CN106701986A - Application of molecular marker in diagnosis and treatment of gastric carcinoma - Google Patents
Application of molecular marker in diagnosis and treatment of gastric carcinoma Download PDFInfo
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Abstract
The invention discloses application of a molecular marker in diagnosis and treatment of gastric carcinoma and specifically high-specificity expression of IncRNA, namely ENSG00000228742, in gastric carcinoma tissues. The experiments prove that proliferation of gastric carcinoma cells can be effectively inhibited by specifically reducing the expression level of ENSG00000228742, the ENSG00000228742 can be prompted to serve as an auxiliary diagnostic indicator of early diagnosis of gastric carcinoma, and the expressed gene interfering ENSG00000228742 can become a novel target for treating the gastric carcinoma.
Description
Technical field
The invention belongs to biomedicine field, it is related to application of the molecular marker in stomach cancer diagnosis and treatment, specific described point
Sub- mark is ENSG00000228742.
Background technology
Stomach cancer is one of most common malignant tumour of alimentary canal, although in the range of world in recent years the incidence of disease of stomach cancer and
The death rate has declined, but still occupies the 2nd and the 3rd of malignant tumour respectively, and the Clinics and Practices of stomach cancer are still oncologist
The study hotspot of common concern.China is the country occurred frequently of stomach cancer, and the morbidity and mortality of China's stomach cancer occupy the world for a long time
Prostatitis.Stomach cancer can be divided into early carcinoma of stomach (early gastric cancer, EGC) and advanced gastric carcinoma (advanced
Gastric cancer, AGC), wherein early carcinoma of stomach refers to the stomach cancer for being confined to mucous layer and submucosa.Early carcinoma of stomach prognosis is good
Good, operability is less than 5%~10%, and 5 years survival rates are up to more than 90%, and 5 years survival rates of patients with advanced gastric cancer are still not enough
20%, therefore the early diagnosis of stomach cancer, early treatment play an important roll to improving patient's prognosis, reducing the death rate.
At present, the control strategy of national ND has turned to the prevention of active from passive treatment and early stage knows
Not, for stomach cancer, it is preferred that emphasis is the discovery of precancerous lesion and the identification of people at highest risk, while improving gastroscope to early carcinoma of stomach
And the recall rate of precancerous lesion.And the early diagnosis rate of China's stomach cancer has larger gap with advanced country, overall stomach cancer early diagnosis rate is low
In 10%, most patients with gastric cancer have been in progressive stage when making a definite diagnosis, and treat costly, and prognosis is not good, is national health thing
Industry brings larger burden, and letter need to be improved.
The difficult point of stomach cancer early diagnosis be early carcinoma of stomach patient most without specific clinical symptoms and sign, may only show
It is non-specific epigastric discomfort, and sensitiveness that the tumor markers such as conventional CEA, CA19-9 diagnose to early carcinoma of stomach and specifically
Property is relatively low.Therefore new biological targets are found for the canceration monitoring of stomach cancer and is intervened, prevent and treat urgently to be resolved hurrily as stomach cancer
Problem.
LncRNA be a class endogenous, fragment length more than the acid of 200 core former times, lack complete special ORFs and
RNA molecule without coded protein ability, it is most to be transcribed by rna plymerase ii and generated through variable sheer.LncRNA and tumour
In close relations, discovery has the expression of lncRNA and adjusts different in the kinds of tumors such as liver cancer, breast cancer, leukaemia and colon cancer
Often.Various lncRNA such as HEIR, HOTAIR, H19 and ANRIL have proto-oncogene or promote the function of metastases, and
The lncRNA such as MEG3 and PTCSC3 then have tumor suppressor gene function, above-mentioned it turns out that lncRNA is in tumorigenesis process
In be respectively provided with important function.The lncRNA related to the development of stomach carcinogenesis is found, preventing and treating and Mechanism Study for stomach cancer all have
There is important meaning.
The content of the invention
In order to make up the deficiencies in the prior art, the molecule mark of stomach cancer diagnosis and treatment is can be used for it is an object of the invention to provide a kind of
Will thing, molecular marker provided by the present invention is a kind of lncRNA, and mark up-regulated in patients with gastric cancer can conduct
Potential molecular target is used for the diagnosis and treatment of stomach cancer.
To achieve these goals, the present invention is adopted the following technical scheme that：
The invention provides the purposes of ENSG00000228742 genes, the medicine group for preparing prevention or treatment stomach cancer
Compound.
