CN109529041A - Application of the spleen tyrosine kinase as intrahepatic cholangiocellular carcinoma therapy target - Google Patents
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Abstract
Application the invention discloses spleen tyrosine kinase as intrahepatic cholangiocellular carcinoma therapy target, inventor are found through experiments that SYK expresses raising in intrahepatic cholangiocellular carcinoma；It is found in cell and interior animal experiment in vitro, can effectively inhibit the proliferation of intrahepatic cholangiocellular carcinoma using SYK antagonist GS-9973, inhibitory effect is close to front-line chemotherapeutic agents gemcitabine.
Description
Technical field
The invention belongs to biomedicine fields, and in particular to spleen tyrosine kinase is as intrahepatic cholangiocellular carcinoma therapy target
Application.
Background technique
Spleen tyrosine kinase (spleen tyrosine kinase, SYK) gene is 1991 for the first time from cDNA grams of pig spleen
It is grand to come out, encode a kind of non-receptor type protein tyrosine kinase.The mankind SYK assignment of genes gene mapping is in No. 9 areas chromosome q22, SYK albumen
It is the specificity protein kinase of a kind of energy catalysis substrate protein-tyrosine residue phosphorylation, including receptor type containing 635 amino acid
Tyrosine kinase in tyrosine kinase, cytoplasm type tyrosine kinase and core.Tyrosine protein kinase be adjusted cell interior and it
Between signal transduction, play an important role in cell differentiation, proliferation and diffusion, and with the occurrence and development of tumour exist closely close
System.Acted in autoimmune disease and hematologic malignancies it is important, as SYK gene high expression can inhibit breast cancer, black
The proliferation and migration of the malignant cells such as plain tumor and liver cancer.It is numerous research shows that SYK gene have cancer suppressing action, these research
Including but not limited to:
Guo Jiazhong spleen tyrosine kinase, vascular endothelial growth factor-C act in non-small cell lung cancer Lymph Node Metastasis
Research [D] Shandong University, 2013.
The expression of Kou Changwei tissues of nasopharyngeal carcinoma spleen tyrosine kinase and its promoter methylation relationship and clinical meaning [D]
.2009.
Expression of the Yang Xing spleen tyrosine kinase in colorectal cancer and its influence [D] .2006. to infiltration metastasis
Expression of the Zhang Qian spleen tyrosine kinase Syk in the cancer of the esophagus and the river research [D] that its biological property is influenced
Northern medical university, 2011.
Influence [D] Tianjin medical courses in general of the Dong Shangwen .DNA promoter methylation in the expression of spleen tyrosine kinase Syk lung cancer are big
It learns, 2009.
The relationship [D] of lucky sea otter spleen source property tyrosine kinase gene promoter methylation and medulloblastoma invasion transfer
.2016. etc..
Further, the expression of SYK (L) gene and its clinical meaning [D] Zhongshan University in Yang Longjun hepatocellular carcinoma,
2012. point out: 1, SYK (L) can inhibit proliferation, migration and the transfer of liver cancer cells；2, SYK (L) protein expression in liver cancer tissue
It reduces, it is related to shift related clinical pathological factors to invasion such as the differentiation of tumour, vascular invasions；3, SYK (L) can be used as evaluation
Effective molecular marker of liver cancer invasion transfer.
Hu Qinggang, Liu little Wei, Zheng Qichang expression of the tyrosine kinase Syk in liver cancer and the relationship with angiogenesis
[J] Chinese Journal of Hepatobiliary Surgery, 2007,13 (7): 463-465. is using R27-PCR detection Syk mRNA in hepatocellular carcinoma
And the expression in Carcinoma side normal tissue, immunohistochemistry SABC method detect the microvessel density of the expression reflection tumour of CD34 in sample
(MVD) Syk mRNA expresses the positive in 24 Carcinoma side normal tissues of result, and Syk mRNA is expressed in 32 hepatocellular carcinomas
Rate is 46.9% (15/32), wherein low differentiation group positive expression rate 23.1% (3/13), is significantly lower than differentiated group positive expression
Rate 63.2% (12/19) (P < 0.05) tumor microvessel density (MVD) detection: low differentiation group (III grade IV grade for 49.2 ±
3.6,54.9 ± 4.3), be apparently higher than differentiated group (I grade II grade is 13.6 ± 4.5,32.3 ± 3.2) and normal tissue (5.9 ±
1.7) the obvious negative correlation (r=- of expression of the expression for, being statistically significant (P < 0.05) .Syk mRNA and CD34
0.97) missing of Syk gene plays an important role to the generation of cancerous tissue blood vessel in conclusion hepatocellular carcinoma.In other words, press down
The expression of SYK gene processed can promote cancerous tissue angiogenesis, and then promote the progress of liver cancer.
