CN109939234A - The purposes of FOXP1 gene and its inhibitor in preparation inhibition lung cancer metastasis drug - Google Patents
The purposes of FOXP1 gene and its inhibitor in preparation inhibition lung cancer metastasis drug Download PDFInfo
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- CN109939234A CN109939234A CN201910198549.9A CN201910198549A CN109939234A CN 109939234 A CN109939234 A CN 109939234A CN 201910198549 A CN201910198549 A CN 201910198549A CN 109939234 A CN109939234 A CN 109939234A
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Abstract
The present invention provides a kind of FOXP1 gene and its inhibitor and inhibits the purposes in lung cancer metastasis drug in preparation.Find that the high expression of FOXP1 dynamic is associated with the transfer of lung cancer based on research inventor.By the variation of FOXP1 Expression level in detection lung carcinoma cell, the highly expressed lung cancer carcinoma strain of FOXP1 dynamic is identified, and can further predict such lung cancer strain metastatic potential；By inhibiting the FOXP1 in mesenchyma lung carcinoma cell, the mesenchyma of lung carcinoma cell is increased to the process of epithelium, it is suppressed that the transfer of lung cancer.The present invention has very positive meaning for the diagnosing and treating of lung cancer.
Description
Technical field
The present invention relates to a kind of FOXP1 genes and its inhibitor to inhibit the purposes in lung cancer metastasis drug in preparation.
Background technique
Malignant tumour is to threaten one of the greatest danger factor of people's health, and tumor mortality number nearly 200 is often only in China
Ten thousand people, and global lung cancer morbidity rate is in rising trend always since the late 1970s.Lung cancer is morbidity and mortality
Growth is most fast, to one of population health and the maximum malignant tumour of life threat.Many countries all report lung cancer in the past 50 years
Morbidity and mortality obviously increase, and male lung cancer morbidity and mortality account for first of all malignant tumours, women
Disease incidence accounts for second, and the death rate accounts for second.The cause of disease of lung cancer is not completely clear so far, and great mass of data shows long-term big
Amount smoking has very close relationship with lung cancer.
FOXP1 gene order can refer to NCBIID:27086, which belongs to the P subfamily in FOX transcription family.
It is had not been reported about the relationship between lung cancer and FOXP1.
Summary of the invention
In view of the foregoing deficiencies of prior art, the purpose of the present invention is to provide a kind of FOXP1 to diagnose and inhibit
Purposes in lung cancer metastasis, for solving the difficult point in the diagnosis prediction and treatment of lung cancer metastasis in the prior art.
Find that the high expression of FOXP1 dynamic is associated with the transfer of lung cancer based on research inventor.By detecting lung carcinoma cell
The variation of middle FOXP1 Expression level identifies the highly expressed lung cancer carcinoma strain of FOXP1 dynamic, and can further predict this
Class lung cancer strain metastatic potential；By inhibiting the FOXP1 in mesenchyma lung carcinoma cell, the mesenchyma for increasing lung carcinoma cell is upward
The process of skin, it is suppressed that the transfer of lung cancer.In order to achieve the above objects and other related objects, following scheme is inventor provided:
One aspect of the present invention provides a kind of FOXP1 gene inhibitor and inhibits in lung cancer metastasis drug preparing or screen
Purposes.
Further, the lung cancer is the high expression type lung cancer of FOXP1 dynamic.
Further, the high expression of FOXP1 dynamic specifically refers to the lung carcinoma cell that TPM is higher than 1000, and TPM refers to every hundred
Transcript number in ten thousand cells.
Above-mentioned FOXP1 gene inhibitor can reduce the expression of FOXP1 gene.
Preferably, the FOXP1 gene inhibitor can completely inhibit the expression of FOXP1.
FOXP1 gene inhibitor can be siRNA, shRNA, antibody, small molecule compound.
The drug necessarily includes FOXP1 gene inhibitor, and using FOXP1 gene inhibitor as the effective of aforementioned function
Ingredient.
In the drug, the effective component for playing aforementioned function can be only FOXP1 gene inhibitor, also may include that other can
Play the molecule of similar function.
Also that is, FOXP1 gene inhibitor is one of sole active ingredient or effective component of the drug.
