白细胞介素6及下游JAK/STAT3信号通路在前列腺相关疾病中的作用及机制研究
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摘要
【研究背景】
白细胞介素6(IL-6)是一种多功能细胞因子。研究发现:IL-6可能参与慢性前列腺炎的病理过程;同时在前列腺癌激素非依赖性形成以及神经内分泌化过程中,IL-6仍可能发挥着重要作用。然而在这两类疾病中,IL-6的具体作用机制仍不清楚。目前为止,仍缺乏在慢性前列腺炎中关于IL-6的分子流行病学研究;同时对于IL-6及其下游信号在前列腺癌发生发展过程中的作用及机制,仍需深入探索。
【目的】
1.针对Ⅲ型慢性前列腺炎,在蛋白质表达及基因多态性层面上,对IL-6进行分子流行病学调查;2.研究IL-6及下游JAK/STAT3信号途径对前列腺癌细胞系生物学行为的影响;3.在前列腺癌细胞系中,建立靶向沉默JAK/STAT3信号途径的RNA干涉体系;4.分析JAK/STAT3信号途径靶向沉默后,前列腺癌细胞系生物学行为的改变及可能机制。
【方法】
1.采用流行病学调查方法,选定IL-6分子流行病学研究的基线人群,结合环境因子及症状差异进一步建立分组研究队列;2.以初次的NIH-CPSI(National Institutes of Health chronic prostatitis symptom index,美国国立卫生研究院慢性前列腺炎症状评分)问卷调查及二次临床筛查为病例纳入方式,筛选Ⅲ型慢性前列腺炎患者并按亚型进一步分组,系统分析IL-6与症状、其他炎症因子及氧化应激水平的关系;3.酶联免疫吸附法测定血清及EPS(Expressed prostatic secretion,前列腺液)中IL-6等细胞因子水平,并分析炎症因子的相互关系;4.利用DCFH2-DA(2',7'-二氯二氢荧光素二乙酯,2′,7′-dichlorofluorescin diacetate)测定EPS中ROS(reactive oxygen species,活性氧)水平增长率,并分析ROS与IL-6水平的关系;5.采用ABTS (2,2'-Azinobis 3-ethylbenzothiazoline-6-sulfonic Acid Ammonium Salt,2,2'-联氮双3-乙基苯并噻唑啉-6-磺酸二铵盐)比色法测定EPS中TAOC(Total antioxidant capacity,总抗氧化能力)相对水平,并分析TAOC与IL-6水平的关系;6.四聚体ARMS-PCR(Amplification refractory mutation system polymerase chain reaction,扩增受阻突变体系聚合酶链反应)检测IL-6分子启动子区-174G/C基因型,并分析与EPS中IL-6水平与症状的关系;7.分子生物学方法构建PSMA(Prostate specific membrane antigen,前列腺特异性膜抗原)特异性单链抗体融合蛋白并鉴定其活性;8.利用分子生物学软件,设计STAT3(Signal transducer and activator 3,信号转导和激活因子3)特异性siRNA(Small interfering RNA,小干扰RNA),并通过流式细胞仪分析及细胞ELISA(Enzyme linked immunosorbent assay,酶联免疫吸附法)方法鉴定PSMA单链抗体融合蛋白对其的靶向递送能力;9.利用IL-6对前列腺癌LNCaP细胞系的双重生物学作用,建立IL-6处理的前列腺癌细胞系研究模型;10.利用STAT3的特异性siRNA处理LNCaP细胞,Western Blot方法检测相关STAT3分子的表达;11.利用MTT [3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-diphenytetrazoliumromide,噻唑蓝]方法描绘细胞进行生长曲线;12.采用PI(Propidium iodide,碘化丙啶)染色流式细胞术检测处理细胞的周期的变化,用Annexin V(膜联蛋白-V)/PI双染色流式细胞术检测凋亡。
【结果】
1. III型慢性前列腺炎IL-6分子流行病学研究
1)各亚型CP/CPPS患者EPS中IL-6水平,较对照组均明显增高,但不伴有血清IL-6的变化。
2)在IIIa亚型症状加重的病理过程中,IL-6与TNF-α、IL-2、IL-8、IL-10共同参与其病理进程,并伴有氧化应激水平的增高及抗氧化能力的下降。
3) IL-6参与IIIb亚型的病理进程,在IIIb亚型症状加重的过程中未发现TNF-α、IL-2、IL-8、IL-10及氧化应激水平的明显变化。
4)尽管对于CP/CPPS镜检分型标准的意义存在争议,但依据此标准的研究发现,IL-6在两型CP/CPPS中参与的病理机制可能不同。
5) IL-6启动子-174 C/G基因型的CP/CPPS患者伴有较高水平的EPS-IL-6,同时其症状分值明显高于GG、CC纯合子患者。
2.外源性IL-6对前列腺癌细胞系生物学行为的影响及其下游信号传导研究
1)在外源性IL-6处理LNCaP细胞的初期,IL-6具有明显的促细胞凋亡,阻滞细胞周期及抑制增殖的作用。
2)在IL-6抑制LNCaP细胞增殖阶段,同时也导致LNCaP细胞分泌PSA水平的增高。
3)在IL-6诱导PSA的信号传导途径中,STAT3发挥了重要作用,因为STAT3被靶向沉默后,随着磷酸化STAT3的减少,PSA的分泌水平出现明显降低。
4) STAT3并没有参与IL-6对LNCaP细胞增殖的抑制过程,因为在STAT3沉默后没有观察到IL-6处理LNCaP细胞生长曲线的变化,这表明:IL-6对LNCaP细胞的增殖抑制是通过其他信号传导途径来完成。
【结论】
1. IL-6参与III型慢性前列腺炎各亚型的病理过程,但由于各亚型病理机制的不同,IL-6发挥的作用机制可能不同;2.对于-174G/C基因型的III型慢性前列腺炎患者,其EPS中有较高水平的IL-6表达;3.外源性IL-6促进前列腺癌LNCaP细胞分泌PSA,JAK/STAT3信号通路参与IL-6促进LNCaP细胞恶性进展的过程。
[Background]
