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前列腺癌神经内分泌分化与化疗耐药的关系研究
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摘要
本课题拟先在组织学水平,利用免疫组织化学技术研究NSE,P-gp,MRP1和Bcl-2在前列腺癌和良性前列腺增生症(BPH)手术标本中的表达。再在体外培养雄激素非依赖的前列腺癌DU145细胞,加入EGF和TGF-α诱导前列腺癌细胞发生NED,并通过光镜、电镜观察和检测NSE在mRNA和蛋白水平证实。然后用不同浓度梯度的顺铂作用于诱导发生NED的和未诱导的前列腺癌细胞,并进行对比研究。以期达到明确EGF和TGF-α是否可诱导NED;以及NED是否可以介导前列腺癌化疗耐药的目的。
     第一章前列腺癌和BPH组织中NSE、P-gp、MRP1和Bcl-2的表达
     目的:探讨NSE、P-gp、MRP1和Bcl-2在前列腺癌和BPH中的表达情况,并且研究这四种蛋白与前列腺癌分化程度的关系,从而为后续研究打下一定基础。
     材料和方法:10例BPH标本(55—75岁,平均61.2岁)和44例前列腺癌标本(61—77岁,平均64.3岁)取自中南大学湘雅医院泌尿外科2000—2007年的手术标本存档蜡块,标本系10%福尔马林固定,常规石蜡包埋。前列腺癌标本按照Gleason评分。前列腺癌患者术前均未接受内分泌治疗或其他治疗。标本4μm厚连续切片,分别做NSE、P-gp、MRP1和Bcl-2免疫组化染色。观察染色切片并计数10个具有代表性的高倍镜视野中阳性细胞的数量。阳性细胞数≤5%者为阴性表达,>5%者为阳性表达。
     结果:P-gp在前列腺癌和BPH组织中均无表达:NSE、MRP1和Bcl-2均有表达。MRP1在两种组织中的表达差异有统计学意义(p<0.01),前列腺癌中的表达高于BPH;NSE和Bcl-2的表达无统计学意义(p>0.05)。NSE、MRP1和Bcl-2的表达均随着前列腺癌分化程度的降低而表达增高。NSE列联系数(P):0.458;MRP1列联系数(P):0.472;Bcl-2列联系数(P):0.375。将前列腺癌标本按有无NSE表达分为两组,MRP1和Bcl-2的表达有统计学差异(p<0.05),且在NSE表达阳性的前列腺癌组织中,两种蛋白的表达均高于表达阴性的组织。
     结论:(1)前列腺癌可表达NSE、MRP1和Bcl-2,且表达阳性率与肿瘤分化程度、Gleason评分相关,即分化差者表达更高。本研究未发现该肿瘤有P-gp阳性表达。
     (2)表达NSE的前列腺癌,有更高的MRP1和Bcl-2表达率,即该肿瘤的NED与其MDR和抗凋亡能力增强有关。
     (3)BPH可表达NSE、MRP1和Bcl-2,提示NED和MRP1、Bcl-2的表达参与了该疾病的发生发展。
     第二章雄激素非依赖前列腺癌细胞株DU145的NED诱导及P-gp、MRP1和Bcl-2变化检测
     目的:探讨DU145细胞在受EGF和TGF-α作用后是否会促进NED,并且检测P-gp、MRP1和Bcl-2的蛋白表达情况。
     材料和方法:将DU145细胞在不同条件下培养三天,每日光镜下观察细胞形态学变化。收集三天后的细胞,Western印迹杂交检测NSE、P-gp、MRP1和Bcl-2的表达情况,实时荧光半定量RT-PCR检测NSEmRNA的表达,电镜观察细胞内神经内分泌颗粒。
     结果:(1)光镜下观察:2%BCS不加生长因子的培养环境下,每天细胞形态无明显变化:加入10ng/ml EGF培养者较5ng/ml者形态学变化明显,以第一天发生NED的细胞数最多,每天逐渐增多,至第三天时,细胞形态变化更加明显,表现为胞体由原来的椭圆形向三角形、多边形转化,细胞伸出神经突出样突起;TGF-α诱导的细胞数目与EGF相似,但形态学变化不如EGF明显。加入AG825(EGFR的酪氨酸激酶抑制剂)的培养细胞,形态无明显变化。
     (2)Western印迹杂交结果:NSE的表达:在不加生长因子的2%BCS细胞中表达很弱,经EGF诱导后表达明显增强,且10ng/ml强于5ng/ml,而加入AG825拮抗EGF作用者,几乎无NSE表达。经TGF-α诱导后的效果与EGF相近。Bcl-2的表达:在不加生长因子的2%细胞有表达,经EGF或TGF-α诱导后表达明显增强,加入AG825拮抗EGF作用者表达较弱。P-gp的表达:各组细胞几乎无表达。MRP1的表达:在不加生长因子的2%细胞有表达,经EGF或TGF-α诱导后表达明显增强,加入AG825拮抗EGF和TGF-α作用者几乎无表达。
     (3)实时荧光半定量RT-PCR:相对于只加入2%BCS培养基的而言,加入EGF 10ng/ml和TGF-α10ng/ml的细胞的NSE mRNA分别增加10.7和10.1倍,提示NED程度增加。而加入AG825拮抗剂者则表达分别下降81%和77%。
     (4)电镜观察:在不加生长因子的2%BCS细胞中几乎无神经内分泌颗粒,经EGF和TGF-α诱导后,颗粒明显增多,而加入AG825拮抗者,几乎无神经内分泌颗粒。
     结论:(1)EGF和TGF-α可诱导前列腺癌DU145细胞发生NED,其诱导作用可被AG825所拮抗。
     (2)DU145细胞经诱导后表达NSE、MRP1和Bcl-2增强,提示抗凋亡性和耐药性增强。
     第三章NED诱导后DU145细胞对顺铂的耐药性研究
     目的:探讨NED诱导后的前列腺癌DU145细胞的顺铂耐药性变化。
     材料和方法:EGF和TGF-α诱导DU145细胞发生NED后,取对数生长期的细胞接种于96孔培养板上。每组均加入不同浓度的顺铂(0.1,0.5,1.5,10,50,100μg/ml)。培养48小时后行MTT比色法检测顺铂对各组DU145细胞增殖的影响。同样方法诱导后,取对数生长期的不同分组DU145细胞,加入浓度为5μg/ml的顺铂,作用48小时后收集各组细胞,经胰酶消化离心后制成细胞悬液,行流式细胞术检测凋亡细胞百分率并行细胞周期分析。
