EBV/LMP1介导SPLUNC1调节miR-141-PTEN通路影响鼻咽癌细胞增殖与凋亡的分子机制
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摘要
[研究背景]
研究发现DNA肿瘤病毒中有些病毒的编码产物能与宿主细胞内抑制细胞生长和促进细胞分化的蛋白结合,使其失活而发挥致瘤作用。EBV(Epstein-Barr virus, EBV)可能也具有此作用。我室克隆得到的鼻咽组织相关的特异性表达基因(nashopharynix associated specific, NASG),即短腭、肺及鼻咽上皮克隆(Short Palate, Lung and Nasal epithelium Clone1, SPLUNC1)在鼻咽癌(nasopharyngeal carcinoma, NPC)组织及细胞系中表达下调,是一个潜在的鼻咽癌抑瘤基因,初步研究发现SPLUNC1能促使感染EBV的细胞裂解,启动补体途径和抗体依赖细胞介导的细胞毒(antibody-dependent cell-mediatedcytotoxicity, ADCC)作用对EBV进行清除,并能通过抑制EBV关键基因潜伏膜蛋白1(Latent membrane protein1, LMP1)的表达降低EBV的致瘤能力。miRNA芯片筛查发现miR-141能受到SPLUNC1的调控。生物信息学分析显示第10号染色体丢失的磷酸酶及张力蛋白同源的基因(phosphatase and tensin homolog deleted on chromosome ten, PTEN)为miR-141的靶基因。那么SPLUNC1能否通过miR-141调控PTEN及其下游信号通路呢?EBV对SPLUNC1的表达会有影响吗?
本课题拟在前期研究的基础上,对EBV与SPLUNC1之间的相互影响进行探讨,并明确SPLUNC1是否通过miR-141调控了PTEN及其下游丝苏氨酸激酶(serine-threonine kinase, Akt)信号通路,探索EBV整合入细胞后是否影响SPLUNC1及受其调控的miR-141-PTEN-Akt信号通路,以期为EBV的致瘤机制和SPLUNC1发挥抑瘤作用的信号通路增添新的一笔。
[SPLUNC1抑制整合入细胞内的EBV关键基因表达的同时SPLUNC1自身表达受损]
由于EBV不能直接感染上皮细胞,因此我们采用共培养的方式使细胞感染EBV。将构建的过表达SPLUNC1的HNE2细胞和空白对昭HNE2/GFP与B95-8细胞(能产EBV)共培养24小时,随后采用补体激活的细胞毒实验去除B95-8细胞并通过扩增猿猴特异性基因CAJA-DRBI明确B95-8细胞是否清除干净；结果显示：整合入过表达SPLUNC1的细胞内的EBV关键基因EBER、BZLF、LMP1表达明显低于空载体组；HNE2/SPLUNC1细胞在第1天细胞接触EBV时,细胞会应激性地增加SPLUNC1的表达以抵抗病毒的侵入,但是在病毒整合入细胞后第2天、3天、5天、7天、9天,细胞内SPLUNC1的表达会逐渐降低,并不能恢复到细胞感染病毒前水平。以上结果证实SPLUNC1能抑制整合入细胞内的EBV关键基因的表达,与此同时EBV整合入细胞后也能抑制SPLUNC1的表达。
[SPLUNC1通过miR-141调控PTEN-Akt信号通路影响NPC细胞的增殖和凋亡]
miRNA芯片显示miR-141受到了SPLUNC1的调控。我们通过实验证实鼻咽癌细胞过表达SPLUNC1能降低miR-141的表达,siRNA瞬时干扰SPLUNC1的表达后,miR-141表达明显增高；且miR-141的表达与细胞分化程度和恶性程度相关。通过显微切割获得纯化后的NPC组织和正常鼻咽上皮(normal nasopharyngeal epithelium,NPE)组织,qRT-PCR检测发现SPLUNC1在NPC组织中的表达明显比NPE组织要低,而miR-141在NPC组织中的表达明显比NPE组织要高,两者的表达呈现负相关。
生物信息学分析显示PTEN为miR-141的靶基因。于是我们将miR-141的mimics及inhibitors转染NP69细胞和NPC细胞系,检测PTEN的表达情况。结果显示miR-141的mimics能显著减少PTEN的表达,而在转染miR-141的inhibitor后细胞内PTEN的表达明显增加；检测NPE和NPC组织中PTEN的表达时,也显示PTEN在NPC组织中的表达明显低于NPE, NPC组织中PTEN和miR-141的表达呈负相关。
既然miR-141受到SPLUNC1的调控,PTEN是miR-141的靶基因,那么SPLUNC1能否调控PTEN的表达。通过过表达SPLUNC1和加入全反式维甲酸来增加NPC细胞SPLUNC1的表达,证实SPLUNC1表达增加后,PTEN的表达也增加了；同时免疫荧光检测显示SPLUNC1并不影响PTEN在细胞内的分布。干扰SPLUNC1的表达又可明显下调PTEN的表达。随后在过表达SPLUNC1的NPC细胞系中转入miR-141的mimics,检测发现miR-141的mimics可部分抑制SPLUNC1上调PTEN的表达。其结果说明SPLUNC1除了通过miR-141影响PTEN外,还可能通过其它通路来影响PTEN的表达。
PTEN参与细胞增殖和凋亡的信号通路主要是通过Akt信号通路来发挥作用。因此我们检测了NPC细胞过表达SPLUNC1后对Akt信号通路的影响,发现过表达SPLUNC1能明显抑制p-Akt的表达,干扰SPLUNC1后p-Akt的表达则明显增加,说明SPLUNC1能通过PTEN影响Akt的磷酸化和活化。通过采用PTEN的抑制剂BPV处理过表达SPLUNC1的细胞系,证实SPLUNC1还能够部分拮抗PTEN的抑制剂BPV对细胞Akt信号通路的影响。
