FOXC2及MUC4促進多形性膠質(zhì)母細胞瘤增殖、遷移與侵襲作用及其分子機制研究
發(fā)布時間：2018-09-09 18:38
【摘要】：第一部分FOXC2促進多形性腦膠質(zhì)母細胞瘤增殖、遷移與侵襲作用及其機制研究 目的：揭示FOXC2(forkhead box C2,叉頭框C2)在GBM (Glioblastoma,多形性膠質(zhì)母細胞瘤)組織及GBM細胞系中的表達情況并利用GBM細胞系構(gòu)建FOXC2高表達細胞模型與FOXC2基因沉默細胞模型。檢測FOXC2對于GBM細胞增殖，遷移及侵襲能力的影響并研究該影響在GBM細胞內(nèi)的調(diào)節(jié)機制。 方法：利用RT-PCR、Western blot以及免疫組織化學實驗測定GBM人腦組織樣本、對照人腦組織樣本以及六種GBM細胞系中FOXC2的表達情況。根據(jù)所得六種GBM細胞系中FOXC2表達結(jié)果，進一步通過質(zhì)粒轉(zhuǎn)染與RNA基因沉默實驗構(gòu)建FOXC2高表達的SNB19-FOXC2細胞模型、FOXC2基因沉默的T98G-shFOXC2細胞模型及EGFR(epidermal growth factor receptor,表皮生長因子)沉默的SNB19-FOXC2-siEGFR細胞模型。應用MTT和細胞克隆形成實驗測定上述所構(gòu)建細胞系中FOXC2表達對SNB19和T98G細胞增殖能力的影響并通過細胞傷口愈合實驗和Boyden小室模型測定SNB19-FOXC2細胞與T98G-shFOXC2的遷移及侵襲能力變化。通過RT-PCR、Western blot和免疫組化實驗測定FOXC2對EGFR在GBM細胞系中表達量的影響。同時在SNB19-FOXC2細胞中構(gòu)建EGFR基因沉默模型SNB19-FOXC2-siEGFR1,2。通過MTT實驗，Boyden小室模型實驗，細胞傷口愈合實驗，研究EGFR對于FOXC2促GBM細胞增殖，遷移以及侵襲能力的調(diào)控作用。 結(jié)果：分別將10份GBM病人大腦樣本與10份對照病人大腦樣本的RT-PCR和Western blot實驗結(jié)果比較得出所有GBM病人大腦樣本中FOXC2的表達量都明顯高于對照病人大腦樣本。免疫組化實驗結(jié)果中也發(fā)現(xiàn)GBM病人大腦樣本中的FOXC2陽性細胞數(shù)也同樣高于對照病人腦組織樣本。在U87, T98G, SNB19,SW1088, SF767和SW1783六種GBM細胞系中，T98G中FOXC2表達量最高而SNB19中FOXC2的表達量最低。根據(jù)此結(jié)果，進一步將T98G細胞用于FOXC2基因沉默實驗構(gòu)建T98G-shFOXC2細胞模型，而將SNB19細胞用于FOXC2基因轉(zhuǎn)染實驗，構(gòu)建FOXC2基因高表達SNB19-FOXC2模型。MTT和細胞克隆形成實驗結(jié)果顯示，SNB19-FOXC2細胞相對與對照組SNB19細胞增殖能力大幅提高，克隆形成總數(shù)明顯增多，克隆形成范圍更廣。而T98G-shFOXC2細胞相對與對照組T98G細胞克隆形成數(shù)目明顯減少，克隆形成范圍也明顯縮小。細胞傷口愈合實驗和Boyden小室實驗結(jié)果顯示，SNB19-FOXC2細胞能夠顯著加快細胞傷口愈合速度并且具有2倍于SNB19細胞穿透Transwell膜的能力。另一方面，F(xiàn)OXC2基因沉默后，T98G-shFOXC2細胞遷移與侵襲的能力顯著降低并且T98G-shFOXC2細胞對于細胞傷口愈合的促進作用以及透過Transwell膜的能力都明顯小于T98G細胞。RT-PCR及Western blot實驗結(jié)果顯示，F(xiàn)OXC2基因沉默能夠明顯降低T98G細胞中EGFR在RNA轉(zhuǎn)錄和蛋白水平的表達。利用RNA干擾技術(shù)，進一步沉默SNB19-FOXC2細胞中EGFR相關基因，構(gòu)建SNB19-FOXC2-siEGFR細胞模型。MTT實驗，，Boyden小室模型實驗及細胞傷口愈合實驗結(jié)果顯示，SNB19-FOXC2-siEGFR細胞的增殖、遷移與侵襲的能力都較SNB19-FOXC2細胞有大幅的下滑。該結(jié)果說明EGFR基因在FOXC2促進GBM細胞的增殖、遷移與侵襲能力的發(fā)揮過程中起著重要的調(diào)控作用。 結(jié)論：（1）FOXC2在GBM病人組織樣本及GBM細胞系中為顯著高表達。