CN107082800A - A kind of inhibitor of MACC1 genes and its anti-hepatocellular carcinoma invasion and attack purposes - Google Patents
A kind of inhibitor of MACC1 genes and its anti-hepatocellular carcinoma invasion and attack purposes Download PDFInfo
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- CN107082800A CN107082800A CN201710268784.XA CN201710268784A CN107082800A CN 107082800 A CN107082800 A CN 107082800A CN 201710268784 A CN201710268784 A CN 201710268784A CN 107082800 A CN107082800 A CN 107082800A
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Abstract
The invention discloses a kind of inhibitor of MACC1 genes and its anti-hepatocellular carcinoma invasion and attack purposes, the inhibitor is a kind of polypeptide, and the polypeptide includes following amino acid sequence：ETMFWYDAK(Xa)PCFTRVPMA(Xb)GTDEQLPDIWN；Wherein, Xa and Xb is selected from M, Y, L, V, W or E.The peptide inhibitor that the present invention is provided can suppress expression of the MACC1 genes in HepG2 cells from transcription and translation level, be effective inhibitor of MACC1 genes；Meanwhile, effective inhibitor of the MACC1 genes can significantly inhibit propagation and the invasion and attack of HepG2 cells, and effective inhibitor of the MACC1 genes can be used for the medicine for being prepared into anti-hepatocellular carcinoma invasion and attack.
Description
Technical field
The invention belongs to gene field, and in particular to a kind of inhibitor of MACC1 genes and its invasion and attack of anti-hepatocellular carcinoma are used
On the way.
Background technology
Primary carcinoma of liver is the malignant tumour that a kind of primary tumor betides liver cell and intrahepatic biliary epithelium cell, wherein liver
Hepatocellular carcinoma (i.e. hepatocellular carcinoma, HCC) is topmost histological type, accounts for primary carcinoma of liver more than 90%.MACC1 genes are
The new gene for being found and being named by STEIN etc. for 2009.The research such as STEIN finds that MACC1 is used as HGF
(HGF) key regulator of/C-met signal paths, is played an important role in the invasion and attack and transfer of colon cancer, this
Outside, Liu Qingquan etc. has found that MACC1 genes may be played an important role in the invasion and attack transfer of hepatocellular carcinoma, it is possible to as liver
(expression and clinical meaning of Liu Qingquan etc., the MACC1 gene in hepatocellular carcinoma, Central China science and technology are big for one of novel targets of cancer treatment
Learn journal, 2010,39：22-24).
At present, there is not yet the report of MACC1 gene polypeptide class inhibitor.
The content of the invention
It is an object of the invention to provide a kind of inhibitor of MACC1 genes and its anti-hepatocellular carcinoma invasion and attack purposes.
Realize that above-mentioned purpose technical scheme of the present invention is as follows：
A kind of inhibitor of MACC1 genes, the inhibitor is a kind of polypeptide, and the polypeptide includes formula (I) amino acid sequence：
ETMFWYDAK(Xa)PCFTRVPMA(Xb)GTDEQLPDIWN； (Ⅰ)
Wherein, Xa and Xb is selected from M, Y, L, V, W or E.
Preferably, Xa and Xb is selected from M or W.
Preferably, the inhibitor is one of following polypeptides：
ETMFWYDAKMPCFTRVPMAMGTDEQLPDIWN；
ETMFWYDAKWPCFTRVPMAWGTDEQLPDIWN；
ETMFWYDAKMPCFTRVPMAWGTDEQLPDIWN；
ETMFWYDAKWPCFTRVPMAMGTDEQLPDIWN。
Preferably, polypeptide N and/or C-terminal are modified by sulphation.
Preferably, the N-terminal of the polypeptide is acetylation modification, and C-terminal is amidated modification.
Preferably, the polypeptide form is as follows：
Ac-ETMFWYDAKMPCFTRVPMAMGTDEQLPDIWN-NH2；
Ac-ETMFWYDAKWPCFTRVPMAWGTDEQLPDIWN-NH2；
Ac-ETMFWYDAKMPCFTRVPMAWGTDEQLPDIWN-NH2；
Ac-ETMFWYDAKWPCFTRVPMAMGTDEQLPDIWN-NH2。
Preferably, the polypeptide is free form or pharmaceutically acceptable salifie form, including hydrochloride, sulfuric acid
Salt, phosphate, sulfonate, acetate, citrate and tartrate.
