CN107488735A - Applications of the 5p of miR 339 in prostate cancer with osseous metastasis and TGF signal beta paths is suppressed - Google Patents
Applications of the 5p of miR 339 in prostate cancer with osseous metastasis and TGF signal beta paths is suppressed Download PDFInfo
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Abstract
The invention discloses applications of the 5p of miR 339 in prostate cancer with osseous metastasis and TGF signal beta paths is suppressed.Present invention research finds the 5p of miR 339 low expressions in prostate cancer with osseous metastasis, further study show that, the 5p of miR 339 are by targetting SMAD2, SMAD3 and TGFBRI in TGF signal beta paths, suppress TGF signal beta pathway activities, so as to suppress the migration and invasion and attack of Bone tumour precedent adenocarcinoma cell, therefore, the 5p of miR 339 are expected to be applied to prepare prostate cancer with osseous metastasis diagnostic reagent, suppress Bone tumour medicine, TGF β/smad inhibitor, SMAD2 inhibitor, SMAD3 inhibitor and TGFBRI inhibitor.
Description
Technical field
The invention belongs to biology field, relate more specifically to miR-339-5p suppress prostate cancer with osseous metastasis and
Application in TGF- signal beta paths.
Background technology
Prostate cancer (Prostate Cancer, PCa) is one of most common malignant tumour of male genitourinary system.
Cancer metastasis can greatly increase the death rate of patients with prostate cancer, and bone is the second most common position of cancer metastasis, is surpassed in China
The patients with prostate cancer for crossing 80% has occurred and that Bone tumour when making a definite diagnosis, and Bone tumour is the weight for causing patients with prostate cancer dead
Want reason, therefore, the early diagnosis to Bone tumour, be clinic diagnosis and prognosis key.In addition, for Late-stage Prostate Cancer
Patient, the effect of operative treatment is poor, most of to use drug therapy.According to the different state of an illness can use chemotherapy,
Integrated application of fluconazole ear drops, radionuclide internal radiotherapy and various therapies etc..However, radiotherapy and chemotherapy medicine is not only made
For tumour, the tissue of tumour adjacent healthy is may also act on, thus while tumour is killed, is also brought very to body
Big side effect, the final therapeutic effect influenceed to tumour.Therefore, there is an urgent need to develop carly fruit drop prostate cancer bone for this area
The Specific marker of transfer, and develop the targeted drug of prostate cancer with osseous metastasis.
TGF-β signal path often shows the effect of complicated even contradiction in cancer, such as cancer early stage, TGF-β signal
Path can suppress growth of cancer cells, and in the cancer later stage, it can but promote the transfer and invasion and attack of cancer cell, particularly Bone tumour, it is existing
There is research to have confirmed that the activation of TGF-β signal path can promote the Bone tumour of prostate gland cancer cell.MiRNA is that have 18~24
The non-coding RNA of individual nucleotides, it combines the complementary site in 3 ' untranslated regions of mRNA and suppresses turning over for they
Translate.Single miRNA can target some mRNA and regulating cell path and cell fate.There are some researches show some miRNA
Nasopharyngeal neoplasms can be promoted, such as the miR-10b in the cancer of the brain, the miR-21 in colorectal cancer, the miR- in prostate cancer
184.Also some miRNA for suppressing prostate cancer with osseous metastasis are found, such as miR-143, miR-145 and miR-203.Do not have still at present
There is the research report between miR-339-5p and prostate cancer with osseous metastasis and TGF-β signal path.
The content of the invention
It is an object of the invention to provide miR-339-5p to prepare prostate cancer with osseous metastasis diagnostic reagent, suppress Bone tumour
Application in medicine, TGF-β/smad inhibitor, SMAD2 inhibitor, SMAD3 inhibitor and TGFBRI inhibitor.
The technical solution used in the present invention is：
MiR-339-5p is in preparing prostate cancer with osseous metastasis diagnostic reagent and/or suppressing prostate cancer with osseous metastasis medicine
Using.
As the preferred of above-mentioned application, the prostate cancer with osseous metastasis diagnostic reagent, which contains, can quantify detection miR-339-5p
And/or the reagent of its encoding gene.
As the preferred of above-mentioned application, the specificity that the prostate cancer with osseous metastasis diagnostic reagent contains miR-339-5p is drawn
One or more in thing, probe and chip.
