CN109529041B - Application of spleen tyrosine kinase as target for treating intrahepatic bile duct cell cancer - Google Patents
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Abstract
The invention discloses application of spleen tyrosine kinase as a target for treating intrahepatic bile duct cell cancer, and the inventor finds that expression of SYK is increased in intrahepatic bile duct cell cancer through experiments; in vitro cell and in vivo animal experiments, the SYK antagonist GS-9973 can effectively inhibit the proliferation of intrahepatic cholangiocellular carcinoma, and the inhibition effect is close to that of first-line chemotherapeutic drug gemcitabine.
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to application of spleen tyrosine kinase as a target for treating intrahepatic bile duct cell cancer.
Background
The spleen tyrosine kinase (SYK) gene was first cloned from pig spleen cDNA in 1991 and encodes an unresponsive protein tyrosine kinase. Human SYK gene is located in chromosome 9, q22 area, SYK protein contains 635 amino acids, and is a specific protein kinase capable of catalyzing substrate protein tyrosine residue phosphorylation, including receptor type tyrosine kinase, cytoplasm type tyrosine kinase and nuclear tyrosine kinase. Tyrosine protein kinases can regulate signal transduction inside and among cells, play an important role in cell differentiation, proliferation and diffusion, and have close relation with the occurrence and development of tumors. The SYK gene plays an important role in autoimmune diseases and hematologic malignant tumors, and for example, the high expression of the SYK gene can inhibit the proliferation and migration of malignant tumor cells such as breast cancer, melanoma, liver cancer and the like. Numerous studies have shown that SYK gene has a cancer-inhibiting effect, including but not limited to:
study of the role of Guojiaseus spleen tyrosine kinase, vascular endothelial growth factor-C in non-small cell lung cancer lymphatic metastasis [ D ]. university of Shandong, 2013.
The relationship between the expression of the spleen tyrosine kinase in nasopharyngeal carcinoma tissues and the methylation of the promoter thereof and the clinical significance [ D ] 2009.
Expression of populin spleen tyrosine kinase in colorectal cancer and its effect on infiltration metastasis [ D ].2006.
Study of expression and impact on biological characteristics of janus qian spleen tyrosine kinase Syk in esophageal cancer [ D ]. hebei college of medical science, 2011.
Effect of DNA promoter methylation in spleen tyrosine kinase Syk lung cancer expression [ D ] tianjin medical university, 2009.
Jihailong, spleen source tyrosine kinase gene promoter methylation and medulloblastoma invasion and transfer relation [ D ].2016.
Further, expression of syk (l) gene in poplar monarch. hepatocellular carcinoma and its clinical significance [ D ] zhongshan university, 2012 pointed out: 1.SYK (L) can inhibit proliferation, migration and metastasis of hepatocarcinoma cells; 2. the expression of SYK (L) protein in liver cancer tissues is reduced, and the expression is related to clinical pathological factors related to invasion and metastasis of tumor differentiation, vascular invasion and the like; 3. SYK (L) can be used as an effective molecular marker for evaluating liver cancer invasion and metastasis.
The relation between the expression of the Syk kinase Syk in liver cancer and angiogenesis [ J ]. China liver and gall surgery journal, 2007,13(7):463 and 465 ], R27-PCR is adopted to detect the expression of the Syk mRNA in liver cell liver cancer and paracancer normal tissues, the expression of CD34 in a specimen is detected by an immunohistochemical SABC method to reflect the tumor microvascular density (MVD), the result shows that the Syk mRNA in 24 paracancer normal tissues is positively expressed, the Syk mRNA expression rate in 32 cases of liver cell cancer is 46.9 percent (15/32), wherein the positive expression rate of a low differentiation group is 23.1 percent (3/13), is obviously lower than the positive expression rate of a high differentiation group 63.2 percent (12/19) (P < 0.05), the tumor microvascular density (MVD) is detected, the low differentiation group (III grade IV grade is 49.2 +/-3.6, 54.9 +/-4.3), and the high differentiation group (I grade II grade is 13.6 +/-4.5, 32.3 +/-3.2) and normal tissues (5.9 +/-1.7) have significant statistical significance (P is less than 0.05), the expression of Syk mRNA is obviously and negatively related to the expression of CD34 (r is-0.97), and the conclusion that the deletion of Syk gene in the hepatocellular carcinoma plays an important role in the generation of cancer tissue blood vessels is concluded. In other words, inhibition of expression of SYK gene promotes angiogenesis in cancer tissue, and thus promotes the progression of liver cancer.
