CN108295259A - Pass through the method and drug of miR-6792-3p progress anticancers and its application - Google Patents
Pass through the method and drug of miR-6792-3p progress anticancers and its application Download PDFInfo
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- CN108295259A CN108295259A CN201710024770.3A CN201710024770A CN108295259A CN 108295259 A CN108295259 A CN 108295259A CN 201710024770 A CN201710024770 A CN 201710024770A CN 108295259 A CN108295259 A CN 108295259A
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- C12N2310/141—MicroRNAs, miRNAs
Abstract
The present invention relates to biomedicine field, disclose through the method and drug of miR 6792 3p progress anticancers and its application.Specifically, the invention discloses application of the expression of the function of inhibiting 6792 3p of miR and/or the target gene for promoting miR 6792 3p in prevention and/or treating cancer and disease similar with its symptom, especially prepare for prevent and/or the drug and/or food for the treatment of cancer and disease similar with its symptom in application.The inhibitor of 6792 3p of miR provided by the invention can fully inhibit the function of 6792 3p of miR and promote the expression of its target gene.This explanation can effectively prevent when by the inhibitor for individual administration and/or treat that miR 6792 3p high are expressed and/or its target gene crosses disease caused by low expression.
Description
Technical field
The present invention relates to biomedicine fields, and in particular, to inhibits the function of miR-6792-3p and/or promotes miR-
Application of the expression of the target gene of 6792-3p in prevention and/or treating cancer and disease similar with its symptom, a kind of miR-
6792-3p inhibitor, a kind of side of the expression of function inhibiting miR-6792-3p and/or the target gene for promoting miR-6792-3p
Method, a kind of pharmaceutical composition, a method of prevent and/or treating cancer and they inhibit miR-6792-3p function
And/or promote miR-6792-3p target gene expression in application and they prepare for inhibiting miR-6792-3p
Function and/or promote miR-6792-3p target gene expression drug in application.
Background technology
MicroRNA (microRNA, miRNA) is the non-coding RNA molecule that a kind of length is 16-25nt
(www.mirbase.org), can by with target gene partial complementarity match identify and silencing of target genes rna expression and/or
Protein expression.After ripe microRNA is loaded on the silencing complex (RISC) of RNA inductions, by base pairing come with target base
Because the complementary series in mRNA 3'-UTR is combined, to cause the degradation of mRNA and/or inhibit the translation of its protein.It is micro-
The second at the ends RNA 5' to the 8th nucleotide is referred to as " core sequence ", this seven nucleotide and the mutual of target gene recruit
To be the key that identification target gene, pairing degree it is higher, in conjunction with adjust target gene possibility and ability it is bigger.It is micro- simultaneously
The complementary pairing of other sequences and target gene except RNA " core sequence " can also enhance its energy for combining and regulating and controlling target gene
Power.It is the expression for identifying and adjusting target gene by non-fully matching just because of microRNA, a microRNA is just enable to exist
One adjusts to varying degrees multiple target genes simultaneously into the cell.
More and more document report microRNAs cancer generation, shift important function, and inhibition or overexpression
Certain microRNAs can play the role of anticancer.Therefore, it is quite necessary to develop the anticancer drug based on microRNA.
Invention content
The purpose of the invention is to develop the new anticancer drug based on microRNA.
To achieve the goals above, in a first aspect, the present invention provides the function of inhibiting miR-6792-3p and/or promotions
Application of the expression of the target gene of miR-6792-3p in prevention and/or treating cancer and disease similar with its symptom.
Second aspect, the present invention also provides a kind of miR-6792-3p inhibitor, wherein the miR-6792-3p inhibits
Agent is the antisense oligonucleotides of miR-6792-3p, the promoter of the siRNA of miR-6792-3p and inhibition miR-6792-3p
Active nucleotide and the like.
The third aspect, the present invention also provides a kind of function inhibiting miR-6792-3p and/or promotion miR-6792-3p
Target gene expression method, this method includes：By the target cell of miR-6792-3p inhibitor and expression miR-6792-3p
Contact, wherein the miR-6792-3p inhibitor is above-mentioned miR-6792-3p inhibitor.
Fourth aspect, the present invention also provides a kind of pharmaceutical compositions, wherein the pharmaceutical composition contains above-mentioned miR-
6792-3p inhibitor and pharmaceutically acceptable carrier.
5th aspect, the present invention also provides a kind of prevention and/or the methods for the treatment of cancer, wherein this method includes：Suppression
The expression of the function of miR-6792-3p processed and/or the target gene of promotion miR-6792-3p；Or above-mentioned miR-6792-3p is pressed down
Preparation and/or aforementioned pharmaceutical compositions are administered to subject.
6th aspect, the present invention also provides above-mentioned miR-6792-3p inhibitor, the work(of above-mentioned inhibition miR-6792-3p
It can and/or promote the method method of expression of the target gene of miR-6792-3p, aforementioned pharmaceutical compositions, above-mentioned prevention and/or control
Treat method the answering in the expression of the function of inhibiting miR-6792-3p and/or the target gene for promoting miR-6792-3p of cancer
With.
7th aspect, the present invention also provides above-mentioned miR-6792-3p inhibitor, aforementioned pharmaceutical compositions to be used in preparation
Inhibit the function of miR-6792-3p and/or promotes the application in the drug of the expression of the target gene of miR-6792-3p.
The present invention is by contacting miR-6792-3p inhibitor with the target cell of excessively high expression miR-6792-3p, energy
Enough functions of fully inhibiting miR-6792-3p (include combination or the reduction miR- of inhibition miR-6792-3p and its target gene
The expression quantity of 6792-3p, to inhibit the function of miR-6792-3p) and/or promote its target gene (QSOX1, TNFSF15,
PHLDA3, HRK, BCL10, BTG2, SULF2, DAB2IP, SIK1, TP53, CYFIP2 and CABLES1) at least two table
It reaches.The excessively high tables of miR-6792-3p can effectively be prevented and/or be treated to this explanation when by the inhibitor for individual administration
Reach and/or its target gene (QSOX1, TNFSF15, PHLDA3, HRK, BCL10, BTG2, SULF2, DAB2IP, SIK1, TP53,
CYFIP2 and CABLES1) at least two unconventionality expressions caused by disease, for example, various cancers or similar to its symptom
Disease, especially at least one of liver cancer, lung cancer and cutaneum carcinoma.