Application of the above-mentioned inhibitor in the medicine of anti-hepatocellular carcinoma propagation and invasion and attack is prepared.
A kind of pharmaceutical composition, containing aforementioned polypeptides inhibitor and pharmaceutically acceptable auxiliary material.
Application of the above-mentioned composition in the medicine of anti-hepatocellular carcinoma propagation and invasion and attack is prepared.
The outstanding advantages of the present invention：
The peptide inhibitor that the present invention is provided can effectively suppress the expression of MACC1 genes in hepatocellular carcinoma, and then effectively
Suppress the invasion and attack transfer of hepatocellular carcinoma, can be used for the medicine for being prepared into anti-hepatocellular carcinoma invasion and attack.
Brief description of the drawings
Fig. 1 is the influence that peptide inhibitor is expressed MACC1mRNA；
Fig. 2 is influence of the peptide inhibitor to MACC1 protein expressions.
Embodiment
The just in conjunction with the embodiments specific essentiality content for introducing the present invention below, due to length reason, experimentation is retouched
Stating can not accomplish very in detail, and the part not being described in detail in every experiment is conventional behaviour well known to those skilled in the art
Make.
First, experiment material
Polypeptide of the present invention is synthesized by reference polypeptide solid phase synthesis technique well known in the art, using fluorenes methoxy carbonyl
Base (Fmoc) N-terminal Preservation tactics.The method synthesized according to resin solid phase is sequentially connected corresponding amino acid, during which sloughs successively
Fmoc- blocking groups, then cut peptide, obtain crude product, crude product is through C18 column separating purifications, you can the polypeptide shown in formula (I) is made.
HPLC and MS detections confirm the structure of polypeptide of the present invention, and purity is >=98%.
Polypeptide I-1 to polypeptide I-4 amino acid sequence are as follows, and N-terminal and C-terminal are without chemical modification：
ETMFWYDAKMPCFTRVPMAMGTDEQLPDIWN (polypeptide I-1)；
ETMFWYDAKWPCFTRVPMAWGTDEQLPDIWN (polypeptide I-2)；
ETMFWYDAKMPCFTRVPMAWGTDEQLPDIWN (polypeptide I-3)；
ETMFWYDAKWPCFTRVPMAMGTDEQLPDIWN (polypeptide I-4).
Human hepatocellular carcinoma Cell Line HepG2 is preserved by our company's molecule pharmacological evaluation room.Hyclone is purchased from the Hangzhou four seasons
Blue or green company.Tetramethyl azo azoles salt and dimethyl sulfoxide (DMSO) are purchased from Sigma Co., USA.Rabbit-anti people MACC1 antibody is purchased from Santa
Cruz companies, HRP mark goat anti-rabbit igg secondary antibodies are purchased from Beijing company of Zhong Shan Golden Bridge.Transwell cells are purchased from
Millipore companies.PCR primer synthesizes sharp rich in Guangzhou, and RT-PCR kit is purchased from Takara companies.
2nd, experimental method
1st, human hepatocellular carcinoma Cell Line HepG2 culture
Human primary liver cancer's cell line is in the RPMI-1640 nutrient solutions containing 10% hyclone, 37 DEG C, 5%CO2Training
Support, 2-3d is with 0.25% pancreatin had digestive transfer culture.The cell in growth period of taking the logarithm is tested.
2nd, influence of the mtt assay detection polypeptide to HepG2 multiplication capacities
Take the logarithm the HepG2 cells in growth period, cell suspension is made, with every hole 5 × 104Individual cell is inoculated in 96 orifice plates
In, per the μ L cell suspensions of hole 100.It is divided into control group, polypeptide I-1 groups, polypeptide I-2 groups, polypeptide I-3 groups, polypeptide I-4 groups.Polypeptide
Group is separately added into 2,4,8,16,32 μM of polypeptide, and control group adds isometric reagent, after culture 24 hours, takes out the training of 96 holes
Plate is supported, nutrient solution is discarded and uses PBS, the μ L of RPMI-1640 nutrient solutions 100 containing MTT (whole mass concentration is 5g/L) are added,
Continue to cultivate after cell 4h, discard nutrient solution, 100 μ L dimethyl sulfoxide (DMSO)s are added per hole, shaking table vibrates dissolving crystallized thing.Adjusted with DMSO
Zero, determined in 490nm per hole OD values.Inhibiting rate according to the following formula, and calculate with return law of the straight line the IC50 values of each polypeptide.
