Ruxolitinib对JAK2V617F阳性骨髓增殖性肿瘤细胞基质金属蛋白酶调控的研究
发布时间：2018-09-08 21:40
【摘要】：目的:探讨Ruxolitinib对JAK2V617F突变阳性骨髓增殖性肿瘤细胞内基质金属蛋白酶调控的影响。观察Ruxolitinib对人红白血病HEL细胞(JAK2V617F突变阳性)增殖、凋亡、迁移及JAK2、MMP-2、MMP-9基因、蛋白表达水平的影响。探讨Ruxolitinib对HEL细胞是否存在抑制增殖、迁移,诱导凋亡作用,以及对骨髓增殖性肿瘤原代细胞及HEL细胞抑制JAK2、MMP-2、MMP-9蛋白、基因表达的作用,为Ruxolitinib应用于临床治疗骨髓增殖性肿瘤提供理论依据。方法:1临床资料:保定市第一医院在2012年1月至2015年12月收治的40例初诊JAK2V617F突变阳性(排除MPLW515K/L及CALR突变)的MPN患者纳入研究(MPN组),男18例、女22例,中位年龄59(34~72)岁,真性红细胞增多症(PV)13例,原发性血小板增多症(ET)10例,原发性骨髓纤维化PMF 17例,以15名健康志愿者作为对照组,其中男8名、女7名,中位年龄55(36~78)岁。所选取的患者诊断均符合《血液病诊断及疗效标准》[1],患者均签署了知情同意。本研究得到保定市第一医院伦理委员会的批准。2基础细胞实验分组选用人红白血病HEL细胞株(JAK2V617F突变阳性)。实验分为:Ruxolitinib处理组、对照组。对照组以含10%新生牛血清的RPMI1640培养基培养。Ruxolitinib处理组以含有不同浓度的Ruxolitinib 10%新生牛血清RPMI1640培养基培养。Ruxolitinib的终浓度分别为(0 nmol/L,50nmol/L,100 nmol/L,250 nmol/L,500 nmol/L,1000 nmol/L)。3应用实时荧光定量PCR检测MPN患者JAK2V617F突变量、MMP-2、MMP-9的m RNA表达。4采用免疫组化检测患者骨髓病理组织p-JAK2、MMP-2、MMP-9蛋白的表达。5 Cell Counting Kit(CCK-8)方法,检测Ruxolitinib作用后HEL细胞增殖抑制情况。6流式细胞术,检测18例MPN Ruxolitinib作用24h后细胞CD34+表达的影响。7 Transwell小室实验,检测Ruxolitinib作用24h后MPN细胞、HEL细胞迁移的影响8采用蛋白印迹(Western blot)技术检测Ruxolitinib作用于MPN细胞、HEL细胞后,各组细胞p-JAK2、MMP-2、MMP-9蛋白的表达情况。结果:1应用荧光定量聚合酶链反应(Quantitative Real-time PCR,q PCR)检测MPN患者JAK2V617F突变量在26.8%-75.4%之间。Ruxolitinib对HEL细胞JAK2、MMP-2、MMP-9基因m RNA表达的影响:不同浓度(0nmol/l,50 nmol/l,100 nmol/l,250 nmol/l,500 nmol/l,1000 nmol/L)Ruxolitinib处理HEL细胞48 h后,JAK2基因表达分别为(0.431±0.043)、(0.362±0.032)、(0.254±0.031)、(0.181±0.022)、(0.143±0.022)、(0.143±0.022);MMP-2基因表达分别为(0.397±0.031)、(0.362±0.030)、(0.235±0.023)、(0.188±0.018)、(0.155±0.010)、(0.098±0.009);MMP-9基因表达分别为(0.321±0.032)、(0.252±0.025)、(0.245±0.024)、(0.215±0.025)、(0.155±0.018)、(0.098±0.009)。JAK2、MMP-2、MMP-9 m RNA表达水平均随Ruxolitinib浓度的增加而逐渐减低(P0.001)。2免疫组织化学检测结果显示:MPN组p-JAK2、MMP-2、MMP-9蛋白表达均高于对照组[(78.56±24.55)%对(41.59±17.29)%、(48.25±18.74)%对(22.79±13.89)%、(53.29±19.28)%对(15.56±14.96)%,P值均0.05]。Spearman相关分析显示MMP-2、MMP-9蛋白水平与JAK2V617F突变量正相关(r=0.526,P0.05;r=0.543,P0.05)]。3 CCK-8结果显示:不同浓度(0nmol/l,50 nmol/l,100 nmol/l,250nmol/l,500 nmol/l,1000 nmol/L)Ruxolitinib处理组HEL细胞的存活率,24h时分别为(76.10±3.09)%、(66.04±3.14)%、(60.06±2.71)%、(59.27±2.86)%、(57.86±2.32)%;48h时分别为(70.14±3.39)%、(59.71±3.34)%、(52.80±2.61)%、(43.30±2.96)%(38.56±2.15)%;72h时分别为(55.83±3.43)%、(47.63±3.12)%、(36.43±2.98)%、(31.05±2.78)%、(14.48±2.86)%。与空白对照组相比,不同浓度Ruxolitinib在作用HEL细胞不同时间(24h、48h、72h)后,HEL细胞的活力明显受到抑制,差别有统计学意义(P0.05)。延长Ruxolitinib作用的时间和增加药物的剂量,细胞活力亦显著减低(P0.05)。4 Ruxolitinib对JAK2V617F阳性MPN患者骨髓CD34+细胞影响:18例初诊MPN患者中CD34+细胞比例高于对照组[(0.29±0.13)%对(0.23±0.05)%,t=0.286,P0.001],250 nmol/L Ruxolitinib干预组MPN患者CD34+细胞水平较低于未干预组[(0.29±0.13)%对(0.14±0.07)%,P0.001]。PV(5例)、ET(6例)、PMF(7例)患者250 nmol/L Ruxolitinib干预组CD34+细胞表达均低于未干预组[(0.18±0.05)对(0.26±0.05)、(0.19±0.04)对(0.25±0.05)、(0.14±0.08)对(0.35±0.08),P值均0.05]。5 Transwell迁移实验观察Ruxolitinib对MPN原代细胞及HEL细胞迁移的影响:5 nmol/L Ruxolitinib作用MPN原代细胞24 h后迁移至下室细胞数少于无Ruxolitinib的空白组(154.7±27.5对320.3±67.3,t=13.47,P0.01)。