CN105886659A - DSTN gene and expression product thereof as diagnosis and treatment target of endometrial cancer - Google Patents
DSTN gene and expression product thereof as diagnosis and treatment target of endometrial cancer Download PDFInfo
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- CN105886659A CN105886659A CN201610491573.8A CN201610491573A CN105886659A CN 105886659 A CN105886659 A CN 105886659A CN 201610491573 A CN201610491573 A CN 201610491573A CN 105886659 A CN105886659 A CN 105886659A
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Abstract
The invention discloses a DSTN gene which can be used as a molecular marker of endometrial cancer diagnosis. A gene chip and a QPCR experiment are utilized to find that the DSTN gene and a coding protein thereof have remarkable difference in expression in a normal endometrial tissue and an endometrial cancer tissue, namely that the expression condition of the DSTN gene in the endometrial tissue can be detected to judge whether a subject suffers from endometrial cancer or has the risk of suffering from endometrial cancer or not. According to the correlation of the two, the invention develops a kit for diagnosing the endometrial cancer, and the kit is used for diagnosing the endometrial cancer by detecting the expression of the DSTN gene. The diagnosis kit can be used for early-stage diagnosis of diseases, and has a wide application prospect clinically. Besides, the invention further discloses the DSTN gene which can be used as a molecular target for treating the endometrial cancer, so that a foundation is provided for developing an endometrial cancer treatment drug.
Description
Technical field
The present invention relates to cancer diagnosis, treat, predict prognosis field, more particularly it relates to detection
DSTN is abnormal is the cancer diagnosis of means, prediction method of prognosis；And activate DSTN gene or the cancer of protein
Remedies.
Background technology
In global range, carcinoma of endometrium (endometrial cancer, EC) is modal female reproductive system
One of malignant tumour.Epidemic data shows, carcinoma of endometrium occupies each system of women whole body in developed country
4th (being only second to breast cancer, colorectal cancer and lung cancer) of malignant tumour and the first of reproductive system malignant tumour
Position (accounting for more than the 50% of whole gynaecologic reproductive system tumour new cases).According to statistics, United States in 2014
Endometrial carcinoma new cases are up to 52630 people, and die from this disease in respect of 8590 patients in advance.Equally,
The onset of endometrial cancer rate in China some areas (city as more flourishing in economy such as Shanghai) is own through exceeding uterine neck
Cancer, occupies first of female reproductive system malignant tumour.According to statistics, normal female suffers from endometrium in life
The risk of cancer is more than 2%, and the reason that its incidence of disease persistently rises includes the huge of life style, eating habit etc.
Change and the notable prolongation of the average life span in global range, and the year of the morbidity crowd of carcinoma of endometrium in recent years
Present obvious rejuvenation trend age.
In clinical position, although most of endometrial carcinomas first appear as vaginal hemorrhage after menopause or not
Rule colporrhagia, and then it is diagnosed as Early endometrial carcinoma (phase), but still the patient having more than is making a definite diagnosis
When for Locally Advanced or occult metastasis, local or DISTANT METASTASES IN have occurred, such patient is to performing the operation, putting
Penetrating therapeutic response poor, case fatality rate is high.And, along with the rejuvenation year by year at onset of endometrial cancer age, to early
Phase, the youth of differentiated carcinoma of endometrium and the patient having fertility to require carry out retaining the treatment of reproductive function and also become
Obtain extremely important.Factors above makes to understand onset of endometrial cancer mechanism in depth, explore for carcinoma of endometrium
One of the prophylactic treatment New Policy important process becoming at present this research field.
Summary of the invention
An object of the present invention is that providing a kind of is examined by detection DSTN gene or protein expression difference
The method of disconnected carcinoma of endometrium.
The two of the purpose of the present invention are that providing a kind of comes pre-by detection DSTN gene or protein expression difference
The method surveying carcinoma of endometrium prognosis.
The three of the purpose of the present invention are that providing a kind of is treated by activation DSTN gene or DSTN albumen
The method of carcinoma of endometrium.
A kind of method that the four of the purpose of the present invention are to provide medicine for screening treatment carcinoma of endometrium.
The five of the purpose of the present invention are to provide a kind of medicine for treating carcinoma of endometrium.
To achieve these goals, present invention employs following technical scheme:
The invention provides the product of detection DSTN gene or DSTN albumen in preparation carcinoma of endometrium diagnosis
Purposes in instrument.
Present invention also offers the product of detection DSTN gene or DSTN albumen at preparation prediction endometrium
Purposes in cancer prognostic tool.
Further, the product of described detection DSTN gene or DSTN albumen include detect DSTN gene or
The product of the expression of DSTN albumen.Described product includes can be in conjunction with the nucleic acid of DSTN gene or energy
Enough combine the material (such as antibody) of DSTN albumen.Described nucleic acid can detect the expression water of DSTN gene
Flat；Described material can detect the expression of DSTN albumen.