CN105664178A and Qu C, Zheng D, Li S, et al.Tyrosine Kinase SYK is a
Potential Therapeutic Target for Liver Fibrosis. [J] .Hepatology, 2018. disclose SYK
As the application of liver fibrosis/hardening treating target spot, specifically discovery SYK gene is expressed in liver fibrosis/hardening process is risen
Height accelerates the process of liver fibrosis by promoting Hepatic Stellate Cell Activation；Use SYK inhibitor or the table of interference SYK gene
It reaches, can effectively slow down liver fibrosis/hardening process, there is therapeutic effect well.
Currently, SYK inhibitor have been used at present the clinic II of rheumatoid arthritis, chronic lymphocytic leukemia etc./
The experiment of III phase, it is as a result encouraging, and drug safety is good.
In cytologic experiment and animal experiment in vivo, a variety of SYK micromolecular compound inhibitors have been developed, including
Entospletinib (GS-9973), Fostamatinib (R788), R406 and PRT062607 (P505-15, BIIB057)
The biological effect trend of HCl, these SYK inhibitor are similar, inhibit Syk kinase activity with Entospletinib (GS-9973)
It is the most stable, significant.There are many clinics that SYK micromolecular compound inhibitor has been applied to a variety of diseases currently on the market
The II/III phase is studied；Wherein GS-9973 is to test clinic II phase of the latest report for chronic lymphocytic leukemia, efficient
Up to 91%, and drug SYK targeting specific is strong, off-target rate is low, biological safety is good.
Intrahepatic cholangiocellular carcinoma is a kind of malignant tumour originating from bile duct epithelial cell, and the differentiation with bile duct cell is special
Property, it can be divided into intrahepatic cholangiocellular carcinoma (ICC), hilar cholangiocarcinoma and extrahepatic bile ducts cell according to anatomical position difference
Cancer (ECC).In past 40 years, the whole disease incidence of intrahepatic cholangiocellular carcinoma is stepped up in the world.
The disease incidence of intrahepatic cholangiocellular carcinoma accounts for the 10%~15% of liver primary malignant neoplasm, and morbidity in recent years
Rate and the death rate increase year by year.The concealment of cholangiocellular carcinoma onset, early stage non-evident sympton and sign, Later development is rapid, Yi Xiang
Surrounding tissue is invaded and transfer.Since bile duct surrounding anatomic relationship is complicated, easily there is local recurrence in infantile tumour after surgical excision
It is sent out with DISTANT METASTASES IN, causes intrahepatic cholangiocellular carcinoma prognosis poor.Currently, cholangiocarcinoma lacks suitable method of early diagnosis and has
The treatment means of effect, patient's prognosis mala, most of patient are dead within some months after clarifying a diagnosis.
Current clinically intrahepatic cholangiocellular carcinoma mainly has surgical resection, local treatment, and (hepatic arterial infusion chemotherapy is penetrated
Frequency ablation, microwave ablation etc.), the treatment methods such as chemotherapy and radiation.But simple surgical operation cannot effectively treat most of trouble
Person's when discovery (pathogenesis is unknown, lacks early diagnosis marker, lost operative chance), and the low (life in 5 years of survival rates
Depositing rate is 8%~47%), high recurrence rate (in postoperative liver recurrence rate up to 46%~68%)；Rather than patient with operation lacks effectively
Treatment means, local treatment may benefit (whole curative effect to the single lesion and hand Postoperative Residual of < 3cm or local recurrence person
Cause anxiety)；To cannot perform the operation excision or with transfer progressive stage cholangiocarcinoma, gemcitabine combine platinum antineoplastic medicine chemotherapy side
Case can extend cholangiocarcinoma patients life cycle, but be limited to the toxicity and drug resistance of drug；The curative effect of radiation alone is very limited, often
Frequently as a kind of adjuvant treatment modality, evidence there is no to show treatment of the short distance radiotherapy to progressive stage cholangiocarcinoma in radiotherapy and conduit in art
Effect is better than standard chemotherapeutic, chemoradiotherapy plus.Up to the present, cholangiocarcinoma there is no the targeted drug of standard, only exists in exploration and faces
Bed experimental stage, there is no the conclusion of determining curative effect.
CN108273062A discloses FOXMl high expression and related to prognosis in cholangiocellular carcinoma, and FOXMl inhibitor leads to
Increase Apoptosis inhibitor cholangiocellular carcinoma proliferation is crossed, FOXMl strikes the low cholangiocellular carcinoma that can increase for the sensibility of cis-platinum, and
FOXMl inhibitor combination with cisplatin inhibits cholangiocellular carcinoma proliferation.It follows that occurrence and development of the FOXMl in cholangiocellular carcinoma
It plays important role in the process, provides new approaches for the Clinics and Practices of cholangiocellular carcinoma.