Further, described pharmaceutical composition includes the lower adjustment of ENSG00000228742.Wherein, described lower adjustment energy
The expression of ENSG00000228742 genes is lowered on gene level；The lower adjustment of the ENSG00000228742 is selected from：With
ENSG0000018480 genes or its transcript are target sequence and can suppress ENSG0000018480 gene expressions or gene turn
The disturbing molecule of record, including：ShRNA (children purpura nephritis), siRNA (siRNA), dsRNA, Microrna, antisensenucleic acids, or
Can expression or formation described shRNA, siRNA, Microrna, the construction of antisensenucleic acids.
Further, described lower adjustment is selected from the group the siRNA of sequence：SEQ ID NO.8、SEQ ID NO.9.
The invention provides a kind of lower adjustment for preventing or treating the ENSG00000228742 of stomach cancer, the downward
Agent is siRNA.
The invention provides a kind of pharmaceutical composition for preventing or treating stomach cancer, described pharmaceutical composition contains：
The lower adjustment of ENSG00000228742 recited above；With
Pharmaceutically acceptable carrier.
The invention provides a kind of purposes of ENSG00000228742 genes, for screening prevention or treating the latent of stomach cancer
In material.
The invention provides a kind of method of the potential material for screening prevention or treatment stomach cancer, methods described includes：
The system expressed or containing ENSG00000228742 genes is processed with candidate substances；With
Detect the expression of ENSG00000228742 genes in the system；
Wherein, if the candidate substances can reduce the expression of ENSG00000228742 genes or activity (preferably significantly drops
It is low, such as low by more than 20%, preferably low by more than 50%, more preferably low more than 80%), then show that the candidate substances are to prevent or control
Treat the potential material of stomach cancer.
Further, described system is included but is not limited to：Cell system, subcellular fraction system, solution system, organizer
System, organ systems or animal system.
The invention provides a kind of purposes of ENSG00000228742 genes, the product for preparing diagnosis of gastric cancer.
Further, the product includes chip, preparation or kit.
Further, the chip includes the probe of specific recognition ENSG00000228742；The kit includes special
Property amplification ENSG00000228742 primer or specific recognition ENSG00000228742 probe or chip.
Wherein, the chip can be used for detect including including ENSG00000228742 genes multiple genes (for example, with
The related multiple genes of stomach cancer) expression；The kit can be used to detect including including ENSG00000228742 genes
Multiple genes (for example, multiple genes related to stomach cancer) expression.
The advantages of the present invention：
Present invention firstly discovers that the differential expression of ENSG00000228742 is to the generation development of stomach cancer related, by inspection
Survey the expression of ENSG00000228742 in subject's sample, it can be determined that whether subject suffers from stomach cancer, so as to instruct clinical doctor
Teacher provides prevention scheme or therapeutic scheme to subject.
Present invention finds a kind of new molecular marker-ENSG00000228742 of stomach cancer, using molecular marker come
Prevention or treatment stomach cancer, it is more sensitive, special.
Brief description of the drawings
Fig. 1 is the expression figure in stomach organization using QPCR detection ENSG00000228742 genes；
Fig. 2 is the expression figure in stomach cancer cell using QPCR detections ENSG00000228742；
Fig. 3 detects ENSG00000228742 gene silencings to the gene expression dose in stomach cancer cell using QPCR
Influence figure；
Fig. 4 is the influence figure that ENSG00000228742 gene pairs proliferation of human gastric cancer cell is detected with MTS methods.
Specific embodiment
The present invention obtains the lncRNA related to stomach cancer by in-depth study extensively by lncRNA cDNA microarrays,
ENSG00000228742 is presented specificity overexpression in being found that stomach cancer first.It is demonstrated experimentally that by special reduction
The expression of ENSG00000228742, can effectively suppress the propagation of stomach cancer cell, point out detection
The expression of ENSG00000228742 genes can turn into one of auxiliary diagnostic index of early gastric caacer diagnosis, interference
ENSG00000228742 gene expressions can turn into the new way of curing gastric cancer.
Molecular marker
Term " molecular marker " 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.
Pharmaceutical composition
Discovery based on the present inventor, the invention provides a kind of purposes of ENSG00000228742 genes, for preparing
Prevention or the pharmaceutical composition for the treatment of stomach cancer.Under wherein ENSG00000228742 of the described pharmaceutical composition including effective dose
Adjust, and/or other medicine classes and pharmaceutically acceptable carrier and/or auxiliary material with the accelerator compatibility.