随后我们又通过流式细胞术证实过表达SPLUNC1能将细胞周期阻滞在G1期；SPLUNC1能上调p27蛋白的表达,下调cyclin D和cyclin E、CDK2蛋白的表达；同时还发现SPLUNC1能拮抗BPV的促增殖和抗凋亡作用。裸鼠成瘤实验进一步证实过表达SPLUNC1能通过调控PTEN-Akt通路抑制细胞增殖和诱导细胞凋亡,进而抑制裸鼠移植瘤的形成。
[EBV/LMP1与SPLUNC1相互影响共同调控miR-141-PTEN-Akt信号通路]
LMP1被广泛认为是EBV基因组中的重要致瘤基因。通过应用过表达LMP1的正常鼻咽上皮细胞系NP69-LMP1,发现细胞内LMP1高表达时SPLUNC1的表达极低,miR-141的表达则较高,引起PTEN表达降低而激活Akt信号通路。但NP69-LMP1细胞过表达SPLUNC1后,LMP1的表达明显被抑制,并上调PTEN的表达而抑制Akt通路的激活。结果说明LMP1能通过抑制：SPLUNC1进而影响miR-141-PTEN-Akt通路,但恢复细胞内SPLUNC1的表达又能抑制LMP1的表达,并增加PTEN的表达,从而导致下游Akt通路的失活。
综上所述,我们发现SPLUNC1能与EBV存在相互影响；SPLUNC1可通过下调miR-141上调PTEN的表达,进而负性调控Akt信号转导通路抑制NPC细胞的增殖,诱导NPC细胞凋亡；EBV/LMP1可通过抑制SPLUNC1的表达影响miR-141-PTEN-Akt信号通路。因此我们提出EBV DNA整合于细胞染色体可能导致了EBV与宿主细胞关键基因相互影响,进而影响了宿主细胞的信号通路,这可能为EBV的致瘤机制之一。
[Background]
It has been reported that some viral proteins in DNA tumor virus such as EBV/HBV can combine with the cell proteins, in which the proteins inhibiting cell proliferation and promoting cell differentiation in the host cell should be inactivated and the host cell can be resulted in malignant transformed. We previously identified a short palate, lung and nasal epithelium clone gene (SPLUNC1), which was a tissue-specific gene of nasopharyngeal epithelia. We also found that SPLUNC1was down-regulated in nasopharyngeal carcinoma (NPC) and proposed that SPLUNC1was a tumor suppression gene candidate. Our previous studies showed that SPLUNC1could accelerate the lysis and apoptosis of EBV infected cells and initiated antibody-dependent cell-mediated cytotoxicity, which participated in clearance process of EBV and also decreased the expression of EBV encoded Latent membrane protein1(LMP1) and consequently inhibited the tumorgencity of EBV. From the differential analysis of the microRNA (miRNA) expression profiles of over-expressed SPLUNC1NPC cells, miR-141expression could be regulated by SPLUNC1in NPC cells. Bioinformatics analysis revealed that probably phosphatase and tensin homolog deleted on chromosome ten (PTEN) was one of the target genes of miR-141. And then whether PTEN and its downstream molecules could be regulated by miR-141and whether EBV have effects on the expression of SPLUNC1is yet unknown.
In this study, we have indentified SPLUNC1as a negative regulatory molecule of LMP1, and the expression of SPLUNC1also can be down-regulated by EBV infection in NPC cells. We have also showed that SPLUNC1can regulate PTEN and Akt signaling pathway through targeting miR-141and that LMP1could regulate the Akt signaling pathway by down-regulating SPLUNC1.