Interleukin-6 (IL-6) is a multi-functional cytokine. It is involved in the inflammatory process of chronic prostatitis. In addition, IL-6 may still play an important role on hormone refractory and neuroendocrine differentiation in prostate cancer. However, the mechanism of IL-6 in chronic prostatitis and prostate cancer is unclear. Molecular epidemiologic investigation of IL-6 in chronic prostatitis and the function of IL-6/STAT3 signal pathway on prostate cancer progression remain to be further explored.
[Objectives]
1. To investage IL-6 expressed level and gene polymorphism in patients with catⅢtype chronic prostatitis by molecular epidemiologic methods; 3. To analyse the influnce of IL-6/STAT3 signaling on biological behavior of prostate cancer cell line; 4. To target inhibite STAT3 signaling pathway with siRNA in prostate cancer cell line; 5. To study the influnce of IL-6/STAT3 signaling pathway on the malignant behavior of prostate cancer cell lines and its possible mechanism after targeted STAT3 silence.
[Methods]
1. For molecular epidemiologic analsis on IL-6 the baseline population was established by epidemiological investigation, according to the differences in environmental factors and symptoms the baseline population was further divided into two study cohorts; 2. Patients with catⅢtype chronic prostatitis type were included by NIH-CPSI questionnaire investation and further clinical screening and further divided intoⅢa andⅢb subtype groups. Levels of IL-6, IL-2, IL-8, IL-10, TNF-α, oxidative stress and the relationship between IL-6 and symptoms were systemic analysed; 3. Levels of IL-6 and other cytokines in EPS and serum were and detected by enzyme-linked immunosorbent assay and the relationship between IL-6 and other inflamatary factors was analysed; 4. ROS level in EPS was examined by DCFH2-DA; 5. TAOC level in EPS was detectd by ABTS; 6. -174G/C genotype of IL-6 promoter was analysed with tetramer ARMS-PCR; 7. PSMA specific single chain antibody fusion protein was constracted and identificated with molecular biology technology; 8. STAT3 specific siRNA were designed using molecular biology software. The targeted delivery ability of the fusion protein was identified by flow cytometry analysis and cell ELISA; 9. The prostate cancer cell line model by IL-6 treatment was established as the dual biological function on LNCaP cell line of IL-6; 10. LNCaP cells in which the STAT3 signaling was suppressed by STAT3 specific siRNA treatment were achieved and the expression of pSTAT3 was detected by Western Blot; 11. MTT method was used to examined the growth of prostate cells and the STAT3 signaling suppressed cells; 12. Cell cycle of LNCaP cells and the STAT3 signaling suppressed cells was examined by FCM analysis; Annexin V/PI dual-staining was used to detect cell apoptosis.