As the preferred of above-mentioned application, the suppression prostate cancer with osseous metastasis medicine contains one kind or more in following material
Kind：1) material that miR-339-5p can be promoted to express；2) material of miR-339-5p activity can be strengthened；3) miR- can be increased
The material of 339-5p effective acting times；4) material of miR-339-5p stability can be strengthened；5) miR-339-5p structures are simulated
Material.
As the preferred of above-mentioned application, the suppression prostate cancer with osseous metastasis medicine contains one kind or more in following material
Kind：1) miR-339-5p molecules；2) miR-339-5p trims；3) miR-339-5p analogies；4) encode miR-339-5p's
DNA；5) miR-339-5p carrier or virus is expressed.
As the preferred of above-mentioned application, the miR-339-5p be selected from pri-miRNA, pre-miRNA, ripe miRNA,
One or more in dsmiRNA and its fragment or variant.
Applications of the miR-339-5p in inhibitor is prepared, the inhibitor is selected from TGF-β/smad inhibitor, SMAD2 presses down
One or more in preparation, SMAD3 inhibitor, TGFBRI inhibitor.
As the preferred of above-mentioned application, the inhibitor contains the one or more in following material：1) miR- can be promoted
The material of 339-5p expression；2) material of miR-339-5p activity can be strengthened；3) miR-339-5p effective acting times can be increased
Material；4) material of miR-339-5p stability can be strengthened；5) material of miR-339-5p structures is simulated.
As the preferred of above-mentioned application, the inhibitor contains the one or more in following material：1)miR-339-5p
Molecule；2) miR-339-5p trims；3) miR-339-5p analogies；4) miR-339-5p DNA is encoded；5) miR- is expressed
339-5p carrier or virus.
As the preferred of above-mentioned application, the miR-339-5p be selected from pri-miRNA, pre-miRNA, ripe miRNA,
One or more in dsmiRNA and its fragment or variant.
The beneficial effects of the invention are as follows：
Present invention research finds miR-339-5p low expressions in prostate cancer with osseous metastasis, further study show that, miR-
For 339-5p by targetting SMAD2, SMAD3 and TGFBRI in TGF-β signal path, suppression TGF-β signal path is active, so as to
Suppress the migration and invasion and attack of Bone tumour precedent adenocarcinoma cell, therefore, miR-339-5p is expected to be applied to prepare prostate cancer bone turn
Move diagnostic reagent, suppress Bone tumour medicine, TGF-β/smad inhibitor, SMAD2 inhibitor, SMAD3 inhibitor and TGFBRI suppressions
Preparation.
Brief description of the drawings
Fig. 1：MiR-339-5p expression quantity in prostate cancer and cancer beside organism/benign tissue in TCGA databases, figure A are
Prostate cancer and miR-339-5p expression quantity in benign tissue in TCGA；It is prostate cancer and group by the cancer of pairing in TCGA to scheme B
Knit middle miR-339-5p expression quantity；
Fig. 2：MiR-339-5p expression in clinical sample and cell line；Wherein, it is prostate cancer with osseous metastasis group to scheme A
Knit the expression that miR-339-5p in tissue is shifted with bone free；It is miR-339-5p expression quantity and the disease of Bone tumour state to scheme B
Example statistical chart, the expression that figure C is miR-339-5p in benign prostate cells and prostate gland cancer cell；In figure, miR-
339-5p-H is miR-339-5p height expression groups, and miR-339-5p-L is miR-339-5p low expression groups；
Fig. 3：The expression quantity of miR-339-5p after miR-339-5p is raised or lowered in different prostate gland cancer cells；
Fig. 4：TGF-β/Smad luciferases element expression is strong after miR-339-5p is raised or lowered in different prostate gland cancer cells
Degree；
Fig. 5：SMAD2, SMAD3 and TGFBRI after miR-339-5p are raised or lowered in different prostate gland cancer cells
Mrna expression amount；
Fig. 6：The albumen of SMAD2, SMAD3 and TGFBRI after miR-339-5p are raised or lowered in different prostate gland cancer cells
Expression quantity；
Fig. 7：MiR-339-5p targets SMAD2, SMAD3 and TGFBRI the result in different prostate gland cancer cells, and figure A is
VCaP cell situations, figure B are PC-3 cell situations, and figure C is C4-2B cell situations；
Fig. 8：MiR-339-5p is raised or lowered in different prostate gland cancer cells to migration of prostate cancer cells and invasion and attack energy
The influence of power；
Fig. 9：In prostate cancer VCaP cells, anti-miR-339-5p and SD208 is jointly processed by cell migration and invasion and attack
The influence of ability.