[The carcinogenesis of EBV can been inhibited by SPLUNCl,in turn, EBV also suppresed the expression of SPLUNC1in NPC.]
We employed co-culture system between B cells and NPC cells to obtain EBV-infected NPC cells and detected the expression level of key genes of EBV in NPC cells by RT-PCR. The results revealed that SPLUNC1could inhibit the expression of EBV related-genes, such as EBER, BZLF and LMP1. We also found that SPLUNC1increased responsively one day after that SPLUNC1-overexpressing HNE2cells contacted with EBV. However, the mRNA level of SPLUNC1decreased gradually after2days. The abovementioned results indicate that SPLUNC1can inhibit the expression of EBV key genes, and also the level of SPLUNC can be regulated by EBV infection.
[SPLUNC1regulates NPC cell proliferation or apoptosis through miR-141-PTEN-Akt pathway]
Previous analysis of miRNA expression profiles showed that miR-141was down-regulated by SPLUNC1. To confirm the result, we detected the expression of miR-141after SPLUNC1was over-expressed or knocked down. The results showed that SPLUNC1actually could decrease the expression of miR-141. We also used qRT-PCR to measure miR-141and SPLUNC1mRNA levels in NPC tissue samples. miR-141showed increased expression levels in NPC tissues compared with nasopharyngeal epithelial tissues, whereas SPLUNC1showed an inverse expression pattern. And the expression of miR-141negatively correlated with SPLUNC1.
Bioinformatics software predicted that miR-141could bind to the3' untranslated region (UTR) of PTEN. We also demonstrated that the expression of PTEN could be down-regulated by miR-141. Meanwhile, expression levels of PTEN were also found to be down-regulated in NPC tissues in contrast to nasopharyngeal epithelial tissues.
Given abovementioned results, we explored the expression of PTEN in SPLUNC1-over-expressed NPC cells and NPC cells treated with ATAR. We demonstrated that SPLUNC1could increase the expression of PTEN, but not have effects on localization of PTEN. These results were furtherly confirmed by the knockdown of SPLUNC1. To determine whether SPLUNC1could regulate the expression of PTEN through targeting miR-141, we assessed the expression of PTEN in SPLUNC1-overexpressed NPC cells, which were transfected with the miR-141mimics. The result showed that the up-regulation of PTEN by SPLUNC1was partially involved with miR-141.