The product of the detection DSTN gene of the present invention can play it based on the known method using nucleic acid molecules
Function: as PCR, as Southern hybridization, Northern hybridization, dot blot, FISH (FISH),
DNA microarray, ASO method, high-flux sequence platform etc..Use this product can qualitatively, quantitatively,
Or semi-quantitatively implement to analyze.
The nucleic acid being included in the said goods can be obtained by chemical synthesis, or by preparing from biomaterial
Containing expectation nucleic acid gene, then use be designed for amplification expectation nucleic acid primer amplification it obtain.
Further, described PCR method is known method, such as, and ARMS (Amplification Refractory
Mutation System, amplification do not answer abruptly-changing system) method, RT-PCR (reverse transcriptase-PCR) method, nesting
PCR method etc..The nucleic acid of amplification can be by using dot blotting hybridization method, Surface Plasmon Resonance (SPR
Method), PCR-RFLP method, B by means of in situ RT PCR, PCR-SSO (sequence specific oligonucleotide) method,
PCR-SSP method, AMPFLP (amplifiable fragment length polymorphism) method, MVR-PCR method and
PCR-SSCP (single-strand conformation polymorphism) method detects.
Nucleic acid recited above includes the primer expanding DSTN gene, and the primer that product includes can be by logical
Crossing chemical synthesis to prepare, the method that be those skilled in the art will know that by use is come suitably with reference to Given information
Design, and prepared by chemical synthesis.
In specific embodiments of the present invention, described nucleic acid is the amplimer used in QPCR experiment, institute
State shown in sequence such as SEQ ID NO.1 (forward sequence) and SEQ ID NO.2 (reverse sequence) of primer.
Nucleic acid recited above may also include probe, and described probe can be prepared by chemical synthesis, by making
Appropriately design with reference to Given information by the method that those skilled in the art will know that, and prepared by chemical synthesis,
Or the gene containing expectation nucleotide sequence from biomaterial preparation can be passed through, and use is designed for the amplification phase
Hope nucleotide sequence primer amplification it prepare.
The product of the detection DSTN albumen of the present invention can play its function based on the known method using antibody:
For example, it is possible to include ELISA, radioimmunoassay, immunohistochemical method, western blot etc..
The product of the detection DSTN albumen of the present invention includes antibody or its sheet of specific binding DSTN albumen
Section.Antibody or its fragment of any structure, size, immunoglobulin class, origin etc. can be used, as long as
It combines target protein.Antibody or its fragment that the detection product of the present invention includes can be monoclonal
Or it is polyclonal.Antibody fragment refers to an antibody part (Partial Fragment) retaining antibody to the combination activity of antigen
Or the peptide containing an antibody part.Antibody fragment can include F (ab ')2, Fab ', Fab, scFv (scFv),
The Fv (dsFv) of disulphide bonding or its polymer, dimerization V district (double antibody) or containing CDR
Peptide.The product of the detection DSTN albumen of the present invention can include the amino acid of encoding antibody or Encoding Antibody Fragment
The nucleic acid of the separation of sequence, comprises the carrier of this nucleic acid, and carries the cell of this carrier.
Antibody can be by well known to a person skilled in the art that method obtains.Such as, preparation retains whole or portion
The polypeptide dividing target protein or the mammalian cell expression vector integrating their polynucleotides of coding are as anti-
Former.Use after antigen-immunized animal, from through the animal adaptive immune cell of immunity fused bone myeloma cells with
Obtain hybridoma.Then antibody is collected from Hybridoma culture.Finally can be used as antigen by use
DSTN albumen or its part antibody to obtaining are implemented antigentic specificity purifying and are obtained for DSTN albumen
Monoclonal antibody.Polyclonal antibody can be prepared as follows: with antigen-immunized animal same as above, from process
The animal of immunity collects blood sample, isolates serum from blood, then uses above-mentioned antigen to implement serum
Antigentic specificity purifies.Can be by the antibody obtained with ferment treatment or the sequence letter of the antibody obtained by use
Breath obtains antibody fragment.