5 nmol/L Ruxolitinib处理HEL细胞24 h后迁移至下室细胞数少于无Ruxolitinib对照组(70.7±10.5对135.3±16.7,t=13.89,P0.01)。6 Western blot检测显示:Ruxolitnib作用于HEL细胞48h后,空白对照组不同浓度(0nmol/l,50 nmol/l,100 nmol/l,250 nmol/l,500 nmol/l,1000nmol/L)Ruxolitnib作用后HEL细胞检测p-JAK2蛋白相对表达(条带的相对灰度比值)分别为(1.52±0.12)、(1.21.±0.10)、(1.12±0.09)、(0.98±0.07)、(0.45±0.04)、(0.15±0.01)。MMP-2蛋白相对表达分别为(0.53±0.04)、(0.42±0.03)、(0.31±0.03)、(0.27±0.02)、(0.23±0.01)、(0.19±0.01)。MMP-9蛋白相对表达分别为(0.78±0.06)、(0.65±0.04)、(0.54±0.04)、(0.30±0.02)、(0.27±0.02)、(0.23±0.01)。β-actin蛋白的表达在三组中无显著差异。Ruxolitinib处理组p-JAK2、MMP-2、MMP-9蛋白的表达与空白对照组相比,均受到抑制(P0.05)。药物浓度增加,蛋白表达量明显减少,差异存在统计学意义(P0.05)。Western blot检测Ruxolitinib对MPN原代细胞p-JAK2、MMP-2、MMP-9蛋白表达的影响:250 nmol/L Ruxolitinib作用48 h能明显抑制MPN原代细胞p-JAK2、MMP-2、MMP-9表达。结果显示,p-JAK2、MMP-2和MMP-9蛋白的表达明显降低,在不同浓度的Ruxolitnib作用后。结论:1在JAK2V617F突变阳性初治组MPN患者中p-JAK2、MMP-2、MMP-9蛋白表达水平明显高于对照组,应用Ruxolitnib后MPN患者p-JAK2、MMP-2、MMP-9表达水平明显降低。2应用Ruxolitnib可明显抑制HEL细胞增殖,并随着Ruxolitnib浓度的增加时间的延长HEL细胞活力明显下降。3体外应用Ruxolitnib对MPN细胞CD34+表达水平明显抑制作用。4应用Ruxolitnib能下调HEL细胞JAK2、MMP-2、MMP-9 m RNA及其p-JAK2、MMP-2、MMP-9蛋白的表达水平,并随Ruxolitnib的浓度增加而进行性减低。5 Ruxolitnib对MPN原代细胞及HEL细胞迁移有明显抑制作用。
[Abstract]:AIM: To investigate the effect of Ruxolitinib on the regulation of matrix metalloproteinases (MMPs) in JAK2V617F mutant positive myeloproliferative tumor cells. To observe the effect of Ruxolitinib on proliferation, apoptosis, migration, JAK2, MMP-2, MMP-9 gene and protein expression of human erythroleukemia HEL cells (JAK2V617F mutant positive). Inhibition of proliferation, migration, induction of apoptosis, and inhibition of JAK2, MMP-2, MMP-9 protein and gene expression in primary cells and HEL cells of myeloproliferative tumors provide theoretical basis for the clinical application of Ruxolitinib in the treatment of myeloproliferative tumors. Methods: 1 Clinical data: Baoding First Hospital from January 2012 to December 2015. Forty MPN patients with positive JAK2V617F mutation (excluding MPLW515K/L and CALR mutations) were included in the study (MPN group), including 18 males and 22 females, with a median age of 59 (34-72), 13 with polycythemia vera (PV), 10 with primary thrombocytosis (ET), 17 with primary myelofibrosis (PMF), and 15 healthy volunteers as control group. The study was approved by the ethical committee of Baoding First Hospital. 2 Basic cell experiment group was selected HEL cell line (JAK2V617F mutation positive). The experiment was divided into: Ruxolitini. The control group was cultured on RPMI1640 medium containing 10% bovine serum. The Ruxolitinib group was cultured on RPMI1640 medium containing 10% bovine serum of different concentrations. The final concentrations of Ruxolitinib were (0 nmol/L, 50 nmol/L, 100 nmol/L, 250 nmol/L, 500 nmol/L, 1000 nmol/L) respectively. 