Considering that PTEN be participated in the signaling pathway of proliferation and apoptosis mainly through regulating Akt pathway, we assessed the activation of Akt in SPLUNC1-overexpressed NPC cells and revealed that Akt phosphorylation were inhibited by SPLUNC1. The downstream molecule, phosphorylated MDM2, was also inhibited by SPLUNC1, but GSK3β and total MDM2. Then we used the PTEN inhibitor BVP and found that the activity of BVP was partly inhibited by SPLUNC1.
Next we detected that SPLUNC1can result in tumor cell growth arrest at the G1to S transition of the cell cycle, increase critical cell cycle regulatory proteins p27expression significantly and decrease the expression of cyclin D1, D2, D3, E2, and cyclin-dependent kinase2(CDK2). We revealed that SPLUNC1could efficiently inhibit the BVP-induced proliferation. We also observed that SPLUNC1could inhibit tumorgenesis through PTEN-Akt pathway in vivo.
[SPLUNC1is involvement in the miR-141-PTEN-Akt pathway and its expression interference by EBV/LMP1]
To clarify the mechanism that SPLUNC1was down-regulated by EBV, We determined the effects of EBV major tumorgenetic gene LMP1on the expression of SPLUNC1. The results showed that LMP1could inhibit the expression of SPLUNC1, up-regulate the level of miR141. And then PTEN expression was decreased and the Akt pathway was activated. However, when SPLUNC1was re-expressed in the LMP1-overexpressed cells, LMP1expression was inhibited and PTEN was increased again.
In conclusion, the carcinogenesis of EBV could be inhibited by SPLUNC1, and in turn, EBV and its major tumorgenetic gene LMP1also could suppress the expression of SPLUNC1in NPC cells. SPLUNC1could regulate NPC cell proliferation or apoptosis through PTEN-Akt pathway by targeting miR-141. Thus EBV/LMP1regulated cell progression and apoptosis probably through SPLUNC1and its downstream molecules.
研究发现DNA肿瘤病毒中有些病毒的编码产物能与宿主细胞内抑制细胞生长和促进细胞分化的蛋白结合,使其失活而发挥致瘤作用。EBV(Epstein-Barr virus, EBV)可能也具有此作用。我室克隆得到的鼻咽组织相关的特异性表达基因(nashopharynix associated specific, NASG),即短腭、肺及鼻咽上皮克隆(Short Palate, Lung and Nasal epithelium Clone1, SPLUNC1)在鼻咽癌(nasopharyngeal carcinoma, NPC)组织及细胞系中表达下调,是一个潜在的鼻咽癌抑瘤基因,初步研究发现SPLUNC1能促使感染EBV的细胞裂解,启动补体途径和抗体依赖细胞介导的细胞毒(antibody-dependent cell-mediatedcytotoxicity, ADCC)作用对EBV进行清除,并能通过抑制EBV关键基因潜伏膜蛋白1(Latent membrane protein1, LMP1)的表达降低EBV的致瘤能力。miRNA芯片筛查发现miR-141能受到SPLUNC1的调控。生物信息学分析显示第10号染色体丢失的磷酸酶及张力蛋白同源的基因(phosphatase and tensin homolog deleted on chromosome ten, PTEN)为miR-141的靶基因。那么SPLUNC1能否通过miR-141调控PTEN及其下游信号通路呢?EBV对SPLUNC1的表达会有影响吗?