Proliferation inhibition rate (%)=(1- administration groups OD values/control group OD values) × 100%
3rd, influence of the cell invasion experiment detection polypeptide to HepG2 invasive abilities
The Matrigel glue and serum-free RPMI-1640 cell culture fluids of 4 DEG C of precoolings are taken, by volume 1：4 are sufficiently mixed
Uniformly.Whole polycarbonate membrane in the 30 above-mentioned mixed liquors of μ L, covering room is added per hole into Transwell plate upper chambers, in 37 DEG C
Stood in incubator after 3h, 100 μ L cell suspensions are added per hole, and (cell density is 1 × 105/ mL) and 200 μ L serum-frees RPMI-
1640 culture medium；Add the RPMI- of 500 μ L hyclones containing volume fraction 30% per hole to room under Transwell plates simultaneously
1640 culture medium.Then, with 0,2,4,8,16,32 μM of polypeptide handle HepG2 cell 24h respectively, then take out cell, suck
Nutrient solution, methanol fixes 30min, violet staining 20min, cell is inverted, just putting microscope with LeicaDC 300F is carried out
Observe and take pictures.Choose cell bottom surface upper and lower, left and right and 5, the center visual field and count cell, calculate invasion and attack rate.Experiment repeats 3
It is secondary, each 10 multiple holes of experimental point.
4th, RT-PCR detects the influence that polypeptide is expressed MACC1mRNA in HepG2 cells
6 orifice plates are added after HepG2 cell dissociations are counted, cell density is 5 × 104After/mL, cell attachment, addition 4,
16 μM of polypeptide culture 24h, collects cell, determines MACC1mRNA in HepG2 cells and expresses.Another to set control group, control group is not
Add polypeptide.Cell total rna is extracted, reverse transcription obtains cDNA, performing PCR is entered as template.Primer is as follows：
MACC1 sense primers：5’-CCTTCGTGGTAATAATGCTTCC-3’
MACC1 anti-sense primers：5’-AGGGCTTCCATTGTATTGAGGT-3’
β-actin sense primers：5’-ACGCACCCCAACTACAACTC-3’
β-actin anti-sense primers：5’-TCTCCTTAATGTCACGCACGA-3’
Prepare 50 μ L reaction systems in the sterile PCR pipe without enzyme, reaction condition is 94 DEG C of 60s, 60 DEG C of 50s, 72 DEG C of 90s,
After 40 circulations, 72 DEG C of extension 10min；4 DEG C preserve in case 20g/L agarose gel electrophoresis.Experiment is repeated 3 times.
5th, Western blot detect influence of the polypeptide to MACC1 protein expressions in HepG2 cells
6 orifice plates are added after HepG2 cell dissociations are counted, cell density is 5 × 104After/mL, cell attachment, addition 4,
16 μM of polypeptide culture 24h, collects cell, determines MACC1 protein expressions in HepG2 cells.Another to set control group, control group is not
Add polypeptide.Total protein of cell is extracted by BCA standard measures, loading buffer, boiling are added in total protein of cell sample
Water makes it fully be denatured.Polyacrylamide gel electrophoresis protein isolate is used, through albumen transferring film, closing, primary antibody (1:5000 dilutions)
And secondary antibody (1:10000 dilution) hybridization after carry out chemiluminescence.Using β-actin as internal reference.Finally, gray scale is carried out to band to sweep
Retouch.MACC1 relative expression quantities=MACC1 bands integral optical density value/β-actin band integral optical density values.
