环境内分泌干扰物对神经母细胞瘤细胞生物学特性影响及神经母细胞瘤全基因组拷贝数变异初步分析
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摘要
神经母细胞瘤(NB)来源于胚胎发育期未分化成熟的神经嵴细胞,是小儿最常见的颅外实体肿瘤。临床上NB以生长迅速,易产生耐药及转移早为特点,患儿尤其是高危组患儿预后不佳。环境与遗传因素的共同作用是导致NB发生发展的主要原因,但目前对NB相关的诱发因素及其致病机制仍不明确。因此,寻找诱发NB的高危因素及相关作用机制将有助于NB的早期预防筛查及临床疗效的提高,改善患者预后。环境内分泌干扰物(EED)是存在于自然界或由人类生产生活活动释放到自然界中的一大类物质,其中以类雌激素物质居多。随着环境污染的加重,EED对人类健康的影响受到关注。已发现,长期暴露于DDT,双酚A (BPA)、邻苯二甲酸二(2-乙基己基)酯(DEHP)等EED,与出生缺陷,神经精神发育障碍,代谢紊乱甚至乳腺癌,前列腺癌等恶性肿瘤发生发展密切相关,但与儿童非生殖系统恶性实体肿瘤相关性未见报道。儿童对EED的作用尤为敏感,观察分析EED与儿童常见病特别是恶性实体肿瘤相关性具有重要的临床价值和社会意义。基因拷贝数变异(CNV)是近来新发现的又一种染色体结构变异。虽然CNV广泛存在于正常人群中,但特定区域CNV则与人类多种疾病发生发展密切相关。已有研究证实,CNV与NB发生发展也存在一定相关性。而目前NB相关CNV研究局限在欧美人群,由于不同种族人群中CNV存在差异,因此对于中国人群NB患者CNV分布及其与NB相关性研究将有助于阐明中国人群中NB发生发展的遗传机制,利于NB的早期诊断,治疗及预后的评价,目前未见相关报道。故本课题拟观察EED对于NB细胞增殖凋亡、多药耐药及侵袭转移等生物学特性的影响,同时检测中国汉族NB患者全基因组CNV,阐明环境因素EED及遗传因素CNV在NB发生发展中的作用,为肿瘤的预防,早期诊断,临床治疗及预后评价提供理论依据。
本课题首先选用BPA及DEHP两种常见的EED,并以雌激素(E2)作为对照,作用于NB体外细胞模型SK-N-SH细胞株,通过细胞增殖实验,流式细胞仪细胞周期分析及western blotting检测凋亡蛋白酶-3活性等,观察BPA、DEHP及E2对SK-N-SH细胞增殖及凋亡活性的影响；通过细胞毒性实验及荧光定量PCR和western blotting检测MDR1、MRP1、MVP、p53多药耐药基因表达变化,观察BPA、DEHP及E2对SK-N-SH细胞多药耐药性的影响；通过体外细胞迁移及侵袭实验及荧光定量PCR和western blotting检测MMP-2, MMP-9及TIMP-2侵袭转移基因表达变化,观察BPA、DEHP及E2对SK-N-SH细胞侵袭转移性的影响。在此基础上,应用雌激素受体(ER)拮抗剂ICI182,780及PI3K特异性抑制剂LY294002处理SK-H-SH细胞,通过上述各种检测方法观察ICI182,780及LY294002对BPA、DEHP及E2在SK-N-SH细胞增殖、多药耐药及侵袭转移特性作用的影响,阐明ER依赖途径及PI3K/Akt信号通路在BPA、DEHP及E2介导的生物学效应中作用。其次,采集中国汉族人群中NB临床标本,应用Agilent244K比较基因组杂交芯片(aCGH)检测各样本全基因组CNV,并通过DNAAnalytics、Nexus Copy Number及Ingeniuty pathway analysis软件分析NB相关性CNV,与NB各临床表型相关CNV及CNV所涉及的基因及机制。
细胞增殖实验显示0.1μM BPA,50μM DEHP或10μM E2干预后24至120h, SK-N-SH细胞数均明显增加,细胞活性明显增高(P<0.001 vs. Control)。流式细胞仪细胞周期检测显示BPA、DEHP及E2干预120h后,S期及G2-M期细胞数百分比较对照组明显升高(P<0.001),细胞DNA合成加速。但干预前后Caspase-3蛋白酶原及其17kD,12kD活性片段表达无明显变化(P>0.05)。细胞毒性实验显示BPA、DEHP及E2干预后24至120 h, SK-N-SH细胞对阿霉素(DOX),顺铂(CP)及依托泊苷(VP-16)三种化疗药物的敏感性均下降,细胞存活率较对照组明显升高(P<0.01)。MDR1, MRP1及MVP基因mRNA及蛋白表达在BPA、DEHP及E2干预后明显升高(P<0.01 vs. Control),而p53基因表达则在干预后明显下降(P<0.05 vs. Control)。体外细胞迁移及侵袭实验显示BPA、DEHP及E2干预24h后,SK-N-SH细胞迁移及侵袭能力较对照组明显升高(P< 0.001)。MMP-2、MMP-9基因mRNA及蛋白水平表达在BPA、DEHP及E2干预后明显升高(P< 0.001 vs. Control),而TIMP-2基因表达则在干预后明显下降(P< 0.01 or P< 0.05 vs. Control)。此外,在10μM ICI182,780或20μMLY294002处理后,SK-N-SH细胞数明显低于BPA、DEHP或E2组,细胞活性无明显升高(P<0.001),S期及G2-M期细胞数百分比也明显低于BPA、DEHP orE2组(P<0.01)。而SK-N-SH细胞对阿霉素,顺铂及VP-16三种化疗药物的敏感性高于BPA、DEHP或E2组(P<0.01), MDR1, MRP1及MVP多药耐药基因mRNA及蛋白表达也较BPA、DEHP或E2组低(P<0.01),而p53基因表达则无明显下降(P< 0.01 vs. BPA、DEHP或E2组)。体外细胞迁移及侵袭实验发现SK-N-SH细胞迁移及侵袭能力在ICI182,780或LY294002干预后较BPA、DEHP或E2组低(P< 0.001)。MMP-2、MMP-9基因mRNA及蛋白表达也较BPA、DEHP或E2组表达水平低(P< 0.001 or P< 0.01),而TIMP-2基因表达则明显高于BPA、DEHP或E2组表达水平(P< 0.001 or P<0.05)。此外,western blotting检测发现磷酸化Akt蛋白表达水平在BPA、DEHP或E2干预后明显升高(P<0.01vs.Control),而ICI182,780及LY294002处理后,磷酸化Akt蛋白表达水平则比BPA、DEHP或E2组明显降低(P<0.01)。Akt总蛋白在干预前后无明显变化(P>0.05)。
