EGFR-TKIs通过下调黏附分子CD44表达抑制非小细胞肺癌的转移
发布时间：2018-08-22 09:23
【摘要】：目的:肺癌是世界上发病率死亡率均居于首位的恶性肿瘤,其中非小细胞肺癌占所有肺癌的80-85%。异质性强、生物学行为复杂易于侵袭转移是其主要特点,而易于远处转移进入晚期又是导致临床治疗失败及患者死亡的最主要原因之一。近年,以表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitors,EGFR-TKIs)为代表的高效、低毒的分子靶向药物在治疗EGFR突变的非小细胞肺癌领域取得了突破性进展,并被美国国立综合癌症网络(National Comprehensive Cancer Network,NCCN)推荐作为表皮生长因子受体(epidermal growth factor receptor,EGFR)突变晚期非小细胞肺癌治疗的首选药物。EGFR-TKI的主要作用机制是通过干预肿瘤细胞EGFR胞内区的酪氨酸激酶结构域,阻止其异常活化,进而阻断下游信号转导,发挥抑制肿瘤细胞增殖、促进肿瘤细胞凋亡等作用。然而临床效果观察发现,部分服用EGFR-TKI的患者不仅肿瘤生长受到抑制,其整体转移趋势也受到影响。这就提示EGFR-TKI可能不仅作用于肿瘤细胞本身,很可能还通过某种潜在途径调节肿瘤微环境,进而对肿瘤转移产生影响,但具体机制目前还尚不明了。黏附分子CD44是肿瘤微环境中黏附分子家族重要成员之一,其可介导细胞与细胞之间、细胞与基质之间的黏附作用,并通过参与一系列信号转导为肿瘤转移提供足够动力。从头颈部肿瘤、乳腺癌等的研究结果中发现,EGFR信号通路与CD44之间可能存在着某种交叉协同关系,并在肿瘤转移中发挥重要作用,但二者在非小细胞肺癌(non-small cell lung cancer,NSCLC)中是否也存在这种交互作用并对转移产生影响以及具体机制目前还不清楚。遂本研究的目的即通过多种体外实验方法探讨在EGFR突变的NSCLC细胞系中,EGFR-TKI抑制肿瘤转移的机制是否与下调黏附分子CD44表达有关,并初步探索连接二者信号通路的关键信号分子。此研究不仅有利于我们对信号通路产生更深入的认识,更为未来寻找更多抑制转移的新药寻求靶点。方法:1细胞培养使用含15%胎牛血清、100U/ml青霉素及100μg/ml链霉素的RPMI-1640培养基培养HCC827细胞(EGFR19外显子突变肺腺癌细胞)和A549细胞(EGFR野生型肺腺癌细胞),置于37℃、5%CO2的恒温培养箱中,隔天换液,细胞长至80%以上处于对数生长期时进行实验。2采用实时无标记细胞增殖实验方法分别检测HCC827细胞(EGFR突变型)和A549细胞(EGFR野生型)对EGFR-TKI代表药物厄洛替尼的敏感性,进一步确定实验用细胞。3四甲基偶氮唑蓝(MTT)法检测不同浓度厄洛替尼对HCC827的增殖抑制作用。在加入相应浓度药物的同时并加入合适浓度(50ng/ml)的EGF刺激因子,以模拟人体内环境,药物作用48h后计算细胞增殖抑制率及半数抑制浓度(IC50),做出增殖抑制率曲线。4采用Transwell小室侵袭实验及划痕实验分别观察四组(control、EGF(50ng/ml)刺激组、厄洛替尼(0.3μM)+EGF(50ng/ml)处理组、CD44中和抗体(20μg/ml)+EGF(50ng/ml)处理组)肿瘤细胞侵袭及迁移能力的变化情况。5采用流式细胞术检测三组(control、EGF(50ng/ml)刺激组、厄洛替尼(0.3μM)+EGF(50ng/ml)处理组)肿瘤细胞表面CD44表达情况。6采用Western-blot实验方法检测三组(control、EGF(50ng/ml)刺激组、厄洛替尼(0.3μM)+EGF(50ng/ml)处理组)肿瘤细胞CD44蛋白表达水平变化。7采用q RT-PCR实验技术检测三组(control、EGF(50ng/ml)刺激组、厄洛替尼(0.3μM)+EGF(50ng/ml)处理组)肿瘤细胞CD44m RNA的表达水平变化。8采用Western-blot实验方法检测四组(control、EGF(50ng/ml)刺激组、厄洛替尼(0.3μM)+EGF(50ng/ml)处理组、STAT3阻断剂(S3I-20150μM)+EGF(50ng/ml)处理组)细胞CD44、STAT3、磷酸化STAT3蛋白表达水平。9统计学方法:采用SPSS 21.0统计软件进行数据处理,计量数据以(?)±s或M±QR表示,组间比较以单因素方差分析或秩和检验进行统计分析,LSD法进行各组间两两比较,检验水准α=0.05,以P0.05为差异具有统计学意义。结果:1实时无标记细胞增殖实验结果如Fig.1所示:EGFR-TKI代表药物厄洛替尼(0.3μM)对EGFR突变的非小细胞肺癌细胞系HCC827具有较强的增殖抑制作用,并呈现时间依赖性;而对EGFR野生型的肺腺癌细胞系A549几乎不产生作用;遂选定HCC827进行后续实验。2 MTT法检测不同浓度厄洛替尼对HCC827细胞的增殖抑制作用,结果显示:随着药物浓度增大(0.001、0.01、0.1、0.5、1、10μM),厄洛替尼作用HCC827细胞48h后的增殖抑制率也逐渐增高,且呈剂量依赖性(Fig.2、Table1,P0.05)。结合细胞增殖抑制率,采用直线回归方法得出IC50为0.323μM;3 Transwell侵袭实验结果如Fig.3、Fig.4和Table2所示:control、EGF刺激组、厄洛替尼+EGF处理组、CD44中和抗体+EGF处理组穿膜细胞数分别为(64.07±1.51)个、(129.53±4.20)个、(21.0±1.06)个、(23.87±1.70)个;实验组与对照组比较差异具有统计学意义(P0.05);划痕实验结果如Fig.5、Fig.6和Table3所示:各组细胞迁移距离分别为(78.65±3.19)μm、(119.98±1.62)μm、(51.73±4.23)μm、(53.18±6.71)μm;实验组与对照组比较差异有统计学意义(P0.05);结果证明厄洛替尼可抑制HCC827细胞的侵袭迁移能力。4流式细胞术检测三组(control、EGF(50ng/ml)刺激组、厄洛替尼(0.3μM)+EGF(50ng/ml)处理组)HCC827细胞表面CD44表达水平分别为(25.87±3.46)%、(48.37±2.21)%、(15.50±1.11)%;结果显示加入厄洛替尼后细胞表面CD44表达显著低于前两组,差异有统计学意义(Fig.7、Table4,P0.05);5 Western-blot方法检测三组(同4)肿瘤细胞CD44蛋白半定量结果分别为(0.72±0.03)、(0.83±0.04)、(0.21±0.03),加入厄洛替尼组CD44蛋白表达显著低于对照组和EGF刺激组,差异有统计学意义(Fig.8、Table5,P0.05);结果从蛋白水平进一步证明厄洛替尼可下调CD44表达。