Other features and advantages of the present invention will be described in detail in subsequent specific embodiment part.
Description of the drawings
Attached drawing is to be used to provide further understanding of the present invention, an and part for constitution instruction, with following tool
Body embodiment is used to explain the present invention together, but is not construed as limiting the invention.In the accompanying drawings：
The antisense oligonucleotides that miR-6792-3p is shown in Fig. 1 inhibits/kills the result figure of liver cancer cells HuH-7；
The antisense oligonucleotides that miR-6792-3p is shown in Fig. 2 inhibits/kills the result figure of hepatocellular carcinoma H22；
The antisense oligonucleotides that miR-6792-3p is shown in Fig. 3 inhibits/kills the result figure of lung cell A549；
Growth effect knot of the antisense oligonucleotides to normal human fibroblasts of miR-6792-3p is shown in Fig. 4
Fruit is schemed；
Result figures of the miR-6792-3p to the inhibiting effect of expression of target gene is shown in Fig. 5；
The antisense oligonucleotides of the antisense oligonucleotides of miR-6792-3p and the miR-6792-3p of mispairing is shown in Fig. 6
To the result figure of the inhibiting effect of miR-6792-3p functions；
The antisense oligonucleotides that the miR-6792-3p of thio-modification is shown in Fig. 7 inhibits/kills liver cancer cells HuH-7
Result figure.
Specific implementation mode
The specific implementation mode of the present invention is described in detail below.It should be understood that described herein specific
Embodiment is merely to illustrate and explain the present invention, and is not intended to restrict the invention.
The endpoint of disclosed range and any value are not limited to the accurate range or value herein, these ranges or
Value should be understood as comprising the value close to these ranges or value.For numberical range, between the endpoint value of each range, respectively
It can be combined with each other between the endpoint value of a range and individual point value, and individually between point value and obtain one or more
New numberical range, these numberical ranges should be considered as specific open herein.
In a first aspect, the present invention provides the function of inhibiting miR-6792-3p and/or the target bases of promotion miR-6792-3p
Application of the expression of cause in prevention and/or treating cancer and disease similar with its symptom is especially being prepared for preventing
And/or the drug and/or the application in food for the treatment of cancer and disease similar with its symptom.
In the present invention, term " function of inhibiting miR-6792-3p " refers to inhibiting miR-6792-3p and its target gene
In conjunction with or reduce miR-6792-3p expression quantity.
In the present invention, the cancer can be at least one of liver cancer, lung cancer and cutaneum carcinoma.
In situations where it is preferred, miR-6792-3p has SEQ ID NO：Nucleotide sequence shown in 1.
In the present invention, the target gene of the miR-6792-3p can be QSOX1, TNFSF15, PHLDA3, HRK,
At least two, at least three kinds, at least four in BCL10, BTG2, SULF2, DAB2IP, SIK1, TP53, CYFIP2 and CABLES1
It plants, at least five kinds, at least six kinds, at least seven kinds, at least eight kinds, at least nine kinds or at least ten kinds.
Second aspect, the present invention also provides miR-6792-3p inhibitor, which can inhibit
The expression of the function of miR-6792-3p and/or the target gene of promotion miR-6792-3p comprising but be not limited to following several：
1) micromolecular compound
MiR-6792-3p inhibitor includes but is not limited to naturally occurring or artificial synthesized micromolecular compound, this kind of
Micromolecular compound directly acts on miR-6792-3p and to be increased by the expression quantity of the miR-6792-3p target genes adjusted,
Typically molecular weight is more than 50 and less than the organic compound of 2500 dalton.This kind of candidate compound possesses and protein, special
It is not the functional group of interaction of hydrogen bond, and generally comprises at least one amine, carbonyl, hydroxyl or carboxylic group.These small point
Sub- miR-6792-3p inhibitor can be found by suitable screening technique or other methods.
2) antisense oligonucleotides
The antisense oligonucleotides can by inhibiting the function of miR-6792-3p with binding directly for miR-6792-3p,
And then promoting the expression of the target gene of miR-6792-3p, the antisense oligonucleotides includes antisense RNA and antisense DNA.It is preferred that
, the antisense oligonucleotides and miR-6792-3p are complementary, the length with 12-30 nucleotide, and have at least with
The sequence of 5 ' the 1-8 nucleotide complementations in end of miR-6792-3p.
It is well known in the art that microRNA can be identified by being matched with target gene partial complementarity and the table of silencing of target genes
It reaches and/or translates, similarly, miR-6792-3p also can be competitive by conjunction with the nucleotide sequence with its partial complementarity
The function of inhibiting its own, to raise miR-6792-3p target gene expression.Therefore, in the present invention, term " complementation " is no
Only include complete complementary, further includes partial complementarity (or non-fully complementary).In addition, 60% complementation refers to miR-6792-3p's
On the basis of sequence, the base complementrity with therein 60%.
Therefore, the antisense oligonucleotides has following nucleotide sequence：
a)SEQ ID NO：Nucleotide sequence shown in 2；
B) in SEQ ID NO：In nucleotide sequence shown in 2 through missing, substitution or one or several nucleotide of addition and
With miR-6792-3p complete complementaries or the nucleotide sequence of partial complementarity.
In the case of non-fully complementary, that is, when the antisense oligonucleotides is by SEQ ID NO：Shown in 2
Nucleotide sequence in the case of the nucleotide sequence that is obtained through missing, substitution or one or several nucleotide of addition, mutual
Mend nucleotide region in, the antisense oligonucleotides preferably should with miR-6792-3p at least have 60%, 65%, 70%,
75%, 80%, 85%, 90% or 95% complementation.More preferably, in the nucleotide area at 5 ' 1-8, the ends of miR-6792-3p
In domain, the antisense oligonucleotides at most mispairing with 2 nucleotide.
As described above, further excellent in the case where the antisense oligonucleotides and miR-6792-3p are non-fully complementary
Choosing, with SEQ ID NO：2 compare, and will at most have 10,9,8,7,6,5,3,2 or 1 in length
The difference of nucleotide.