Embodiment
The present invention is expanded on further in conjunction with specific experiment example, but is not limited thereto.Used in following experimental examples
Experimental method is conventional method unless otherwise specified, and actual conditions is unreceipted, routinely operation or producer proposed by bar
Part, material used, reagent etc., unless otherwise specified, are commercially obtained in following experimental examples.
On human prostate cancer cell line 22RV1, PC-3, VCaP, DU145, LNCaP and normal human prostate of the present invention
Chrotoplast RWPE-1 is provided by ATCC cell banks；Human Prostate Cancer Cells C4-2B is purchased from MD Andersons Cancer center；Above cell
It is cultural method by this area routine operation；115 prostate cancer tissues (including 73 without Bone tumour and 42 Bone tumours) by
Guangzhou City No.1 People's Hospital provides, and above clinical samples are all from surgical procedure or aspiration biopsy, made a definite diagnosis through clinicopathologia.
Experimental example 1, the miR-339-5p high expression in prostate cancer tissue, and it is then low in Bone tumour prostate cancer tissue
Expression
Inventor carries out bioinformatic analysis using the data in TCGA databases, finds miR-339-5p in prostate
High expression in cancerous tissue, as shown in figure 1, compared with 52 cancer beside organisms, miR-339-5p is expressed in 498 prostate cancer tissues
Amount significantly improves (Figure 1A), as one man, compared with the cancer beside organism of pairing, miR-339- in the prostate cancer tissue of 52 pairings
The high expression (Figure 1B) of 5p.But unexpected is that inventor studies discovery, and miR-339-5p is in Bone tumour prostate cancer tissue
In but low expression, research method are as follows：
RNA extractions, reverse transcription and real-time quantitative RT-PCR detection miR-339-5p：Using TRIzol lysates (Life
Technologies companies) specification extraction the total serum IgE with cell in a organized way, according to Revert Aid First Strand
CDNA Synthesis Kit (Thermo Fisher companies) specification carries out reverse transcription, is entered from 2-ddCt relative quantification methods
Row fluorogenic quantitative detection, using U6 as internal reference, seek the relative expression quantity for calculating miR-339-5p.
As a result：
MiR-339-5p expression quantity result in clinical samples and cell line as shown in Fig. 2 Fig. 2A shows, relative to non-bone
Metastasized prostate cancer tissue, miR-339-5p expression quantity is lower in Bone tumour prostate cancer tissue, by prostate cancer tissue
Patient is divided into miR-339-5p low expressions group and miR-339-5p height expression groups by the median of miR-339-5p expression quantity, system
Count miR-339-5p expression quantity and patients with prostate cancer Bone tumour state relation as shown in Figure 2 B, miR-339-5p low expressions are with before
Row gland cancer Bone tumour is related, further, reference picture 2C, contrasts normal human prostatic epithelial cell system RWPE-1, prostate
The high expression of miR-339-5p in cancerous cell line 22RV1 and lymphatic metastasis prostate cell line LNCaP, and in brain metastes prostate
MiR-339-5p then low expressions, above knot in cancerous cell line DU145 and Bone tumour prostate cancer cell line PC-3, C4-2B, VCaP
Fruit unanimously shows that miR-339-5p low expressions in Bone tumour prostate cancer tissue/cell, therefore, miR-339-5p can conduct
The biomarker of prostate cancer with osseous metastasis, it can be applied to prepare the diagnostic reagent of prostate cancer with osseous metastasis.
Experimental example 2, miR-339-5p suppress the molecular mechanism of prostate cancer with osseous metastasis
Experimental method：
(1) RNA extractions, reverse transcription and real-time quantitative PCR
Using TRIzol lysates (Life Technologies companies) specification extraction it is total with cell in a organized way
RNA, mRNA and miRNA are according to Revert Aid First Strand cDNA Synthesis Kit (Thermo Fisher
Company) specification carries out reverse transcription, carry out fluorogenic quantitative detection from 2-ddCt relative quantifications method, miRNA and mRNA respectively with
U6 and GAPDH is internal reference, seeks calculation relative expression quantity.