The combination of label and antibody or its fragment can be implemented by method as commonly known in the art.Such as,
Can fluorescent marker protein or peptide as follows: clean protein or peptide with phosphate buffer, add with DMSO,
Buffer, etc. preparation dyestuff, then mixed solution, then at room temperature place 10 minutes.It addition, mark can
The labelling kit of commodity in use, such as biotin labeling reagent box, as biotin labeling reagent box-NH2,
Biotin labeling reagent box-SH (DojindoLaboratories)；Alkali phosphatase enzyme mark kit such as alkalescence phosphorus
Acid enzyme labeling kit-NH2, alkali phosphatase enzyme mark kit-SH (Dojindo Laboratories)；Peroxide
Compound enzyme labeling kit such as peroxidase labelling kit-NH2, peroxidase labelling kit
-NH2(Dojindo Laboratories)；Phycobniliprotein labelling kit such as phycobniliprotein labelling kit
-NH2, phycobniliprotein labelling kit-SH, B-phycoerythrin labelling kit-NH2, B-phycoerythrin
Labelling kit-SH, R-PE labelling kit-NH2, R-PE labelling kit
SH(DojindoLaboratories)；Fluorescent labeling reagent box such as fluorescein labelling kit-NH2, HiLyte
Fluor (TM) 555 labelling kit-NH2, HiLyte Fluor (TM) 647 labelling kit-NH2 (Dojindo
Laboratories)；And DyLight 547 and DyLight647 (Techno Chemical Corp.), Zenon (TM),
Alexa Fluor (TM) antibody labeling kit, Qdot (TM) antibody labeling kit (Invitrogen
And EZ-label Protein Labeling Kit (Funakoshi Corporation) Corporation).In order to correctly
Mark, it is possible to use suitable instrument detects the antibody through mark or its fragment.
Sample as the detection product according to the present invention, it is possible to use the tissue such as obtained from biopsy experimenter
Sample or fluid.Sample is not particularly limited, as long as it is suitable to the mensuration of the present invention；Such as, it can include
Tissue, blood, blood plasma, serum, lymph liquid, urine, serous cavity liquid, spinal fluid, synovia, aqueous humor, tear
Liquid, saliva or its fraction or treated material.
In specific embodiments of the present invention, described sample is from the tissue of experimenter.
In the present invention, " prognosis " refer to that cancer patient is by the suppression such as surgical procedure or alleviate tumor growth
After process or result.In this manual, prognosis can be to be suppressed by surgical procedure or alleviate tumor growth
Life state when latter 1,2,3,4,5,6,7,8,9,10,15,20 years or more long.Prognosis can
With by checking that the gene of biomarker i.e. DSTN albumen or encoding D STN albumen is predicted.Prognosis is pre-
Survey can be performed such that according to biomarker with or without, or be raised and lowered, determine the prognosis of patient
It is good or bad, or determines the probability of good prognosis or poor prognosis.
In the present invention, " prognosis bona " refers to suppressed or alleviation tumour life for patient by surgical procedure etc.
After length, patient (such as 3,5,6,7,8,9,10,15,20 years or longer) over a long time not danger
Anxious situation.Or, good prognosis can mean to survive in the most long-time, without transfer, without recurrence or without again
Send out.Such as, prognosis bona can mean at least 3 years or survival in especially at least 5 years, preferably without transfer
Or recurrence.The most preferred state of prognosis bona is the long-term survival without disease.As used herein, " pre-
Rear good " can also include any such state, wherein it appeared that disease such as transfer, but pernicious low and
Do not severely impact survival ability.
In the present invention, " prognosis mala " refers to that patient is by the suppression such as surgical procedure or alleviation tumor growth
After short-term (such as 1,2,3,4,5 years or shorter) in occur fatal condition.Or, poor prognosis is
Refer to death in such short-term, shift, recur or send out again.Such as, poor prognosis can mean at least 3
Year or Preventive or death in especially at least 5 years.
Prediction prognosis refers to predict process or the result of status of patient, and being not meant to can be with the degree of accuracy of 100%
The process of prediction status of patient or result.Prediction prognosis refers to whether the possibility determining some process or result increases
Add, and be not meant to be compared by situation about not occurring with some process or result determine generation some process
Or the possibility of result.For the present invention, the level fall of DSTN gene or DSTN albumen in the present invention
In low patient, compared with the patient not showing this feature, more likely observe particular procedure or result.
Further, the product of described detection DSTN gene or DSTN albumen can be detection DSTN gene
Or the reagent of DSTN albumen, can also be to comprise the kit of described reagent, chip, test paper etc., it is also possible to
It it is the high-flux sequence platform using described reagent.
Present invention also offers the instrument of a kind of diagnosis of endometrial carcinoma, described instrument can detect DSTN gene
Or the expression of DSTN albumen.Described instrument includes can be in conjunction with the nucleic acid of DSTN gene or can
Material (such as antibody) in conjunction with DSTN albumen.Described nucleic acid can detect the expression of DSTN gene；
Described material can detect the expression of DSTN albumen.
Further, the character of described nucleic acid and described material is with noted earlier.
Further, the instrument of described diagnosis of endometrial carcinoma include but not limited to chip, kit, test paper or
High-flux sequence platform；High-flux sequence platform is the instrument of a kind of special diagnosis of endometrial carcinoma, along with height
The development of flux sequencing technologies, will become the structure of the gene expression profile of a people and work the most easily.Logical
Cross contrast Disease and the gene expression profile of normal population, easily analyze exception and the disease phase of which gene
Close.Therefore, in high-flux sequence, know that the exception of DSTN gene is relevant to carcinoma of endometrium fall within DSTN
The purposes of gene, equally within protection scope of the present invention.