In a preferred case, non-fully complementary antisense oligonucleotides has SEQ ID with miR-6792-3p
NO：Nucleotide sequence described in 3.
In addition, few to improve the antisense the invention also includes some conventional modifications are carried out to the antisense oligonucleotides
The stability and activity of nucleotide, these are all belonged to the scope of the present invention.
In the present invention, the antisense oligonucleotides contains nucleotide groups (or nucleotide residue) as basic structure list
Member, the nucleotide groups contain phosphate group, ribose groups and base, and under preferable case, the antisense oligonucleotides contains
The nucleotide groups of at least one modification.The nucleotide groups of the modification will not cause the antisense oligonucleotides to inhibit miR-
The function of the expression of the function of 6792-3p and/or the target gene of promotion miR-6792-3p is lost.
In the present invention, the nucleotide groups of the modification are the nucleotide that phosphate group and/or ribose groups are modified
Group.For example, the modification of phosphate group refers to modifying the oxygen in phosphate group, including thio-modification, boranated modification
Deng.Phosphate group is modified the structure for capableing of stabilization of nucleic acids, keeps the high specific and high-affinity of base pairing.Preferably,
The nucleotide groups of thio-modification refer to the core that nonbridging oxygen atom in wherein all phosphodiester bonds is replaced as sulphur atom
Thuja acid group.
The modification of ribose groups refer to 2 ' in ribose groups-modification of hydroxyl (2 '-OH).In 2 '-hydroxyls of ribose groups
After base location introduces certain substituent groups such as methoxyl group or fluorine, makes ribalgilase be not easy to cut nucleic acid, thereby increase nucleic acid
Stability makes nucleic acid have the stronger performance for resisting nuclease hydrolysis.Modification to 2 '-hydroxyls in nucleotide pentose includes
2 '-fluorine modify (2 '-fluro modification), 2 '-methoxyl groups modification (2 '-OME), 2 '-methoxyethyls modification (2 '-
MOE), 2 ' -2,4- dinitrophenol modification (2 '-DNP modification), lock nucleic acid modification (LNA modification),
2 '-amido modified (2 '-Amino modification), 2 '-deoxidations modification (2 '-Deoxy modification) etc..
In situations where it is preferred, the antisense oligonucleotides contains the nucleotide groups of at least one modification, the modification
Nucleotide groups be thio-modification nucleotide groups and/or lock nucleic acid modification nucleotide groups；It is highly preferred that described anti-
Oligonucleotide has SEQ ID NO：Nucleotide sequence shown in 2, and the nucleotidyl at 1-5 and 17-21, wherein 5 ' ends
Phosphate group in group is by thio-modification.
The present invention is pointed out that with the complete of characteristic as above or non-fully complementary RNA also the present invention's
In protection domain.Consider stability in the cell, the preferably described antisense oligonucleotides of the present invention is DNA.
3) RNAi reagents
It is well known in the art that RNA interference (RNA interference, RNAi) is by double-stranded RNA (double-
Stranded RNA, dsRNA) induce, homologous mRNA efficient selective degradation the phenomenon that.It can be special due to the use of RNAi technology
The expression of specific gene is rejected or closed to the opposite sex, thus the technology have been widely used for exploring gene function and communicable disease and
The therapy field of malignant tumour.
RNAi reagents can be siRNA molecule, and typically one can theoretically form bobby pin (small
Hairpin) the single-stranded deoxy-oligonucleotide (shRNA) of structure, length do not exceed 100 nucleotide generally, typically not
Can be more than 75 nucleotide；The either double-strand deoxy-oligonucleotide (siRNA) of a 15-30bp, most typically 20-
23bp。
In some applications, RNAi reagents can also be the template DNA for encoding shRNA or siRNA.These template DNAs
It is likely to be present in carrier, such as the carriers such as plasmid vector or viral vectors；Can not also exist with carrier, only compile for one section
The template DNA of code shRNA or siRNA adds a common promoter sequence segment for controlling its transcription.
In the present invention, the miR-6792-3p inhibitor is the siRNA of miR-6792-3p；Preferably, described
The nucleotide groups that siRNA contains at least one modification (modification mode is referred to antisense oligonucleotides acid moieties)；It is more excellent
The nucleotide groups modified described in selection of land are the nucleotide groups of dimethoxy modification and/or short peptide modified nucleotide groups.
4)Inhibit the nucleotide and the like of promoter activity
MiR-6792-3p inhibitor of the present invention can also include the promoter activity for inhibiting miR-6792-3p
Nucleotide and the like.Specifically, the nucleotide of promoter activity and the like for inhibiting miR-6792-3p can
It is combined with the promoter of miR-6792-3p, and inhibits its promoter activity, for example, morpholinyl (morpholino) modification
Nucleotide and the like.
The third aspect, the present invention also provides a kind of function inhibiting miR-6792-3p and/or promotion miR-6792-3p
Target gene expression method, this method includes：By the target cell of miR-6792-3p inhibitor and expression miR-6792-3p
Contact, wherein the concrete type of the miR-6792-3p inhibitor can with as described above, in order to avoid unnecessary repetition,
This is no longer described in detail.
Preferably, the target gene of the miR-6792-3p be QSOX1, TNFSF15, PHLDA3, HRK, BCL10, BTG2,
At least two, at least three kinds, at least four, at least five in SULF2, DAB2IP, SIK1, TP53, CYFIP2 and CABLES1
It plants, at least six kinds, at least seven kinds, at least eight kinds, at least nine kinds or at least ten kinds；
In the present invention, when the miR-6792-3p inhibitor is above-mentioned antisense oligonucleotides, due to antisense widow
Nucleotide can with miR-6792-3p complementary (complete complementary or partial complementarity), therefore, when the antisense oligonucleotides in vivo
Or when being contacted in vitro with the target cell of expression miR-6792-3p, the antisense oligonucleotides can carry out mutual with miR-6792-3p
It recruits pair, and inhibits miR-6792-3p and the combination (that is, inhibiting activity of miR-6792-3p) of its target gene, to break
Silences of the miR-6792-3p to its target gene.