CN105664178A and Qu C, Zheng D, Li S, et al.Tyrosine Kinase SYK is a systemic Therapeutic Target for Liver Fibrosis [ J ]. Hepatology,2018. the application of SYK as a hepatic Fibrosis/cirrhosis treatment Target is disclosed, in particular to the discovery that expression of SYK gene is increased in the hepatic Fibrosis/cirrhosis process, and the process of hepatic Fibrosis is accelerated by promoting the activation of hepatic stellate cells; the SYK inhibitor or the interference with the expression of the SYK gene can effectively slow down the progress of hepatic fibrosis/cirrhosis and has good treatment effect.
At present, SYK inhibitors are currently used in clinical phase II/III experiments of rheumatoid arthritis, chronic lymphocytic leukemia and the like, and have encouraging results and good drug safety.
In cytology experiments and in-animal experiments, various SYK small-molecule compound inhibitors including Entosplitib (GS-9973), Fostamatinib (R788), R406 and PRT062607(P505-15, BIIB057) HCl have been developed, and the biological effect trends of the SYK inhibitors are similar, so that the inhibition of SYK kinase activity by Entosplitib (GS-9973) is most stable and remarkable. At present, various SYK small molecule compound inhibitors are applied to clinical II/III phase researches of various diseases on the market; GS-9973 is the latest reported clinical phase II experiment for chronic lymphocytic leukemia, the effective rate is up to 91%, and the medicine SYK has strong target specificity, low off-target rate and good biological safety.
Intrahepatic cholangiocellular carcinoma is a malignant tumor originated from bile duct epithelial cells, has the differentiation characteristic of bile duct cells, and can be classified into Intrahepatic Cholangiocellular Carcinoma (ICC), hepatoportal cholangiocellular carcinoma, and Extrahepatic Cholangiocellular Carcinoma (ECC) according to anatomical locations. The overall incidence of intrahepatic cholangiocellular carcinoma has increased worldwide over the past forty years.
The incidence of intrahepatic cholangiocellular carcinoma accounts for 10% -15% of primary liver malignancies, and the incidence and mortality have increased year by year in recent years. Biliary tract cell cancer has hidden onset, no obvious symptoms and signs in the early stage, rapid development in the later stage, and easy invasion and metastasis to peripheral tissues. Because the anatomical relationship around the bile duct is complex, local recurrence and distant metastasis of early-stage tumor are easy to occur after surgical resection, and the prognosis of intrahepatic cholangiocellular carcinoma is poor. Currently, bile duct cancer lacks a suitable early diagnosis method and an effective treatment means, the prognosis of patients is poor, and most patients die within several months after a clearly diagnosed diagnosis.