3 were determined by real-time fluorescence. The expression of JAK2, MMP-2 and MMP-9 was detected by immunohistochemistry. 5 Cell Counting Kit (CCK-8) assay was used to detect the proliferation inhibition of HEL cells after Ruxolitinib treatment. 6 Flow cytometry was used to detect the expression of MMP-2 and MMP-9 m RNA in 18 MPN Ruxolitinib treated HEL cells 24 hours later. The effect of Ruxolitinib on MPN cell migration was detected by Western blot. The expression of p-JAK2, MMP-2 and MMP-9 in MPN cells and HEL cells was detected by Western blot. Results: 1. Quantitative polymerase chain reaction (Quantita) was used. The mutations of JAK2V617F in MPN patients were 26.8% - 75.4%. The effects of Ruxolitinib on the expression of JAK2, MMP-2, MMP-9 gene m RNA in HEL cells were (0.431 [0.043], (0.043]) at different concentrations (0 nmol/l, 50 nmol/l, 100 nmol/l, 250 nmol/l, 500 nmol/l, 1000 nmol/L) Ruxolitinib for 48 hours. The expression of MMP-2 gene was (0.397 [(0.397 [(0.031), (0.362 [(0.362 [0.032), (0.235 [(0.235 [0.023), (0.188 [0.188 [0.018], (0.1885 [0.010.018, (0.155 [0.010 0 0.010 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0.010), (0.143 [0.098 [0.098 [0.090.090.143 [0.143 [0.022]], (0.143 [0.14(0.025), (0.245 + 0.024), (0.215 + 0.025), (0.155 + 0.018), (0.098 + 0.0) 09). JAK2, MMP-2, and MMP-9 m RNA expression levels gradually decreased with the increase of Ruxolitinib concentration (P 0.001). 2 Immunohistochemical results showed that the expression of p-JAK2, MMP-2, and MMP-9 protein in MPN group was higher than that in control group [(78.56 24.55)% vs. (41.59 17.29)%, (48.25 18.74)% vs. (22.79 13.89)%, (53.29 (19.28)% vs. (15.56 14.96)%, P Spearman correlation analysis showed that MMP-2 and MMP-9 protein levels were positively correlated with JAK2V617F mutation (r = 0.526, P 0.05; r = 0.543, P 0.05). 3 CCK-8 results showed that the survival rates of HEL cells treated with different concentrations (0 nmol/l, 50 nmol/l, 100 nmol/l, 250 nmol/l, 500 nmol/l, 1000 nmol/L) Ruxolitinib were (76.10 (+3.09)%, (66.04 (+3.14)%, (60.14)% respectively at 24 h. 06 [(56.27 [2.71)%, (59.27 [2.86)%, (57.86 [2.32)%, (57.86 [2.32)%, (57.86 [2.32)%, (70.14 [3.39)%, (59.71 [3.34%, (59.71 [59.71 [3.34)%, (52.80 [2.61%, (52.80 [(52.80 [2.61)%, (43.30 [2.96%, (43.30 [38.30 [38.56 [2.56 [38.56 [2.56 [2.15)%, (38.56 [[38.56 [38.56 [ib acted on HEL cells at different time. After 24h, 48h, 72h, the activity of HEL cells was significantly inhibited, the difference was statistically significant (P 0.05). prolonging the time of action of Ruxolitinib and increasing the dosage of the drug, the cell viability was also significantly decreased (P 0.05). 