The drug can be single composition substance, also can be multi-component compound.
The form of the drug can be the various substance shapes such as solid, liquid, gel, semi-fluid, aerosol without specifically limited
Formula.
The drug mainly for object be mammal, such as rodent, primate.
The lung cancer metastasis can be the lung cancer metastasis after lung cancer is postoperative or chemicotherapy.
Another aspect of the present invention provides a kind of drug for inhibiting lung cancer metastasis, includes effectively to control in the drug
The FOXP1 gene inhibitor for the treatment of amount.
The drug necessarily includes FOXP1 gene inhibitor, and using FOXP1 gene inhibitor as the effective of aforementioned function
Ingredient.
In the drug, the effective component for playing aforementioned function can be only FOXP1 gene inhibitor, also may include that other can
Play the molecule of similar function.
Also that is, FOXP1 gene inhibitor is one of sole active ingredient or effective component of the drug.
The drug can be single composition substance, also can be multi-component compound.
The form of the drug can be the various substance shapes such as solid, liquid, gel, semi-fluid, aerosol without specifically limited
Formula.
The drug mainly for object be mammal, such as rodent, primate.
Further, the lung cancer refers to the high expression type lung cancer of FOXP1 gene dynamic.
Another aspect of the present invention provides a kind of method for inhibiting lung cancer metastasis, to apply FOXP1 base to object
Because of inhibitor.
The object can be the lung carcinoma cell of mammal or mammal.The mammal is preferably Rodentia
Animal, artiodactylous animals, Perissodactyla animal, Lagomorph, primate etc..The primate is preferably monkey, ape
Or people.
The object can be the patient for suffering from lung cancer or expect to inhibit the individual of lung cancer metastasis.Or the object is
Patients with lung cancer or the in vitro lung carcinoma cell for expecting to inhibit lung cancer metastasis.
The FOXP1 gene inhibitor can be applied before, during and after receiving lung cancer therapy to object.
Another aspect of the invention provides a kind of inhibition lung cancer metastasis combination therapy pharmaceutical composition, the composition
Including a effective amount of FOXP1 gene inhibitor and other at least one lung cancer therapy drugs.
The combination therapy pharmaceutical composition can be any one in following form:
One) independent preparation is respectively prepared in FOXP1 gene inhibitor and other lung cancer therapy drugs, the dosage form of preparation can
Identical or different, administration route also may be the same or different.
When other lung cancer therapy drugs are antibody, parenteral type is generally used.When other lung cancer therapy drugs are
When chemicals, form of medication can be relatively abundanter, and can be gastrointestinal administration can also be parenteral administration.It is general to recommend
For the known administration route administration of each chemicals.
Two) FOXP1 gene inhibitor and other lung cancer therapy drugs are configured to compound preparation, pressed down by FOXP1 gene
Preparation and other lung cancer therapy drugs can be used the two being configured to compound using the administration of identical administration route and when applying simultaneously
The form of preparation.
Further, the lung cancer therapy can be the drug for inhibiting lung cancer increment, tumor vessel hyperplasia, be also possible to it
He has the drug for inhibiting lung cancer metastasis function.
Another aspect of the invention provides a kind of method for inhibiting lung cancer metastasis, a effective amount of to apply to object
FOXP1 gene inhibitor and inhibits lung cancer metastasis drugs to a effective amount of other of object application and/or to object implement other
Inhibit lung cancer metastasis means.
A effective amount of FOXP1 gene inhibitor and other at least one a effective amount of suppressions can concurrently or sequentially be given
Lung cancer metastasis drug processed.
Be based on FOXP1 gene present invention firstly discovers that inhibition lung cancer metastasis target spot, with FOXP1 gene inhibitor with
Other outer effects for inhibiting at least play curative effect addition in lung cancer metastasis combination therapies, further enhance inhibition
Lung cancer metastasis effect.
Others inhibition lung cancer metastasis drug includes but is not limited to: antibody drug, chemicals or target medicinal etc..
The FOXP1 gene inhibitor can be gastrointestinal administration or parenteral.Described other inhibit lung cancer to turn
Moving drug can be gastrointestinal administration or parenteral.For antibody drug, parenteral is generally used.