     结果:(1)顺铂可抑制DU145细胞的增殖。在各浓度点上,尤其在较高的顺铂浓度点上,经EGF 10ng/ml处理的细胞存活率大于EGF 5ng/ml,经TGF-α10ng/ml处理的细胞存活率大于TGF-α5ng/ml,相同浓度生长因子处理后的细胞,经相同浓度顺铂作用后细胞存活率相近。加入AG825拮抗生长因子作用者,细胞存活率明显降低。
     (2)浓度为5μg/ml的顺铂作用48小时后,经生长因子诱导过的细胞凋亡率低,且EGF 10ng/ml低于EGF 5ng/ml(p<0.05),TGF-α10ng/ml低于TGF-α5ng/ml(p<0.05);细胞周期也发生变化,G_0/G_1细胞数减少,S期和G2/M期细胞相应增多。
     结论:(1)EGF和TGF-α诱导前列腺癌DU145细胞发生NED后耐顺铂能力增强。
     (2)较高浓度的EGF或TGF-α诱导的细胞耐药性更强,两种生长因子相比,诱导的细胞耐药性相近。
Present study is planning to evaluate expression of NSE,P-gp,MRP1 and Bcl-2 in the surgical samples of prostate cancer and BPH.EGF and TGF-αwould be added to the medium of androgen-independent prostate cancer cell line DU145.NED would be confirmed by light microscope, electron microscope and examination of NSE protein and mRNA. Whether EGF and TGF-αcould induce NED and whether NED could mediate chemoresistance of prostate cancer would be investigated.
     Part one Expression of NSE、P-gp、MRP1 and Bcl-2 in prostate cancer and BPH
     Aim:To investigate expression of NSE、P-gp、MRP1 and Bcl-2 in prostate cancer and BPH,and relationship between expressions and prostate cancer differentiation.
     Materials and Methods:ten cases of BPH(55-75 years old,averagely 61.2 years old)and 44 cases of prostatic cancer paraffin-embeded tissues were provided by urological department of XiangYa Hospital during 2000-2007.Prostatic cancer tissues were categorized according to Gleason scoring.No prostate cancer patients received endocrine therapy or other treatment.Consecutive resection specimens of 4μm were performed. Immunohistochemistry was carried out to detect NSE、P-gp、MRP1 and Bcl-2 expression.Count of positive cells in ten representive high power fields was performed.Less than 5%of positive cells were defined as negative expression,while more than 5%as positive.
     Results:No P-gp expression was detected in both cancer and BPH resections,while NSE、MRP1 and Bcl-2 showed expression.There was significant difference in MRP1 between two tissues(p<0.01),and expression in cancer was higher than in BPH.There was no difference in NSE and Bcl-2 expression between two tissues(p>0.05).Expression of NSE, MRP1 and Bcl-2 increased with decreasing of cancer differentiation levels. Coefficient of determination of NSE was 0.438.MRP1 was 0.472.Bcl-2 was 0.375.Prostate cancer tissues were categorized into two groups according to whether NSE expression was positive.Expression of MRP1 and Bcl-2 showed significant difference between two groups(p<0.05). Expression in positive group was higher than negative group.