本课题拟在前期研究的基础上,对EBV与SPLUNC1之间的相互影响进行探讨,并明确SPLUNC1是否通过miR-141调控了PTEN及其下游丝苏氨酸激酶(serine-threonine kinase, Akt)信号通路,探索EBV整合入细胞后是否影响SPLUNC1及受其调控的miR-141-PTEN-Akt信号通路,以期为EBV的致瘤机制和SPLUNC1发挥抑瘤作用的信号通路增添新的一笔。
[SPLUNC1抑制整合入细胞内的EBV关键基因表达的同时SPLUNC1自身表达受损]
由于EBV不能直接感染上皮细胞,因此我们采用共培养的方式使细胞感染EBV。将构建的过表达SPLUNC1的HNE2细胞和空白对昭HNE2/GFP与B95-8细胞(能产EBV)共培养24小时,随后采用补体激活的细胞毒实验去除B95-8细胞并通过扩增猿猴特异性基因CAJA-DRBI明确B95-8细胞是否清除干净；结果显示：整合入过表达SPLUNC1的细胞内的EBV关键基因EBER、BZLF、LMP1表达明显低于空载体组；HNE2/SPLUNC1细胞在第1天细胞接触EBV时,细胞会应激性地增加SPLUNC1的表达以抵抗病毒的侵入,但是在病毒整合入细胞后第2天、3天、5天、7天、9天,细胞内SPLUNC1的表达会逐渐降低,并不能恢复到细胞感染病毒前水平。以上结果证实SPLUNC1能抑制整合入细胞内的EBV关键基因的表达,与此同时EBV整合入细胞后也能抑制SPLUNC1的表达。
[SPLUNC1通过miR-141调控PTEN-Akt信号通路影响NPC细胞的增殖和凋亡]
miRNA芯片显示miR-141受到了SPLUNC1的调控。我们通过实验证实鼻咽癌细胞过表达SPLUNC1能降低miR-141的表达,siRNA瞬时干扰SPLUNC1的表达后,miR-141表达明显增高；且miR-141的表达与细胞分化程度和恶性程度相关。通过显微切割获得纯化后的NPC组织和正常鼻咽上皮(normal nasopharyngeal epithelium,NPE)组织,qRT-PCR检测发现SPLUNC1在NPC组织中的表达明显比NPE组织要低,而miR-141在NPC组织中的表达明显比NPE组织要高,两者的表达呈现负相关。
生物信息学分析显示PTEN为miR-141的靶基因。于是我们将miR-141的mimics及inhibitors转染NP69细胞和NPC细胞系,检测PTEN的表达情况。结果显示miR-141的mimics能显著减少PTEN的表达,而在转染miR-141的inhibitor后细胞内PTEN的表达明显增加；检测NPE和NPC组织中PTEN的表达时,也显示PTEN在NPC组织中的表达明显低于NPE, NPC组织中PTEN和miR-141的表达呈负相关。
既然miR-141受到SPLUNC1的调控,PTEN是miR-141的靶基因,那么SPLUNC1能否调控PTEN的表达。通过过表达SPLUNC1和加入全反式维甲酸来增加NPC细胞SPLUNC1的表达,证实SPLUNC1表达增加后,PTEN的表达也增加了；同时免疫荧光检测显示SPLUNC1并不影响PTEN在细胞内的分布。干扰SPLUNC1的表达又可明显下调PTEN的表达。随后在过表达SPLUNC1的NPC细胞系中转入miR-141的mimics,检测发现miR-141的mimics可部分抑制SPLUNC1上调PTEN的表达。其结果说明SPLUNC1除了通过miR-141影响PTEN外,还可能通过其它通路来影响PTEN的表达。
PTEN参与细胞增殖和凋亡的信号通路主要是通过Akt信号通路来发挥作用。因此我们检测了NPC细胞过表达SPLUNC1后对Akt信号通路的影响,发现过表达SPLUNC1能明显抑制p-Akt的表达,干扰SPLUNC1后p-Akt的表达则明显增加,说明SPLUNC1能通过PTEN影响Akt的磷酸化和活化。通过采用PTEN的抑制剂BPV处理过表达SPLUNC1的细胞系,证实SPLUNC1还能够部分拮抗PTEN的抑制剂BPV对细胞Akt信号通路的影响。
随后我们又通过流式细胞术证实过表达SPLUNC1能将细胞周期阻滞在G1期；SPLUNC1能上调p27蛋白的表达,下调cyclin D和cyclin E、CDK2蛋白的表达；同时还发现SPLUNC1能拮抗BPV的促增殖和抗凋亡作用。裸鼠成瘤实验进一步证实过表达SPLUNC1能通过调控PTEN-Akt通路抑制细胞增殖和诱导细胞凋亡,进而抑制裸鼠移植瘤的形成。
[EBV/LMP1与SPLUNC1相互影响共同调控miR-141-PTEN-Akt信号通路]
LMP1被广泛认为是EBV基因组中的重要致瘤基因。通过应用过表达LMP1的正常鼻咽上皮细胞系NP69-LMP1,发现细胞内LMP1高表达时SPLUNC1的表达极低,miR-141的表达则较高,引起PTEN表达降低而激活Akt信号通路。但NP69-LMP1细胞过表达SPLUNC1后,LMP1的表达明显被抑制,并上调PTEN的表达而抑制Akt通路的激活。结果说明LMP1能通过抑制：SPLUNC1进而影响miR-141-PTEN-Akt通路,但恢复细胞内SPLUNC1的表达又能抑制LMP1的表达,并增加PTEN的表达,从而导致下游Akt通路的失活。