As used in the present invention, the lower adjustment of ENSG00000228742 includes but is not limited to inhibitor, blocking agent, nucleic acid
Mortifier etc., as long as the expression of ENSG00000228742 genes can be lowered on gene level.
Used as a kind of preferred embodiment of the invention, the lower adjustment of the ENSG00000228742 is a kind of
The specific siRNAs of ENSG00000228742.Described " siRNA " refers to a kind of short-movie section double stranded rna molecule,
Can be the target specific mRNA of degraded with the mRNA of homologous complementary sequence, this process is exactly RNA interference (RNA
Interference) process.SiRNA can be prepared into the form of double-strandednucleic acid, and it contains a positive-sense strand and one anti-
Adopted chain, this two chains only form double-strand under conditions of hybridization.One double-stranded RNA compound can be by the positive-sense strand that is separated from each other
Prepared with antisense strand.Therefore, for example, complementary positive-sense strand and antisense strand are chemical syntheses, thereafter can be by annealing
Hybridization, produces the double-stranded RNA compound of synthesis.
When effective siRNA sequence is screened, the present inventor compares analysis by substantial amounts of, optimal effective so as to find out
Fragment.The present inventor's design has synthesized various siRNA sequences, and they are entered by transfection reagent transfection gastric carcinoma cell lines respectively
Row checking, as a result detects 2 kinds of preferable disturbing molecules of interference effect, and they have SEQ ID NO.8, SEQ IDNO.9 respectively
Shown sequence, further tests in cellular level, as a result proves that suppression efficiency is very high for cell experiment.
Nucleic acid inhibitor of the invention such as siRNA can be with chemical synthesis, it is also possible to by a recombinant nucleic acid structure
Expression cassette is prepared after being transcribed into single stranded RNA.The nucleic acid inhibitors such as siRNA, can be by using appropriate transfection reagent quilt
It is transported to intracellular, or can be also transported to using multiple technologies known in the art intracellular.
Used as a kind of optional mode of the invention, the lower adjustment of described ENSG00000228742 can also be a kind of " small
Hairpin RNA ", it is the non-coding small RNA molecular that can form hairpin structure, children purpura nephritis can by RNA interference channels come
The expression of suppressor.As described above, shRNA can be expressed by the double-stranded DNA template of the transcript of coding needs.Coding needs
The double-stranded DNA template of transcript be inserted into a carrier, then such as plasmid or viral vectors are connected in vitro or in vivo
One promoter is expressed.ShRNA can be cut into siRNA molecule in the presence of DICER enzymes in eukaryotic,
Hence into RNAi approach." shRNA expression vectors " refers to the plasmid that some this areas are conventionally used for building shRNA structures, is led to
There is " intervening sequence " and the MCS positioned at " intervening sequence " both sides on the normal plasmid or for replacing sequence, so that people
Can by shRNA (or the like) corresponding DNA sequence dna inserts MCS or replacement by way of forward and reverse
Sequence is replaced in confession thereon, and the RNA after DNA sequence dna transcription can form shRNA (Short Hairpin) structure.Described
" shRNA expression vectors " can be bought by commercially available approach obtain at present completely, such as some viral vectors.
Expression vector can be various carriers known in the art, such as commercially available carrier, including plasmid, clay, bite
Thalline, virus etc..Expression vector can use electroporation, calcium phosphate method, liposome method, DEAE to the importing in host cell
The known methods such as the combination of glucan method, microinjection, virus infection, liposome transfection and cell-membrane permeable peptide.
Those skilled in the art can utilize expression vector of the well known method needed for the present invention is built.These methods
Including recombinant DNA technology in vi, DNA synthetic technologys, In vivo recombination technology etc..Described expression vector preferably comprising one or
Multiple selected markers, to provide the phenotypic character of the host cell for selecting conversion, such as kalamycin, celebrating is big mould
Element, hygromycin, amicillin resistance.
In the present invention, term " host cell " includes prokaryotic and eukaryotic.The example of conventional prokaryotic host cell
Attached bag includes Escherichia coli, hay bacillus etc..Conventional eukaryotic host cell includes that yeast cells, insect cell and mammal are thin
Born of the same parents.It is preferred that the host cell is eukaryotic, such as Chinese hamster ovary celI, COS cells.
