双功能基因APE1与miRNAs相互调控介导骨肉瘤放疗敏感性的机制研究
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摘要
研究背景
放疗是骨肉瘤治疗的重要手段之一。放疗抵抗是影响患者疗效和预后的关键因素。前期研究表明，脱嘌呤脱嘧啶核酸内切酶(APE1)具有DNA损伤修复和氧化还原双功能，在骨肉瘤放疗抵抗中发挥核心调节作用，敲低APE1能显著增强骨肉瘤放疗敏感性。然而其介导骨肉瘤放疗敏感性的机制不清。MicroRNAs(miRNAs)能在转录后水平负性调节靶基因的表达，对肿瘤发生、细胞凋亡和应激反应具有重要的调控作用，为研究和发现APE1基因调控通路和相互作用蛋白，阐明APE1介导的骨肉瘤放疗敏感性的机制提供了新的研究方向。此外，miRNAs作为内源性的小分子，在调控肿瘤细胞放疗敏感性中具有明显的优势，为骨肉瘤的分子靶向治疗提供了新的策略。晚近的研究陆续报道了p53等肿瘤关键基因相互作用的miRNAs，但与APE1相互作用的miRNAs国内外鲜见报道。
研究目的
本研究旨在鉴定和研究APE1相互作用miRNAs及其在骨肉瘤放疗抵抗中的作用。
研究方法
1.通过生物信息学、miRNAs芯片和qRT-PCR筛选鉴定APE1-knockdown骨肉瘤细胞的miRNAs差异表达谱，分析其靶基因涉及的细胞生物学功能和信号通路。
2.通过生物信息学、 EMSA、 RNAi和qRT-PCR实验初步验证APE1-转录因子-miRNAs的作用关系。
3.利用生物信息学、双荧光素酶报告基因实验、AP位点切除实验及EMSA鉴定miRNAs对APE1的靶向调控作用，在细胞和动物水平验证miRNAs靶向抑制APE1对骨肉瘤细胞放疗后增殖和凋亡的影响。
研究结果
1. APE1-knockdown骨肉瘤细胞中有13个miRNAs显著变化，其中miR-451、miR-1290、miR-765、miR-483-5p、miR-513a-5p、miR-129-5p和miR-31上调，miR-29b、miR-197、let-7b、miR-324-5p、let-7i和miR-484下调，其靶基因分别涉及TGF-β、Wnt、MAPK和p53等细胞信号通路，与细胞生存、增殖、粘附和肿瘤发生有关。
2.生物信息学分析提示，转录因子与miRNAs启动子区有结合位点； APE1-knockdown后可下调NF-κB的DNA结合活性，而抑制NF-κB可下调let-7b和let-7i的表达。
3. miR-513a-5p和miR-765能与APE1mRNA3’UTR区结合抑制APE1蛋白表达；miR-513a-5p可抑制APE1的AP位点剪切活性和NF-κB、p53、AP-1的DNA结合活性；在细胞和动物水平给予X射线照射后，过表达miR-513a-5p可增加凋亡，抑制骨肉瘤细胞增殖和Bcl-2的表达。
结论
1. APE1能直接影响骨肉瘤细胞miRNAs的表达；生物信息学分析表明APE1通过调控miRNAs可能影响下游靶基因的表达，参与肿瘤发生、细胞生存、增殖、粘附等生物学过程和多个信号通路，与骨肉瘤的发生发展、侵袭转移密切相关。
2.生物信息学分析表明APE1-转录因子-miRNAs具有相互作用；初步证实APE1通过调控NF-κB的DNA结合活性可能调控let-7b和let-7i的表达。
3.首次证实APE1是miR-513a-5p和miR-765的靶基因，二者可靶向结合APE1mRNA3’UTR区抑制APE1蛋白表达。
4. miR-513a-5p通过抑制APE1的DNA损伤修复和氧化还原双功能，抑制骨肉瘤细胞增殖，诱导细胞凋亡，在细胞及动物水平均能增加骨肉瘤的放疗敏感性。
Background
Radiation therapy is one of the most commonly used clinical treatments forosteosarcoma. The resistance of osteosarcoma to radiotherapy remains an important elementinterfering with therapeutic effect and prognosis. Apurinic/apyrimidinic endonuclease/redoxeffector factor (APE1), with dual functions of both DNA repair and redox activity, is the keygene in regulating radioresistance in osteosarcoma. Previous studies have shown thatknocking down APE1expression by siRNA significantly sensitized human osteosarcomacells to radiation. Although the essential function of APE1has been confirmed, knowledge ofits regulation or interactome in mediating radioresistance is still scanty. Through suppressinggene expression by binding to the3’-untranslated region (3’-UTR) of target genes,microRNAs (miRNAs) play a large range of biological roles in tumorigenesis, apoptosis andstress reactions. We postulated that miRNAs may play important roles in APE1regulatorynetwork and interactome. It might also provide a plausible explanation to the APE1-dependent radioresistance in osteosarcoma. Additionally, as a class of endogenous singlestranded non-coding RNA, miRNAs has been considered to be a more effective andpromising target to increase radiosensitivity of cancer. Recently, studies have reported somemiRNAs interaction with many important tumor-associated genes such as p53. However, todate, little report concerning the interaction between APE1and miRNAs are available in thecurrent scientific literature.