At present, the intrahepatic bile duct cell cancer is mainly treated by surgical excision, local treatment (hepatic artery perfusion chemotherapy, radio frequency ablation, microwave ablation and the like), chemotherapy, radiotherapy and the like clinically. However, the simple surgical operation can not effectively treat most patients (the pathogenesis is unknown, early diagnosis markers are lacked, and the operation chance is lost when the early diagnosis markers are found), the postoperative survival rate is low (the 5-year survival rate is 8-47%), and the recurrence rate is high (the postoperative intrahepatic recurrence rate is 46-68%); while non-surgical patients lack effective treatment, local treatment may benefit from <3cm of single lesions, and post-operative residual or local recurrence (overall efficacy is great); for advanced bile duct cancer which cannot be resected by surgery or is accompanied with metastasis, the survival period of patients with bile duct cancer can be prolonged by a chemotherapy scheme of combining gemcitabine with a platinum anti-tumor agent, but the chemotherapy scheme is limited by the toxicity and drug resistance of drugs; the curative effect of simple radiotherapy is very limited, and the simple radiotherapy is often used as an auxiliary treatment mode, and no evidence shows that the curative effect of the intraoperative radiotherapy and the intraductal short-distance radiotherapy on the advanced bile duct cancer is better than the curative effect of the standard chemotherapy and the radiotherapy and chemotherapy combination. Until now, there is no standard target medicine for bile duct cancer, and it is only in the stage of exploration and clinical test, and there is no conclusion about the curative effect.
CN108273062A discloses that FOXMl is highly expressed in cholangiocellular carcinoma and is associated with prognosis, FOXMl inhibitors inhibit cholangiocellular carcinoma proliferation by increasing apoptosis, FOXMl knockdown can increase the sensitivity of cholangiocellular carcinoma to cisplatin, and FOXMl inhibitors in combination with cisplatin inhibit cholangiocellular carcinoma proliferation. Therefore, FOXMl plays an important role in the occurrence and development process of cholangiocellular carcinoma, and provides a new idea for the diagnosis and treatment of cholangiocellular carcinoma.
The development of a medicament capable of effectively treating or improving the intrahepatic cholangiocellular carcinoma has very important significance for the intrahepatic cholangiocellular carcinoma patients.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides application of spleen tyrosine kinase as a target for treating intrahepatic cholangiocellular carcinoma.
The technical scheme adopted by the invention is as follows:
application of SYK gene or SYK protein as target for treating intrahepatic cholangiocellular carcinoma.
Application of SYK antagonist in preparing medicine for treating intrahepatic cholangiocellular carcinoma is provided.
Further, the SYK antagonist is selected from GS-9973, Fostamatinib, R406, PRT 062607.
Application of SYK expression inhibitor in preparing medicine for treating intrahepatic cholangiocellular carcinoma is provided.
Further, the SYK expression inhibitor is selected from nucleic acids which regulate and reduce SYK expression, such as SYK-siRNA, miRNA or antisense nucleotide taking SYK as target, and the like.
Furthermore, the intrahepatic cholangiocarcinoma is intrahepatic cholangiocarcinoma with SYK expression level significantly higher than that of normal intrahepatic cholangiocarcinoma.
The invention has the beneficial effects that:
the inventor finds that SYK is expressed in intrahepatic cholangiocellular carcinoma in an increasing way through experiments; in vitro cell and in vivo animal experiments, the SYK antagonist GS-9973 can effectively inhibit the proliferation of intrahepatic cholangiocellular carcinoma, and the inhibition effect is close to that of first-line chemotherapeutic drug gemcitabine.
Drawings
FIG. 1 shows SYK expression in normal and hepatobiliary cells of humans;
FIG. 2 shows the inhibition of bile duct carcinoma cells (HuCCT-1, RBE) by the SYK antagonist GS-9973;
FIG. 3 shows the therapeutic effect of the SYK antagonist GS-9973 on a biliary duct cancer cell nude mouse subcutaneous transplantation tumor model.
Detailed Description
Application of SYK gene or SYK protein as target for treating intrahepatic cholangiocellular carcinoma.
Application of SYK antagonist in preparing medicine for treating intrahepatic cholangiocellular carcinoma is provided.
Further, the SYK antagonist is selected from GS-9973, Fostamatinib, R406, PRT 062607.
Application of SYK expression inhibitor in preparing medicine for treating intrahepatic cholangiocellular carcinoma is provided.
Further, the SYK expression inhibitor is selected from nucleic acids which regulate and reduce SYK expression, such as SYK-siRNA, miRNA or antisense nucleotide taking SYK as target, and the like.