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, can directly by the lower adjustment of ENSG00000228742
Subject is delivered medicine to by the method such as injecting；Or, ENSG00000228742 can will be carried by certain approach and lowered
The ceneme (such as expression vector or virus etc., or siRNA or shRNA) of agent is delivered on target spot, and concrete condition need to regard institute
Depending on the type of the lower adjustment stated, these are well-known to those skilled in the art.
The effective dose of the lower adjustment of ENSG00000228742 of the present invention can be with the pattern and disease to be treated of administration
Order of severity etc. of disease and change.The selection of preferred effective dose can by those of ordinary skill in the art according to various factors come
It is determined that (such as by clinical test).Described factor is included but is not limited to：The lower adjustment of described ENSG00000228742
Pharmacokinetic parameter such as bioavailability, metabolism, half-life period etc.；The order of severity, the patient of the disease to be treated of patient
Body weight, the immune state of patient, the approach etc. of administration.For example, by an urgent demand for the treatment of situation, can give daily several times
Separate dosage, or dosage is reduced pari passu.
Drug screening
The invention provides purposes of the ENSG00000228742 in human gastric cancer diagnosis and treatment medicine is screened.I.e.：Use candidate substances
The system for the treatment of expression ENSG00000228742；With the expression or activity for detecting ENSG00000228742 in the system；If
The candidate substances can lower expression or the activity of ENSG00000228742, then show that the candidate substances are to suppress diving for stomach cancer
In material.The system of described expression ENSG00000228742 for example can be cell (or cell culture) system, described
Cell can be the cell of endogenous expression ENSG00000228742；Or can be the thin of recombination expression ENSG00000228742
Born of the same parents.The system of described expression ENSG00000228742 can also be subcellular fraction system, solution system, organizational framework, organ body
System or animal system (such as animal model, the preferably animal model of non-human mammal, such as mouse, rabbit, sheep, monkey)) etc..
The expression of ENSG00000228742 genes in the system of test group is detected, and is compared with control group, wherein described
Control group is the system without the expression of the candidate substances or containing ENSG00000228742 genes；If in test group
The expression of ENSG00000228742 genes is statistically less than control group, indicates that the material prevents or treat stomach cancer
Potential material.
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 part or all of shown in ENSG00000228742
Sequence.
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.
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 ENSG00000228742 genes can be that DNA, RNA, DNA-RNA are embedding
Fit, PNA or other derivatives.The length of the probe is not limited, as long as completing specific hybrid and purpose nucleotides sequence
Row specific binding, any length can.The length of the probe can be as short as 25,20,15,13 or 10 bases longs.Together
Sample, the length of the probe can be grown to 60,80,100,150,300 base-pairs or longer, or even whole gene.Due to difference
Probe length have different influences to hybridization efficiency, signal specificity, the length of the probe is typically at least 14 bases
Right, most long to be usually no more than 30 base-pairs, complementary length is optimal with 15-25 base-pair with purpose nucleotide sequence.Institute
Probe self-complementary sequences most preferably less than 4 base-pairs are stated, 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 ENSG00000228742 chips can be using the conventionally fabricated side of biochip known in the art
Method.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
Oligonucleotide probe is configured to solution, then uses point sample instrument by its point on modification slide or silicon chip, be arranged in predetermined
Sequence or array, are 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 ENSG00000228742.
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.
Medicine in the present invention can also be with single composition or the dosage form different from main active component
Individually give other therapeutic compounds.The Fractional of main component can be administered simultaneously with other therapeutic compounds, and
Other dosage can be administered alone.Over the course for the treatment of, can be according to the order of severity of symptom, the frequency of recurrence and therapeutic scheme
Physiologic response, adjust the dosage of pharmaceutical composition of the present invention.
Medicine of the invention can also with the drug combination of other treatment stomach cancer, other therapeutic compound can with it is main
Active component is administered simultaneously, or even is administered simultaneously in same composition.
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 stomach cancer
1st, sample collection
8 stomach cancer cancer beside organisms are collected respectively and stomach organization sample all cases do not receive chemotherapy and put before surgery
Treat, all of patient informed consent, and obtain the agreement by the committee of organizational ethics.
2nd, the preparation of RNA sample (utilizes E.Z.N.A.Kit is operated)
1) clinical samples are taken out from -80 DEG C of ultra low temperature freezers, is placed in and is thawed on ice.About 20mg tissues are weighed to be positioned over
In 2mL centrifuge tubes, it is placed in and adds 1mL Trizol on ice.Fully homogenate will be organized to without solid using the automatic pulp grinder of hand-held
Body, is stored at room temperature 10min.