6 qRT-PCR法检测三组(同4)肿瘤细胞CD44 m RNA表达变化:设对照组为1,EGF刺激组及厄洛替尼+EGF处理组CD44 m RNA表达量分别是对照组的(2.22±0.17)倍和(0.50±0.04)倍;差异有统计学意义(Fig.9、Table6,P0.05);实验结果从基因水平上再次证明厄洛替尼可下调CD44表达。7 Western-blot方法检测四组(control、EGF(50ng/ml)刺激组、厄洛替尼(0.3μM)+EGF(50ng/ml)处理组、STAT3阻断剂(S3I-201 50μM)+EGF(50ng/ml)处理组)肿瘤细胞CD44、STAT3、磷酸化STAT3蛋白表达水平,结果如Fig.10、Fig.11、Fig.12和Table7所示:与对照组比较,厄洛替尼组CD44和p-STAT3蛋白表达水平均被显著下调(P0.05),而在使用STAT3特异性阻断剂阻断STAT3信号通路后CD44蛋白表达仍被下调(P0.05);综合以上结果初步得出,厄洛替尼阻断EGFR信号通路的同时,其间接下调黏附分子CD44表达很可能是通过EGFR/STAT3信号通路进行的,但其深入机制还需进一步探索。结论:1 HCC827细胞对EGFR-TKI代表药物厄洛替尼高度敏感,适合作为本实验用细胞。2 EGFR-TKI药物不仅可显著抑制EGFR突变NSCLC细胞株HCC827细胞的增殖,还对其侵袭转移能力产生明显影响,并可能与CD44被下调有关。3 EGFR-TKI药物可明显下调黏附分子CD44表达,且可能与EGFR/STAT3信号通路有关。
[Abstract]:Objective: Lung cancer is one of the most common malignant tumors in the world, in which non-small cell lung cancer accounts for 80-85% of all lung cancers. In recent years, low-toxicity molecular targeted drugs, represented by epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), have made breakthroughs in the treatment of EGFR-mutated non-small cell lung cancer (NSCLC), and have been used by the National Compreh Cancer Network (NCN). The main mechanism of EGFR-TKI is to block the abnormal activation of tyrosine kinase domains in the intracellular domain of EGFR, thereby blocking the downstream signal. However, some patients taking EGFR-TKI not only inhibited tumor growth, but also affected the overall metastasis trend. This suggests that EGFR-TKI may not only affect tumor cells themselves, but also possibly regulate them through some potential pathways. Adhesion molecule CD44 is one of the important members of the adhesion molecule family in tumor microenvironment, which mediates cell-to-cell and cell-to-matrix adhesion, and provides sufficient information for tumor metastasis by participating in a series of signal transduction pathways. Dynamics. In the study of head and neck tumors, breast cancer and so on, we found that there may be some cross-synergistic relationship between EGFR signaling pathway and CD44, which plays an important role in tumor metastasis, but whether EGFR signaling pathway and CD44 signaling pathway also have this interaction in non-small cell lung cancer (NSCLC) and affect metastasis. The purpose of this study is to investigate whether the mechanism of EGFR-TKI inhibiting tumor metastasis is related to the down-regulation of CD44 expression in NSCLC cell lines with EGFR mutation and to explore the key signaling molecules linking the two signaling pathways. Methods: 1. HCC 827 cells (EGFR19 exon mutant lung adenocarcinoma cells) and A549 cells (EGFR wild type lung adenocarcinoma cells) were cultured in RPMI-1640 medium containing 15% fetal bovine serum, 100U/ml penicillin and 100ug/ml streptomycin. HCC 827 cells (EGFR mutant) and A549 cells (EGFR wild type) were tested for their sensitivity to erlotinib, a representative