(2) plasmid construction, siRNA are using human genome as template, and (miRBase is numbered amplification people miR-339-5p
MIMAT0000764) gene, and be cloned into pMSCV-puro retroviral vectors (Clontech companies), obtain miR-
339-5p expression plasmids, for raising the expression quantity of miR-339-5p in cell；By people miR-339-5p GEM 132 gram
It is grand to anti-miR-339-5p expression plasmids (Promega companies design and synthesis) on carrier, are obtained, for lowering miR-
339-5p expression quantity.For quantitatively detecting TGF-β/Smad luciferases element report of TGF-β signal path constitutive transcriptional activity
Plasmid is purchased from Clontech companies；Using human genome as template, SMAD2-3`UTR, SMAD2-3`UTR and TGFBRI-3` are expanded
UTR sequence, it is cloned into respectively on pmirGLO luciferase elements reporter plasmid (Promega companies), is built into pmirGLO-
SMAD2-3 ' UTR, pmirGLO-SMAD3-3 ' UTR and pmirGLO-TGFBR1-3 ' UTR this 3 luciferase element reporter plasmids, pin
To 3 plasmids more than building, miR-339-5p binding site is subjected to mutation processing respectively, corresponding 3 is obtained and dashes forward
Become plasmid pmirGLO-SMAD2-3`UTR-mut, pmirGLO-SMAD2-3`UTR-mut and pmirGLO-TGFBRI-3`UTR-
Mut, for luciferase element targeting checking test.
(3) migrated using transwell cells method and Matrigel, experimental method press this area routine operation.
(4) luciferase element detection
By target prostate gland cancer cell (4 × 104) be inoculated into 24 orifice plates and cultivate 24h, by pmirGLO-SMAD2-3 '
UTR, pmirGLO-SMAD3-3 ' UTR and pmirGLO-TGFBR1-3 ' UTR luciferase element reporter plasmids or mutant plasmid
PmirGLO-SMAD2-3`UTR-mut, pmirGLO-SMAD2-3`UTR-mut and pmirGLO-TGFBRI-3`UTR-mut with
MiR-339-5p expression plasmids or anti-miR-339-5p expression plasmids cotransfection are carried out glimmering into target prostate gland cancer cell
Light enzyme element targeting checking test, by miR-339-5p expression plasmids or anti-miR-339-5p expression plasmids and TGF-β/Smad
Luciferase element reporter plasmid cotransfection, for detecting TGF-β/Smad transcriptional activities, transfects 36h into target prostate gland cancer cell
Afterwards, the fluorescence intensity of each group cell is detected, fluorescence intensity level is counted, calculates relative intensity of fluorescence value.
(5) Western blotting are detected
Anti- SMAD2, SMAD3, TGFBRI antibody are purchased from CST companies, and anti alpha-tubulin antibody is internal reference, detection method
By this area routine operation.
Experimental result：
(1) miR-339-5p suppresses TGF-β signal path activity
According to the result of study of experimental example 1, further ground in Bone tumour prostate gland cancer cell PC-3, C4-2B, VCaP
Study carefully, by raising low expression miR-339-5p PC-3 and C4-2B cells, miR-339-5p VCaP is expressed in up-regulation or downward
Cell studies effects of the miR-339-5p to TGF-β signal path, each group cell miR-339-5p expression quantity such as Fig. 3 institutes
Show, TGF-β/Smad luciferases element report testing result raises miR- as shown in figure 4, in PC-3, C4-2B, VCaP cell
339-5p suppresses TGF-β/Smad transcriptional activities, and lowers miR-339-5p and promote TGF-β/Smad transcriptional activities.
(2) miR-339-5p targets SMAD2, SMAD3 and TGFBRI in TGF-β signal path
MiR-339-5p expression plasmids or anti-miR-339-5p expression plasmids are transfected into Bone tumour prostate cancer respectively
In cell PC-3, C4-2B, VCaP, real-time quantitative PCR and Western blotting analysis results such as Fig. 5 and Fig. 6 are shown, on
The mRNA and expressing quantity for adjusting miR-339-5p to reduce SMAD2, SMAD3 and TGFBRI；Luciferase element targeting checking display
(such as Fig. 7), up-regulation miR-339-5p reduce SMAD2, SMAD3 and TGFBRI activity, SMAD2, SMAD3 to mutation and
TGFBRI 3 '-UTR do not influence, it was confirmed that miR-339-5p targeting TGF-β signal path in SMAD2, SMAD3 and
TGFBRI。
(3) miR-339-5p, which is overexpressed, to suppress prostate cancer migration and invasion and attack
MiR-339-5p expression plasmids or anti-miR-339-5p expression plasmids are transfected into Bone tumour prostate cancer respectively
In cell PC-3, C4-2B, VCaP, migration and invasion and attack situation are as shown in Figure 8, it is seen that miR-339-5p is overexpressed can be before suppression
Row gland cancer migrates and invasion and attack.