In the present invention, the method includes introducing the antisense oligonucleotides of a effective amount of and miR-6792-3p complementations
Into the target cell of expression miR-6792-3p.Wherein, described " effective quantity " according to expression miR-6792-3p target cell not
It is same and different, and certain dosage effect is showed, those skilled in the art are according to conventional laboratory facilities and institute
The expected purpose reached can readily determine the effective quantity of the target cell for expression miR-6792-3p.
It, can be by way of conventional nucleic acid administration by antisense widow's core of the present invention when the contact is contacts in vivo
Thuja acid is administered in individual.It is, for example, possible to use following mode carries out the administration of the antisense oligonucleotides：The antisense is few
Nucleotide can be administered by way of virus infection, microinjection or Vesicle fusion, or can also be noted by jet stream
The mode penetrated is used for the intramuscular delivery of the antisense oligonucleotides.Alternatively, it is also possible to which the antisense oligonucleotides is coated to gold
On particle, then percutaneous dosing is carried out by the known manners such as particle bombardment equipment or " particle gun ".These are that this field is normal
The technological means of rule, this is no longer going to repeat them by the present invention.
Furthermore the antisense oligonucleotides can also be introduced into expression miR-6792-3p's in a manner of expression vector
In target cell.This kind of expression vector has the convenience restriction site positioned at promotor-proximal sequence in order to the antisense widow core
The insertion of thuja acid.Wherein, the transcription box in the expression vector may include transcription initiation region, target gene or its segment and
Transcription termination region.The carrier for example can be but be not limited to that plasmid, virus etc., those skilled in the art can basis
Actual conditions are voluntarily selected.
In addition, the antisense oligonucleotides can also be introduced in expression by way of respiratory tract spray delivery
In the target cell of miR-6792-3p, such as it is administered by way of being prepared into spray formulation.
In addition, the mode that the antisense oligonucleotides can also be administered orally is to be introduced in expression miR-
It in the target cell of 6792-3p, such as is administered by way of being prepared into oral preparation, or by by the antisense oligonucleotides
The mode mixed with food is administered orally.
When it is described contact be vitro exposure when, can by by the antisense oligonucleotides or contain the antisense oligonucleotides
The carrier (for example, drug containing the antisense oligonucleotides) of acid, which is added directly into culture, the target of expression miR-6792-3p
It is contacted in the matrix of cell, and to being imported with the expression of the antisense oligonucleotides under conventional cell culture condition
The target cell of miR-6792-3p is cultivated.
In the present invention, when the miR-6792-3p inhibitor is above-mentioned RNAi reagents, the method includes will be effective
The siRNA of the miR-6792-3p of amount is introduced into the target cell of expression miR-6792-3p.The RNAi reagents and expression
The contact of the target cell of miR-6792-3p may be internal contact or vitro exposure.The effective quantity of the RNAi reagents and
Medication is referred to the as above description to antisense oligonucleotides and carries out, and in order to avoid unnecessary repetition, the present invention is herein
No longer it is described in detail.
Fourth aspect, the present invention also provides a kind of pharmaceutical compositions, wherein the pharmaceutical composition contains above-mentioned miR-
6792-3p inhibitor and pharmaceutically acceptable carrier.
In the pharmaceutical composition of the present invention, miR-6792-3p inhibitor as described above as active constituent contains
Amount can change in the larger context, for example, can be 0.0001-99.99 weight %, preferably 0.01-99 weight %, more
Preferably 1-70 weight %, further preferably 5-30 weight %.
In the present invention, described pharmaceutical composition can be prepared as the various dosage forms of this field routine, the present invention to this simultaneously
It is not particularly limited, for example, solid can be configured to, semisolid, liquid or gas form, for example, tablet, capsule, the wine made of broomcorn millet
Agent, suspension, syrup, powder, particle, ointment, suppository, injection, inhalant, aerosol etc., the present invention be not another herein
One enumerates.
Therefore, the administrations of diversified forms can also be carried out according to the difference of pharmaceutical dosage form, such as, but not limited to, take orally to
Medicine, buccal administration, rectally, parenteral, Intraperitoneal medication, respiratory tract inhalation, intradermal administration, percutaneous dosing.
Wherein, the pharmaceutically acceptable carrier can carry out different selections according to the difference of dosage form, these are
It is known in those skilled in the art.Such as, but not limited to, the pharmaceutically acceptable carrier can be starch, colloid,
Lactose, glucose, sucrose, microcrystalline cellulose, kaolin, mannitol, calcium monohydrogen phosphate, sodium chloride, alginic acid etc..
Furthermore it is also possible to which conventional additive such as solubilizer, isotonic agent, suspending agent, emulsifier, stabilizer and anti-corrosion is added
Agent.
In addition, the pharmaceutically acceptable carrier can also be specific including that can improve the antisense oligonucleotides targeting
The targeting agent of organ or tissue or cell, the targeting agent for example can be targeting peptides, can also include that can carry institute
It states antisense oligonucleotides to be easier to wear membrane reagent, such as cell-penetrating peptide into the target cell of expression miR-6792-3p, liposome,
Microcapsule bubble and membrane lipoprotein etc..
In the present invention, flavoring agent can also be added in described pharmaceutical composition, for example, peppermint, wintergreen etc..Separately
Outside, colorant can also be added in described pharmaceutical composition so that prepared dosage form has certain attraction in appearance
Power, or distinguished with other products.
In the present invention, the antisense oligonucleotides can also can play the conventional medicine progress of similar effect with other
Combine to be prepared into combined medicinal composition.
5th aspect, the present invention also provides a kind of preventions and/or the method for the treatment of cancer, this method to include：Inhibit
The expression of the function of miR-6792-3p and/or the target gene of promotion miR-6792-3p；Or above-mentioned miR-6792-3p is inhibited
Agent and/or aforementioned pharmaceutical compositions are administered to subject.
In the present invention, the effective quantity of the administration, mode and dosage form are as described above, details are not described herein.
In situations where it is preferred, the subject be liver cancer subject, lung cancer subject and cutaneum carcinoma subject in extremely
Few one；It is highly preferred that the target gene of the internal expression miR-6792-3p and/or miR-6792-3p of the subject；Into one
Preferably, in the internal of the subject, the expression of target gene of the excessively high expression of miR-6792-3p and/or miR-6792-3p are different for step
Often (including too high or too low).