2) 13000rpm, 4 DEG C of centrifugation 10min.
3) with pipettor, carefully Aspirate supernatant is transferred in the l.5mL centrifuge tube of clean RNase-Free.
4) dichloromethane of 0.2mL is added, 15s is shaken with vortex mixer, be stored at room temperature 10min.
5) 3000rpm, 4 DEG C of centrifugation 10min.
6) carefully with pipettor extract water phase and it is transferred in the centrifuge tube of 1.5mL RNase-free.
7) add with step 6) medium volume isopropanol, with vortex mixer shake 4s to precipitate total serum IgE, be stored at room temperature
30min。
8) 13000rpm is centrifuged 10min at 4 DEG C, abandons supernatant.75% alcohol 1mL is added, is mixed again.13000rpm
10min is centrifuged at 4 DEG C, supernatant is abandoned.
9) it is placed in and dries 10min at room temperature, adds 12 μ L RNase-Free water dissolving RNAs and be positioned over standby on ice.
3rd, total serum IgE is quantified and purity analysis
OD value of the total serum IgE at 280nm and 260nm is determined using Bio-Red ultraviolet specrophotometers.The amount of RNA
By 1OD260nm- 40 μ g RNA are calculated, and work as OD260/OD280Value think at 1.8~2.0 the purity of total serum IgE be it is reliable, can
For the experiment of next step.
4th, lncRNA expression chips analysis
Stomach organization and cancer beside organism are detected using the Arraystar Human 1ncRNA Array of Arraystar companies
The difference of middle lncRNA express spectras.Arraystar 1ncRNA chips design probe is the oligonucleotides of 60nt length, these length
Oligonucleotide probe can obtain high sensitivity and specific gedanken experiment result under the strict hybridization conditions of height.For
Every sequence all devises a plurality of probe, increased the reliability of signal.
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 ENSG00000228742 in stomach organization is significantly higher than the expression in cancer beside organism
Amount.
The differential expression of embodiment 2QPCR sequence verification ENSG00000228742 genes
1st, large sample QPCR checkings are carried out to ENSG00000228742 gene differential expressions.According to the sample in embodiment 1
Collection mode selects stomach cancer cancer beside organism and each 50 of stomach organization.
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, 4 DEG C of insulation 60min.
3) polymerase chain reaction
Design of primers：
According to ENSG00000228742 genes in Genebank and the sequences Design QPCR amplimers of GAPDH genes, by
Shanghai bioengineering Co., Ltd synthesizes.Specific primer sequence is as follows：
ENSG00000228742 genes：
Forward primer is 5 '-CTCTTCAGCACAGAATCAG-3 ' (SEQ ID NO.2)；
Reverse primer is 5 '-ACTACAACCTACTCAATTACATT-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..
Using SYBR Green as fluorescent marker, in the enterprising performing PCR reaction of Light Cycler quantitative real time PCR Instruments, by melting
Tracing analysis and electrophoresis determine purpose band, and Δ Δ CT methods carry out relative quantification.
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
As shown in figure 1, compared with stomach cancer cancer beside organism, ENSG00000228742 is raised result in expression in gastric carcinoma,
Difference has statistical significance (P<0.05) it is, consistent with chip detection result.
Expressions of the embodiment 3ENSG00000228742 in stomach cancer cell
1st, cell culture
People immortalizes gastric epithelial cell system GES-1, SGC-7901 HGC-27, MGC-803, AGS and (is purchased from wide
Your bio tech ltd of state Rider) the RPMI1640 cultures containing 10% hyclone and 1%P/S based on 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, takes the cell in exponential phase for testing.
2nd, the extraction of RNA
Complete medium is discarded, with trypsin digestion cell is used after PBS 2 times, cell suspension is made and is added 2mL centrifuge tubes
In, 1200rpm centrifugation 8min add 1mL Trizol pipettors to blow and beat repeatedly more than 15 times after abandoning supernatant, make cell abundant
Cracking.Remaining operating procedure is with embodiment 1.
3rd, reverse transcription
Specific steps are with embodiment 2.
4th, 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, difference between the two is checked using t, it is believed that work as P<Have when 0.05
It is statistically significant.