aCGH检测NB肿瘤标本全基因CNV显示,11例标本中有10例都存在数量不等CNV,其中9例标本均存在病理性CNV。CNV的数量与肿瘤病例分期具有正相关性趋势。同时,CNV引起的Loss区域明显多于Gain区域,发生缺失的基因总数及OMIM基因数也较发生复制的基因多。在2个以上的标本中均出现相同或类似CNV的区域包括14q, 1p,9q,16p及Xq。基因功能分析显示变异的基因具有传导细胞间信号,调控组织器官生长发育,基因转录后修饰及蛋白修饰等功能,参与编码Tight Junction, ILK等经典信号通路中关键蛋白。变异基因之间也存在相互作用,在神经性疾病,器官损伤或畸形,DNA损伤修复机制异常及肿瘤和信号传导方面发挥主要作用。
综上,BPA、DEHP及E2可促进SK-N-SH细胞体外增殖、多药耐药性和侵袭转移特性的提高,ER依赖途径及PI3K/Akt信号通路可能是介导BPA、DEHP及E2作用的主要机制之一。CNV亦普遍存在于中国NB患者中,14q,1p,9q,16p及Xq可能是NB相关的关键CNV区域。CNV引起基因功能及信号通路活性异常,与变异基因之间相互作用共同介导了NB病理过程。因此,EED是促进NB发生发展的重要环境因素而CNV则是引发NB的重要遗传机制。
Neuroblastoma (NB) derives from neural crest cells which can not be differentiated normally during embryo development. It is the most common extracranial tumor in children. Clinically NB is characterized by its rapid growth, susceptibility to multidrug resistance and metastasis. Both genetic and environmental factors may contribute to neuroblastoma oncogenesis. However, little is known about risk factors and their mechanisms that induce NB. Exploring risk factors and their mechanisms related to NB will improve NB early diagnosis and clinical therapies as well as the prognosis. Environmental endocrine disruptors (EED) are a large number of either natural or man-made exogenous compounds. Most of them mainly mimick the action of natural hormone estrogens such as 17β-estradiol (E2) in the body. With aggravation of global environmental problems, there have been growing concerns on relationships between daily exposure to EED and human health. Accumulating evidence suggested that EED are causative factors for multiple human diseases including birth defects, neurological disorders and metabolism disorders as well as adult malignant tumors such as breast cancer, prostate cancer, and etc. However, no studies is focused on the relationship between EED and children solid malignant tumors now. It is necessary to investigate the role of EED on pediatric diseases including cancer since they are more susceptible to adverse effects of EED exposure. Copy number variant (CNV) is a novel structural variation in human chromosomes. CNV is highly associated with various human diseases although it widely exists in the normal population. It is reported that CNV also contributes to the NB's initiation. However, the relationship between NB and CNV in Chinese patients is still unclear. Therefore, it is necessary to explore genetic mechanisms of NB in Chinese population, which will be useful for NB's early diagnosis, therapies and prognosis evaluation.