综上所述,我们发现SPLUNC1能与EBV存在相互影响；SPLUNC1可通过下调miR-141上调PTEN的表达,进而负性调控Akt信号转导通路抑制NPC细胞的增殖,诱导NPC细胞凋亡；EBV/LMP1可通过抑制SPLUNC1的表达影响miR-141-PTEN-Akt信号通路。因此我们提出EBV DNA整合于细胞染色体可能导致了EBV与宿主细胞关键基因相互影响,进而影响了宿主细胞的信号通路,这可能为EBV的致瘤机制之一。
[Background]
It has been reported that some viral proteins in DNA tumor virus such as EBV/HBV can combine with the cell proteins, in which the proteins inhibiting cell proliferation and promoting cell differentiation in the host cell should be inactivated and the host cell can be resulted in malignant transformed. We previously identified a short palate, lung and nasal epithelium clone gene (SPLUNC1), which was a tissue-specific gene of nasopharyngeal epithelia. We also found that SPLUNC1was down-regulated in nasopharyngeal carcinoma (NPC) and proposed that SPLUNC1was a tumor suppression gene candidate. Our previous studies showed that SPLUNC1could accelerate the lysis and apoptosis of EBV infected cells and initiated antibody-dependent cell-mediated cytotoxicity, which participated in clearance process of EBV and also decreased the expression of EBV encoded Latent membrane protein1(LMP1) and consequently inhibited the tumorgencity of EBV. From the differential analysis of the microRNA (miRNA) expression profiles of over-expressed SPLUNC1NPC cells, miR-141expression could be regulated by SPLUNC1in NPC cells. Bioinformatics analysis revealed that probably phosphatase and tensin homolog deleted on chromosome ten (PTEN) was one of the target genes of miR-141. And then whether PTEN and its downstream molecules could be regulated by miR-141and whether EBV have effects on the expression of SPLUNC1is yet unknown.
In this study, we have indentified SPLUNC1as a negative regulatory molecule of LMP1, and the expression of SPLUNC1also can be down-regulated by EBV infection in NPC cells. We have also showed that SPLUNC1can regulate PTEN and Akt signaling pathway through targeting miR-141and that LMP1could regulate the Akt signaling pathway by down-regulating SPLUNC1.
[The carcinogenesis of EBV can been inhibited by SPLUNCl,in turn, EBV also suppresed the expression of SPLUNC1in NPC.]