In situations where it is preferred, the target gene of the miR-6792-3p be QSOX1, TNFSF15, PHLDA3, HRK,
At least two, at least three kinds, at least four in BCL10, BTG2, SULF2, DAB2IP, SIK1, TP53, CYFIP2 and CABLES1
It plants, at least five kinds, at least six kinds, at least seven kinds, at least eight kinds, at least nine kinds or at least ten kinds；
6th aspect, the present invention also provides above-mentioned miR-6792-3p inhibitor, the work(of above-mentioned inhibition miR-6792-3p
It can and/or promote method, aforementioned pharmaceutical compositions, above-mentioned prevention and/or the treatment cancer of the expression of the target gene of miR-6792-3p
Application of the method for disease in the expression of the function of inhibiting miR-6792-3p and/or the target gene for promoting miR-6792-3p；It is special
It is not the application in prevention and/or treating cancer and disease similar with its symptom；Preferably, the cancer is liver cancer, lung
At least one of cancer and cutaneum carcinoma；It is highly preferred that the target gene of the miR-6792-3p be QSOX1, TNFSF15,
In PHLDA3, HRK, BCL10, BTG2, SULF2, DAB2IP, SIK1, TP53, CYFIP2 and CABLES1 at least two, at least
Three kinds, at least four, at least five kinds, at least six kinds, at least seven kinds, at least eight kinds, at least nine kinds or at least ten kinds.
7th aspect, the present invention also provides above-mentioned miR-6792-3p inhibitor, aforementioned pharmaceutical compositions to be used in preparation
Inhibit the function of miR-6792-3p and/or promotes the application in the drug of the expression of the target gene of miR-6792-3p；Especially
Prepare for prevent and/or the drug for the treatment of cancer and disease similar with its symptom in application；Preferably, the cancer
For at least one of liver cancer, lung cancer and cutaneum carcinoma；It is highly preferred that the target gene of the miR-6792-3p be QSOX1,
In TNFSF15, PHLDA3, HRK, BCL10, BTG2, SULF2, DAB2IP, SIK1, TP53, CYFIP2 and CABLES1 at least
Two kinds, at least three kinds, at least four, at least five kinds, at least six kinds, at least seven kinds, at least eight kinds, at least nine kinds or at least ten
Kind.
In the present invention, the treatment refers to subject and the disease caused by miR-6792-3p or the relevant disease of state
The improvement of shape completely disappears, wherein the improvement on wide significance refers to reducing or increasing at least one parameter.Specific to this
Application, for example, can for target gene QSOX1, TNFSF15 of miR-6792-3p, PHLDA3, HRK, BCL10, BTG2, SULF2,
In DAB2IP, SIK1, TP53, CYFIP2 and CABLES1 at least two, at least three kinds, at least four, at least five kinds, at least
Six kinds, at least seven kinds, at least eight kinds, at least nine kinds or at least ten kinds of expression increases.
The present invention will be described in detail by way of examples below.
Embodiment 1
The present embodiment is used to illustrate the antisense oligonucleotides of miR-6792-3p provided by the invention to the external of cancer cell
Adjustment effect
Entrust the antisense oligonucleotides of the English dimension fine horse outstanding person artificial chemical synthesis miR-6792-3p of (Invitrogen) company
(miR-6792-3p ASO, such as SEQ ID NO：Shown in 2) and commission Ji Ma companies synthesis Polo samples kinases 1 (PKL1) siRNA
(positive-sense strand：Such as SEQ ID NO：Shown in 4, antisense strand：Such as SEQ ID NO：Shown in 5).
(1) effect of the antisense oligonucleotides of miR-6792-3p to liver cancer cells
Use miR-6792-3p in RT-PCR methods detection liver cancer cells HuH-7 (being purchased from ATCC) and HepG2 (being purchased from ATCC)
Expression.Using Trizol extracting HuH-7 cells, the total serum IgE of HepG2 cells and normal primary human liver cell, then
Take the RNA of 1ug anti-with Catch-All miRNA＆mRNA RT-PCR kits (the Kunshan bio tech ltd Peng Ji Kai Feng)
It is transcribed into cDNA, then by specification carries out Q-PCR detections.The result shows that compared with normal primary human liver cell (control),
MiR-6792-3p expresses higher in HuH-7 and HepG2 cells.
Liver cancer cells HuH-7 and HepG2 are seeded in respectively in 384 well culture plates, culture contains 10% tire ox in 50 μ L
In the DMEM culture mediums of serum.Cell incubator it is constant keep 37 DEG C and 5% CO2.With Lipofectamine 2000
(Invitrogen) respectively transfect 1 μM miR-6792-3p ASO or 40nM PKL1 siRNA (positive controls), or with
Machine sequence (negative control group, such as SEQ ID NO：Shown in 6), separately there is one group only to add the control wells (transfection reagent of transfection reagent
Group).Cell is fixed with 4% paraformaldehyde (PFA) after transfecting 72 hours, and cytometer is carried out after contaminating nucleus using DAPI
Number.As a result as depicted in figs. 1 and 2, wherein data indicate with mean+SD, n=3, * * * P<0.001, * * P<0.01.
It can be seen from Fig. 1 and 2 compared with negative control group, the siRNA (positive control) and miR-6792-3p of PKL1
ASO can be such that the number of HuH-7 and HepG2 cells significantly reduces；Also, compared with the siRNA of PKL1, miR-6792-3p
ASO makes the number of HuH-7 and HepG2 cells reduce more.
(2) effect of the antisense oligonucleotides of miR-6792-3p to lung carcinoma cell
It is carried out according to the method for step as above (1), the difference is that replacing walking using lung cell A549 (being purchased from ATCC)
Suddenly the liver cancer cells HuH-7 and HepG2 used in (1).
RT-PCR the result shows that, compared with normal primary human pneumonocyte's (control), miR-6792-3p is in A549 cells
Expression is higher.
The result (as shown in Figure 3) of cell count shows compared with negative control group, the siRNA (positive control) of PKL1
The number of A549 cells can be made to significantly reduce with miR-6792-3p ASO；Also, compared with the siRNA of PKL1, miR-
6792-3p ASO make the number of A549 cells reduce more.