In the current study, we investigate the effects of biphenol A (BPA) and di(2-ethylhexyl) phthalate (DEHP) as well as E2 on human SK-N-SH neuroblastoma cell line in vitro. The number of variable cells was detected by using cell proliferation assay. The percentage of cells in both S and G2-M phases was tested with cell flow cytometry analysis. Also, caspase-3 activation was determined by western blotting. Moreover, cell survival rate and its sensitivity to the chemotherapy were detected by using cell cytotoxicity assay. MDR1, MRP1, MVP and p53 mRNA and protein expression were investigated by using both real-time PCR and western blotting. Furthermore, the capacity of cell migration and invasion were detected by cell migration and invasion assay. MMP-2, MMP-9 and TIMP-2 RNA and protein expression were determined by using both real-time PCR and western blotting respectively. Then cells were pretreated with estrogen receptor (ER) antagonist ICI 182,780 or phosphoinositide 3-kinase (PI3K) specific inhibitor LY294002 to see whether these agents can block EED-induced effects on NB cells with the same methods described above. In addition,11 NB samples from Chinese Han patients were collected and the whole genome CNV was detected in these samples by using Agilent 244k array comparative genomic hybridization (aCGH). Data were analysized by DNA analytics, Nexus Copy Number and Ingeunity pathway analysis software to explore NB related CNVs, recurrent CNVs and phenotype dependent CNVs as well as their molecular mehchanisms.
After 24 h 0.1μM BPA,50μM DEHP or 10μM E2 treatments, the number of variable cells was significantly increased and the cell activity was elevated (P< 0.001 vs. Control). This trend maintained to 120 h. The percentage of cells in S and G2-M phase obviously increased in group treated with BPA, DEHP or E2 (P< 0.001 vs. Control). However, no significant change was observed in caspase-3 expression (P> 0.05). In the cell cytotoxicity assay, BPA, DEHP or E2-treated SK-N-SH cells had a higher cell survival rate than the control (P< 0.01). Significantly elevated mRNA and protein expression of MDR1, MRP and MVP gene were detected in groups treated with BPA, DEHP or E2 (P< 0.01 vs. Control) but decreased mRNA and protein expression of p53 were detected in the BPA, DEHP or E2 group (P< 0.05 vs. Control). Moreover, the cell migration and invasion assay showed enhanced capacity of cell migration and invasion in the BPA, DEHP or E2 group (P< 0.001 vs. Control). Significantly elevated mRNA and protein expression of MMP-2 and MMP-9 gene were detected in groups treated with BPA, DEHP or E2 (P< 0.001 vs. Control) but decreased mRNA and protein expression of TIMP-2 were also detected in the BPA, DEHP or E2 group (P< 0.01 or P< 0.05 vs. Control). Furthermore, cells pretreated with ICI182,780 or LY294002 showed lower cell growth rate, lower percentage of cell in S and G2-M phase but higher sensitivity to chemotherapy compared with BPA, DEHP or E2-only treated groups (P< 0.001 or P< 0.01). Lower mRNA and protein expression of MDR1, MRP1,and MVP as well as higher mRNA and protein expression of p53 were detected in the groups treated both ICI182,780 or LY294002 and EED compared with BPA, DEHP or E2-only treated groups (P< 0.01). The capacity of cell migration and invasion can not be enhanced by BPA, DEHP or E2 after pretreatment with ICI182,780 or LY294002. Lower mRNA and protein expression of MMP-2 and MMP-9 as well as higher mRNA and protein expression of TIMP-2 were observed in the groups treated both ICI 182,780 or LY294002 and EED compared with BPA, DEHP or E2-only treated groups (P< 0.001 or P< 0.05). Akt (Ser473) phosphorylation level was enhanced by BPA, DEHP or E2 treatement compared with the control group but not in ICI182,780 or LY294002 pretreated groups (P<0.01).