Objective
To identify the interaction network between APE1and miRNAs in osteosarcoma andinvestigate the APE1-dependent modulation of radiation sensitivity by miRNAs in humanosteosarcoma.
Materials and Methods
1. Microarray and qRT-PCR were used to confirm the change of microRNAs (miRNAs) in APE1-knockdown osteosarcoma HOS cells followed by analysis with comprehensivebioinformatics-based analysis.
2. APE1-transcription factors-miRNAs network was predicted and identified bybioinformatics-based analysis, EMSA, RNAi and qRT-PCR in osteosarcoma HOS cells.
3. Then we used luciferase report gene vectors, Western blot, AP site activity assay andEMSA to identify miRNAs are the targeted regulation factor of APE1. At last, we generatedmiRNA overexpression lentiviral vector and used cell proliferation assay, cell apoptosis,immunohistochemisty, Western blot and qRT-PCR to investigate the miRNAs increaseosteosarcoma radiosensitivity by targeting APE1in vitro and vivo.
Results
1. Both microarray and qRT-PCR demonstrated that13miRNAs were significantlychanged (>2-fold) in APE1-knockdown HOS cells; seven of them (miR-451, miR-1290,miR-765, miR-483-5p, miR-513a-5p, miR-129-5p and miR-31) were up-regulated and theother six (miR-29b, miR-197, let-7b, miR-324-5p, let-7i and miR-484) were down-regulated.Furthermore, pathway analysis showed that these miRNAs and their target genes affected bythe expression of APE1were involved in pathways relating to cell signaling (such as TGF-β,Wnt, MAPK and the p53signaling pathway), cell survival, proliferation, adhesion andcancers.
2. APE1could regulate both miRNAs and transcription factors. There were putativebinding sites of NF-κB, p53, HIF-1α, AP-1, PEBP2, ATF, NF-Y, Pax-2, CREB and c-Myb inthe promoters of several downregulated miRNAs, indicating that APE1may regulatemiRNAs via transcription factors. The DNA binding activity of NF-κB was inhibited afterAPE1-knockdown in osteosarcoma cells. And the expressions of let-7b and let-7i weredecreased by NF-κB siRNA.
3. MiR-513a-5p and miR-765significantly suppressed APE1protein expression bybinding to the3’UTR of APE1mRNA. Overexpression of miR-513a-5p could inhibit theactivity of APE1in AP site repair and the DNA binding activity of NF-κB、p53and AP-1.Flowing with ionizing radiation, overexpression of miR-513a-5p in osteosarcoma couldinhibit cells proliferation and promote cell apoptosis in vitro and vivo. Besides, the expressionof Bcl-2was decreased in osteosarcoma HOS cells. Conclusion
1. Our data provide evidence that APE1appears to have a direct influence on globalmiRNAs expression. According to the bioinformatics-based analysis, APE1may regulatemiRNAs to affect the expression of target genes. These interactions may be involved incancers, cell survival, cells proliferation, adhesion and many cell signal pathways, especiallywith regard to the tumorigenesis, development, invasion and metastasis of osteosarcoma.
2. The bioinformatics-based analysis has showed the network associated with APE1,transcription factors and miRNAs. APE1may regulate the expression of let-7b and let-7i viatranscription factor NF-κB.
3. APE1is the target gene of miR-513a-5p and miR-765. MiR-513a-5p can suppressDNA damage repair activity and redox activity of APE1, and sensitize human osteosarcomato radiation through suppressing cells proliferation and promoting apoptosis in vitro and vivo.