Present invention also offers a kind of instrument predicting carcinoma of endometrium prognosis, described prediction carcinoma of endometrium prognosis
Instrument includes can be in conjunction with the nucleic acid of DSTN gene or can be (the most anti-in conjunction with the material of DSTN albumen
Body).Described nucleic acid can detect the mRNA level in-site of DSTN gene；Described material can detect DSTN egg
White expression.
Further, the character of described nucleic acid and described material is with noted earlier.
Further, the instrument of described prediction carcinoma of endometrium prognosis include but not limited to chip, kit, test paper,
Or high-flux sequence platform；High-flux sequence platform is the instrument of a kind of special diagnosis of endometrial carcinoma, along with
The development of high throughput sequencing technologies, will become the structure of the gene expression profile of a people and work the most easily.
By contrast Disease and the gene expression profile of normal population, easily analyze exception and the disease of which gene
Relevant.Therefore, in high-flux sequence, know that the exception of DSTN gene is relevant to carcinoma of endometrium fall within
The purposes of DSTN gene, equally within protection scope of the present invention.
The amino that the anti-DSTN antibody used in detection product, the diagnostic tool of the present invention or its fragment are identified
The number of acid is not particularly limited, as long as antibody can be in conjunction with DSTN.
Present invention also offers a kind of diagnosis of endometrial carcinoma or the method for prediction carcinoma of endometrium prognosis, described side
Method comprises the steps:
(1) sample of experimenter is obtained；
(2) DSTN gene or the expression of albumen in detection Samples subjects；
(3) the DSTN gene recorded or the expression of albumen are associated with the whether ill of experimenter.
(4) compared with the control, the expression of DSTN gene or albumen reduces, then this experimenter is diagnosed
For carcinoma of endometrium, or this experimenter is confirmed as prognosis mala.
Present invention also offers the methods for the treatment of of a kind of carcinoma of endometrium, described method includes activating DSTN gene
Or DSTN albumen.
Further, described method includes the expression promoting DSTN gene, or promotes the expression of DSTN albumen
Or strengthen the activity of DSTN albumen.
Present invention also offers the screening technique of a kind of cancer drug, can be by cancer cell being added test medicine
Certain period after thing or after cancer model animal is used testing drug measures DSTN gene or DSTN
The expression of albumen measures cancer drug and improves the effect of cancer prognosis.More specifically, when DSTN base
Because of or the expression of DSTN albumen when adding or raise after using testing drug or recover normal water
At ordinary times, this medicine optional is as the medicine improving cancer prognosis.
Present invention also offers a kind of containing DSTN gene or the medicine of the activator of DSTN albumen.
Present invention also offers the application in the medicine of preparation treatment carcinoma of endometrium of the above-mentioned activator.
The DSTN gene of the present invention or the activator of DSTN albumen are unrestricted, as long as can promote or
Person strengthens DSTN or the expression of material relating to DSTN upstream or downstream pathway or activity, and for treatment
The effective medicine of cancer.
Further, described activator includes DSTN gene, DSTN albumen, promoted type miRNA, promotion
Type transcription regulatory factor or promoted type targeting micromolecular compound.
Described activator also includes comprising carrier or the host cell carrying DSTN gene.
On the one hand the activator of the present invention may be used for supplementing disappearance or the deficiency of endogenic DSTN albumen, logical
Cross the expression improving DSTN albumen, thus treat the carcinoma of endometrium caused because of DSTN hypoproteinosis.Another
Aspect may be used for strengthening the activity of DSTN albumen, thus treats carcinoma of endometrium.