Furthermore, various CNVs were observed in 10/11 samples and pathogenic CNVs also existed in 9/10 samples. CNV amounts could be dependent on NB's phathological grades. CNV- induced loss was significantly more than CNV-induced gain.14q, 1p,9q,16p and Xq could be recurrent region related to NB. Genes in CNV regions contributed to cell to cell transaction, tissue development, post-transcription modification and protein folds. These genes were involved in Tight Junction, and ILK pathway. The action among these genes contributed to neurological disease, organ injury and cancer.
In summary, BPA, DEHP and E2 can promote SK-N-SH cell proliferation, multidrug resistance, migration and invasion in vitro. ER dependent and PI3K/Akt pathway may be involved. CNV exists widely in Chinese Han NB patients,14q, 1p, 9q,16p and Xq may be key regions to NB pathogenesis. Multiple mechanisms may be involved in NB oncogenesis.
本课题首先选用BPA及DEHP两种常见的EED,并以雌激素(E2)作为对照,作用于NB体外细胞模型SK-N-SH细胞株,通过细胞增殖实验,流式细胞仪细胞周期分析及western blotting检测凋亡蛋白酶-3活性等,观察BPA、DEHP及E2对SK-N-SH细胞增殖及凋亡活性的影响；通过细胞毒性实验及荧光定量PCR和western blotting检测MDR1、MRP1、MVP、p53多药耐药基因表达变化,观察BPA、DEHP及E2对SK-N-SH细胞多药耐药性的影响；通过体外细胞迁移及侵袭实验及荧光定量PCR和western blotting检测MMP-2, MMP-9及TIMP-2侵袭转移基因表达变化,观察BPA、DEHP及E2对SK-N-SH细胞侵袭转移性的影响。在此基础上,应用雌激素受体(ER)拮抗剂ICI182,780及PI3K特异性抑制剂LY294002处理SK-H-SH细胞,通过上述各种检测方法观察ICI182,780及LY294002对BPA、DEHP及E2在SK-N-SH细胞增殖、多药耐药及侵袭转移特性作用的影响,阐明ER依赖途径及PI3K/Akt信号通路在BPA、DEHP及E2介导的生物学效应中作用。其次,采集中国汉族人群中NB临床标本,应用Agilent244K比较基因组杂交芯片(aCGH)检测各样本全基因组CNV,并通过DNAAnalytics、Nexus Copy Number及Ingeniuty pathway analysis软件分析NB相关性CNV,与NB各临床表型相关CNV及CNV所涉及的基因及机制。
细胞增殖实验显示0.1μM BPA,50μM DEHP或10μM E2干预后24至120h, SK-N-SH细胞数均明显增加,细胞活性明显增高(P<0.001 vs. Control)。流式细胞仪细胞周期检测显示BPA、DEHP及E2干预120h后,S期及G2-M期细胞数百分比较对照组明显升高(P<0.001),细胞DNA合成加速。但干预前后Caspase-3蛋白酶原及其17kD,12kD活性片段表达无明显变化(P>0.05)。细胞毒性实验显示BPA、DEHP及E2干预后24至120 h, SK-N-SH细胞对阿霉素(DOX),顺铂(CP)及依托泊苷(VP-16)三种化疗药物的敏感性均下降,细胞存活率较对照组明显升高(P<0.01)。MDR1, MRP1及MVP基因mRNA及蛋白表达在BPA、DEHP及E2干预后明显升高(P<0.01 vs. Control),而p53基因表达则在干预后明显下降(P<0.05 vs. Control)。体外细胞迁移及侵袭实验显示BPA、DEHP及E2干预24h后,SK-N-SH细胞迁移及侵袭能力较对照组明显升高(P< 0.001)。MMP-2、MMP-9基因mRNA及蛋白水平表达在BPA、DEHP及E2干预后明显升高(P< 0.001 vs. Control),而TIMP-2基因表达则在干预后明显下降(P< 0.01 or P< 0.05 vs. Control)。此外,在10μM ICI182,780或20μMLY294002处理后,SK-N-SH细胞数明显低于BPA、DEHP或E2组,细胞活性无明显升高(P<0.001),S期及G2-M期细胞数百分比也明显低于BPA、DEHP orE2组(P<0.01)。而SK-N-SH细胞对阿霉素,顺铂及VP-16三种化疗药物的敏感性高于BPA、DEHP或E2组(P<0.01), MDR1, MRP1及MVP多药耐药基因mRNA及蛋白表达也较BPA、DEHP或E2组低(P<0.01),而p53基因表达则无明显下降(P< 0.01 vs. BPA、DEHP或E2组)。体外细胞迁移及侵袭实验发现SK-N-SH细胞迁移及侵袭能力在ICI182,780或LY294002干预后较BPA、DEHP或E2组低(P< 0.001)。MMP-2、MMP-9基因mRNA及蛋白表达也较BPA、DEHP或E2组表达水平低(P< 0.001 or P< 0.01),而TIMP-2基因表达则明显高于BPA、DEHP或E2组表达水平(P< 0.001 or P<0.05)。此外,western blotting检测发现磷酸化Akt蛋白表达水平在BPA、DEHP或E2干预后明显升高(P<0.01vs.Control),而ICI182,780及LY294002处理后,磷酸化Akt蛋白表达水平则比BPA、DEHP或E2组明显降低(P<0.01)。Akt总蛋白在干预前后无明显变化(P>0.05)。