4 Ruxolitinib on JAK2V617F positive MPN patients with bone marrow CD34 + cells: 18 patients with newly diagnosed MPN CD34 + cell ratio was higher than the control group [(0.05). The levels of CD34+ cells in MPN patients with 250 nmol/L Ruxolitinib intervention group were lower than those in non-intervention group [(0.29+0.13)% vs. (0.14+0.07)%, P 0.001]. The expression of CD34+ cells in PV (5 cases), ET (6 cases) and PMF (7 cases) patients with 250 nmol/L Ruxolitinib intervention group was lower than that in non-intervention group [(0.18+0.05)% vs. (0.24+0.07)%, P 0.001]. 5 Transwell migration assay was used to observe the effect of Ruxolitinib on the migration of MPN primary cells and HEL cells. The number of MPN primary cells migrated to the lower chamber after 24 hours of treatment with 5 nmol/L Ruxolitinib was less than that without Ruxolitinib (154.7+27.5 vs 320.3+67.3, t=13.47, P 0.01). The number of HEL cells migrated to the lower chamber after 24 hours of treatment with l/L Ruxolitinib was less than that of the control group without Ruxolitinib (70.7+10.5 vs 135.3+16.7, t=13.89, P 0.01). 6 Western blot assay showed that the effect of Ruxolitnib on HEL cells at different concentrations (0 nmol/l, 50 nmol/l, 100 nmol/l, 250 nmol/l, 500 nmol/l, 1000 nmol/L) was observed in the blank control group. The relative expression of p-JAK2 protein in HEL cells was (1.52 (+ 0.12), (1.21 (+ 0.10), (1.21 (+ (+0.10), (1.12 + (+0.10), (1.12 (+0.09), (0.12 (+0.09,,,, (0.98 +0.07,,,,, (0.98 +,,,,, (0.45 +,,,, (0.04,, (0.45 +,,,, (0.15 +0.01), (0.MMP-2 protein relative expression was (0.53 ((0.53 + (0.42 (0.42 +0.03,,, (0.Express differently The expression of P-JAK2, MMP-2 and MMP-9 protein in Ruxolitinib treatment group was inhibited compared with the blank control group (P 0.05). Drug concentration increased, protein expression decreased significantly, and the difference was statistically significant. Western blot analysis of Ruxolitinib on MPN primary cells p-JAK2, MMP-2, MMP-9 protein expression: 250 nmol/L Ruxolitinib 48 hours can significantly inhibit the expression of p-JAK2, MMP-2, MMP-9 in MPN primary cells. The results showed that the expression of p-JAK2, MMP-2 and MMP-9 protein was significantly reduced, after the effect of different concentrations of Ruxolitinib. The expression levels of p-JAK2, MMP-2 and MMP-9 in MPN patients with positive JAK2V617F mutation were significantly higher than those in the control group. The expression levels of p-JAK2, MMP-2 and MMP-9 in MPN patients with positive JAK2V617F mutation were significantly decreased after the application of Ruxolitnib. 3. Ruxolitnib significantly inhibited the expression of CD34+ in MPN cells in vitro. 4 Ruxolitnib could down-regulate the expression of JAK2, MMP-2, MMP-9m RNA and its p-JAK2, MMP-2 and MMP-9 proteins in HEL cells. Ruxolitnib significantly inhibited the migration of primary MPN cells and HEL cells.