放疗是骨肉瘤治疗的重要手段之一。放疗抵抗是影响患者疗效和预后的关键因素。前期研究表明，脱嘌呤脱嘧啶核酸内切酶(APE1)具有DNA损伤修复和氧化还原双功能，在骨肉瘤放疗抵抗中发挥核心调节作用，敲低APE1能显著增强骨肉瘤放疗敏感性。然而其介导骨肉瘤放疗敏感性的机制不清。MicroRNAs(miRNAs)能在转录后水平负性调节靶基因的表达，对肿瘤发生、细胞凋亡和应激反应具有重要的调控作用，为研究和发现APE1基因调控通路和相互作用蛋白，阐明APE1介导的骨肉瘤放疗敏感性的机制提供了新的研究方向。此外，miRNAs作为内源性的小分子，在调控肿瘤细胞放疗敏感性中具有明显的优势，为骨肉瘤的分子靶向治疗提供了新的策略。晚近的研究陆续报道了p53等肿瘤关键基因相互作用的miRNAs，但与APE1相互作用的miRNAs国内外鲜见报道。
研究目的
本研究旨在鉴定和研究APE1相互作用miRNAs及其在骨肉瘤放疗抵抗中的作用。
研究方法
1.通过生物信息学、miRNAs芯片和qRT-PCR筛选鉴定APE1-knockdown骨肉瘤细胞的miRNAs差异表达谱，分析其靶基因涉及的细胞生物学功能和信号通路。
2.通过生物信息学、 EMSA、 RNAi和qRT-PCR实验初步验证APE1-转录因子-miRNAs的作用关系。
3.利用生物信息学、双荧光素酶报告基因实验、AP位点切除实验及EMSA鉴定miRNAs对APE1的靶向调控作用，在细胞和动物水平验证miRNAs靶向抑制APE1对骨肉瘤细胞放疗后增殖和凋亡的影响。
研究结果
1. APE1-knockdown骨肉瘤细胞中有13个miRNAs显著变化，其中miR-451、miR-1290、miR-765、miR-483-5p、miR-513a-5p、miR-129-5p和miR-31上调，miR-29b、miR-197、let-7b、miR-324-5p、let-7i和miR-484下调，其靶基因分别涉及TGF-β、Wnt、MAPK和p53等细胞信号通路，与细胞生存、增殖、粘附和肿瘤发生有关。
2.生物信息学分析提示，转录因子与miRNAs启动子区有结合位点； APE1-knockdown后可下调NF-κB的DNA结合活性，而抑制NF-κB可下调let-7b和let-7i的表达。
3. miR-513a-5p和miR-765能与APE1mRNA3’UTR区结合抑制APE1蛋白表达；miR-513a-5p可抑制APE1的AP位点剪切活性和NF-κB、p53、AP-1的DNA结合活性；在细胞和动物水平给予X射线照射后，过表达miR-513a-5p可增加凋亡，抑制骨肉瘤细胞增殖和Bcl-2的表达。
结论
1. APE1能直接影响骨肉瘤细胞miRNAs的表达；生物信息学分析表明APE1通过调控miRNAs可能影响下游靶基因的表达，参与肿瘤发生、细胞生存、增殖、粘附等生物学过程和多个信号通路，与骨肉瘤的发生发展、侵袭转移密切相关。
2.生物信息学分析表明APE1-转录因子-miRNAs具有相互作用；初步证实APE1通过调控NF-κB的DNA结合活性可能调控let-7b和let-7i的表达。
3.首次证实APE1是miR-513a-5p和miR-765的靶基因，二者可靶向结合APE1mRNA3’UTR区抑制APE1蛋白表达。
4. miR-513a-5p通过抑制APE1的DNA损伤修复和氧化还原双功能，抑制骨肉瘤细胞增殖，诱导细胞凋亡，在细胞及动物水平均能增加骨肉瘤的放疗敏感性。
Background
Radiation therapy is one of the most commonly used clinical treatments forosteosarcoma. The resistance of osteosarcoma to radiotherapy remains an important elementinterfering with therapeutic effect and prognosis. Apurinic/apyrimidinic endonuclease/redoxeffector factor (APE1), with dual functions of both DNA repair and redox activity, is the keygene in regulating radioresistance in osteosarcoma. Previous studies have shown thatknocking down APE1expression by siRNA significantly sensitized human osteosarcomacells to radiation. Although the essential function of APE1has been confirmed, knowledge ofits regulation or interactome in mediating radioresistance is still scanty. Through suppressinggene expression by binding to the3’-untranslated region (3’-UTR) of target genes,microRNAs (miRNAs) play a large range of biological roles in tumorigenesis, apoptosis andstress reactions. We postulated that miRNAs may play important roles in APE1regulatorynetwork and interactome. It might also provide a plausible explanation to the APE1-dependent radioresistance in osteosarcoma. Additionally, as a class of endogenous singlestranded non-coding RNA, miRNAs has been considered to be a more effective andpromising target to increase radiosensitivity of cancer. Recently, studies have reported somemiRNAs interaction with many important tumor-associated genes such as p53. However, todate, little report concerning the interaction between APE1and miRNAs are available in thecurrent scientific literature.