aCGH检测NB肿瘤标本全基因CNV显示,11例标本中有10例都存在数量不等CNV,其中9例标本均存在病理性CNV。CNV的数量与肿瘤病例分期具有正相关性趋势。同时,CNV引起的Loss区域明显多于Gain区域,发生缺失的基因总数及OMIM基因数也较发生复制的基因多。在2个以上的标本中均出现相同或类似CNV的区域包括14q, 1p,9q,16p及Xq。基因功能分析显示变异的基因具有传导细胞间信号,调控组织器官生长发育,基因转录后修饰及蛋白修饰等功能,参与编码Tight Junction, ILK等经典信号通路中关键蛋白。变异基因之间也存在相互作用,在神经性疾病,器官损伤或畸形,DNA损伤修复机制异常及肿瘤和信号传导方面发挥主要作用。
综上,BPA、DEHP及E2可促进SK-N-SH细胞体外增殖、多药耐药性和侵袭转移特性的提高,ER依赖途径及PI3K/Akt信号通路可能是介导BPA、DEHP及E2作用的主要机制之一。CNV亦普遍存在于中国NB患者中,14q,1p,9q,16p及Xq可能是NB相关的关键CNV区域。CNV引起基因功能及信号通路活性异常,与变异基因之间相互作用共同介导了NB病理过程。因此,EED是促进NB发生发展的重要环境因素而CNV则是引发NB的重要遗传机制。
Neuroblastoma (NB) derives from neural crest cells which can not be differentiated normally during embryo development. It is the most common extracranial tumor in children. Clinically NB is characterized by its rapid growth, susceptibility to multidrug resistance and metastasis. Both genetic and environmental factors may contribute to neuroblastoma oncogenesis. However, little is known about risk factors and their mechanisms that induce NB. Exploring risk factors and their mechanisms related to NB will improve NB early diagnosis and clinical therapies as well as the prognosis. Environmental endocrine disruptors (EED) are a large number of either natural or man-made exogenous compounds. Most of them mainly mimick the action of natural hormone estrogens such as 17β-estradiol (E2) in the body. With aggravation of global environmental problems, there have been growing concerns on relationships between daily exposure to EED and human health. Accumulating evidence suggested that EED are causative factors for multiple human diseases including birth defects, neurological disorders and metabolism disorders as well as adult malignant tumors such as breast cancer, prostate cancer, and etc. However, no studies is focused on the relationship between EED and children solid malignant tumors now. It is necessary to investigate the role of EED on pediatric diseases including cancer since they are more susceptible to adverse effects of EED exposure. Copy number variant (CNV) is a novel structural variation in human chromosomes. CNV is highly associated with various human diseases although it widely exists in the normal population. It is reported that CNV also contributes to the NB's initiation. However, the relationship between NB and CNV in Chinese patients is still unclear. Therefore, it is necessary to explore genetic mechanisms of NB in Chinese population, which will be useful for NB's early diagnosis, therapies and prognosis evaluation.