Another aspect of the present invention, providing FOXP1 gene inhibitor in preparation has any one of following or multinomial effect
Drug in purposes: inhibit lung carcinoma cell multiplication rate, change lung carcinoma cell period profile, inhibit cancerous lung tissue growth.
Another aspect of the present invention provides FOXP1 and is preparing or screening the use in lung cancer metastasis diagnostic reagent
On the way.
Further, the FOXP1 is biomarker or serum biomarkers.
Above content includes two aspects, first, FOXP1 is used to prepare lung cancer metastasis diagnosis diagnostic reagent, is referred to FOXP1
It is applied to the preparation of lung cancer metastasis diagnostic reagent as lung cancer metastasis diagnosis index, it can be using FOXP1 as standard items or the positive
Control, the detection for FOXP1 in serum；Second, FOXP1 for screen lung cancer metastasis diagnostic reagent refer to using FOXP1 as
Lung cancer identifies the reagent of target sieving specific recognition FOXP1, thus as lung cancer metastasis diagnostic reagent, to detect FOXP1 base
Because of high expression type lung cancer.
Another aspect of the present invention provides purposes of the specific recognition agent of FOXP1 in lung cancer metastasis diagnosis.
FOXP1 can be used as a kind of biomarker.
Another aspect of the present invention provides the agent of FOXP1 specific recognition in preparation lung cancer metastasis diagnostic reagent
Purposes.
FOXP1 specific recognition agent is the antibody or ligand for referring to specific binding FOXP1.Further, described
Antibody is monoclonal antibody or polyclonal antibody.
Another aspect of the present invention provides a kind of lung cancer metastasis diagnostic reagent, contains specificity in the kit
Identify the reagent of FOXP1.
Another aspect of the present invention provides a kind of method of screening inhibition lung cancer metastasis drug, which comprises
(1) system of expression FOXP1 is handled with candidate substances；With
(2) expression of FOXP1 in the system is detected.
As described above, FOXP1 gene inhibitor of the invention preparation inhibit lung cancer metastasis drug in purposes, have with
It is lower the utility model has the advantages that
By the study found that FOXP1 high expression be the increased mark of lung carcinoma cell transfer ability, inhibited using inhibitor
The expression of FOXP1 can effectively inhibit lung cancer metastasis, inhibit the degree of transfer directly proportional to the degree of FOXP1 is inhibited.
Detailed description of the invention
Fig. 1 be shown as to transfer intermediate state lung cell A549 carry out classics TGFb induce after, epithelial cell between fill
The schematic diagram of qualitative change；
Fig. 2 is shown as after carrying out the induction of epithelium mesenchyma to transfer intermediate state lung cell A549, on the expression quantity of FOXP1
Rise schematic diagram；
Fig. 3 is shown as after carrying out the induction of epithelium mesenchyma to transfer intermediate state lung cell A549, then inhibits FOXP1 that can make
Epithelium status diagram is returned to transfer intermediate state lung cell A549.
Specific embodiment
Illustrate embodiments of the present invention below by way of specific specific example, those skilled in the art can be by this specification
Other advantages and efficacy of the present invention can be easily understood for disclosed content.The present invention can also pass through in addition different specific realities
The mode of applying is embodied or practiced, the various details in this specification can also based on different viewpoints and application, without departing from
Various modifications or alterations are carried out under spirit of the invention.It should be clear that the process equipment or device that are not indicated specifically in the following example
It is all made of conventional equipment or device in the art.
Before further describing the specific embodiments of the present invention, it should be appreciated that protection scope of the present invention is not limited to down
State specific specific embodiment；It is also understood that term used in the embodiment of the present invention is specific specific in order to describe
Embodiment, rather than limiting the scope of protection of the present invention；In description of the invention and claims, unless in text
In addition explicitly point out, singular "one", " one " and " this " include plural form.
When embodiment provides numberical range, it should be appreciated that except non-present invention is otherwise noted, two ends of each numberical range
Any one numerical value can be selected between point and two endpoints.Unless otherwise defined, the present invention used in all technologies and
Scientific term is identical as the normally understood meaning of those skilled in the art of the present technique.Except specific method, equipment used in embodiment,
Outside material, grasp and record of the invention according to those skilled in the art to the prior art can also be used and this
Any method, equipment and the material of the similar or equivalent prior art of method described in inventive embodiments, equipment, material come real
The existing present invention.