5th, result
Result is as shown in Fig. 2 compared with gastric epithelial cell, ENSG00000228742 genes are in stomach cancer cell HGC-
27th, expressed in MGC-803, AGS and raised, difference has statistical significance (P<0.05) it is, consistent with RNA-sep results.
The silence of embodiment 4ENSG00000228742 genes
1st, cell culture step is with embodiment 3.
2nd, the design of siRNA
Negative control siRNA sequence (siRNA-NC)：
Positive-sense strand is 5 '-UUCUCCGAACGUGUCACGU-3 ' (SEQ ID NO.6)
Antisense strand is 5 '-ACGUGACACGUUCGGAGAA-3 ' (SEQ ID NO.7)
siRNA-1：
Positive-sense strand is 5 '-AAAUGGUUUAUAGUACAAGAU-3 ' (SEQ ID NO.8)
Antisense strand is 5 '-CUUGUACUAUAAACCAUUUGU-3 ' (SEQ ID NO.9)
siRNA-2：
Positive-sense strand is 5 '-UUUAGACUCCCAUUUGGAGAG-3 ' (SEQ ID NO.10)
Antisense strand is 5 '-CUCCAAAUGGGAGUCUAAAGG-3 ' (SEQ ID NO.11)
Cell is pressed 4 × 104/ hole is inoculated into six porocyte culture plates, in 37 DEG C, 5%CO2Cell culture in incubator
24h, in without DMEM culture mediums dual anti-, containing 10%FBS, transfection (is purchased from according to lipofectamine 2000
Invitrogen companies) specification transfection.
Experiment is divided into three groups：Control group (HGC-27), negative control group (siRNA-NC) and experimental group (siRNA1,
SiRNA2), with the sequence of ENSG00000228742 genes without homology, concentration is 20nM/ holes to wherein negative control group siRNA,
Transfected respectively simultaneously.
3rd, QPCR detects the transcriptional level of ENSG00000228742 genes
The extraction step of 3.1 cell total rnas is with embodiment 3.
3.2 reverse transcription steps are with embodiment 2.
3.3 QPCR amplification steps are with embodiment 2.
4th, 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, between ENSG00000228742 Gene Experiments group and control group
Difference is checked using t, it is believed that work as P<There is statistical significance when 0.05.
5th, result
Result such as Fig. 3 shows that compared with non-transfection group, transfection siRNA-NC groups, experimental group can be significantly reduced
The expression of ENSG00000228742 genes, difference has statistical significance (P<0.05).
The influence of embodiment 5ENSG00000228742 gene pairs proliferation of human gastric cancer cell
Using MTS experiment detection ENSG00000228742 gene pairs proliferation of human gastric cancer cell capacities.
1st, cell culture and transfection procedure are with embodiment 4.
2nd, re-suspended cell, counting after the cell of each group treatment digests through pancreatin, adjustment cell concentration is l × 105/ ml is pressed
The density in 100 μ L/ holes is inoculated in 96 orifice plates, i.e., be 1 × 10 per hole cell number4It is individual.
3rd, after cell reaches corresponding detection time point (0d, 24h, 48h, 72h, 96h), added by 10 μ L/ holes
Mono- Solution Cell Proliferation detection (MTS) reagents of CelITiter96AQ, micro oscillator vibrates 1~2min；It is placed in 5%CO2、37
DEG C cell culture incubator in be incubated 4h.
4th, ELIASA read plate, its absorbance (A) value is determined in 490nm wavelength.
5th, 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.
6th, result
Result is as shown in figure 4, compared with the control, after siRNA-1 is transfected, the propagation of cell substantially receives suppression to experimental group
System, difference has statistical significance (P<0.05), illustrate that ENSG00000228742 has the effect for promoting cell propagation.