[Result]
1. Molecular Epidemiologic investation of IL-6 in cat III type chronic prostatitis
1) The IL-6 level in EPS were significantly higher than that of control group in patients with both subtypes CP/CPPS, but not accompanying the changes of serum IL-6 level.
2) IL-6, TNF-α, IL-2, IL-8 and IL-10 participated the pathological process of IIIa subtype CP/CPPS accompanying by the increased ROS level and decreased TAOC level.
3) IL-6 was involved in the pathological process of subtype IIIb CP/CPPS. However, significant changes of the levels of TNF-α, IL-2, IL-8, IL-10 and oxidative stress were not found in the course of the symptoms aggravation.
4) Although the type criterion of CP / CPPS is disputed we found the pathological mechanism of IL-6 in the two types CP / CPPS may be different based on the typing standard.
5) CP/CPPS patients with IL-6 promoter -174 C / G genotype have a higher EPS IL-6 levels and the symptoms score was significantly higher than that of GG and CC homozygous patients.
2. Exogenous IL-6 biological behavior of prostate cancer cell lines and its downstream signal transduction
1) In initial phage of exogenous IL-6 treatment IL-6 can inhibite induce LNCaP proliferation by inducing cell cycle arrest and apoptosis.
2) In inhibition phage of exogenous IL-6 treatment elevated PSA levels were deteced in LNCaP cells, indicating that IL-6 can induce the malignant phenotype of LNCaP cells.
3) After targeting inhabite STAT3, with the reduction of phosphorylation STAT3, PSA secretion levels appeared significantly reduced. Therefore STAT3 plays an important role during the process which IL-6 induces the increased PSA levels in LNCaP cells.
4) STAT3 is not involved in proliferation inhibition of IL-6 treatment as the MTT growth curve of IL-6-treatment-LNCaP cell is not influnced after siRNA targeting STAT3 silence.
[Conclusions]
1. IL-6 is involved in the pathological process of bothⅢa andⅢb subtype CP/CPPS, but the pathological mechanism of IL-6 may be different in the two subtypes CP/CPPS; 2. CP/CPPS patients with -174G/C genotype in IL-6 promoter have high expression levels of IL-6 in their EPS; 3. Exogenous IL-6 can induce the malignant phenotype of LNCaP cells with the increased secretion of PSA and JAK/STAT3 signaling pathway is involved in the malignant progression.
白细胞介素6(IL-6)是一种多功能细胞因子。研究发现:IL-6可能参与慢性前列腺炎的病理过程;同时在前列腺癌激素非依赖性形成以及神经内分泌化过程中,IL-6仍可能发挥着重要作用。然而在这两类疾病中,IL-6的具体作用机制仍不清楚。目前为止,仍缺乏在慢性前列腺炎中关于IL-6的分子流行病学研究;同时对于IL-6及其下游信号在前列腺癌发生发展过程中的作用及机制,仍需深入探索。
【目的】
1.针对Ⅲ型慢性前列腺炎,在蛋白质表达及基因多态性层面上,对IL-6进行分子流行病学调查;2.研究IL-6及下游JAK/STAT3信号途径对前列腺癌细胞系生物学行为的影响;3.在前列腺癌细胞系中,建立靶向沉默JAK/STAT3信号途径的RNA干涉体系;4.分析JAK/STAT3信号途径靶向沉默后,前列腺癌细胞系生物学行为的改变及可能机制。
【方法】