of EGFR-TKI, by real-time labeled cell proliferation assay. Cell proliferation inhibitory effect of erlotinib on HCC 827 was detected by MTT assay. The proliferation inhibitory rate and half inhibitory concentration (IC50) were calculated 48 hours after the drug was added to the corresponding concentration of erlotinib and the appropriate concentration of EGF stimulator (50ng/ml) was added to simulate the human body environment. The invasion and migration of tumor cells were observed by Transwell chamber invasion test and scratch test respectively in four groups (control, EGF (50ng/ml), erlotinib (0.3ugM) + EGF (50ng/ml) and CD44 neutralizing antibody (20ug/ml) + EGF (50ng/ml). Flow cytometry was used to detect the invasion and migration of tumor cells in three groups (control, EGF (50n/ml). The expression of CD44 on the surface of tumor cells was detected by Western blot. The expression of CD44 on tumor cells was detected by Q RT-PCR in three groups (control, EGF (50ng/ml) and erlotinib (0.3 mu M) + EGF (50ng/ml) respectively. The expression of CD44m RNA in tumor cells of EGF (50ng/ml) stimulation group, Erlotinib (0.3ugM) + EGF (50ng/ml) treatment group and Western blot assay were used to detect CD44, STAT3, phosphoric acid in four groups (control, EGF (50ng/ml) stimulation group, Erlotinib (0.3ugM) + EGF (50ng/ml) treatment group, STAT3 blocker (S3I-20150ugM) + EGF (50ng/ml) treatment group. Statistical methods: SPSS 21.0 statistical software was used to process the data. The measurement data were expressed as (?) + s or M + QR. Single factor analysis of variance or rank sum test were used to analyze the statistical data. LSD method was used to compare the expression of STAT3 protein between groups. The test level was alpha = 0.05, and the difference was statistically significant with P 0.05. Real-time label-free cell proliferation experiment showed that the EGFR-TKI representative drug Erlotinib (0.3 mu M) inhibited the proliferation of non-small cell lung cancer cell line HCC827 with EGFR mutation in a time-dependent manner, but had little effect on wild-type lung adenocarcinoma cell line A549 with EGFR. HCC827 was selected for follow-up study. 2 MTT assay was used to detect the inhibitory effect of different concentrations of erlotinib on the proliferation of HCC 827 cells. The results showed that with the increase of the concentration of erlotinib (0.001, 0.01, 0.1, 0.5, 1, 10 mu M), the inhibitory rate of proliferation of HCC 827 cells increased gradually after 48 hours and was dose-dependent (Fig.2, Table1, P 0.05). Combined with the inhibitory rate of cell proliferation, the inhibitory rate of erlotinib was linear. Regression analysis showed that IC50 was 0.323 mu M; 3 Transwell invasion test results were shown as Fig.3, Fig.4 and Table2: control, EGF stimulation group, erlotinib + EGF treatment group, CD44 neutralizing antibody + EGF treatment group, the