（2）FOXC2在GBM細胞增殖、遷移與侵襲過程中起到至關重要的作用。（3）FOXC2調(diào)控EGFR在GBM細胞中的表達（4）EGFR是FOXC2調(diào)控GBM細胞增殖、遷移與侵襲的重要調(diào)控因子。 第二部分MUC4粘蛋白上調(diào)表皮生長因子受體表達及其對多型性膠質(zhì)母細胞瘤增殖、遷移與侵襲促進作用研究 目的：探究MUC4(mucin4,4型粘蛋白)在GBM病人組織與GBM細胞系中表達情況。構(gòu)建MUC4高表達與MUC4基因沉默細胞模型。揭示MUC4對于GBM細胞增殖、遷移及侵襲活性的影響及其分子機制。 方法：通過RT-PCR、免疫組化以及Western blot實驗測定對照病人腦組織樣品、GBM病人腦組織樣品與六種GBM細胞系中MUC4表達量高低。根據(jù)六種GBM細胞中MUC4的表達情況進而通過基因轉(zhuǎn)染與RNA干擾實驗構(gòu)建MUC4過表達SNB19-MUC4細胞、MUC4沉默T98G-shMUC4細胞模型及EGFR (epidermal growthfactor receptor,表皮生長因子)沉默SNB19-MUC4-siEGFR細胞模型。利用MTT和細胞克隆形成實驗測定MUC4對GBM細胞增殖能力影響。通過傷口愈合實驗和Boyden小室模型測定SNB19-MUC4細胞以及T98G-shMUC4細胞的遷移及侵襲能力。通過RT-PCR、Western blot和免疫組化實驗測定MUC4對EGFR表達的影響。同時構(gòu)建EGFR基因沉默SNB19-MUC4-siEGFR1,2,3細胞模型。通過MTT實驗，Boyden小室模型實驗，細胞愈合實驗，研究EGFR沉默后MUC4促GBM細胞增殖，遷移以及侵襲能力的變化情況。 結(jié)果： RT-PCR實驗測定11份對照病人大腦樣本與11份GBM病人大腦樣本中MUC4的表達發(fā)現(xiàn)，11份GBM病人大腦樣本中MUC4的表達明顯高于對照大腦樣本并且在免疫組織化學實驗結(jié)果中GBM病人大腦樣本中的MUC4陽性細胞數(shù)也同樣明顯多于對照樣本。利用RT-PCR及Western blot實驗測定了六種GBM細胞系中MUC4的表達量，結(jié)果顯示其中T98G細胞系中MUC4表達量最高而SNB19細胞系中MUC4的表達量最低，進而將T98G細胞用于構(gòu)建MUC4基因沉默T98G-shMUC4細胞模型而將SNB19細胞用于MUC4基因轉(zhuǎn)染實驗構(gòu)建MUC4基因過表達SNB19-MUC4細胞模型。在細胞增殖實驗中，MTT和細胞克隆形成實驗結(jié)果顯示SNB19-MUC4細胞相對于對照組SNB19細胞增殖能力大幅提高，克隆數(shù)量更多且克隆范圍更廣。另一方面，T98G-shMUC細胞相對與照組T98G細胞克隆數(shù)量明顯下降，范圍上也有所縮小。細胞傷口愈合實驗證明SNB19-MUC4細胞能夠顯著加快細胞傷口愈合速度。Boyden小室模型結(jié)果顯示SNB19-MUC4細胞具有3倍與對照組細胞透過Transwell膜的能力。然而，細胞傷口愈合實驗與Boyden小室模型結(jié)果說明經(jīng)MUC4基因沉默后T98G-shMUC4細胞對于傷口愈合的促進作用以及透過Transwell膜的能力都明顯小于未沉默組細胞。RT-PCR及Western blot實驗結(jié)果顯示，MUC4基因沉默能夠明顯降低T98G細胞中EGFR在RNA和蛋白水平的表達。利用RNA干擾技術(shù)，進一步將SNB19-MUC4細胞中EGFR相關基因EGFR-1,2,3沉默。MTT實驗，Boyden小室模型實驗，細胞愈合實驗結(jié)果顯示，SNB19-MUC4細胞的增殖、遷移與侵襲的能力都較沉默前有大幅的下降。說明EGFR基因在MUC4促進GBM細胞的增殖、遷移與侵襲能力的過程中發(fā)揮重要的調(diào)控作用。 結(jié)論：（1）MUC4在GBM細胞系中顯著表達并且在GBM細胞的增殖、遷移與侵襲過程中發(fā)揮重要作用。（2）MUC4能夠調(diào)控EGFR在GBM細胞中的表達，EGFR對于MUC4促進GBM細胞的增殖、遷移與侵襲能力有重要的影響。
[Abstract]:Part one: FOXC2 promotes the proliferation, migration and invasion of glioblastoma multiforme and its mechanism.