3rd, experimental result
1st, influence of the polypeptide to HepG2 multiplication capacities
Compared with control group, the propagation of each polypeptide administration group HepG2 cells is substantially suppressed, and proliferation inhibition rate with
Peptide concentration is relevant, and concentration is higher, and inhibitory action is stronger, with obvious concentration dependent.As a result such as table 1.
Proliferation inhibition rate (%) of the various concentrations polypeptide of table 1 to HepG2
| 2μM | 4μM | 8μM | 16μM | 32μM | |
| Polypeptide I-1 groups | 13.55 | 24.32 | 40.69 | 64.95 | 78.32 |
| Polypeptide I-2 groups | 18.60 | 28.58 | 45.46 | 69.36 | 84.58 |
| Polypeptide I-3 groups | 10.84 | 21.72 | 38.06 | 59.84 | 72.44 |
| Polypeptide I-4 groups | 11.56 | 22.85 | 39.73 | 62.08 | 75.73 |
The above results show that polypeptide I-1, polypeptide I-2, polypeptide I-3, polypeptide I-4 have obvious to the propagation of HepG2 cells
Inhibitory action, certain concentration-dependent relation is presented in this inhibitory action, and IC50 is about 12 μM, and drug effect is excellent.
2nd, influence of the polypeptide to HepG2 invasive abilities
Each polypeptide can substantially suppress the invasion and attack of HepG2 cells, and the invasion and attack rate of HepG2 cells is with the rise of peptide concentration
Reduction.
As a result it is as shown in table 2.
Influence of the various concentrations polypeptide of table 2 to HepG2 invasion and attack rate (%)
| 2μM | 4μM | 8μM | 16μM | 32μM | |
| Polypeptide I-1 groups | 83.48 | 62.69 | 44.94 | 23.84 | 11.25 |
| Polypeptide I-2 groups | 80.16 | 61.20 | 43.04 | 22.28 | 9.64 |
| Polypeptide I-3 groups | 86.85 | 65.74 | 47.35 | 26.52 | 13.12 |
| Polypeptide I-4 groups | 85.26 | 64.92 | 46.03 | 25.06 | 12.03 |
Transwell Matrigels prove that polypeptide I-1, polypeptide I-2, polypeptide I-3, polypeptide I-4 are invaded HepG2 cells
Attack with obvious inhibitory action, certain concentration-dependent relation is presented in this inhibitory action.
3rd, the influence that polypeptide is expressed MACC1mRNA in HepG2 cells
After polypeptide I-1, polypeptide I-2, polypeptide I-3, polypeptide I-4 administrations are handled 24 hours, MACC1mRNA in HepG2 cells
Expression is remarkably decreased, and peptide concentration is higher, and MACC1mRNA expressions decline more obvious.
Each group MACC1mRNA relative expression quantities are as shown in Figure 1.
As a result show, the transcription water of polypeptide I-1, polypeptide I-2, polypeptide I-3, polypeptide I-4 to HepG2 cell MACC1 genes
It is flat that there is obvious inhibitory action.
4th, influence of the polypeptide to MACC1 protein expressions in HepG2 cells
After polypeptide I-1, polypeptide I-2, polypeptide I-3, polypeptide I-4 administrations are handled 24 hours, MACC1 albumen in HepG2 cells
Expression is remarkably decreased, and peptide concentration is higher, and MACC1 protein expression levels decline more obvious.
Each group MACC1 albumen relative expression quantities are as shown in Figure 2.
As a result show, the translation water of polypeptide I-1, polypeptide I-2, polypeptide I-3, polypeptide I-4 to HepG2 cell MACC1 genes
It is flat that there is obvious inhibitory action.
Summary experiment can be drawn the following conclusions：Polypeptide I-1, polypeptide I-2, polypeptide I-3, polypeptide I-4 can from turn
Record and translation skill suppress expression of the MACC1 genes in HepG2 cells, are effective inhibitor of MACC1 genes；Meanwhile, should
Effective inhibitor of MACC1 genes can significantly inhibit propagation and the invasion and attack of HepG2 cells, effective suppression of the MACC1 genes
Agent can be used for the medicine for being prepared into anti-hepatocellular carcinoma invasion and attack.