(3) effect of the antisense oligonucleotides of miR-6792-3p to melanoma cells
It is carried out according to the method for step as above (1), the difference is that (being purchased from using melanoma cells SK-MEL-28
ATCC the liver cancer cells HuH-7 and HepG2 that are used in step (1)) are replaced.
RT-PCR the result shows that, compared with normal primary human dermal's cell (control), miR-6792-3p is in SK-MEL-
Expression in 28 cells is higher.
Cell count the result shows that, compared with negative control group, the siRNA (positive control) and miR-6792- of PKL1
3p ASO can be such that the number of SK-MEL-28 cells significantly reduces；Also, compared with the siRNA of PKL1, miR-6792-3p
ASO makes the number of SK-MEL-28 cells reduce more.
(4) effect of the antisense oligonucleotides of miR-6792-3p to normal human fibroblasts
It is carried out according to the method for step as above (1), the difference is that (being purchased from using normal human fibroblasts HS27
ATCC the liver cancer cells HuH-7 and HepG2 that are used in step (1)) are replaced.
The result (as shown in Figure 4) of cell count shows that compared with negative control group miR-6792-3p ASO are to normal
The growths of human fibroblasts have no significant effect.
Embodiment 2
The present embodiment is for illustrating that the target gene of miR-6792-3p is lowered in liver cancer cells
The target gene of miR-6792-3p is predicted using TargetScan algorithms, and filters out 10 and Apoptosis, growth
Inhibition or the relevant gene of histone deacetylation, as shown in table 1.HepG2 liver cancer cells and normal primary human liver cell are used
Trizol cracks (Invitrogen), and then by specification extracts total serum IgE.With the water dissolution RNA of nuclease free, life is then used
Object analyzer (bioanalyzer) detects the integrality of RNA, and the concentration of RNA is measured with Qubit3.TruSeq is used later
Stranded mRNA Sample Prep Kit (Illumina/USA) construction cDNAs library, and in 2500 sequenators of Hiseq
(Illumina) it is sequenced on.Obtain expressing one group of gene of downward in HepG2 cells through analysis, and it was found that 12 miR-
10 in the target gene of 6792-3p are to lower, and the results are shown in Table 1.
Table 1
Embodiment 3
The present embodiment is for illustrating that miR-6792-3p is adjusted by binding directly the binding site on the UTR of target gene to bear
Save the expression of target gene
Respectively by target gene QSOX1, TNFSF15, PHLDA3, HRK, BCL10, BTG2, SULF2, DAB2IP, SIK1,
The sequence (being shown in Table 2) of the non-translational region (UTR) containing miR-6792-3p binding sites of TP53, CYFIP2 and CABLES1 is direct
Synthesis is loaded to the sites xbaI in the downstreams fiery luciferase (Fire luciferase) gene 3' of pGL3-SV40 carriers, is obtained
MiR-6792-3p to above-mentioned each target gene experiences carrier (the commission Suzhou bio tech ltd Hong Xun carries out).
The UTR sequence for the binding site containing miR-6792-3p that table 2 is cloned
| Gene | The UTR sequence (binding site containing miR-6792-3p) 5 ' -3 ' of clone |
| QSOX1 | AGCCAGCCTTGACCCTGGAGGAA |
| TNFSF15 | AGCCAAGACCTTCCCTGGAGGAC |
| PHLDA3 | GAAGGCATGGACGTGTGGAGGAG |
| HRK | ATTCCCATTTTACAGTGGAGGAA |
| BCL10 | GCCTCTTTTTGATACTGGAGGAA |
| BTG2 | GGTCCCAGGAGGGTCTGGAGGAA |
| SULF2 | CAACATGACAGATTCTGGAGGAT |
| DAB2IP | AGAGACAGATGCTGGTGGAGGAA |
| SIK1 | CTGTGGAACCTCTTTTGGAGGAC |
| TP53 | CCCCATCCCACACCCTGGAGGAT |
| CYFIP2 | CTGCAGACCCTTATCTGGAGGAG |
| CABLES1 | GATTCTTGACAGTCTTGGAGGAT |
By human embryonic kidney cells HEK-293T (being purchased from ATCC) culture in the DMEM culture mediums containing 10% fetal calf serum.Carefully
Born of the same parents' incubator it is constant keep 37 DEG C and 5% CO2.With the inoculum concentration of 100,000 cells in every hole by HEK-293T cell inoculations to 24
In porocyte culture plates, volume of culture is 500 μ L.It second day to specifications will be as follows with liposome 2000 (Invitrogen)
In the configuration reagent cotransfection to HEK-293T cells of table 3, measured with dual-luciferase assay experiment (Promega) after 36 hours
The vigor for the luciferase expressed in carrier is experienced from miR-6792-3p.Three repeating holes of setting every time, experiment is in triplicate.
Wherein, in each group, miR-6792-3p experiences the amount of being transferred to of carrier in terms of every hole：MiR-6792-3p experiences carrier
500ng, miR-6792-3p (SEQ ID NO：1, synthesized by the Kunshan bio tech ltd Peng Ji Kai Feng) 1pmol, control
RNA (synthesis of Con RNA, cgugacacguucggagaa Ji Ma companies) 1pmol.
Table 3
The results are shown in Figure 5.As seen in Figure 5, miR-6792-3p by be incorporated in target gene QSOX1,
On the UTR of TNFSF15, PHLDA3, HRK, BCL10, BTG2, SULF2, DAB2IP, SIK1, TP53, CYFIP2 and CABLES1
Binding site inhibits the expression of target gene, wherein * * * P<0.001.**P<0.01.
Embodiment 4
The present embodiment is used to illustrate the miR- of the antisense oligonucleotides and mispairing of miR-6792-3p provided by the invention
The antisense oligonucleotides of 6792-3p can inhibit the function of miR-6792-3p
By human embryonic kidney cells HEK-293T cultures in the DMEM culture mediums containing 10% fetal calf serum.Cell incubator is permanent
Surely keep 37 DEG C and 5% CO2.With the inoculum concentration of 100,000 cells in every hole by HEK-293T cell inoculations to 24 hole cell culture
In plate, volume of culture is 500 μ L.Second day with liposome 2000 (Invitrogen) to specifications by the configuration of such as the following table 4
In reagent cotransfection to HEK-293T cells, measured from miR- with dual-luciferase assay experiment (Promega) after 36 hours
6792-3p experiences the vigor for the luciferase expressed in carrier.Three repeating holes of setting every time, experiment is in triplicate.