(4) miR-339-5p suppresses the migration of precedent gland cancer and invasion and attack by suppressing TGF-β signal path
SD208 is dose-dependent TGF-β signal pathway inhibitor, by transfecting SD208 and anti-miR-339-5p tables
Up to plasmid, whether checking miR-339-5p suppresses the migration of precedent gland cancer and attacks by suppressing TGF-β signal path, as a result as schemed
Shown in 9, SD208 can also suppress the migration of precedent gland cancer and invasion and attack of anti-miR-339-5p promotions, therefore, it can be stated that bright
MiR-339-5p suppresses the migration of precedent gland cancer and invasion and attack by suppressing TGF-β signal path.
Result above shows that miR-339-5p can be applied to the diagnosis and treatment of prostate cancer with osseous metastasis, pass through quantitative inspection
Survey miR-339-5p or its encoding gene, it is possible to achieve the diagnosis of prostate cancer with osseous metastasis, in addition, up-regulation miR-339-5p energy
Suppress the activation of TGF-β signal path, and targeted inhibition SMAD2, SMAD3 and TGFBRI expression, so as to suppress prostate
Cancer Bone tumour, it can be applied to prepare TGF-β/smad inhibitor, SMAD2 inhibitor, SMAD3 inhibitor and TGFBRI inhibitor,
Further, can be applied to prepare the medicine for suppressing prostate cancer with osseous metastasis.
It is described above to be only for explaining the present invention, it is noted that for those skilled in the art, not
On the premise of departing from the principle of the invention, some improvements and modifications can also be made, these improvements and modifications also should be regarded as the present invention
Protection domain.
Claims (10)
1.miR-339-5p answering in preparing prostate cancer with osseous metastasis diagnostic reagent and/or suppressing prostate cancer with osseous metastasis medicine
With.
2. application according to claim 1, the prostate cancer with osseous metastasis diagnostic reagent, which contains, can quantify detection miR-
339-5p and/or its encoding gene reagent.
3. application according to claim 1, the prostate cancer with osseous metastasis diagnostic reagent contains the special of miR-339-5p
One or more in property primer, probe and chip.
4. application according to claim 1, the suppression prostate cancer with osseous metastasis medicine contains one kind in following material
It is or a variety of：1) material that miR-339-5p can be promoted to express；2) material of miR-339-5p activity can be strengthened；3) miR- can be increased
The material of 339-5p effective acting times；4) material of miR-339-5p stability can be strengthened；5) miR-339-5p structures are simulated
Material.
5. application according to claim 1, the suppression prostate cancer with osseous metastasis medicine contains one kind in following material
It is or a variety of：1) miR-339-5p molecules；2) miR-339-5p trims；3) miR-339-5p analogies；4) miR-339- is encoded
5p DNA；5) miR-339-5p carrier or virus is expressed.
6. application according to claim 1, the miR-339-5p is selected from pri-miRNA, pre-miRNA, maturation
One or more in miRNA, dsmiRNA and its fragment or variant.
Applications of the 7.miR-339-5p in inhibitor is prepared, the inhibitor is selected from TGF-β/smad inhibitor, SMAD2 suppresses
One or more in agent, SMAD3 inhibitor, TGFBRI inhibitor.
8. application according to claim 7, the inhibitor contains the one or more in following material：1) can promote
The material of miR-339-5p expression；2) material of miR-339-5p activity can be strengthened；3) miR-339-5p useful effects can be increased
The material of time；4) material of miR-339-5p stability can be strengthened；5) material of miR-339-5p structures is simulated.
9. application according to claim 1, the inhibitor contains the one or more in following material：1)miR-339-
5p molecules；2) miR-339-5p trims；3) miR-339-5p analogies；4) miR-339-5p DNA is encoded；5) miR- is expressed
339-5p carrier or virus.
10. application according to claim 1, the miR-339-5p is selected from pri-miRNA, pre-miRNA, maturation
One or more in miRNA, dsmiRNA and its fragment or variant.
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| CN110643711A (en) * | 2019-11-20 | 2020-01-03 | 广州医科大学附属第二医院 | Biomarkers for bone metastasis of prostate cancer |
| CN113528522A (en) * | 2021-07-09 | 2021-10-22 | 复旦大学 | miR-339-enhancer-target gene network activation model and application thereof |
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