     Conclusions:(1)Expressions of NSE、MRP1 and Bcl-2 were detected in prostate cancer.And expression was correlated with cancer differentiation, Gleason scores.The worse differentiated cancer showed higher expression. This cancer showed no P-gp expression.
     (2)Prostate cancer with NSE positive expression showed higher expression of MRP1 and Bcl-2.It was suggested that NED was related to MDR and increasing ability of anti-apoptosis.
     (3)Expressions ofNSE、MRP1 and Bcl-2 were detected in PBH.It was indicated that the three proteins participated in development of BPH.
     Part two NED induction of androgen-independent prostate cancer cell line DU145 and detection of P-gp、MRP1 and Bcl-2
     Aim:To investigate NED after DU145 was exposed to EGF and TGF-α.Expressions of P-gp、MRP1 and Bcl-2 were examed.
     Materials and Methods:DU145 cells were cultured under various conditions for three days.Morphology was observed under light microscope. Cells were collected after three days.Western blotting was used to exam expression of P-gp、MRP1 and Bcl-2.Real-time semiquantitiy PCR was used to detect NSE mRNA.Electron microscope was utilized to observe neuroendocrine differentiation particles.
     Results:(1)light microscope observation:no apparent morphological changes were observed in cells with only 2%BCS.More apparent changes in cells with 10ng/ml EGF were observed than those with 5 ng/ml EGF.The largest number of NED cells was counted at first day.The number increased everyday.At the third day,morphology changes were much more apparent. Cells shape changed from oval to triangle or polygon-shaped.NED cells had long branching dendrite-like processes.The effect in cells treated by TGF-αwas similar to EGF.But morphological changes were less apparent.No morphological changes were observed in cells treated with AG825.
     (2)Western blotting results:NSE expression:mild expression was detected in cells with only 2%BCS.Expression increased after exposed to EGF.Cells with 10ng/ml showed stronger expression than 5ng/ml.Those added with AG825 showed no apparent expression.The effect in cells treated by TGF-αwas similar to EGF.Bcl-2 expression:Expression was detected in cells with only 2%BCS.Expression increased strongly after exposed to growth factors.Those with AG825 showed mild expression. P-gp expression:No expression was detected in any cells.MRP1 expression: Expression was detected in cells with only 2%BCS.Expression increased strongly after exposed to growth factors.Those with AG825 showed no apparent expression.
     (3)Real-time semiquantitiy PCR:compared with cells with only 2%BCS,expression of NSE mRNA in cells with EGF 10 ng/ml and TGF-α 10 ng/ml increased 10.7 and 10.1 fold respectively.It was suggested that level of NED increased.Those with AG825 decreased 81%and 77%.
     (4)Electron microscope:No neuroendocrine particles were detected in cells treated only with 2%BCS.After exposed to EGF and TGF-α,numbers of particles increased dramatically.No particles were detected in cells with AG825
     Conclusions:(1)NED could be induced by EGF and TGF-αin DU145 cells.The effect could be counteracted by AG825.
     (2)After induction,expression of NSE、MRP1 and Bcl-2 increased.It was suggested that ability of anti-apoptosis and MDR increased.
     Part three Chemoresistance of DU145 to cisplatin after NED induction
     Aim:To investigate chemoresistance of DU145 to cisplatin after NED induction.
     Materials and Methods:Cells of exponential phase were implanted in 96-cell plate after induced by EGF and TGF-α.Each group cells were added into various concentrations of cisplatin(0.1,0.5,1,5,10,50,100μg/ml). After 48 hours culture,MTT assay was used to test effect of cisplatin on viability.With similar treatment cells were exposed to 5μg/ml cisplatin for 48 hours.Flow cytometry was used to test percentage of apoptotic cells and cell cycle.
     Results:(1)Cisplatin could suppress growth of DU145.At every concentration point,especially higher concentration,viability treated by EGF 10 ng/ml was higher than treated by EGF 5 ng/ml.Viability treated by TGF-α10 ng/ml was higher than treated by TGF-α5 ng/ml.The effect of EGF was similar to TGF-α.Viability apparently decreased for those treated with AG825.
     (2)After exposed to 5μg/ml cisplatin for 48 hours,those treated with growth factors showed less percentage of apoptosis,and those treated with EGF 10 ng/ml showed less percentage than EGF 5 ng/ml(p<0.05).It was similar for TGF-α.Changers in cell cycles were observed.Cells number of G_0/G_1 decreased.Cells of S and G2/M phase increased.
     Conclusions:(1)Chemoresistance of DU145 to cisplatin increased after NED induction by EGF and TGF-α.
     (2)Cells treated with higher concentration growth factor showed stronger chemoresistance.The effect was similar comparing one growth factor with each other.
引文
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