Objective
To identify the interaction network between APE1and miRNAs in osteosarcoma andinvestigate the APE1-dependent modulation of radiation sensitivity by miRNAs in humanosteosarcoma.
Materials and Methods
1. Microarray and qRT-PCR were used to confirm the change of microRNAs (miRNAs) in APE1-knockdown osteosarcoma HOS cells followed by analysis with comprehensivebioinformatics-based analysis.
2. APE1-transcription factors-miRNAs network was predicted and identified bybioinformatics-based analysis, EMSA, RNAi and qRT-PCR in osteosarcoma HOS cells.
3. Then we used luciferase report gene vectors, Western blot, AP site activity assay andEMSA to identify miRNAs are the targeted regulation factor of APE1. At last, we generatedmiRNA overexpression lentiviral vector and used cell proliferation assay, cell apoptosis,immunohistochemisty, Western blot and qRT-PCR to investigate the miRNAs increaseosteosarcoma radiosensitivity by targeting APE1in vitro and vivo.
Results
1. Both microarray and qRT-PCR demonstrated that13miRNAs were significantlychanged (>2-fold) in APE1-knockdown HOS cells; seven of them (miR-451, miR-1290,miR-765, miR-483-5p, miR-513a-5p, miR-129-5p and miR-31) were up-regulated and theother six (miR-29b, miR-197, let-7b, miR-324-5p, let-7i and miR-484) were down-regulated.Furthermore, pathway analysis showed that these miRNAs and their target genes affected bythe expression of APE1were involved in pathways relating to cell signaling (such as TGF-β,Wnt, MAPK and the p53signaling pathway), cell survival, proliferation, adhesion andcancers.
2. APE1could regulate both miRNAs and transcription factors. There were putativebinding sites of NF-κB, p53, HIF-1α, AP-1, PEBP2, ATF, NF-Y, Pax-2, CREB and c-Myb inthe promoters of several downregulated miRNAs, indicating that APE1may regulatemiRNAs via transcription factors. The DNA binding activity of NF-κB was inhibited afterAPE1-knockdown in osteosarcoma cells. And the expressions of let-7b and let-7i weredecreased by NF-κB siRNA.
3. MiR-513a-5p and miR-765significantly suppressed APE1protein expression bybinding to the3’UTR of APE1mRNA. Overexpression of miR-513a-5p could inhibit theactivity of APE1in AP site repair and the DNA binding activity of NF-κB、p53and AP-1.Flowing with ionizing radiation, overexpression of miR-513a-5p in osteosarcoma couldinhibit cells proliferation and promote cell apoptosis in vitro and vivo. Besides, the expressionof Bcl-2was decreased in osteosarcoma HOS cells. Conclusion
1. Our data provide evidence that APE1appears to have a direct influence on globalmiRNAs expression. According to the bioinformatics-based analysis, APE1may regulatemiRNAs to affect the expression of target genes. These interactions may be involved incancers, cell survival, cells proliferation, adhesion and many cell signal pathways, especiallywith regard to the tumorigenesis, development, invasion and metastasis of osteosarcoma.
2. The bioinformatics-based analysis has showed the network associated with APE1,transcription factors and miRNAs. APE1may regulate the expression of let-7b and let-7i viatranscription factor NF-κB.
3. APE1is the target gene of miR-513a-5p and miR-765. MiR-513a-5p can suppressDNA damage repair activity and redox activity of APE1, and sensitize human osteosarcomato radiation through suppressing cells proliferation and promoting apoptosis in vitro and vivo.
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