【学位授予单位】：承德医学院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R733.3
本文编号：2231773
[Abstract]:AIM: To investigate the effect of Ruxolitinib on the regulation of matrix metalloproteinases (MMPs) in JAK2V617F mutant positive myeloproliferative tumor cells. To observe the effect of Ruxolitinib on proliferation, apoptosis, migration, JAK2, MMP-2, MMP-9 gene and protein expression of human erythroleukemia HEL cells (JAK2V617F mutant positive). Inhibition of proliferation, migration, induction of apoptosis, and inhibition of JAK2, MMP-2, MMP-9 protein and gene expression in primary cells and HEL cells of myeloproliferative tumors provide theoretical basis for the clinical application of Ruxolitinib in the treatment of myeloproliferative tumors. Methods: 1 Clinical data: Baoding First Hospital from January 2012 to December 2015. Forty MPN patients with positive JAK2V617F mutation (excluding MPLW515K/L and CALR mutations) were included in the study (MPN group), including 18 males and 22 females, with a median age of 59 (34-72), 13 with polycythemia vera (PV), 10 with primary thrombocytosis (ET), 17 with primary myelofibrosis (PMF), and 15 healthy volunteers as control group. The study was approved by the ethical committee of Baoding First Hospital. 2 Basic cell experiment group was selected HEL cell line (JAK2V617F mutation positive). The experiment was divided into: Ruxolitini. The control group was cultured on RPMI1640 medium containing 10% bovine serum. The Ruxolitinib group was cultured on RPMI1640 medium containing 10% bovine serum of different concentrations. The final concentrations of Ruxolitinib were (0 nmol/L, 50 nmol/L, 100 nmol/L, 250 nmol/L, 500 nmol/L, 1000 nmol/L) respectively. 3 were determined by real-time fluorescence. The expression of JAK2, MMP-2 and MMP-9 was detected by immunohistochemistry. 5 Cell Counting Kit (CCK-8) assay was used to detect the proliferation inhibition of HEL cells after Ruxolitinib treatment. 6 Flow cytometry was used to detect the expression of MMP-2 and MMP-9 m RNA in 18 MPN Ruxolitinib treated HEL cells 24 hours later. The effect of Ruxolitinib on MPN cell migration was detected by Western blot. The expression of p-JAK2, MMP-2 and MMP-9 in MPN cells and HEL cells was detected by Western blot. Results: 1. Quantitative polymerase chain reaction (Quantita) was used. The mutations of JAK2V617F in MPN patients were 26.8% - 75.4%. The effects of Ruxolitinib on the expression of JAK2, MMP-2, MMP-9 gene m RNA in HEL cells were (0.431 [0.043], (0.043]) at different concentrations (0 nmol/l, 50 nmol/l, 100 nmol/l, 250 nmol/l, 500 nmol/l, 1000 nmol/L) Ruxolitinib for 48 hours. The expression of MMP-2 gene was (0.397 [(0.397 [(0.031), (0.362 [(0.362 [0.032), (0.235 [(0.235 [0.023), (0.188 [0.188 [0.018], (0.1885 [0.010.018, (0.155 [0.010 0 0.010 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0.010), (0.143 [0.098 [0.098 [0.090.090.143 [0.143 [0.022]], (0.143 [0.14(0.025), (0.245 + 0.024), (0.215 + 0.025), (0.155 + 0.018), (0.098 + 0.0) 09). JAK2, MMP-2, and MMP-9 m RNA expression levels gradually decreased with the increase of Ruxolitinib concentration (P 0.001). 2 Immunohistochemical results showed that the expression of p-JAK2, MMP-2, and MMP-9 protein in MPN group was higher than that in control group [(78.56 24.55)% vs. (41.59 17.29)%, (48.25 18.74)% vs. (22.79 13.89)%, (53.29 (19.28)% vs. (15.56 14.96)%, P Spearman correlation analysis showed that MMP-2 and MMP-9 protein levels were positively correlated with JAK2V617F mutation (r = 0.526, P 0.05; r = 0.543, P 0.05). 