number of penetrating membrane cells were (64.07 [1.51], (129.53 [4.20], (21.0 [1.06], (23.87 [1.70], respectively; the experimental group compared with the control group. Scratch test showed that the migration distances of HCC 827 cells in each group were (78.65 (+ 3.19) micron, (119.98 (+ 1.62) micron, (51.73 (+ 4.23) micron, (53.18 (+ 6.71) micron), respectively. There was significant difference between the experimental group and the control group (P 0.05); the results showed that erlotinib could inhibit the invasion and migration of HCC 827 cells. The expression of CD44 on the surface of HCC 827 cells in three groups (control, EGF (50ng/ml) and erlotinib (0.3 mu M) + EGF (50ng/ml) was detected by flow cytometry. The results showed that the expression of CD44 on the surface of HCC 827 cells in the control, EGF (50 ng/ml) and erlotinib (0.3 mu) + EGF (50 ng/ml) groups was significantly lower than that in the former two groups (Fig) respectively. The semi-quantitative results of CD44 protein in tumor cells of the three groups (the same 4) by Western-blot were (0.72.03), (0.83.04), (0.21.03), respectively. The expression of CD44 protein in erlotinib group was significantly lower than that in control group and EGF stimulation group (Fig.8, Table5, P 0.05). Lotinib could down-regulate the expression of CD44. 6 qRT-PCR assay was used to detect the expression of CD44 m RNA in tumor cells of three groups (the same 4). The expression of CD44 m RNA in EGF-stimulated group and Erlotinib+EGF-treated group was (2.22+0.17) and (0.50+0.04) times higher than that in control group (Fig.9, Table6, P 0.05), respectively. Western-blot method was used to detect the expression of CD44, STAT3 and phosphorylated STAT3 protein in tumor cells of four groups (control, EGF (50ng/ml) stimulation group, erlotinib (0.3ugm) + EGF (50ng/ml) treatment group, STAT3 blocker (S3I-201 50ugM) + EGF (50ng/ml) treatment group). Compared with the control group, the expression of CD44 and p-STAT3 protein in the erlotinib group were significantly down-regulated (P 0.05), while the expression of CD44 protein was still down-regulated after STAT3 specific blocker was used to block the STAT3 signaling pathway (P 0.05); based on the above results, it was preliminarily concluded that erlotinib blocked the EGFR signaling pathway and indirectly down-regulated the adhesion molecule C. The expression of D44 may be mediated by EGFR/STAT3 signaling pathway, but its mechanism still needs further exploration. Conclusion: 1. HCC827 cells are highly sensitive to erlotinib, which is the representative drug of EGFR-TKI. 2 EGFR-TKI drugs can not only inhibit the proliferation of EGFR mutant NSCLC cell line HCC827, but also inhibit its invasion. The ability of metastasis may be related to the down-regulation of CD44. 3 EGFR-TKI can down-regulate the expression of CD44 and may be related to the EGFR/STAT3 signaling pathway.