Developing one kind can effectively treat or improve the drug of intrahepatic cholangiocellular carcinoma to intrahepatic cholangiocellular carcinoma patient
It has very important significance.
Summary of the invention
It is an object of the invention to overcome the deficiencies of the prior art and provide spleen tyrosine kinases as intrahepatic cholangiocellular carcinoma
The application of therapy target.
The technical solution used in the present invention is:
The application of SYK gene or SYK albumen as intrahepatic cholangiocellular carcinoma therapy target.
Application of the SYK antagonist in preparation treatment intrahepatic cholangiocellular carcinoma drug.
Further, SYK antagonist is selected from GS-9973, Fostamatinib, R406, PRT062607.
The agent of SYK expression inhibiting is in the application in preparation treatment intrahepatic cholangiocellular carcinoma drug.
Further, the agent of SYK expression inhibiting is selected from SYK-siRNA, using SYK as miRNA of target or GEM 132 etc.
Downgrade the nucleic acid of SYK expression.
Further, intrahepatic cholangiocellular carcinoma is the stones in intrahepatic bile duct that SYK expression quantity is significantly higher than bile duct cell in normal hepatocytes
Cell cancer.
The beneficial effects of the present invention are:
Inventor is found through experiments that SYK expresses raising in intrahepatic cholangiocellular carcinoma；Cell and internal animal in vitro
It is found in experiment, can effectively inhibit the proliferation of intrahepatic cholangiocellular carcinoma using SYK antagonist GS-9973, inhibitory effect connects
It is bordering on front-line chemotherapeutic agents gemcitabine.
Detailed description of the invention
Fig. 1 is the SYK expression of bile duct cell and intrahepatic cholangiocellular carcinoma in people's normal hepatocytes；
Fig. 2 is suppression result of the SYK antagonist GS-9973 to cholangiocarcinoma cell (HuCCT-1, RBE)；
Fig. 3 is therapeutic effect of the SYK antagonist GS-9973 to cholangiocarcinoma cell Xenografts in nude mice model.
Specific embodiment
The application of SYK gene or SYK albumen as intrahepatic cholangiocellular carcinoma therapy target.
Application of the SYK antagonist in preparation treatment intrahepatic cholangiocellular carcinoma drug.
Further, SYK antagonist is selected from GS-9973, Fostamatinib, R406, PRT062607.
The agent of SYK expression inhibiting is in the application in preparation treatment intrahepatic cholangiocellular carcinoma drug.
Further, the agent of SYK expression inhibiting is selected from SYK-siRNA, using SYK as miRNA of target or GEM 132 etc.
Downgrade the nucleic acid of SYK expression.
Further, intrahepatic cholangiocellular carcinoma is the stones in intrahepatic bile duct that SYK expression quantity is significantly higher than bile duct cell in normal hepatocytes
Cell cancer.The variation of SYK expression quantity can be used method commonly used in the art and determine, such as scores by comparing immunohistochemical staining
Method evaluation expression amount variation.By comparing the variation of its expression quantity, determine whether its expression quantity is significantly high.
Below with reference to experiment, technical solution of the present invention is further illustrated.
Expression of the SYK in cholangiocarcinoma
Both using bile duct cell and intrahepatic cholangiocellular carcinoma in immunohistochemistry staining method's detection people's normal hepatocytes, compare
The expression of SYK.
If experiment is as shown in Figure 1.As can be known from Fig. 1, to 5 normal bile duct tissues and 43 liver liners collected at present
Scoring analysis is carried out after the SYK immunohistochemical staining of solencyte cancerous tissue, in all intrahepatic cholangiocellular carcinoma tissues SYK
Color, and compared with normal bile duct cell in liver, SYK expression is significant to be increased, and average immunohistochemistry intensity ratings increase more than 1 point
(* * *, < 0.001).
The influence that SYK is proliferated cholangiocarcinoma cell
Select two kinds of cholangiocarcinoma cell strains of HuCCT-1 and RBE, respectively using GS-9973 processing for 24 hours, 48h and 72h, and make
The influence that cholangiocarcinoma cell is proliferated with CCK8 reagent detection different time points GS-9973.HuCCT-1 and RBE cell is made
Single cell suspension, about 3000 cells of 100 μ l are added in every hole in 96 orifice plates.(about 6h) replacement contains GS- after cell is adherent
The culture medium of 9973 (concentration be 2 μM), cultivate respectively for 24 hours, 48h, 72h.The CCK8 reagent of 10 μ l is added in every hole in 96 orifice plates,
Continuation cultivates 2h30min in 37 DEG C of incubators.450nm is selected to measure absorbance.