1.采用流行病学调查方法,选定IL-6分子流行病学研究的基线人群,结合环境因子及症状差异进一步建立分组研究队列;2.以初次的NIH-CPSI(National Institutes of Health chronic prostatitis symptom index,美国国立卫生研究院慢性前列腺炎症状评分)问卷调查及二次临床筛查为病例纳入方式,筛选Ⅲ型慢性前列腺炎患者并按亚型进一步分组,系统分析IL-6与症状、其他炎症因子及氧化应激水平的关系;3.酶联免疫吸附法测定血清及EPS(Expressed prostatic secretion,前列腺液)中IL-6等细胞因子水平,并分析炎症因子的相互关系;4.利用DCFH2-DA(2',7'-二氯二氢荧光素二乙酯,2′,7′-dichlorofluorescin diacetate)测定EPS中ROS(reactive oxygen species,活性氧)水平增长率,并分析ROS与IL-6水平的关系;5.采用ABTS (2,2'-Azinobis 3-ethylbenzothiazoline-6-sulfonic Acid Ammonium Salt,2,2'-联氮双3-乙基苯并噻唑啉-6-磺酸二铵盐)比色法测定EPS中TAOC(Total antioxidant capacity,总抗氧化能力)相对水平,并分析TAOC与IL-6水平的关系;6.四聚体ARMS-PCR(Amplification refractory mutation system polymerase chain reaction,扩增受阻突变体系聚合酶链反应)检测IL-6分子启动子区-174G/C基因型,并分析与EPS中IL-6水平与症状的关系;7.分子生物学方法构建PSMA(Prostate specific membrane antigen,前列腺特异性膜抗原)特异性单链抗体融合蛋白并鉴定其活性;8.利用分子生物学软件,设计STAT3(Signal transducer and activator 3,信号转导和激活因子3)特异性siRNA(Small interfering RNA,小干扰RNA),并通过流式细胞仪分析及细胞ELISA(Enzyme linked immunosorbent assay,酶联免疫吸附法)方法鉴定PSMA单链抗体融合蛋白对其的靶向递送能力;9.利用IL-6对前列腺癌LNCaP细胞系的双重生物学作用,建立IL-6处理的前列腺癌细胞系研究模型;10.利用STAT3的特异性siRNA处理LNCaP细胞,Western Blot方法检测相关STAT3分子的表达;11.利用MTT [3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-diphenytetrazoliumromide,噻唑蓝]方法描绘细胞进行生长曲线;12.采用PI(Propidium iodide,碘化丙啶)染色流式细胞术检测处理细胞的周期的变化,用Annexin V(膜联蛋白-V)/PI双染色流式细胞术检测凋亡。
【结果】
1. III型慢性前列腺炎IL-6分子流行病学研究
1)各亚型CP/CPPS患者EPS中IL-6水平,较对照组均明显增高,但不伴有血清IL-6的变化。
2)在IIIa亚型症状加重的病理过程中,IL-6与TNF-α、IL-2、IL-8、IL-10共同参与其病理进程,并伴有氧化应激水平的增高及抗氧化能力的下降。
3) IL-6参与IIIb亚型的病理进程,在IIIb亚型症状加重的过程中未发现TNF-α、IL-2、IL-8、IL-10及氧化应激水平的明显变化。
4)尽管对于CP/CPPS镜检分型标准的意义存在争议,但依据此标准的研究发现,IL-6在两型CP/CPPS中参与的病理机制可能不同。
5) IL-6启动子-174 C/G基因型的CP/CPPS患者伴有较高水平的EPS-IL-6,同时其症状分值明显高于GG、CC纯合子患者。
2.外源性IL-6对前列腺癌细胞系生物学行为的影响及其下游信号传导研究
1)在外源性IL-6处理LNCaP细胞的初期,IL-6具有明显的促细胞凋亡,阻滞细胞周期及抑制增殖的作用。
2)在IL-6抑制LNCaP细胞增殖阶段,同时也导致LNCaP细胞分泌PSA水平的增高。
3)在IL-6诱导PSA的信号传导途径中,STAT3发挥了重要作用,因为STAT3被靶向沉默后,随着磷酸化STAT3的减少,PSA的分泌水平出现明显降低。
4) STAT3并没有参与IL-6对LNCaP细胞增殖的抑制过程,因为在STAT3沉默后没有观察到IL-6处理LNCaP细胞生长曲线的变化,这表明:IL-6对LNCaP细胞的增殖抑制是通过其他信号传导途径来完成。
【结论】
1. IL-6参与III型慢性前列腺炎各亚型的病理过程,但由于各亚型病理机制的不同,IL-6发挥的作用机制可能不同;2.对于-174G/C基因型的III型慢性前列腺炎患者,其EPS中有较高水平的IL-6表达;3.外源性IL-6促进前列腺癌LNCaP细胞分泌PSA,JAK/STAT3信号通路参与IL-6促进LNCaP细胞恶性进展的过程。
[Background]
Interleukin-6 (IL-6) is a multi-functional cytokine. It is involved in the inflammatory process of chronic prostatitis. In addition, IL-6 may still play an important role on hormone refractory and neuroendocrine differentiation in prostate cancer. However, the mechanism of IL-6 in chronic prostatitis and prostate cancer is unclear. Molecular epidemiologic investigation of IL-6 in chronic prostatitis and the function of IL-6/STAT3 signal pathway on prostate cancer progression remain to be further explored.
