is dyeed after culture terminates using DAPI.Small ventricular cell is first rinsed 2 times with PBS, DAPI working solutions are put into
Middle room temperature dyes 5-20min.Rinsed 2 times with PBS, be put into fluorescence microscopy Microscopic observation and count.
5th, result
Result as shown in Figure 5 and Figure 6, after lung adenocarcinoma cell transfected plasmids, compared with control group, the migration of experimental group
And invasive ability is decreased obviously, as a result illustrate that LOC105371720 can suppress the migration and invasion and attack of adenocarcinoma of lung.
The explanation of above-described embodiment is only intended to understand the method for the present invention and its core concept.It should be pointed out that for this
For the those of ordinary skill in field, under the premise without departing from the principles of the invention, some improvement can also be carried out to the present invention
And modification, these are improved and modification will be also fallen into the protection domain of the claims in the present invention.
SEQUENCE LISTING
<110>Shandong Prov. Hospital Beijing Yang Shen biology information technologies Co., Ltd
<120>A kind of lncRNA biomarker related to adenocarcinoma of lung
<160> 5
<170> PatentIn version 3.5
<210> 1
<211> 494
<212> DNA
<213>People source
<400> 1
ctgaggcgga aaggagaggg ctctacctct ccccaagagg aggccaggaa cgataggaag 60
tagaagaccg aaaggaaata gcagtgacaa gtttgcagct ccagagaagc caccgcccct 120
tgtacttgga ggaactgacc cctgaaaact gtgcggccgg ttgggctgag cgtctagagg 180
gactgagctg gacaaccacg ggcaagcgag ggcagctccc agcgggtgga gtccgcgcgg 240
gattctggtg ccacctagac gccagggcgg ggaccgcaag gcaagggcaa cagaaaacgc 300
aaagtgtcct ttccaggagg gccaaaggag gggggcaggg acgctgggaa gaggcgccaa 360
agcggaggac ggctgcaggg gtgacttcag cgcttggcta ccaagaccag gtgtttctct 420
tcctcctgcc ctgggtacca tcccacagag aggccaggcc cacctgcagg tcctcacctc 480
cacagagcca gcct 494
<210> 2
<211> 19
<212> DNA
<213>Artificial sequence
<400> 2
acgataggaa gtagaagac 19
<210> 3
<211> 18
<212> DNA
<213>Artificial sequence
<400> 3
agttcctcca agtacaag 18
<210> 4
<211> 21
<212> DNA
<213>Artificial sequence
<400> 4
aatcccatca ccatcttcca g 21
<210> 5
<211> 19
<212> DNA
<213>Artificial sequence
<400> 5
gagccccagc cttctccat 19
Claims (10)
- Applications of the 1.LOC105371720 in the product for preparing diagnosis adenocarcinoma of lung.
- 2. application according to claim 1, it is characterised in that the sequence of the LOC105371720 such as SEQ ID NO.1.
- 3. application according to claim 1 and 2, it is characterised in that the product includes chip, preparation or kit.
- 4. a kind of chip, preparation or kit, it is characterised in that it contains the LOC105371720 described in claim 1.
- 5. application of the chip, preparation or kit described in claim 4 in the product for preparing diagnosis adenocarcinoma of lung.
- 6. the LOC105371720 described in claim 1 screen human lung adenocarcinoma diagnosis and treatment medicine in purposes.
- Applications of the 7.LOC105371720 in the pharmaceutical composition for preparing prevention or treatment adenocarcinoma of lung.
- 8. application according to claim 7, it is characterised in that described pharmaceutical composition includes LOC105371720 genes And/or the accelerator of its expression product.
- 9. a kind of pharmaceutical composition for preventing or treating adenocarcinoma of lung, it is characterised in that described pharmaceutical composition includes treatment Accelerator described in the claim 8 of effective dose.
- 10. pharmaceutical composition according to claim 9, it is characterised in that described pharmaceutical composition also includes and the rush Enter other medicine classes and pharmaceutically acceptable carrier and/or auxiliary material of agent compatibility.
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| CN107805663A (en) * | 2017-09-29 | 2018-03-16 | 中南大学 | Application of the Lnc03729 genes as biomarker in the pre- diagnostic reagent of adenocarcinoma of lung |
| CN107988375A (en) * | 2018-01-22 | 2018-05-04 | 中日友好医院 | Biomarker and its application for predication of chemotherapy effect and diagnosis |
| CN108085389A (en) * | 2017-12-29 | 2018-05-29 | 北京泱深生物信息技术有限公司 | A kind of and the relevant lncRNA of breast cancer and its application |
| CN110358834A (en) * | 2019-07-12 | 2019-10-22 | 深圳大学 | The application of lncRNA a kind of and kit and drug |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107805663A (en) * | 2017-09-29 | 2018-03-16 | 中南大学 | Application of the Lnc03729 genes as biomarker in the pre- diagnostic reagent of adenocarcinoma of lung |
| CN107805663B (en) * | 2017-09-29 | 2020-12-04 | 中南大学 | Application of Lnc03729 gene as biomarker in lung adenocarcinoma pre-diagnosis reagent |
| CN108085389A (en) * | 2017-12-29 | 2018-05-29 | 北京泱深生物信息技术有限公司 | A kind of and the relevant lncRNA of breast cancer and its application |
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| CN107988375A (en) * | 2018-01-22 | 2018-05-04 | 中日友好医院 | Biomarker and its application for predication of chemotherapy effect and diagnosis |
| CN110358834A (en) * | 2019-07-12 | 2019-10-22 | 深圳大学 | The application of lncRNA a kind of and kit and drug |
| CN110358834B (en) * | 2019-07-12 | 2023-05-16 | 深圳大学 | Application of lncRNA, kit and medicine |
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