We employed co-culture system between B cells and NPC cells to obtain EBV-infected NPC cells and detected the expression level of key genes of EBV in NPC cells by RT-PCR. The results revealed that SPLUNC1could inhibit the expression of EBV related-genes, such as EBER, BZLF and LMP1. We also found that SPLUNC1increased responsively one day after that SPLUNC1-overexpressing HNE2cells contacted with EBV. However, the mRNA level of SPLUNC1decreased gradually after2days. The abovementioned results indicate that SPLUNC1can inhibit the expression of EBV key genes, and also the level of SPLUNC can be regulated by EBV infection.
[SPLUNC1regulates NPC cell proliferation or apoptosis through miR-141-PTEN-Akt pathway]
Previous analysis of miRNA expression profiles showed that miR-141was down-regulated by SPLUNC1. To confirm the result, we detected the expression of miR-141after SPLUNC1was over-expressed or knocked down. The results showed that SPLUNC1actually could decrease the expression of miR-141. We also used qRT-PCR to measure miR-141and SPLUNC1mRNA levels in NPC tissue samples. miR-141showed increased expression levels in NPC tissues compared with nasopharyngeal epithelial tissues, whereas SPLUNC1showed an inverse expression pattern. And the expression of miR-141negatively correlated with SPLUNC1.
Bioinformatics software predicted that miR-141could bind to the3' untranslated region (UTR) of PTEN. We also demonstrated that the expression of PTEN could be down-regulated by miR-141. Meanwhile, expression levels of PTEN were also found to be down-regulated in NPC tissues in contrast to nasopharyngeal epithelial tissues.
Given abovementioned results, we explored the expression of PTEN in SPLUNC1-over-expressed NPC cells and NPC cells treated with ATAR. We demonstrated that SPLUNC1could increase the expression of PTEN, but not have effects on localization of PTEN. These results were furtherly confirmed by the knockdown of SPLUNC1. To determine whether SPLUNC1could regulate the expression of PTEN through targeting miR-141, we assessed the expression of PTEN in SPLUNC1-overexpressed NPC cells, which were transfected with the miR-141mimics. The result showed that the up-regulation of PTEN by SPLUNC1was partially involved with miR-141.
Considering that PTEN be participated in the signaling pathway of proliferation and apoptosis mainly through regulating Akt pathway, we assessed the activation of Akt in SPLUNC1-overexpressed NPC cells and revealed that Akt phosphorylation were inhibited by SPLUNC1. The downstream molecule, phosphorylated MDM2, was also inhibited by SPLUNC1, but GSK3β and total MDM2. Then we used the PTEN inhibitor BVP and found that the activity of BVP was partly inhibited by SPLUNC1.
Next we detected that SPLUNC1can result in tumor cell growth arrest at the G1to S transition of the cell cycle, increase critical cell cycle regulatory proteins p27expression significantly and decrease the expression of cyclin D1, D2, D3, E2, and cyclin-dependent kinase2(CDK2). We revealed that SPLUNC1could efficiently inhibit the BVP-induced proliferation. We also observed that SPLUNC1could inhibit tumorgenesis through PTEN-Akt pathway in vivo.
[SPLUNC1is involvement in the miR-141-PTEN-Akt pathway and its expression interference by EBV/LMP1]
To clarify the mechanism that SPLUNC1was down-regulated by EBV, We determined the effects of EBV major tumorgenetic gene LMP1on the expression of SPLUNC1. The results showed that LMP1could inhibit the expression of SPLUNC1, up-regulate the level of miR141. And then PTEN expression was decreased and the Akt pathway was activated. However, when SPLUNC1was re-expressed in the LMP1-overexpressed cells, LMP1expression was inhibited and PTEN was increased again.
In conclusion, the carcinogenesis of EBV could be inhibited by SPLUNC1, and in turn, EBV and its major tumorgenetic gene LMP1also could suppress the expression of SPLUNC1in NPC cells. SPLUNC1could regulate NPC cell proliferation or apoptosis through PTEN-Akt pathway by targeting miR-141. Thus EBV/LMP1regulated cell progression and apoptosis probably through SPLUNC1and its downstream molecules.
引文
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