In the current study, we investigate the effects of biphenol A (BPA) and di(2-ethylhexyl) phthalate (DEHP) as well as E2 on human SK-N-SH neuroblastoma cell line in vitro. The number of variable cells was detected by using cell proliferation assay. The percentage of cells in both S and G2-M phases was tested with cell flow cytometry analysis. Also, caspase-3 activation was determined by western blotting. Moreover, cell survival rate and its sensitivity to the chemotherapy were detected by using cell cytotoxicity assay. MDR1, MRP1, MVP and p53 mRNA and protein expression were investigated by using both real-time PCR and western blotting. Furthermore, the capacity of cell migration and invasion were detected by cell migration and invasion assay. MMP-2, MMP-9 and TIMP-2 RNA and protein expression were determined by using both real-time PCR and western blotting respectively. Then cells were pretreated with estrogen receptor (ER) antagonist ICI 182,780 or phosphoinositide 3-kinase (PI3K) specific inhibitor LY294002 to see whether these agents can block EED-induced effects on NB cells with the same methods described above. In addition,11 NB samples from Chinese Han patients were collected and the whole genome CNV was detected in these samples by using Agilent 244k array comparative genomic hybridization (aCGH). Data were analysized by DNA analytics, Nexus Copy Number and Ingeunity pathway analysis software to explore NB related CNVs, recurrent CNVs and phenotype dependent CNVs as well as their molecular mehchanisms.
After 24 h 0.1μM BPA,50μM DEHP or 10μM E2 treatments, the number of variable cells was significantly increased and the cell activity was elevated (P< 0.001 vs. Control). This trend maintained to 120 h. The percentage of cells in S and G2-M phase obviously increased in group treated with BPA, DEHP or E2 (P< 0.001 vs. Control). However, no significant change was observed in caspase-3 expression (P> 0.05). In the cell cytotoxicity assay, BPA, DEHP or E2-treated SK-N-SH cells had a higher cell survival rate than the control (P< 0.01). Significantly elevated mRNA and protein expression of MDR1, MRP and MVP gene were detected in groups treated with BPA, DEHP or E2 (P< 0.01 vs. Control) but decreased mRNA and protein expression of p53 were detected in the BPA, DEHP or E2 group (P< 0.05 vs. Control). Moreover, the cell migration and invasion assay showed enhanced capacity of cell migration and invasion in the BPA, DEHP or E2 group (P< 0.001 vs. Control). Significantly elevated mRNA and protein expression of MMP-2 and MMP-9 gene were detected in groups treated with BPA, DEHP or E2 (P< 0.001 vs. Control) but decreased mRNA and protein expression of TIMP-2 were also detected in the BPA, DEHP or E2 group (P< 0.01 or P< 0.05 vs. Control). Furthermore, cells pretreated with ICI182,780 or LY294002 showed lower cell growth rate, lower percentage of cell in S and G2-M phase but higher sensitivity to chemotherapy compared with BPA, DEHP or E2-only treated groups (P< 0.001 or P< 0.01). Lower mRNA and protein expression of MDR1, MRP1,and MVP as well as higher mRNA and protein expression of p53 were detected in the groups treated both ICI182,780 or LY294002 and EED compared with BPA, DEHP or E2-only treated groups (P< 0.01). The capacity of cell migration and invasion can not be enhanced by BPA, DEHP or E2 after pretreatment with ICI182,780 or LY294002. Lower mRNA and protein expression of MMP-2 and MMP-9 as well as higher mRNA and protein expression of TIMP-2 were observed in the groups treated both ICI 182,780 or LY294002 and EED compared with BPA, DEHP or E2-only treated groups (P< 0.001 or P< 0.05). Akt (Ser473) phosphorylation level was enhanced by BPA, DEHP or E2 treatement compared with the control group but not in ICI182,780 or LY294002 pretreated groups (P<0.01).
Furthermore, various CNVs were observed in 10/11 samples and pathogenic CNVs also existed in 9/10 samples. CNV amounts could be dependent on NB's phathological grades. CNV- induced loss was significantly more than CNV-induced gain.14q, 1p,9q,16p and Xq could be recurrent region related to NB. Genes in CNV regions contributed to cell to cell transaction, tissue development, post-transcription modification and protein folds. These genes were involved in Tight Junction, and ILK pathway. The action among these genes contributed to neurological disease, organ injury and cancer.
In summary, BPA, DEHP and E2 can promote SK-N-SH cell proliferation, multidrug resistance, migration and invasion in vitro. ER dependent and PI3K/Akt pathway may be involved. CNV exists widely in Chinese Han NB patients,14q, 1p, 9q,16p and Xq may be key regions to NB pathogenesis. Multiple mechanisms may be involved in NB oncogenesis.
引文
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