The medicine of the present invention can be administered alone as medicine or use together with other medicines.Can be with the present invention
The other medicines used together of medicine unrestricted, as long as it does not damage the therapeutic of the present invention or preventative medicine
The effect of thing, it is preferred that the medicine for treatment or pre-anti-cancer can include such as alkylating agent, all
As ifosfamide, endoxan, Dacarbazine, Temozolomide, Nimustine, busulfan, procarbazine,
Melphalan and Ranimustine；Antimetabolite, such as enocitabine, capecitabine, Carmofur, Cladribine,
Gemcitabine, cytarabine, cytarabine octadecyl phosphate (cytarabine ocfosfate), Tegafur,
UFT, Tegafur gimeracil oteracil potassium, doxifluridine, hydroxycarbamide, fluorouracil,
Fludarabine, pemetrexed, Pentostatin, mercaptopurine and methotrexate (MTX)；Plant alkaloid, such as Yi Li
For health, Etoposide, Sobuzoxane, docetaxel, nogitecan, Pa Litasai, vinorelbine, Changchun
Pungent and the vincaleukoblastinum in ground；Antitumor antibiotic, such as actinomycin D, Aclarubicin, Amrubicin, Yi Da ratio
Star, epirubicin, Zinostatin stimalamer, daunorubicin, Doxorubicin, THP, rich come mould
Element, Peplomycin, mitomycin C and mitoxantrone；Medicine based on platinum, such as oxaliplatin, carboplatin,
Cis-platinum and Nedaplatin；Hormonal medicaments, such as Anastrozole, Exemestane, Estramustine, ethinyloestradiol, chlorine
Ground progesterone, Goserelin, TAM, dexamethasone, Toremifene, Bicalutamide, Flutamide, bold and vigorous Buddhist nun
Song Long, Fosfestrol, mitotane, methyltestosterone, Medroxyprogesterone, Mepitiostane, Leuprorelin and Letrozole；Raw
Thing reaction dressing agent, such as interferon-' alpha ', interferon beta, interferon gamma, interleukin, ubenimex, dry BCG,
And lentinan；And molecular targeted agents, such as Imatinib (imatinib), Gefitinib (gefitinib), Ji
Nurse monoclonal antibody, ozogamicin, Tamibarotene, trastuzumab, Tretinoin, bortezomib (bortezomib),
With Rituximab etc..
The medicine of the present invention can be prepared as various formulation as required.Include but not limited to, percutaneous, mucous membrane, nose,
Buccal, sublingual or the tablet of per os use, solution, granule, patch, paste, capsule, aerosol
Or suppository.
The route of administration of the medicine of the present invention is unrestricted, as long as it can play desired result for the treatment of or pre-preventive effect
Fruit, includes but not limited to intravenous, intraperitoneal, intraocular, intra-arterial, in lung, is administered orally, in vesicle,
In muscle, tracheal strips, subcutaneous, by skin, by pleura, local, suck, by mucous membrane, skin
Skin, stomach, in joint, in ventricle, rectum, vagina, in skull, in urethra, in liver, in knurl.At certain
In the case of Xie, can systematically be administered.It is to be administered partly in some cases.
The dosage of the medicine of the present invention is unrestricted, as long as obtaining desired result for the treatment of or preventive effect,
Appropriate determination can be carried out according to symptom, sex, age etc..The medicine of the present invention or the agent of prophylactic agent
Amount can use such as result for the treatment of or preventive effect to disease to determine as index.
In the context of the present invention, " diagnosis of endometrial carcinoma " both includes judging that experimenter has suffered from
Carcinoma of endometrium, also include judging whether experimenter exists the risk suffering from carcinoma of endometrium.
" treatment " used herein contains treatment phase in the mammal such as mankind suffering from relevant disease or illness
The disease closed or morbid state, and include:
(1) prevention disease or morbid state occur in mammal, especially susceptible in institute when this mammal
State morbid state, but be not yet diagnosed when suffering from this morbid state；
(2) suppression disease or morbid state, i.e. stop it to occur；Or
(3) disease or morbid state are alleviated, even if disease or morbid state disappear.
Term " is treated " and is usually directed to treat the mankind or animal (such as, applied by animal doctor), wherein can reach certain
Some intended results for the treatment of, such as, the development (including reducing development speed, making development stop) of suppression illness,
Improve illness and cure illness.Also include the treatment as precautionary measures (such as prevention).To the most not developing into
Illness but have develops into the purposes of the dangerous patient of this illness, is also included within during term " treats ".
Advantages of the present invention and beneficial effect:
The molecular marker being found that a kind of diagnosis of endometrial carcinoma of the present invention, uses this molecular marker permissible
The early stage that Endometrial Carcinomas occurs can be used as judging, it is provided that the survival rate of patient.
It addition, by the prognosis predicting patient, the present invention can provide significant information to determine to control for patient
Treat scheme policies.
The medicine of the activator including DSTN gene or albumen of the present invention can be used as new endometrium
The medicine of cancer.
Accompanying drawing explanation
Fig. 1 shows and utilizes Western blot detection DSTN albumen endometrial tissues and normal endometrial tissue
In expression；
Fig. 2 show utilize Western blot detect DSTN gene overexpression situation.
Specific embodiment
The present invention is further detailed explanation with embodiment below in conjunction with the accompanying drawings.Following example are only used for
The bright present invention rather than restriction the scope of the present invention.The experimental technique of unreceipted actual conditions in embodiment is logical
Often according to normal condition, such as Sambrook et al., molecular cloning: laboratory manual (New York:Cold
Spring HarborLaboratory Press, 1989) condition described in, or according to the bar proposed by manufacturer
Part.
Embodiment 1 genetic chip screening difference expression gene
1, sample collection:
Endometrial sample: collect endometrial carcinoma, the equal underwent operative of all patients is treated, operation
Paraffin specimen 10 example.All patients all make a definite diagnosis through pathologic finding suffers from carcinoma of endometrium.Other enter set condition
Any treatment was not accepted: do not merge other malignant tumours before being admitted to hospital for: all patients；Do not merge other hormones
Diseases related；Complete clinical data.