AIM: To investigate the expression of FOXC2 (forkhead box C2) in GBM (Glioblastoma multiforme glioblastoma) tissues and GBM cell lines, and to construct FOXC2 high expression cell model and FOXC2 gene silencing cell model using GBM cell lines. The regulation mechanism in GBM cells.
METHODS: The expression of FOXC2 in GBM human brain tissue samples was detected by RT-PCR, Western blot and immunohistochemical assay, and compared with human brain tissue samples and six GBM cell lines. 2 cell model, T98G-shFOXC2 cell model with FOXC2 gene silencing and SNB19-FOXC2-siEGFR cell model with EGFR (epidermal growth factor receptor) silencing. MTT and clone formation assay were used to determine the effect of FOXC2 expression on the proliferation of SNB19 and T98G cells and cell injury. The migration and invasiveness of SNB19-FOXC2 cells and T98G-shFOXC2 cells were measured by oral healing test and Boyden cell model. The effect of FOXC2 on EGFR expression in GBM cell lines was determined by RT-PCR, Western blot and immunohistochemistry. The EGFR gene silencing model SNB19-FOXC2-siEGFR1,2 was constructed in SNB19-FOXC2 cells by MTT. The effects of EGFR on FOXC2-induced proliferation, migration and invasion of GBM cells were studied by Boyden cell model and wound healing test.
Results: The expression of FOXC2 in brain samples of 10 GBM patients was significantly higher than that of 10 control patients by RT-PCR and Western blot. The number of FOXC2 positive cells in brain samples of GBM patients was also found by immunohistochemistry. In U87, T98G, SNB19, SW1088, SF767 and SW1783 GBM cell lines, the expression of FOXC2 was the highest in T98G and the lowest in SNB19. According to this result, T98G cells were further used in FOXC2 gene silencing experiment to construct T98G-shFOXC2 cell model, while SNB19 cells were used in FOXC2 gene silencing experiment. The results of MTT and cell cloning showed that the proliferation ability of SNB19-FOXC2 cells was greatly improved, the total number of cloning formation was significantly increased, and the range of cloning formation was wider. Cell wound healing test and Boyden chamber test showed that SNB19-FOXC2 cells significantly accelerated wound healing and had the ability to penetrate Transwell membrane twice as fast as SNB19 cells. On the other hand, after FOXC2 gene was silenced, T98G-shFOXC2 cells showed significant migration and invasion ability. The results of RT-PCR and Western blot showed that FOXC2 gene silencing could significantly reduce the expression of EGFR at RNA transcription and protein levels in T98G cells. EGFR-related genes in B19-FOXC2 cells were used to construct SNB19-FOXC2-siEGFR cell model. MTT, Boyden chamber and wound healing experiments showed that the proliferation, migration and invasion of SNB19-FOXC2-siEGFR cells were significantly lower than those of SNB19-FOXC2 cells. It plays an important regulatory role in the process of proliferation, migration and invasion.
CONCLUSION: (1) FOXC2 is highly expressed in GBM tissues and GBM cell lines. (2) FOXC2 plays an important role in the proliferation, migration and invasion of GBM cells. (3) FOXC2 regulates the expression of EGFR in GBM cells. (4) EGFR is an important regulator of GBM cell proliferation, migration and invasion.
Part 2 MUC4 mucin up-regulates the expression of epidermal growth factor receptor and promotes the proliferation, migration and invasion of glioblastoma multiforme
Objective: To investigate the expression of MUC4 (mucin 4,4 mucin) in GBM tissues and GBM cell lines, and to construct a cell model of MUC4 overexpression and MUC4 gene silencing.