【学位授予单位】：河北医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R734.2
本文编号：2196676
[Abstract]:Objective: Lung cancer is one of the most common malignant tumors in the world, in which non-small cell lung cancer accounts for 80-85% of all lung cancers. In recent years, low-toxicity molecular targeted drugs, represented by epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), have made breakthroughs in the treatment of EGFR-mutated non-small cell lung cancer (NSCLC), and have been used by the National Compreh Cancer Network (NCN). The main mechanism of EGFR-TKI is to block the abnormal activation of tyrosine kinase domains in the intracellular domain of EGFR, thereby blocking the downstream signal. However, some patients taking EGFR-TKI not only inhibited tumor growth, but also affected the overall metastasis trend. This suggests that EGFR-TKI may not only affect tumor cells themselves, but also possibly regulate them through some potential pathways. Adhesion molecule CD44 is one of the important members of the adhesion molecule family in tumor microenvironment, which mediates cell-to-cell and cell-to-matrix adhesion, and provides sufficient information for tumor metastasis by participating in a series of signal transduction pathways. Dynamics. In the study of head and neck tumors, breast cancer and so on, we found that there may be some cross-synergistic relationship between EGFR signaling pathway and CD44, which plays an important role in tumor metastasis, but whether EGFR signaling pathway and CD44 signaling pathway also have this interaction in non-small cell lung cancer (NSCLC) and affect metastasis. The purpose of this study is to investigate whether the mechanism of EGFR-TKI inhibiting tumor metastasis is related to the down-regulation of CD44 expression in NSCLC cell lines with EGFR mutation and to explore the key signaling molecules linking the two signaling pathways. Methods: 1. HCC 827 cells (EGFR19 exon mutant lung adenocarcinoma cells) and A549 cells (EGFR wild type lung adenocarcinoma cells) were cultured in RPMI-1640 medium containing 15% fetal bovine serum, 100U/ml penicillin and 100ug/ml streptomycin. HCC 827 cells (EGFR mutant) and A549 cells (EGFR wild type) were tested for their sensitivity to erlotinib, a representative of EGFR-TKI, by real-time labeled cell proliferation assay. Cell proliferation inhibitory effect of erlotinib on HCC 827 was detected by MTT assay. The proliferation inhibitory rate and half inhibitory concentration (IC50) were calculated 48 hours after the drug was added to the corresponding concentration of erlotinib and the appropriate concentration of EGF stimulator (50ng/ml) was added to simulate the human body environment. The invasion and migration of tumor cells were observed by Transwell chamber invasion test and scratch test respectively in four groups (control, EGF (50ng/ml), erlotinib (0.3ugM) + EGF (50ng/ml) and CD44 neutralizing antibody (20ug/ml) + EGF (50ng/ml). Flow cytometry was used to detect the invasion and migration of tumor cells in three groups (control, EGF (50n/ml). The expression of CD44 on the surface of tumor cells was detected by Western blot. The expression of CD44 on tumor cells was detected by Q RT-PCR in three groups (control, EGF (50ng/ml) and erlotinib (0.3 mu M) + EGF (50ng/ml) respectively. The expression of CD44m RNA in tumor cells of EGF (50ng/ml) stimulation group, Erlotinib (0.3ugM) + EGF (50ng/ml) treatment group and Western blot assay were used to detect CD44, STAT3, phosphoric acid in four groups (control, EGF (50ng/ml) stimulation group, Erlotinib (0.3ugM) + EGF (50ng/ml) treatment group, STAT3 blocker (S3I-20150ugM) + EGF (50ng/ml) treatment group. Statistical methods: SPSS 21.0 statistical software was used to process the data. The measurement data were expressed as (?) + s or M + QR. Single factor analysis of variance or rank sum test were used to analyze the statistical data. LSD method was used to compare the expression of STAT3 protein between groups. The test level was alpha = 0.05, and the difference was statistically significant with P 0.05. Real-time label-free cell proliferation experiment showed that the EGFR-TKI representative drug Erlotinib (0.3 mu M) inhibited the proliferation of non-small cell lung cancer cell line HCC827 with EGFR mutation in a time-dependent manner, but had little effect on wild-type lung adenocarcinoma cell line A549 with EGFR. HCC827 was selected for follow-up study. 