10 patients with endometrial cancer, fall ill 58 years old mean age.Patient's main clinical manifestation is that vagina is not advised
The most hemorrhage, hypogastralgia, paramenia, neoplasm etc., also have some patients non-evident sympton to look in health
Body finds.Carcinoma of endometrium sample is diagnosed as carcinoma of endometrium through HE stained slice, tectology.
Normal endometrial tissue sample: 10 example normal endometrium operation paraffin specimens.The disease of samples sources
People's illnesses includes: fibroid, the prolapse of uterus, wing moon bright bulging, Rectocele.
2, the acquisition of RNA is organized
Use Trizol one-step method to extract total tissue RNA, read 260nm by Nanodrop ND-1000
With the purity that the absorbance (A) at 280nm measures RNA solution.Through 1% denaturing formaldehyde Ago-Gel electricity
Swimming, observes under ultraviolet transmission light, the integrality of detection RNA.
3, gene chip hybridization and scanning
After the linearized amplification of total serum IgE, cy3-UTP marks, and the cRNAs after fluorescence labeling uses RNEASY
Mini Kit purifies, and enters, with the RNA Fragmentation Reagents of Amhion, the cRNAs marked
Row fragmentation processes.Use people's full genome chip of expression spectrum (4x 44K gene) of Agilent company of the U.S.,
In chip hybridization stove, 65 DEG C of hybridization 17h, then elute, dye, finally use Agilent DNA
MicroarrayScanner scanner scanning.
4, chip data processes and analyzes
Chip after hybridization, after chip scanner reads data point, imports data to analyze software, for two groups
The natural logrithm absolute value of the ratio gene more than 2.0 or less than 0.5 is as difference expression gene.
5, statistical procedures
Using SPSS 13.0 statistical software to carry out data analysis, group difference compares employing one-way analysis of variance
Method, P < 0.05 difference has significant.
6, result
Chip results shows, filters out 654 differences between endometrial and normal endometrial tissue altogether
Different expressing gene, the gene 421 that wherein expression raises, the gene 233 that expression is lowered.
The difference expression gene filtered out verified by embodiment 2 large sample
Consider that yet there are no the gene carrying out studying about this gene and carcinoma of endometrium correlation in prior art makees
For candidate gene, considering the result of gene sequencing, (it expresses Endometrial Carcinomas to select DSTN gene simultaneously
Tissue is lowered) verify.
1, sample collection
Endometrial 50 example, normal endometrial tissue 60 example is collected according to the method for embodiment 1.
2, verify in mRNA level in-site
2.1 extract tissue RNA
Step is with embodiment 1.
2.2 reverse transcription
Use Reverse Transcriptase kit, with RT Buffer, l μ g total serum IgE is carried out converse record and synthesize cDNA.
Using 25 μ l reaction systems, each sample takes 1 μ g total serum IgE as template ribonucleic acid, in PCR pipe point
Do not add following components: DEPC water, 5 × RT Buffer, 10mmol/l dNTP, 0.1mmol/l DTT,
30 μm mol/l Oligo dT, 200U/ μ l MMLVRT, template ribonucleic acid.Hatch 1 hour for 42 DEG C, 72 DEG C 10
Minute, of short duration centrifugal.
2.3PCR
Primer-design software Primer Premier 5.0 is used to design mRNA fluorescent quantitation upstream and downstream PCR primer,
Synthetic primer sequence, uses the operation of SYBR Green PCR Master Mix kit, and concrete steps are normally
Bright book operates, and uses 25 μ l reaction systems, and each sample arranges 3 parallel pipes, all amplified reactions
Above to ensure the reliability of result.Prepare following reaction system (as shown in table 1), every
Operation is all carried out on ice:
The each component of table 1 quantitative fluorescent PCR and respective volume
With GAPDH as internal reference, using SYBR Green I as fluorescent marker, at Light Cycler fluorescence
The enterprising performing PCR of quantitative PCR apparatus reacts, and determines purpose band, Δ Δ CT by melt curve analysis analysis and electrophoresis
Method carries out relative quantification.
DSTN gene primer sequence is as follows:
Upstream primer: 5 '-AATGCTCCACACCAGAAG-3 ' (SEQ ID NO.1)；
Downstream primer: 5 '-CACCAACATCTCCAACCA-3 ' (SEQ ID NO.2).
GAPDH gene primer sequence is as follows:
Upstream primer: 5 '-TTTAACTCTGGTAAAGTGGATAT-3 ' (SEQ ID NO.3)；
Downstream primer: 5 '-GGTGGAATCATATTGGAACA-3 ' (SEQ ID NO.4)
2.4 result
Result shows, compared with normal endometrial tissue, and DSTN gene in endometrial
MRNA level in-site is substantially lowered, and relative expression quantity is 0.11 ± 0.013, and difference has statistical significance (P < 0.05).