Furthermore, the intrahepatic cholangiocarcinoma is intrahepatic cholangiocarcinoma with SYK expression level significantly higher than that of normal intrahepatic cholangiocarcinoma. The change in expression of SYK can be determined by methods commonly used in the art, such as by evaluating the change in expression by comparing immunohistochemical staining scores. And determining whether the expression level is remarkably high or not by comparing the change of the expression level.
The technical scheme of the invention is further explained by combining experiments.
Expression of SYK in cholangiocarcinoma tissues
And detecting normal intrahepatic bile duct cell and intrahepatic bile duct cell cancer of the human by adopting an immunohistochemical staining method, and comparing the expression conditions of SYK of the human normal intrahepatic bile duct cell and the intrahepatic bile duct cell cancer.
The experiment is shown in FIG. 1. As can be seen from fig. 1, when score analysis was performed after SYK immunohistochemical staining of 5 normal bile duct tissues and 43 intrahepatic cholangiocellular carcinoma tissues collected so far, SYK was stained in all intrahepatic cholangiocellular carcinoma tissues, and SYK expression was significantly increased compared to intrahepatic normal cholangiocellular carcinoma tissues, and mean immunohistochemical intensity score was increased by more than 1 point (×, < 0.001).
Effect of SYK on cholangiocarcinoma cell proliferation
Two bile duct cancer cell strains of HuCCT-1 and RBE are selected, GS-9973 is used for treating for 24 hours, 48 hours and 72 hours respectively, and CCK8 reagent is used for detecting the influence of GS-9973 on the proliferation of bile duct cancer cells at different time points. HuCCT-1 and RBE cells were made into single cell suspensions and 100. mu.l of about 3000 cells were added per well in 96-well plates. After the cells are attached to the wall (about 6h), the culture medium containing GS-9973 (with the concentration of 2 mu M) is replaced and cultured for 24h, 48h and 72h respectively. Mu.l of CCK8 reagent was added to each well of a 96-well plate and incubation was continued for 2h30min at 37 ℃ in an incubator. The absorbance was measured at 450 nm.
The experiment is shown in FIG. 2. As can be seen from FIG. 2, GS-9973 (2. mu.M) can significantly inhibit the proliferation of bile duct carcinoma cells HuCCT-1 and RBE.
SYK specific siRNA is used for knocking down SYK expression in HuCCT-1 and RBE bile duct cancer cells, the influence of the knocked-down SYK expression on the proliferation of the two bile duct cancer cells is detected, and the result shows that the knocking-down SYK can obviously inhibit the proliferation of the two bile duct cancer cells, and the effect of the knocking-down SYK is similar to that of a SYK inhibitor.
Targeted SYK treatment of nude mouse subcutaneous transplantable tumors
HuCCT-1 cells in logarithmic growth phase are treated by trypsinization and the like, and then are re-suspended by PBS to prepare single cell suspension, and the cell concentration is adjusted to be 1 x 10^ 7/ml. After Balb/c nude mice were sterilized conventionally, 200. mu.l of the cell mixture was aspirated by a 1ml syringe and injected subcutaneously into the right armpit of the nude mice. Observing the nude mice every 3 days, measuring and recording the length, the length and the weight of a tumor body, and drawing a growth curve; the SYK antagonist GS-9973 is administered by gavage, 5mg/kg once daily, starting on day 9 and continuing until day 30.
The results of the experiment are shown in FIG. 3. As can be seen from FIG. 3, GS-9973 significantly reduced the growth rate and tumor size of tumors, and the inhibitory effect was slightly inferior to that of gemcitabine, the first-line chemotherapeutic drug (the inhibitory effect was stronger than that of gemcitabine during the pre-treatment period).
Claims (1)
- The application of a SYK antagonist in preparing a medicine for treating intrahepatic cholangiocellular carcinoma is disclosed, wherein the SYK antagonist is GS-9973.
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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 |
| 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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