Wherein, in each group, miR-6792-3p experiences the amount of being transferred to of carrier in terms of every hole：MiR-6792-3p experiences carrier
(QSOX1UTR) 500ng, miR-6792-3p (such as SEQ IDNO：Shown in 1, closed by the Kunshan bio tech ltd Peng Ji Kai Feng
At) 1pmol, control nucleotide (Con RNA, cgugacacgu ucggagaa and Con DNA, attgcttctc
Aagcatccttgcg) 1pmol, miR-6792-3p ASO 1pmol, miR-6792-3p ASO (such as SEQ ID NO of mispairing：3
It is shown) 1pmol.
The results are shown in Figure 6.As seen in Figure 6, miR-6792-3p ASO can completely inhibit miR-6792-3p
Function, but the nucleotide of random controls cannot inhibit the function of miR-6792-3p.And the miR- containing base mismatch
6792-3p ASO (mismatch miR-6792-3p ASO, such as SEQ ID NO：Shown in 3) it also can partly inhibit miR-
The function of 6792-3p.***P<0.001, * * P<0.01.
Table 4
Embodiment 5
The present embodiment is used to illustrate the antisense oligonucleotides of the miR-6792-3p of thio-modification provided by the invention to cancer
The external adjustment effect of cell
The procedure of Example 1 was followed except that in the positions 1-2 and 20-21 phosphodiester bonds held using 5 '
Nonbridging oxygen atom by the antisense oligonucleotides (5 ' of the miR-6792-3p of thio-modification
AsTsGAGCAGGGGCTGTGGAGGsAsG3 ') replace the antisense of unmodified miR-6792-3p used in embodiment 1 few
Nucleotide (miR-6792-3p ASO, such as SEQ ID NO：Shown in 2).
The result (as shown in Figure 7) of cell count shows compared with unmodified miR-6792-3p ASO, thio to repair
It is more that the miR-6792-3p ASO of decorations make the number of liver cancer cells HuH-7 reduce.
By the result of above example 1-5 it is found that the present invention is by by inhibitor (such as miR- of miR-6792-3p
The miR-6792-3p ASO of 6792-3p ASO, miR-6792-3p ASO of mispairing, thio-modification) and high expression miR-6792-
The target cell (such as liver cancer cells, lung carcinoma cell, melanoma cells) of 3p is contacted, and miR-6792- can be fully inhibited
The function of 3p and promote its target gene (QSOX1, TNFSF15, PHLDA3, HRK, BCL10, BTG2, SULF2, DAB2IP, SIK1,
TP53, CYFIP2 and CABLES1) expression.This explanation can effectively prevent when by the inhibitor for individual administration
And/or treatment miR-6792-3p high expression and/or its target gene (QSOX1, TNFSF15, PHLDA3, HRK, BCL10, BTG2,
At least two in SULF2, DAB2IP, SIK1, TP53, CYFIP2 and CABLES1) disease caused by abnormal expression, for example,
Various cancers or disease similar with its symptom, especially at least one of liver cancer, lung cancer and cutaneum carcinoma.
The preferred embodiment of the present invention has been described above in detail, still, during present invention is not limited to the embodiments described above
Detail can carry out a variety of simple variants to technical scheme of the present invention within the scope of the technical concept of the present invention, this
A little simple variants all belong to the scope of protection of the present invention.
It is further to note that specific technical features described in the above specific embodiments, in not lance
In the case of shield, it can be combined by any suitable means.In order to avoid unnecessary repetition, the present invention to it is various can
The combination of energy no longer separately illustrates.
In addition, various embodiments of the present invention can be combined randomly, as long as it is without prejudice to originally
The thought of invention, it should also be regarded as the disclosure of the present invention.
<110>The Kunshan bio tech ltd Peng Ji Kai Feng
<120>Pass through the method and drug of miR-6792-3p progress anticancers and its application
<130>
<160> 6
<170> PatentIn version 3.3
<210> 1
<211> 22
<212> RNA
<213> Human
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cuccuccaca gccccugcuc au 22
<210> 2
<211> 22
<212> DNA
<213> Artificial
<220>
<223> The sequence is synthesized.
<400> 2
atgagcaggg gctgtggagg ag 22
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<211> 22
<212> DNA
<213> Artificial
<220>
<223> The sequence is synthesized.
<400> 3
atcagcaggg gctgtggacc ag 22
<210> 4
<211> 21
<212> RNA
<213> Artificial
<220>
<223> The sequence is synthesized.
<400> 4
agaucacccu ccuuaaauau u 21
<210> 5
<211> 21
<212> RNA
<213> Artificial
<220>
<223> The sequence is synthesized.
<400> 5
uauuuaagga gggugaucuu u 21
<210> 6
<211> 23
<212> DNA
<213> Artificial
<220>
<223> The sequence is synthesized.
<400> 6
attgcttctc aagcatcctt gcg 23
Claims (9)
1. inhibiting the function of miR-6792-3p and/or the expression of the target gene of miR-6792-3p being promoted to prevent and/or treating
Application in cancer and disease similar with its symptom, especially prepare for prevent and/or treating cancer and with its symptom
The drug of similar disease and/or the application in food；
The miR-6792-3p has SEQ ID NO：Nucleotide sequence shown in 1；
Preferably, the cancer is at least one of liver cancer, lung cancer and cutaneum carcinoma；
Preferably, the target gene of the miR-6792-3p be QSOX1, TNFSF15, PHLDA3, HRK, BCL10, BTG2,
At least two in SULF2, DAB2IP, SIK1, TP53, CYFIP2 and CABLES1.