3, verify on protein level
3.1 extract tissue total protein
The operation of protein extraction is carried out according to the specification of EpiQuik tissue/cell total protein extraction kit.
3.2Western blot detects
The protein quantification of extraction is carried out SDS-PAGE electrophoresis, carry out afterwards transferring film, closing, one anti-hatch,
Two anti-hatch, develop the color.
3.3 statistical procedures
Image J software is used to be analyzed, with β-actin as internal reference, by DSTN the gray value of protein band
The gray value of protein band is normalized.Result data is all to carry out table in the way of mean+SD
Showing, using SPSS13.0 statistical software to carry out statistical analysis, difference between the two uses t inspection,
Think when P < has statistical significance when 0.05.
3.4 result
Result as it is shown in figure 1, compared with normal endometrial tissue, DSTN albumen in endometrial
Level significantly reduces, and difference has statistical significance (P < 0.05).
Embodiment 3 DSTN gene overexpression
1, plasmid construction
According to DSTN gene coded sequence design amplimer, primer be designed as those skilled in the art institute
Know.Amplification total length from the cDNA library (clontech company, article No.: 638831) becoming Human fetal spleen
The coded sequence of DSTN gene, above-mentioned cDNA sequence is inserted in eukaryotic expression vector pcDNA3.1,
Connect the recombinant vector pcDNA3.1-DSTN obtained for subsequent experimental.
2, the cultivation of endometrial carcinoma cell and transfection
2.1 cells are cultivated
Ishikawa3-H-12 clone all (contains in RPMI 1640 culture medium by the blake bottle adhere-wall culture of 50ml
10% hyclone, 100U/ml penicillin, 100g/ml streptomysin) in, at 37 DEG C, 5%CO2Saturated
The incubator of humidity is cultivated continuously.
2.2 cell transfecting
1, day before transfection is by 0.5-2*105Individual tumour cell is suspended in the 500 μ l culture medium without antibiotic,
It is seeded to 24 well culture plates.
2, transfection cell density on the same day should reach 80%-90%, prepares following compound A: by 1 μ g DNA
It is diluted in serum free medium, mixes gently；Compound B: take 4 μ l Lipofectamine2000 and be diluted in
In serum free medium, mixing.
3, compound A and B is mixed, mix gently, incubated at room.
4,100 μ l liposome compounds are added in tumour cell, mix the most gently, cell is put
Enter 37 DEG C containing 5%CO2Incubator hatches 5-7 hour.
5, add 1ml and contain 2 times of normal serums and the growth medium of antibiotic concentration, continue to cultivate cell 18-24
Hour.
3, the process LAN situation of QPCR experiment detection pcDNA3.1-DSTN is utilized
3.1 extract cell total rna utilizes conventional method to operate.
3.2 reverse transcription
Step is with embodiment 2.
3.3QPCR
Step is with embodiment 2.
3.4 result
Result shows, pcDNA3.1-DSTN can success process LAN, relative expression quantity is 6.28 ± 0.85,
Difference has statistical significance (P < 0.05).
3, Western blot experiment detection pcDNA3.1-DSTN process LAN situation
Step is with embodiment 2.
Result is as in figure 2 it is shown, compared with transfection pcDNA3.1 group, transfect the cell of pcDNA3.1-DSTN
The content of middle DSTN albumen substantially increases, and difference has statistical significance (P < 0.05).
The expression of the embodiment 4 DSTN gene mensuration to endometrial carcinoma cell multiplication capacity
1, step:
The application bromo-2 ' Brdurds of 5-(Brd U) mark and detection kit.Reference reagent box operation instruction,
Cell transfecting (transfection procedure is with embodiment 3), after 48 hours, is inhaled and is abandoned culture medium, adds Brd U mark training
Foster base, 37 DEG C, 5%CO2Incubator is cultivated 60min.Discard culture medium, after PBS rinses, with 70%
Ethanol is fixed, overnight.Resisting the anti-Brd U antibody for mouse with one, two resist the anti-mouse for band FITC
Fluorescence antibody, carries out immune response.Then flow cyctometry detection is carried out.
2, Brd U incorporation result:
Result shows: transfection pcDNA3.1 groups of cells incorporation efficiency average out to: (29.01 ± 1.23) %；
PcDNA3.1-DSTN groups of cells incorporation efficiency average out to (10.29 ± 0.48) %, difference has statistical significance
(P<0.05).Above-mentioned test result indicate that, the DSTN gene expression inhibition propagation of endometrial carcinoma cell.
The impact of embodiment 7 Transwell experiment detection DSTN gene expression cell migration
Step:
1, from the refrigerator of-80 DEG C, frozen Matrigel thing is taken out, then mistake under 4 DEG C of temperature conditionss
Night so that it is become liquid.