2 MTT assay was used to detect the inhibitory effect of different concentrations of erlotinib on the proliferation of HCC 827 cells. The results showed that with the increase of the concentration of erlotinib (0.001, 0.01, 0.1, 0.5, 1, 10 mu M), the inhibitory rate of proliferation of HCC 827 cells increased gradually after 48 hours and was dose-dependent (Fig.2, Table1, P 0.05). Combined with the inhibitory rate of cell proliferation, the inhibitory rate of erlotinib was linear. Regression analysis showed that IC50 was 0.323 mu M; 3 Transwell invasion test results were shown as Fig.3, Fig.4 and Table2: control, EGF stimulation group, erlotinib + EGF treatment group, CD44 neutralizing antibody + EGF treatment group, the number of penetrating membrane cells were (64.07 [1.51], (129.53 [4.20], (21.0 [1.06], (23.87 [1.70], respectively; the experimental group compared with the control group. Scratch test showed that the migration distances of HCC 827 cells in each group were (78.65 (+ 3.19) micron, (119.98 (+ 1.62) micron, (51.73 (+ 4.23) micron, (53.18 (+ 6.71) micron), respectively. There was significant difference between the experimental group and the control group (P 0.05); the results showed that erlotinib could inhibit the invasion and migration of HCC 827 cells. The expression of CD44 on the surface of HCC 827 cells in three groups (control, EGF (50ng/ml) and erlotinib (0.3 mu M) + EGF (50ng/ml) was detected by flow cytometry. The results showed that the expression of CD44 on the surface of HCC 827 cells in the control, EGF (50 ng/ml) and erlotinib (0.3 mu) + EGF (50 ng/ml) groups was significantly lower than that in the former two groups (Fig) respectively. The semi-quantitative results of CD44 protein in tumor cells of the three groups (the same 4) by Western-blot were (0.72.03), (0.83.04), (0.21.03), respectively. The expression of CD44 protein in erlotinib group was significantly lower than that in control group and EGF stimulation group (Fig.8, Table5, P 0.05). Lotinib could down-regulate the expression of CD44. 6 qRT-PCR assay was used to detect the expression of CD44 m RNA in tumor cells of three groups (the same 4). The expression of CD44 m RNA in EGF-stimulated group and Erlotinib+EGF-treated group was (2.22+0.17) and (0.50+0.04) times higher than that in control group (Fig.9, Table6, P 0.05), respectively. Western-blot method was used to detect the expression of CD44, STAT3 and phosphorylated STAT3 protein in tumor cells of four groups (control, EGF (50ng/ml) stimulation group, erlotinib (0.3ugm) + EGF (50ng/ml) treatment group, STAT3 blocker (S3I-201 50ugM) + EGF (50ng/ml) treatment group). Compared with the control group, the expression of CD44 and p-STAT3 protein in the erlotinib group were significantly down-regulated (P 0.05), while the expression of CD44 protein was still down-regulated after STAT3 specific blocker was used to block the STAT3 signaling pathway (P 0.05); based on the above results, it was preliminarily concluded that erlotinib blocked the EGFR signaling pathway and indirectly down-regulated the adhesion molecule C. The expression of D44 may be mediated by EGFR/STAT3 signaling pathway, but its mechanism still needs further exploration. Conclusion: 1. HCC827 cells are highly sensitive to erlotinib, which is the representative drug of EGFR-TKI. 2 EGFR-TKI drugs can not only inhibit the proliferation of EGFR mutant NSCLC cell line HCC827, but also inhibit its invasion. The ability of metastasis may be related to the down-regulation of CD44. 3 EGFR-TKI can down-regulate the expression of CD44 and may be related to the EGFR/STAT3 signaling pathway.
【学位授予单位】：河北医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R734.2
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