[Objectives]
1. To investage IL-6 expressed level and gene polymorphism in patients with catⅢtype chronic prostatitis by molecular epidemiologic methods; 3. To analyse the influnce of IL-6/STAT3 signaling on biological behavior of prostate cancer cell line; 4. To target inhibite STAT3 signaling pathway with siRNA in prostate cancer cell line; 5. To study the influnce of IL-6/STAT3 signaling pathway on the malignant behavior of prostate cancer cell lines and its possible mechanism after targeted STAT3 silence.
[Methods]
1. For molecular epidemiologic analsis on IL-6 the baseline population was established by epidemiological investigation, according to the differences in environmental factors and symptoms the baseline population was further divided into two study cohorts; 2. Patients with catⅢtype chronic prostatitis type were included by NIH-CPSI questionnaire investation and further clinical screening and further divided intoⅢa andⅢb subtype groups. Levels of IL-6, IL-2, IL-8, IL-10, TNF-α, oxidative stress and the relationship between IL-6 and symptoms were systemic analysed; 3. Levels of IL-6 and other cytokines in EPS and serum were and detected by enzyme-linked immunosorbent assay and the relationship between IL-6 and other inflamatary factors was analysed; 4. ROS level in EPS was examined by DCFH2-DA; 5. TAOC level in EPS was detectd by ABTS; 6. -174G/C genotype of IL-6 promoter was analysed with tetramer ARMS-PCR; 7. PSMA specific single chain antibody fusion protein was constracted and identificated with molecular biology technology; 8. STAT3 specific siRNA were designed using molecular biology software. The targeted delivery ability of the fusion protein was identified by flow cytometry analysis and cell ELISA; 9. The prostate cancer cell line model by IL-6 treatment was established as the dual biological function on LNCaP cell line of IL-6; 10. LNCaP cells in which the STAT3 signaling was suppressed by STAT3 specific siRNA treatment were achieved and the expression of pSTAT3 was detected by Western Blot; 11. MTT method was used to examined the growth of prostate cells and the STAT3 signaling suppressed cells; 12. Cell cycle of LNCaP cells and the STAT3 signaling suppressed cells was examined by FCM analysis; Annexin V/PI dual-staining was used to detect cell apoptosis.
[Result]
1. Molecular Epidemiologic investation of IL-6 in cat III type chronic prostatitis
1) The IL-6 level in EPS were significantly higher than that of control group in patients with both subtypes CP/CPPS, but not accompanying the changes of serum IL-6 level.
2) IL-6, TNF-α, IL-2, IL-8 and IL-10 participated the pathological process of IIIa subtype CP/CPPS accompanying by the increased ROS level and decreased TAOC level.
3) IL-6 was involved in the pathological process of subtype IIIb CP/CPPS. However, significant changes of the levels of TNF-α, IL-2, IL-8, IL-10 and oxidative stress were not found in the course of the symptoms aggravation.
4) Although the type criterion of CP / CPPS is disputed we found the pathological mechanism of IL-6 in the two types CP / CPPS may be different based on the typing standard.
5) CP/CPPS patients with IL-6 promoter -174 C / G genotype have a higher EPS IL-6 levels and the symptoms score was significantly higher than that of GG and CC homozygous patients.
2. Exogenous IL-6 biological behavior of prostate cancer cell lines and its downstream signal transduction
1) In initial phage of exogenous IL-6 treatment IL-6 can inhibite induce LNCaP proliferation by inducing cell cycle arrest and apoptosis.
2) In inhibition phage of exogenous IL-6 treatment elevated PSA levels were deteced in LNCaP cells, indicating that IL-6 can induce the malignant phenotype of LNCaP cells.
3) After targeting inhabite STAT3, with the reduction of phosphorylation STAT3, PSA secretion levels appeared significantly reduced. Therefore STAT3 plays an important role during the process which IL-6 induces the increased PSA levels in LNCaP cells.
4) STAT3 is not involved in proliferation inhibition of IL-6 treatment as the MTT growth curve of IL-6-treatment-LNCaP cell is not influnced after siRNA targeting STAT3 silence.
[Conclusions]
1. IL-6 is involved in the pathological process of bothⅢa andⅢb subtype CP/CPPS, but the pathological mechanism of IL-6 may be different in the two subtypes CP/CPPS; 2. CP/CPPS patients with -174G/C genotype in IL-6 promoter have high expression levels of IL-6 in their EPS; 3. Exogenous IL-6 can induce the malignant phenotype of LNCaP cells with the increased secretion of PSA and JAK/STAT3 signaling pathway is involved in the malignant progression.
引文
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