2, take out 200 μ l serum-free cell culture mediums, add the Matrigel reagent of 50 μ l, at cryogenic conditions,
Preferably operate on ice face and be mixed evenly, respectively add 100 μ l, be placed on 37 DEG C, carbon dioxide
Incubator is cultivated 5h, the most often observes liquid case, when liquid becomes slightly white, illustrate that it has turned into
Solidification state.
3, cell (according to the embodiment 3 step operation) trypsinization that will transfect, with without serum
Culture medium cleans 3 times, then counts, then is made into cell suspending liquid.
4, gel is washed 1 time gently, then by 2*10 with the culture medium of serum-free5Cell is suspended in 100 μ l
In RPMI 1640, it is inoculated in room on transwell.
5, lower room adds 600 μ l 10%FBS RPMI 1640.
6, in 37 DEG C of incubators, after cultivating 12h, take out transwell cell, often organize all 4 samples of repetition.
7, wherein 1 cell discards culture medium, washes 3 times with the PBS without calcium, and 4% poly first ferment fixes 10min,
The cell that upper strata does not migrates wiped by cotton swab, and PBS washes 3 times, and violet staining or Giemsa dyeing, micro-
Microscopic observation.Remaining 3 cells to be digested with 0.25% membrane proteolytic enzyme by its lower floor's migrating cell, computation migration is thin
Born of the same parents' number.
Result:
Migration experimental result shows, transfects pcDNA3.1 groups of cells cell migration number average out to 240, turns
Dye pcDNA3.1-DSTN groups of cells cell migration number average out to 114, difference has statistical significance
(P<0.05)。
The explanation of above-described embodiment is only intended to understand the method for the present invention and core concept thereof.It is right to it should be pointed out that,
For those of ordinary skill in the art, under the premise without departing from the principles of the invention, it is also possible to the present invention
Carrying out some improvement and modification, these improve and modify also by the protection domain falling into the claims in the present invention.
Claims (10)
1. the product of detection DSTN gene or DSTN albumen is preparing diagnosis of endometrial carcinoma or prediction uterus
Application in the instrument of endometrial carcinomas prognosis.
Application the most according to claim 1, it is characterised in that described detection DSTN gene or DSTN
The product of albumen includes the product detecting the expression of DSTN gene or DSTN albumen.
Application the most according to claim 1 and 2, it is characterised in that described product includes can be in conjunction with DSTN
The nucleic acid of gene or can be in conjunction with the material of DSTN albumen；Described nucleic acid can detect the table of DSTN gene
Reach level；Described material can detect the expression of DSTN albumen.
Application the most according to claim 3, it is characterised in that described nucleic acid is to make in real-time quantitative PCR
The primer of specific amplified DSTN gene as shown in SEQ ID NO.1 and SEQ ID NO.2.
5. a diagnosis of endometrial carcinoma or the instrument of prediction carcinoma of endometrium prognosis, it is characterised in that described
Instrument includes the instrument that can detect the expression of DSTN gene or DSTN albumen.
Instrument the most according to claim 5, it is characterised in that described instrument includes can be in conjunction with DSTN
The nucleic acid of gene or can be in conjunction with the material of DSTN albumen；Described nucleic acid can detect the table of DSTN gene
Reach level；Described material can detect the expression of DSTN albumen.
Instrument the most according to claim 6, it is characterised in that described nucleic acid is to make in real-time quantitative PCR
The primer of specific amplified DSTN gene as shown in SEQ ID NO.1 and SEQ ID NO.2.
8. the medicine treating carcinoma of endometrium, it is characterised in that described medicine comprise DSTN gene or
The activator of DSTN albumen.
Medicine the most according to claim 8, it is characterised in that described activator can promote or strengthen
DSTN or relate to the expression of material or the activity of DSTN upstream or downstream pathway.
10. the application in the medicine of preparation treatment carcinoma of endometrium of the activator described in claim 8 or 9.
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| CN106119399A (en) * | 2016-08-29 | 2016-11-16 | 北京泱深生物信息技术有限公司 | ZNF385C is as the purposes of hypopharyngeal cancer diagnosis and treatment mark |
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| CN110172512A (en) * | 2019-05-27 | 2019-08-27 | 清华大学深圳研究生院 | A kind of application of carcinoma of endometrium biomarker in cancer diagnosis and the prediction of prognosis situation |
| CN111596067A (en) * | 2020-06-03 | 2020-08-28 | 四川大学华西第二医院 | Application of ZC3H8 in early warning, diagnosis and prognosis evaluation of POP (Point of Presence) |
| CN111596067B (en) * | 2020-06-03 | 2021-06-22 | 四川大学华西第二医院 | Application of ZC3H8 in early warning, diagnosis and prognosis evaluation of POP (Point of Presence) |
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