METHODS: The expression of MUC4 in brain tissue samples of GBM patients and six GBM cell lines was determined by RT-PCR, immunohistochemistry and Western blot. According to the expression of MUC4 in six GBM cells, the over-expressed SNB19-MUC4 cells were constructed by gene transfection and RNA interference, and T98G-shM was silenced by MUC4. UC4 cell model and EGFR (epidermal growth factor receptor) silencing SNB19-MUC4-siEGFR cell model. MTT and cell clone formation assays were used to determine the effect of MUC4 on the proliferation of GBM cells. The effect of MUC4 on EGFR expression was determined by RT-PCR, Western blot and immunohistochemical staining. The SNB19-MUC4-siEGFR 1,2,3 cell model with EGFR gene silencing was constructed. The proliferation, migration and invasiveness of GBM cells after EGFR silencing were studied by MTT test, Boyden cell model test and cell healing test.
Results: The expression of MUC4 in 11 brain samples of GBM patients and 11 brain samples of GBM patients was detected by RT-PCR. The expression of MUC4 in 11 brain samples of GBM patients was significantly higher than that in control brain samples, and the number of MUC4 positive cells in brain samples of GBM patients was also significantly higher than that in control brain samples. The expression of MUC4 in six GBM cell lines was measured by RT-PCR and Western blot. The results showed that MUC4 was the highest in T98G cell line and the lowest in SNB19 cell line. T98G cells were used to construct mutant T98G-shMUC4 cell model and SNB19 cells were used to construct MUC4 gene transfection experiment. In cell proliferation experiments, MTT and cell clone formation assays showed that SNB19-MUC4 cells had significantly higher proliferation capacity, more clones and a wider range of clones than the control group. On the other hand, T98G-shMUC cells had significantly lower number of clones than the control group T98G cells. Cell wound healing experiments showed that SNB19-MUC4 cells significantly accelerated wound healing. Boyden's compartment model showed that SNB19-MUC4 cells had three times the ability of control and control cells to penetrate Transwell membranes. The results of RT-PCR and Western blot showed that MUC4 gene silencing could significantly reduce the expression of EGFR at RNA and protein levels in T98G cells. SNB19-MUC4 cells were further treated with RNA interference technique. EGFR-1,2,3 gene was silenced. MTT test, Boyden chamber model test and cell healing test showed that the proliferation, migration and invasion of SNB19-MUC4 cells were significantly decreased compared with those before silencing.
Conclusion: (1) MUC4 is highly expressed in GBM cells and plays an important role in the proliferation, migration and invasion of GBM cells. (2) MUC4 can regulate the expression of EGFR in GBM cells. EGFR plays an important role in the proliferation, migration and invasion of GBM cells.
【學位授予單位】：大連醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2014
【分類號】：R739.41
本文編號：2233233
[Abstract]:Part one: FOXC2 promotes the proliferation, migration and invasion of glioblastoma multiforme and its mechanism.
AIM: To investigate the expression of FOXC2 (forkhead box C2) in GBM (Glioblastoma multiforme glioblastoma) tissues and GBM cell lines, and to construct FOXC2 high expression cell model and FOXC2 gene silencing cell model using GBM cell lines. The regulation mechanism in GBM cells.
METHODS: The expression of FOXC2 in GBM human brain tissue samples was detected by RT-PCR, Western blot and immunohistochemical assay, and compared with human brain tissue samples and six GBM cell lines. 2 cell model, T98G-shFOXC2 cell model with FOXC2 gene silencing and SNB19-FOXC2-siEGFR cell model with EGFR (epidermal growth factor receptor) silencing. MTT and clone formation assay were used to determine the effect of FOXC2 expression on the proliferation of SNB19 and T98G cells and cell injury. The migration and invasiveness of SNB19-FOXC2 cells and T98G-shFOXC2 cells were measured by oral healing test and Boyden cell model. The effect of FOXC2 on EGFR expression in GBM cell lines was determined by RT-PCR, Western blot and immunohistochemistry. The EGFR gene silencing model SNB19-FOXC2-siEGFR1,2 was constructed in SNB19-FOXC2 cells by MTT. The effects of EGFR on FOXC2-induced proliferation, migration and invasion of GBM cells were studied by Boyden cell model and wound healing test.