If experiment is as shown in Figure 2.As can be known from Fig. 2, GS-9973 (2 μM) can significantly inhibit cholangiocarcinoma cell
The proliferation of HuCCT-1 and RBE.
The SYK in two kinds of cholangiocarcinoma cells of low HuCCT-1 and RBE is struck using SYK specific siRNA to express, and is detected and struck
Low SYK expresses the influence to both cell Proliferations, as a result, it has been found that the increasing of both bile duct cells can obviously be inhibited by striking low SYK
It grows, result is similar with using the effect of SYK inhibitor.
The targeting SYK of Xenografts in nude mice is treated
The HuCCT-1 cell of logarithmic growth phase is resuspended cell with PBS after the processing such as pancreatin digestion, is prepared into slender
Born of the same parents' suspension, adjustment cell concentration are 1*10^7/ml.After Balb/c nude mice routine disinfection, 200 μ l cells are drawn with 1ml syringe
Mixed liquor, the armpit subcutaneous injection on the right side of nude mice.Every 3 days observation nude mices, measure and record the line of apsides and weight of knurl, draw
Growth curve；SYK antagonist GS-9973 uses stomach-filling mode drug treatment, and 5mg/kg was opened from the 9th day by daily single
Begin, successive administration was to the 30th day.
Experimental result is as shown in Figure 3.As can be known from Fig. 3, the speed of growth and tumour of tumour can be significantly reduced in GS-9973
Size, inhibitory effect are slightly inferior to front-line chemotherapeutic agents gemcitabine (phase inhibitory effect is better than gemcitabine before the treatment).
Claims (6)
- The application of 1.SYK gene or SYK albumen as intrahepatic cholangiocellular carcinoma therapy target.
- Application of the 2.SYK antagonist in preparation treatment intrahepatic cholangiocellular carcinoma drug.
- 3. application according to claim 2, it is characterised in that: SYK antagonist be selected from GS-9973, Fostamatinib, R406、PRT062607。
- The agent of 4.SYK expression inhibiting is in the application in preparation treatment intrahepatic cholangiocellular carcinoma drug.
- 5. application according to claim 4, it is characterised in that: SYK expression inhibiting agent is selected from SYK-siRNA, using SYK as target Target miRNA or GEM 132 etc. downgrade the nucleic acid of SYK expression.
- 6. described in any item applications according to claim 1~5, it is characterised in that: intrahepatic cholangiocellular carcinoma is aobvious for SYK expression quantity Write the intrahepatic cholangiocellular carcinoma for being higher than bile duct cell in normal hepatocytes.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811294814.5A CN109529041B (en) | 2018-11-01 | 2018-11-01 | Application of spleen tyrosine kinase as target for treating intrahepatic bile duct cell cancer |
| PCT/CN2019/091268 WO2020087938A1 (en) | 2018-11-01 | 2019-06-14 | Use of spleen tyrosine kinase as therapeutic target of intrahepatic cholangiocarcinoma |
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| CN201811294814.5A CN109529041B (en) | 2018-11-01 | 2018-11-01 | Application of spleen tyrosine kinase as target for treating intrahepatic bile duct cell cancer |
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|---|---|---|---|---|
| WO2020087938A1 (en) * | 2018-11-01 | 2020-05-07 | 南方医科大学中西医结合医院 | Use of spleen tyrosine kinase as therapeutic target of intrahepatic cholangiocarcinoma |
| CN114903899A (en) * | 2021-02-08 | 2022-08-16 | 华中科技大学同济医学院附属同济医院 | Medicine for treating intrahepatic cholangiocellular carcinoma |
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| WO2014113729A2 (en) * | 2013-01-18 | 2014-07-24 | Foundation Mecicine, Inc. | Methods of treating cholangiocarcinoma |
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| CN109529041B (en) * | 2018-11-01 | 2021-05-07 | 南方医科大学中西医结合医院 | Application of spleen tyrosine kinase as target for treating intrahepatic bile duct cell cancer |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2014113729A2 (en) * | 2013-01-18 | 2014-07-24 | Foundation Mecicine, Inc. | Methods of treating cholangiocarcinoma |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020087938A1 (en) * | 2018-11-01 | 2020-05-07 | 南方医科大学中西医结合医院 | Use of spleen tyrosine kinase as therapeutic target of intrahepatic cholangiocarcinoma |
| CN114903899A (en) * | 2021-02-08 | 2022-08-16 | 华中科技大学同济医学院附属同济医院 | Medicine for treating intrahepatic cholangiocellular carcinoma |
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