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>Taishan Hospital
<120>Application of the molecular marker in stomach cancer diagnosis and treatment
<160> 11
<170> PatentIn version 3.5
<210> 1
<211> 3049
<212> DNA
<213>People source
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gaaatttggg tgcagacagg cacacaggga gaacaccatg tcaacacgaa ggcagaagtt 60
ggagtgatga gtctacaagc caaggattgc cagcaattca tcagaggcca ggacagcagc 120
ctggggcagc cccctacatg gtaccaactc catcaacacc ttgatctcag acttccaacc 180
tccagaactg tccagccctc catgaatgag gaacttcctg gggccactag tgcatgctgc 240
agctcacaca gtcaactcca tccacacctc cacaaacagc tgccctttgg ccactactca 300
ggcgtaagga cacacccagc agggtatgcc ctctggaggt cagaccaggg aagaagccct 360
tgcacagtca ggagccagct cagcacctgt gatgctgaat tctatgtggc aacttgactg 420
gacgcaggtg ctcggattaa acctgatttc tgggtatgtc tgtgagggta tttccagagg 480
agattagaat ttgaatccgt ggattggcaa agttggtgtc tgccccagtg tgggtggtca 540
ccatctactc tcctgagggc ctgaagagaa caaaaggcaa aggaaggagg aattcgccct 600
taacttgctt gccgcctgcc tgcttgagca gagacatttc atcacatctt ctctggccct 660
cgactgagat tcacaccatt ggcttccctg gttctcaggc attttgactt ggactgaact 720
acaccattgg ctttcctggg ctccagcttg cacatagcag attgtgggat ttctcagcct 780
ctattattac aggcgccagt tcttcaaaat caacctctct ctctctgtct ctctctctct 840
ccctagatca cagtctggaa gtctgctcac agtctcaagg ttggcatatc ccctagagcc 900
cccagactcc tcatcccatg gagaccaaca tggccagggg agggccagag cagggccttc 960
taaatcacag accccagggc aggagcccct ccggtctgga tctaaggatg gtattttcaa 1020
caattcctaa atttttatcc taggctctcc aaatgggagt ctaaaggtct caaaacatgg 1080
tccagaagaa gtatgcaaaa atgtaaattc ctaggcccca acccagacct atgaatcaga 1140
tgatctgtat gggggttcaa ggaatctata ttattaaaca atcttcctaa atgacttgta 1200
ttcatactaa agcttgagaa ttgctatcaa acagctagaa gttggagtga agggtcctgc 1260
ctttcccatg aaattcatca actctatgcc ctcaaaagct gggctcttgg atgagctgct 1320
ctccattcta gagacattac cagctaggta gcctgctggt cctcaggaag ttaagcccag 1380
actcttcagc acagaatcag ataaacactg attacattgt actctacagt tctgagaaca 1440
ccattactta attcccggca agttgcaatg taattgagta ggttgtagtt ttttgggttt 1500
ggggtttttt tgttttttaa atatatcagg cgtagttagc cagcttccta gaaacaccat 1560
gatctcttgg tgaaaattcc agaaatatgc atcacttcct aattaaagta gggaattttt 1620
aaaaattatt aaaccacatg ctttctaatt cctattgccc tttcttttca cccaccattc 1680
agcagtcagc agacactttc tgggtacaac agggtaggac catccaggca gaacaaaagc 1740
cattgatcat gaactacaga ggagagtttg gtaaatggac accagaaacc atggcctaca 1800
ggggcctggt tttctcccat ctaaatacta actaggccca acgctagttg ggcttagctt 1860
cctagatcag atgaaattgg gcacatttag ggttgggggt atggctctct attgtaagta 1920
gcaagagttt gagagaagaa aaaagggatt ttcttttttt tttcttttaa attttagagc 1980
attaacttta aacatcaaga tccaaacccc aaggattcag agaatcttgt actataaacc 2040
atttgtatta gtcagggttc tccagagaaa cagaacccat aggaggtata gagatagaga 2100
aatatggaat tggctcccat gattatggag gctgagaagt ccctcaatct gctgtctgtg 2160
agctggagac ctaggaaagc ttagctggtg gtacaaacca gcccaagtgc aaaggcccaa 2220
gaactaagag caccattgtc agagagcagg aaaagacaga tgtcccagct caaaaagaga 2280
gagcaaattc accttccttc caccatttta ttccgtcctg ttccattcct caacaggttg 2340
gatgatgagg gagatcttta tccatctcaa gttttttgtg caaatatgga atacaaatga 2400
aaaatactta aagcacatca tcattgattt ccaacttaga ctagtttaac ttcccttttt 2460
cttctatcct gtcagttcct tgagggatcc tctctccttg ttcatctctg catctctagt 2520
aattagcaca gtgccaggca catggtaata tggctaaaac agtggattat tggtctccaa 2580
cataattaag cccatccaaa agaaaaacca acctcataaa tctgctttgc aaagttcata 2640
aacaatggat atgctatgtc tcaaaggtgc tggccaaaaa aatttaagaa cttgggaatt 2700
atgtgttatt ttgtttgttt ttttcaccaa gcctactttt ctgtcacaag agcccatatc 2760
aacaacacac ccatgtatgt ccttcttttt atctactttt ctccatgaag tttgtcacca 2820
tcaactgtta aaactgtaaa gatttgatca gctaaataag tggtctttga actaattcct 2880
ctcgtacttc ctaaaggaac tttgaaaaac tatgtatccc cttgcacatt ttcaagcaga 2940
cacctaagat ttttcatcat aaatttgaat aacttcaaaa tatgtactta ttagcatatt 3000
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<210> 2
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actacaacct actcaattac att 23
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<213>Artificial sequence
<400> 4