2. a kind of miR-6792-3p inhibitor, which is characterized in that the miR-6792-3p inhibitor is the anti-of miR-6792-3p
The nucleotide and its class of the promoter activity of oligonucleotide, the siRNA of miR-6792-3p and inhibition miR-6792-3p
Like object；
The antisense oligonucleotides includes antisense DNA and antisense RNA；
Preferably, the antisense oligonucleotides and miR-6792-3p are complementary, and the length with 12-30 nucleotide, and have
There is the sequence of the positions the 1-8 nucleotide complementation at the 5 ' ends at least with miR-6792-3p.
3. miR-6792-3p inhibitor according to claim 2, wherein the antisense oligonucleotides has following core
Nucleotide sequence：
a）SEQ ID NO：Nucleotide sequence shown in 2；
b）In SEQ ID NO：In nucleotide sequence shown in 2 through missing, substitution or one or several nucleotide of addition and with
The nucleotide sequence of miR-6792-3p complete complementaries or partial complementarity；
Or the antisense oligonucleotides has in SEQ ID NO：Through missing, substitution or addition one in nucleotide sequence shown in 2
A or several nucleotide and the nucleotide sequence at least with miR-6792-3p with 60% complementation；
Or the antisense oligonucleotides is at least with the 5 ' positions the 1-8 nucleotide held of miR-6792-3p at most with 2 nucleosides
The nucleotide sequence of the mispairing of acid；
Or the antisense oligonucleotides has SEQ ID NO：Nucleotide sequence shown in 3；
Or the antisense oligonucleotides contains the nucleotide groups of at least one modification, the nucleotide groups of the modification are thio
The nucleotide groups of nucleotide groups and/or the lock nucleic acid modification of modification；
Preferably, the antisense oligonucleotides has SEQ ID NO：Nucleotide sequence shown in 2, and wherein 5 ' end 1-5 with
18-22 nucleotide groups are by thio-modification.
4. miR-6792-3p inhibitor according to claim 2, wherein the miR-6792-3p inhibitor is miR-
The siRNA of 6792-3p；
Preferably, the siRNA contains the nucleotide groups of at least one modification；
Preferably, the nucleotide groups of the modification are the nucleotide groups of dimethoxy modification and/or short peptide modified nucleosides
Acid groups.
5. a kind of method of the expression of function inhibiting miR-6792-3p and/or the target gene for promoting miR-6792-3p, special
Sign is that this method includes：MiR-6792-3p inhibitor is contacted with the target cell of expression miR-6792-3p, wherein described
MiR-6792-3p inhibitor is the miR-6792-3p inhibitor described in any one of claim 2-4；
Preferably, the target gene of the miR-6792-3p be QSOX1, TNFSF15, PHLDA3, HRK, BCL10, BTG2,
At least two in SULF2, DAB2IP, SIK1, TP53, CYFIP2 and CABLES1.
6. a kind of pharmaceutical composition, which is characterized in that the pharmaceutical composition contains described in any one of claim 2-4
MiR-6792-3p inhibitor and pharmaceutically acceptable carrier.
7. a kind of method of prevention and/or treating cancer, which is characterized in that this method includes：
Inhibit the function of miR-6792-3p and/or promotes the expression of the target gene of miR-6792-3p；Or
By the miR-6792-3p inhibitor described in any one of claim 2-4 and/or the medicine group described in claim 6
It closes object and is administered to subject；
Preferably, the subject is at least one of liver cancer subject, lung cancer subject and cutaneum carcinoma subject；
Preferably, the target gene of the internal expression miR-6792-3p and/or expression miR-6792-3p of the subject；
Preferably, in the internal of the subject, miR-6792-3p high is expressed and/or the low table of target gene of miR-6792-3p
It reaches；
Preferably, the target gene of the miR-6792-3p be QSOX1, TNFSF15, PHLDA3, HRK, BCL10, BTG2,
At least two in SULF2, DAB2IP, SIK1, TP53, CYFIP2 and CABLES1.
8. the method described in miR-6792-3p inhibitor, claim 5, the right described in any one of claim 2-4 are wanted
The pharmaceutical composition described in 6, method of claim 7 are asked in the function of inhibiting miR-6792-3p and/or promotes miR-
Application in the expression of the target gene of 6792-3p；Especially in prevention and/or treating cancer and disease similar with its symptom
Application；
Preferably, the cancer is at least one of liver cancer, lung cancer and cutaneum carcinoma；
Preferably, the target gene of the miR-6792-3p be QSOX1, TNFSF15, PHLDA3, HRK, BCL10, BTG2,
At least two in SULF2, DAB2IP, SIK1, TP53, CYFIP2 and CABLES1.
9. the medicine group described in miR-6792-3p inhibitor and/or claim 6 described in any one of claim 2-4
In the drug for closing expression of the object in the function of preparing for inhibiting miR-6792-3p and/or the target gene for promoting miR-6792-3p
Application；Especially prepare for prevent and/or the drug for the treatment of cancer and disease similar with its symptom in application；
Preferably, the cancer is at least one of liver cancer, lung cancer and cutaneum carcinoma；
Preferably, the target gene of the miR-6792-3p be QSOX1, TNFSF15, PHLDA3, HRK, BCL10, BTG2,
At least two in SULF2, DAB2IP, SIK1, TP53, CYFIP2 and CABLES1.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014100252A1 (en) * | 2012-12-18 | 2014-06-26 | University Of Washington Through Its Center For Commercialization | Methods and compositions to modulate rna processing |
| WO2015183667A1 (en) * | 2014-05-28 | 2015-12-03 | The Regents Of The University Of California | HYBRID tRNA/pre-miRNA MOLECULES AND METHODS OF USE |
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2017
- 2017-01-13 CN CN201710024770.3A patent/CN108295259A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014100252A1 (en) * | 2012-12-18 | 2014-06-26 | University Of Washington Through Its Center For Commercialization | Methods and compositions to modulate rna processing |
| WO2015183667A1 (en) * | 2014-05-28 | 2015-12-03 | The Regents Of The University Of California | HYBRID tRNA/pre-miRNA MOLECULES AND METHODS OF USE |
Non-Patent Citations (2)
| Title |
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| LADEWIG,E.等: "NR_106850.1：Homo sapiens microRNA 6792 (MIR6792),microRNA", 《NCBI GENBANK》 * |
| 李爱洁: "中心型与周围型小细胞肺癌差异表达microRNA初步筛选", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
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