3 CCK-8 results showed that the survival rates of HEL cells treated with different concentrations (0 nmol/l, 50 nmol/l, 100 nmol/l, 250 nmol/l, 500 nmol/l, 1000 nmol/L) Ruxolitinib were (76.10 (+3.09)%, (66.04 (+3.14)%, (60.14)% respectively at 24 h. 06 [(56.27 [2.71)%, (59.27 [2.86)%, (57.86 [2.32)%, (57.86 [2.32)%, (57.86 [2.32)%, (70.14 [3.39)%, (59.71 [3.34%, (59.71 [59.71 [3.34)%, (52.80 [2.61%, (52.80 [(52.80 [2.61)%, (43.30 [2.96%, (43.30 [38.30 [38.56 [2.56 [38.56 [2.56 [2.15)%, (38.56 [[38.56 [38.56 [ib acted on HEL cells at different time. After 24h, 48h, 72h, the activity of HEL cells was significantly inhibited, the difference was statistically significant (P 0.05). prolonging the time of action of Ruxolitinib and increasing the dosage of the drug, the cell viability was also significantly decreased (P 0.05). 4 Ruxolitinib on JAK2V617F positive MPN patients with bone marrow CD34 + cells: 18 patients with newly diagnosed MPN CD34 + cell ratio was higher than the control group [(0.05). The levels of CD34+ cells in MPN patients with 250 nmol/L Ruxolitinib intervention group were lower than those in non-intervention group [(0.29+0.13)% vs. (0.14+0.07)%, P 0.001]. The expression of CD34+ cells in PV (5 cases), ET (6 cases) and PMF (7 cases) patients with 250 nmol/L Ruxolitinib intervention group was lower than that in non-intervention group [(0.18+0.05)% vs. (0.24+0.07)%, P 0.001]. 5 Transwell migration assay was used to observe the effect of Ruxolitinib on the migration of MPN primary cells and HEL cells. The number of MPN primary cells migrated to the lower chamber after 24 hours of treatment with 5 nmol/L Ruxolitinib was less than that without Ruxolitinib (154.7+27.5 vs 320.3+67.3, t=13.47, P 0.01). The number of HEL cells migrated to the lower chamber after 24 hours of treatment with l/L Ruxolitinib was less than that of the control group without Ruxolitinib (70.7+10.5 vs 135.3+16.7, t=13.89, P 0.01). 6 Western blot assay showed that the effect of Ruxolitnib on HEL cells at different concentrations (0 nmol/l, 50 nmol/l, 100 nmol/l, 250 nmol/l, 500 nmol/l, 1000 nmol/L) was observed in the blank control group. The relative expression of p-JAK2 protein in HEL cells was (1.52 (+ 0.12), (1.21 (+ 0.10), (1.21 (+ (+0.10), (1.12 + (+0.10), (1.12 (+0.09), (0.12 (+0.09,,,, (0.98 +0.07,,,,, (0.98 +,,,,, (0.45 +,,,, (0.04,, (0.45 +,,,, (0.15 +0.01), (0.MMP-2 protein relative expression was (0.53 ((0.53 + (0.42 (0.42 +0.03,,, (0.Express differently The expression of P-JAK2, MMP-2 and MMP-9 protein in Ruxolitinib treatment group was inhibited compared with the blank control group (P 0.05). Drug concentration increased, protein expression decreased significantly, and the difference was statistically significant. Western blot analysis of Ruxolitinib on MPN primary cells p-JAK2, MMP-2, MMP-9 protein expression: 250 nmol/L Ruxolitinib 48 hours can significantly inhibit the expression of p-JAK2, MMP-2, MMP-9 in MPN primary cells. The results showed that the expression of p-JAK2, MMP-2 and MMP-9 protein was significantly reduced, after the effect of different concentrations of Ruxolitinib. The expression levels of p-JAK2, MMP-2 and MMP-9 in MPN patients with positive JAK2V617F mutation were significantly higher than those in the control group. The expression levels of p-JAK2, MMP-2 and MMP-9 in MPN patients with positive JAK2V617F mutation were significantly decreased after the application of Ruxolitnib. 3. Ruxolitnib significantly inhibited the expression of CD34+ in MPN cells in vitro. 4 Ruxolitnib could down-regulate the expression of JAK2, MMP-2, MMP-9m RNA and its p-JAK2, MMP-2 and MMP-9 proteins in HEL cells. Ruxolitnib significantly inhibited the migration of primary MPN cells and HEL cells.
【学位授予单位】：承德医学院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R733.3
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