aatcccatca ccatcttcca g 21
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<213>Artificial sequence
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gagccccagc cttctccat 19
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uucuccgaac gugucacgu 19
<210> 7
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<213>Artificial sequence
<400> 7
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<210> 8
<211> 21
<212> RNA
<213>Artificial sequence
<400> 8
aaaugguuua uaguacaaga u 21
<210> 9
<211> 21
<212> RNA
<213>Artificial sequence
<400> 9
cuuguacuau aaaccauuug u 21
<210> 10
<211> 21
<212> RNA
<213>Artificial sequence
<400> 10
uuuagacucc cauuuggaga g 21
<210> 11
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<213>Artificial sequence
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Claims (10)
- The purposes of 1.ENSG00000228742 genes, it is characterised in that the drug regimen for preparing prevention or treatment stomach cancer Thing.
- 2. purposes according to claim 1, it is characterised in that described pharmaceutical composition includes ENSG00000228742's Lower adjustment.
- 3. purposes according to claim 2, it is characterised in that described lower adjustment is selected from the group the siRNA of sequence：SEQ ID NO.8、SEQ ID NO.9。
- 4. a kind of lower adjustment for preventing or treating the ENSG00000228742 of stomach cancer, it is characterised in that it is described it is lower adjustment be siRNA。
- 5. a kind of pharmaceutical composition for preventing or treating stomach cancer, it is characterised in that described pharmaceutical composition contains：The lower adjustment of the ENSG00000228742 described in claim any one of 2-4；WithPharmaceutically acceptable carrier.
- 6. a kind of purposes of ENSG00000228742 genes, it is characterised in that the potential thing for screening prevention or treatment stomach cancer Matter.
- 7. it is a kind of screen prevention or treatment stomach cancer potential material method, it is characterised in that methods described includes：The system expressed or containing ENSG00000228742 genes is processed with candidate substances；WithDetect the expression of ENSG00000228742 genes in the system；Wherein, if the candidate substances can reduce expression or the activity of ENSG00000228742 genes, the candidate substances are shown It is the potential material for preventing or treating stomach cancer.
- 8. a kind of purposes of ENSG00000228742 genes, it is characterised in that the product for preparing diagnosis of gastric cancer.
- 9. purposes according to claim 8, it is characterised in that the product includes chip, preparation or kit.
- 10. purposes according to claim 9, it is characterised in that the chip includes specific recognition The probe of ENSG00000228742；The kit includes that the primer of specific amplification ENSG00000228742 or specificity are known The probe or chip of other ENSG00000228742.
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| CN108034722A (en) * | 2017-12-13 | 2018-05-15 | 广州医科大学附属肿瘤医院 | A kind of lncRNA SGOL1-AS1 are in the application as diagnosing gastric cancer marker |
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| CN108220446A (en) * | 2018-03-29 | 2018-06-29 | 北京泱深生物信息技术有限公司 | Applications of the LINC01356 as molecular marker in gastric cancer |
| CN108192977B (en) * | 2018-03-29 | 2020-05-19 | 青岛泱深生物医药有限公司 | Molecular marker related to occurrence and development of gastric cancer |
| CN108220446B (en) * | 2018-03-29 | 2020-06-30 | 青岛泱深生物医药有限公司 | Application of LINC01356 as molecular marker in gastric cancer |
| CN108531596A (en) * | 2018-04-25 | 2018-09-14 | 北京泱深生物信息技术有限公司 | A kind of application of lncRNA as biomarker in gastric cancer diagnosis and treatment |
| CN113151469A (en) * | 2021-04-19 | 2021-07-23 | 温州医科大学 | Tumor classification marker combination and application thereof |
| CN116904588A (en) * | 2022-08-12 | 2023-10-20 | 温州医科大学附属第一医院 | Application of LINC01633 in diagnosis and treatment of gastric cancer |
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