FOXP1, sequence can refer to NCBIID:27086.
Research is found: the epithelium mesenchyma progress faster of the high expression expression lung carcinoma cell of FOXP1 dynamic, and epithelium mesenchyma
Transformation can all occur in 90% metastases, therefore show that the high expression of FOXP1 dynamic is that lung carcinoma cell transfer ability increases
Marker.Experiment discovery, MCF10A increased to transfer ability carry out knockout FOXP1, mesenchymal cell can be made to return to epithelium
State, it is seen that inhibit its transfer that there is significant therapeutic potential FOXP1 gene high expression type lung cancer.
FOXP1 gene inhibitor
FOXP1 gene inhibitor has the function of inhibiting the substance of FOXP1 gene expression.Can have for FOXP1 gene
Inhibiting effect includes but is not limited to: reducing the transcription or expression of FOXP1 gene.
Inhibitor using FOXP1 gene is the oncotherapy of one of main active ingredient or main active ingredient preparation
Drug.In general, will also include one or more according to the needs of different dosage forms in addition to effective ingredient in drug and pharmaceutically may be used
The carrier or auxiliary material of receiving.
" pharmaceutically acceptable " refer to when biomolecule ontology and composition is appropriate give animal or people when, they will not
Generate unfavorable, allergy or other adverse reactions.
" pharmaceutically acceptable auxiliary material " refers to should be compatible with FOXP1 inhibitor, can be blended without logical
The effect of pharmaceutical composition is greatly lowered in normal situation.It can be used as some substances of pharmaceutically acceptable carrier or auxiliary material
Specific example is carbohydrate, such as lactose, dextrose and saccharose；Starch, such as cornstarch and potato starch；Cellulose and its derivative
Object, such as sodium carboxymethylcellulose pyce, ethyl cellulose and methylcellulose；Tragacanth powder；Malt；Gelatin；Talcum；Solid lubrication
Agent, such as stearic acid and magnesium stearate；Calcium sulfate；Vegetable oil, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and can
It can oil；Polyalcohol, such as the third two liquor-saturated, glycerol, D-sorbite, mannitol and polyethylene glycol；Alginic acid；Emulsifier, such as Tween；
Wetting agent, such as NaLS；Colorant；Flavoring agent；Tablet agent, stabilizer；Antioxidant；Preservative；Apirogen water etc.,
Seep salting liquid；With phosphate buffer etc..These substances are used to help the stability of formula as needed or help to improve work
Property or its biological effectiveness generate acceptable mouthfeel or smell in the case where oral.
Combination therapy pharmaceutical composition and method of administration:
The combination therapy pharmaceutical composition can be any one in following form:
One) independent preparation is respectively prepared in FOXP1 gene inhibitor and other lung cancer therapy drugs, the dosage form of preparation can
Identical or different, administration route also may be the same or different.In use, can several medicines use simultaneously, can also several medicines successively use.
When consecutive administration, formerly still it should apply other drugs to body in body effective period with drug.
Two) FOXP1 gene inhibitor and other lung cancer therapy drugs are configured to compound preparation, inhibited in FOXP1 gene
Agent and other lung cancer therapy drugs can be used the two being configured to compound system using the administration of identical administration route and when applying simultaneously
The form of agent.
A effective amount of FOXP1 gene inhibitor and other at least one a effective amount of lungs can concurrently or sequentially be given
Cancer therapeutic agent.
In use, a effective amount of FOXP1 gene inhibitor and other a effective amount of lung cancer therapy drugs can be used simultaneously,
A effective amount of FOXP1 gene inhibitor and other a effective amount of lung cancer therapy drugs can also successively be used.When consecutive administration, answer
Still apply other drugs to organism in organism effective period with drug when formerly.
Its transfer ability increases after the lung cell A549 that embodiment a pair shifts intermediate state induces
TGF-β (4ng/ml is purchased from Invitrogen) is added to A549 cell to be induced, TGF-β is complete using cell
Culture medium is prepared, and replaces culture medium once containing TGF-β in Induction Process daily.Cell is after 48 small inductions
Metamorphosis occurs, carries out mesenchyma state, micro- sem observation can be passed through.