Applicant is also tested for after aforementioned polypeptides end modified (N-terminal is acetylation modification, and C-terminal is amidated modification)
Pharmacological action, as a result prove that there is similar pharmacological action and strong drug action with unmodified form after aforementioned polypeptides are end modified
Degree.
Above-described embodiment is the embodiment to essentiality content of the present invention, for preferably explaining the present invention, but this area skill
Art personnel are it is to be understood that protection scope of the present invention should not be confined to above-mentioned specific embodiment.
Claims (10)
1. a kind of inhibitor of MACC1 genes, the inhibitor is a kind of polypeptide, the polypeptide includes formula (I) amino acid sequence：
ETMFWYDAK(Xa)PCFTRVPMA(Xb)GTDEQLPDIWN； (Ⅰ)
Wherein, Xa and Xb is selected from M, Y, L, V, W or E.
2. inhibitor according to claim 1, it is characterised in that：Xa and Xb is selected from M or W.
3. inhibitor according to claim 2, it is characterised in that the inhibitor is one of following polypeptides：
ETMFWYDAKMPCFTRVPMAMGTDEQLPDIWN；
ETMFWYDAKWPCFTRVPMAWGTDEQLPDIWN；
ETMFWYDAKMPCFTRVPMAWGTDEQLPDIWN；
ETMFWYDAKWPCFTRVPMAMGTDEQLPDIWN。
4. inhibitor according to claim 3, it is characterised in that：Polypeptide N and/or C-terminal are modified by sulphation.
5. inhibitor according to claim 4, it is characterised in that：The N-terminal of the polypeptide is acetylation modification, C-terminal
It is amidated modification.
6. inhibitor according to claim 5, it is characterised in that the polypeptide form is as follows：
Ac-ETMFWYDAKMPCFTRVPMAMGTDEQLPDIWN-NH2；
Ac-ETMFWYDAKWPCFTRVPMAWGTDEQLPDIWN-NH2；
Ac-ETMFWYDAKMPCFTRVPMAWGTDEQLPDIWN-NH2；
Ac-ETMFWYDAKWPCFTRVPMAMGTDEQLPDIWN-NH2。
7. inhibitor according to claim 1, it is characterised in that：The polypeptide is free form or can pharmaceutically received
Salifie form, including hydrochloride, sulfate, phosphate, sulfonate, acetate, citrate and tartrate.
8. application of any inhibitor of claim 1-7 in the medicine of anti-hepatocellular carcinoma propagation and invasion and attack is prepared.
9. a kind of pharmaceutical composition, containing any peptide inhibitors of claim 1-7 and pharmaceutically acceptable auxiliary material.
10. application of the composition in the medicine of anti-hepatocellular carcinoma propagation and invasion and attack is prepared described in claim 9.
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| CN201710268784.XA CN107082800B (en) | 2017-04-24 | 2017-04-24 | Inhibitor of MACC1 gene and application thereof in resisting hepatocellular carcinoma invasion |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104725398A (en) * | 2015-01-29 | 2015-06-24 | 杨威 | JAK/STAT3 phosphorylation inhibitor as well as preparation method and application thereof |
| WO2016020427A1 (en) * | 2014-08-05 | 2016-02-11 | Charité - Universitätsmedizin Berlin | Macc1 inhibitors and use thereof in the treatment of cancer |
-
2017
- 2017-04-24 CN CN201710268784.XA patent/CN107082800B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016020427A1 (en) * | 2014-08-05 | 2016-02-11 | Charité - Universitätsmedizin Berlin | Macc1 inhibitors and use thereof in the treatment of cancer |
| CN104725398A (en) * | 2015-01-29 | 2015-06-24 | 杨威 | JAK/STAT3 phosphorylation inhibitor as well as preparation method and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| LI HF ET AL.: "Downregulation of MACC1 inhibits invasion, migration and proliferation, attenuates cisplatin resistance and induces apoptosis in tongue squamous cell carcinoma", 《ONCOL REP.》 * |
| 张秀梅等: "肝细胞癌中MACC1基因的表达及其临床意义 ", 《长江大学学报(自科版)》 * |
| 张秀梅等: "肝细胞癌中MACC1基因的表达及其临床意义", 《长江大学学报(自科版)》 * |
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