Results: The expression of FOXC2 in brain samples of 10 GBM patients was significantly higher than that of 10 control patients by RT-PCR and Western blot. The number of FOXC2 positive cells in brain samples of GBM patients was also found by immunohistochemistry. In U87, T98G, SNB19, SW1088, SF767 and SW1783 GBM cell lines, the expression of FOXC2 was the highest in T98G and the lowest in SNB19. According to this result, T98G cells were further used in FOXC2 gene silencing experiment to construct T98G-shFOXC2 cell model, while SNB19 cells were used in FOXC2 gene silencing experiment. The results of MTT and cell cloning showed that the proliferation ability of SNB19-FOXC2 cells was greatly improved, the total number of cloning formation was significantly increased, and the range of cloning formation was wider. Cell wound healing test and Boyden chamber test showed that SNB19-FOXC2 cells significantly accelerated wound healing and had the ability to penetrate Transwell membrane twice as fast as SNB19 cells. On the other hand, after FOXC2 gene was silenced, T98G-shFOXC2 cells showed significant migration and invasion ability. The results of RT-PCR and Western blot showed that FOXC2 gene silencing could significantly reduce the expression of EGFR at RNA transcription and protein levels in T98G cells. EGFR-related genes in B19-FOXC2 cells were used to construct SNB19-FOXC2-siEGFR cell model. MTT, Boyden chamber and wound healing experiments showed that the proliferation, migration and invasion of SNB19-FOXC2-siEGFR cells were significantly lower than those of SNB19-FOXC2 cells. It plays an important regulatory role in the process of proliferation, migration and invasion.
CONCLUSION: (1) FOXC2 is highly expressed in GBM tissues and GBM cell lines. (2) FOXC2 plays an important role in the proliferation, migration and invasion of GBM cells. (3) FOXC2 regulates the expression of EGFR in GBM cells. (4) EGFR is an important regulator of GBM cell proliferation, migration and invasion.
Part 2 MUC4 mucin up-regulates the expression of epidermal growth factor receptor and promotes the proliferation, migration and invasion of glioblastoma multiforme
Objective: To investigate the expression of MUC4 (mucin 4,4 mucin) in GBM tissues and GBM cell lines, and to construct a cell model of MUC4 overexpression and MUC4 gene silencing.
METHODS: The expression of MUC4 in brain tissue samples of GBM patients and six GBM cell lines was determined by RT-PCR, immunohistochemistry and Western blot. According to the expression of MUC4 in six GBM cells, the over-expressed SNB19-MUC4 cells were constructed by gene transfection and RNA interference, and T98G-shM was silenced by MUC4. UC4 cell model and EGFR (epidermal growth factor receptor) silencing SNB19-MUC4-siEGFR cell model. MTT and cell clone formation assays were used to determine the effect of MUC4 on the proliferation of GBM cells. The effect of MUC4 on EGFR expression was determined by RT-PCR, Western blot and immunohistochemical staining. The SNB19-MUC4-siEGFR 1,2,3 cell model with EGFR gene silencing was constructed. The proliferation, migration and invasiveness of GBM cells after EGFR silencing were studied by MTT test, Boyden cell model test and cell healing test.
Results: The expression of MUC4 in 11 brain samples of GBM patients and 11 brain samples of GBM patients was detected by RT-PCR. The expression of MUC4 in 11 brain samples of GBM patients was significantly higher than that in control brain samples, and the number of MUC4 positive cells in brain samples of GBM patients was also significantly higher than that in control brain samples. The expression of MUC4 in six GBM cell lines was measured by RT-PCR and Western blot. The results showed that MUC4 was the highest in T98G cell line and the lowest in SNB19 cell line. T98G cells were used to construct mutant T98G-shMUC4 cell model and SNB19 cells were used to construct MUC4 gene transfection experiment. In cell proliferation experiments, MTT and cell clone formation assays showed that SNB19-MUC4 cells had significantly higher proliferation capacity, more clones and a wider range of clones than the control group. On the other hand, T98G-shMUC cells had significantly lower number of clones than the control group T98G cells. Cell wound healing experiments showed that SNB19-MUC4 cells significantly accelerated wound healing. Boyden's compartment model showed that SNB19-MUC4 cells had three times the ability of control and control cells to penetrate Transwell membranes. The results of RT-PCR and Western blot showed that MUC4 gene silencing could significantly reduce the expression of EGFR at RNA and protein levels in T98G cells. SNB19-MUC4 cells were further treated with RNA interference technique. EGFR-1,2,3 gene was silenced. MTT test, Boyden chamber model test and cell healing test showed that the proliferation, migration and invasion of SNB19-MUC4 cells were significantly decreased compared with those before silencing.
Conclusion: (1) MUC4 is highly expressed in GBM cells and plays an important role in the proliferation, migration and invasion of GBM cells. (2) MUC4 can regulate the expression of EGFR in GBM cells. EGFR plays an important role in the proliferation, migration and invasion of GBM cells.
【學位授予單位】：大連醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2014
【分類號】：R739.41
【共引文獻】
相關期刊論文 前10條
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