As a result as shown in Figure 1, A is intermediate state A549 cell, B is the A549 cell after induction, it is seen that A549 cell can
Transfering state is induced to from intermediate state.
The lung cell A549 that embodiment two shifts intermediate state, which is overexpressed FOXP1, can increase its transfer ability
Method to A549 cell by transiently transfecting is turned using lipofactamine 2000 with every 1,000,000 cells
The amount of dye 5ug exogenous DNA is transferred to FOXP1 and is overexpressed plasmid.After 48 small inductions metamorphosis can occur for cell,
Carry out mesenchyma state.
By micro- sem observation, as a result as shown in Figure 2, it is seen that control group is transferred to the control plasmid of only over-express vector
Vector then has found that cellular morphology does not change.Significant changes occur for the cellular morphology of experimental group, carry out mesenchyma state.
The A549 cell increased to transfer ability of embodiment three, which carries out knockout FOXP1, can make mesenchymal cell return to epithelium shape
State
FOXP1 is knocked out using the method for RNA I to the A549 cell shifted.
As a result as shown in Figure 3, it is possible to find represent the marker CDH1 expression up-regulation of epithelium, and represent the marker of mesenchyma
CDH2 is lowered, and illustrates that cell returns to epithelium state.
Above embodiment is can not to be interpreted as in order to illustrate embodiment disclosed by the invention to limit of the invention
System.In addition, in various modifications and invention listed herein method, composition variation, do not departing from the scope of the present invention
Be obvious for those skilled in the art under the premise of spirit.Although having combined of the invention a variety of specific
Preferred embodiment has carried out specific description to the present invention, it is to be understood that, the present invention should not be limited only to these specific embodiments.
In fact, various obviously modify as described above for those skilled in the art to obtain invention all should include
Within the scope of the invention.
Claims (10)
1.FOXP1 gene inhibitor is preparing or is screening the purposes inhibited in lung cancer metastasis drug.
2. purposes according to claim 1, it is characterised in that: the lung cancer is the high expression type lung cancer of FOXP1 dynamic.
3. a kind of drug for inhibiting lung cancer metastasis, it is characterised in that: the FOXP1 gene in the drug comprising effective therapeutic dose presses down
Preparation.
4. a kind of inhibition lung cancer metastasis combination therapy pharmaceutical composition, it is characterised in that: the composition includes a effective amount of
FOXP1 gene inhibitor and other at least one lung cancer therapy drugs.
5.FOXP1 is preparing or is screening the purposes in lung cancer metastasis diagnostic reagent.
Purposes of the 6.FOXP1 specific recognition agent in preparation lung cancer metastasis diagnostic reagent.
7. a kind of lung cancer metastasis diagnostic reagent, which is characterized in that the reagent containing specific recognition FOXP1 in the kit.
8. lung cancer metastasis diagnostic reagent according to claim 7, it is characterised in that: the lung cancer is the high table of FOXP1 dynamic
Up to type lung cancer.
Purposes of the 9.FOXP1 as biomarker.
10. a kind of method that screening inhibits lung cancer metastasis drug, which comprises
(1) system of expression FOXP1 is handled with candidate substances；With
(2) expression of FOXP1 in the system is detected.
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2019
- 2019-03-15 CN CN201910198549.9A patent/CN109939234A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013063019A1 (en) * | 2011-10-28 | 2013-05-02 | The Wistar Institute Of Anatomy And Biology | Methods and compositions for enhancing the therapeutic effect of anti-tumor t cells |
| CN105126098A (en) * | 2015-07-31 | 2015-12-09 | 南京壬辰生物科技有限公司 | Application of monoclonal antibody NJ001-1 to preparation of drug for inhibiting invasion and metastasis of NSCLC (non-small-cell lung cancer) |
| CN107299084A (en) * | 2017-06-27 | 2017-10-27 | 中国人民解放军第二军医大学第二附属医院 | Occur application of the circulating tumor stem cell of Epithelial and stromal in lung cancer propagation, resistance and transfer disease |
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Application publication date: 20190628 |