基于miR-199调控靶向肝癌细胞的溶瘤腺病毒系统研究
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摘要
肝癌严重威胁着我国人民生命健康。基因-病毒治疗是继手术、放疗、化疗之后，肝癌靶向治疗的一种非常有前景的生物治疗方案。其中，溶瘤腺病毒本身具有裂解肿瘤的能力，又能介导外源基因高效表达，已成为基因-病毒治疗领域重要载体。目前已建立多种腺病毒调控策略，使其特异杀伤肿瘤细胞，而对正常组织细胞基本无毒性。然而，野生型腺病毒对肝脏具有较强的嗜性，如何减少甚至避免腺病毒对正常肝细胞的毒性，仍是应用腺病毒作为载体开展肝癌基因-病毒治疗所面临的巨大挑战。
microRNA（miRNA）是生物体内源，长度约为19-25个核苷酸的非编码小RNA，它能通过与靶基因mRNA上的靶序列互补配对结合，在转录后水平对基因表达起负调控作用，导致mRNA的降解或翻译抑制。研究表明，miRNA具有高度的时空表达特异性，一些特定的miRNA常在一类肿瘤细胞（如肝癌）中异常下调，与肿瘤发生发展关系密切。因而，可以根据microRNA的调控方式与表达特点，将miRNA引入溶瘤腺病毒的靶向性调控中，即利用肝癌细胞特异性下调的miRNA调控腺病毒增殖必需基因E1A的表达，使其在相应miRNA高水平表达的正常肝细胞内不增殖（E1A被抑制），而在相应miRNA表达缺失的肝癌细胞内有效增殖（E1A正常表达），从而特异杀伤肝癌细胞，避免对正常肝细胞的毒副作用。
miR-199a/b-3p是正常肝细胞内一种表达量非常高的miRNA（绝对表达量居第三），且在多种类型组织中高水平表达。研究发现，miR-199a/b-3p在肝癌细胞内广谱低水平表达。在本研究中，我们将miR-199a/b-3p靶序列插入E1A的3’非翻译区中，同时将5型腺病毒纤毛替换为5/35型嵌合纤毛，以提高病毒对肿瘤细胞的感染效率，建立基于miR-199调控靶向肝癌细胞的溶瘤腺病毒载体系统。通过Westernblotting、RT-PCR等技术研究在该调控方式作用下，腺病毒E1A的表达情况；通过病毒增殖实验、绿色荧光报告系统等手段检测病毒的增殖特性；应用MTT法检测病毒对肝癌细胞的体外杀伤作用及对正常肝细胞的毒副作用；建立肝癌细胞裸鼠移植瘤模型，研究病毒对移植瘤的抑制作用。
结果表明，包含8个拷贝miR-199a/b-3p靶序列的溶瘤腺病毒SG7035199T能在miR-199a/b-3p低表达的肝癌细胞株（Hep3B与Huh7）中有效增殖并发挥杀伤作用，病毒感染后E1A能正常表达；而在miR-199a/b-3p高表达的正常肝细胞株（L02）及卵巢癌细胞株（SK-OV3）中基本不增殖，基本不发挥杀伤作用，病毒感染后E1A被有效抑制。而对照病毒，如包含5/35型嵌合纤毛，不具有任何调控的增殖型腺病毒WAd5/35以及包含8个拷贝“种子”序列突变后的miR-199a/b-3p靶序列的溶瘤腺病毒SG7035199MT则能在Hep3B、Huh7、L02、SK-OV3中均能有效增殖并发挥杀伤作用。体内方面，SG7035199T能有效抑制Hep3B移植瘤的生长，其抑瘤能力与WAd5/35、SG7035199MT相当；对于SK-OV3移植瘤，SG7035199T基本无抑制作用，而对照病毒WAd5/35、SG7035199MT能有效抑制移植瘤的生长。综上所述，SG7035199T能特异杀伤肝癌细胞，而对正常肝细胞基本无毒性，是一种较为理想的靶向肝癌细胞的溶瘤腺病毒系统。
Hepatocellular carcinoma (HCC) is a widespread cancer in our country，causingmillions deaths every year. The gene-virology therapy is one of promising strategy totreat for HCC. To this end, various viral vectors have been engineered to carryingtransgenes. Among them, oncolytic adenovirus has unique advantages. It can directlydestroy cancer cells, and mediate effective transgenic expression in the process of viralproduction as well. To date, a series of approaches have been developed to ensureoncolytic adenovirus to conditionally kill cancer cells. However, systemic administrationof adenoviruses can cause significant infection of hepatocytes and may lead to livertoxicity. Therefore, it remains a challenge to selectively target the cancer cells andleaving the normal cells, especial normal liver cells unharmed in the therapeutic use ofoncolytic adenovirus for HCC.
MicroRNAs (miRNAs) are versatile, noncoding RNAs, which exertposttranscriptional regulation by targeting mRNAs through specific recognition of shortsequences, leading to decreased protein production. It has been well documented thatmiRNA is expressed in tissue-and differentiation state-specific patterns, and is greatlyassociated with cancer development. Because of its tissue-specific expression profile andshort targeting site, miRNA provides considerable flexibility in the design ofconditionally replicative adenoviruses. By introduction of miRNA target sequence intothe3’-untranslated region (UTR) of a key gene that has an essential role in viral growthand replication (e.g. E1A), the virus replication can be controlled by the tissue-specificendogenous miRNA, thus eliminating the unwanted pathology of wild-type adenovirus.
The miR-199a/b-3p is highly expressed in hepatocytes and several types of tissues.Data have shown that miR-199a/b-3p is downregulated in almost all of primary HCCtissues and HCC cell lines, making it an ideal candidate for adenoviral regulation. In thisstudy, we have engineered an oncolytic adenovirus, SG7011199T, by introducing eightcopies of miR-199a/b-3p target sites into the3’ untranslated region of E1A, a key geneassociated with adenoviral replication, to control the expression of the E1A gene,subsequently the replication and cytotoxicity of the virus. The results showed that theE1A expression (both RNA and protein levels) of the SG7011199Twas tightly regulatedaccording to the endogenous expression level of the miR-199a/b-3p gene. As contrastedwith wild-type adenovirus, the replication of SG7011199Twas distinctly inhibited in normal liver cells lines (i.e. L02) and ovarian cancer cell line (i.e. SK-OV3) expressedhigh level of miR-199a/b-3p, whereas was almost not disturbed in HCC cells (i.e. Hep3Band Huh7) with low level of miR-199a/b-3p. Consequently, the cytotoxicity ofSG7011199Tto normal liver cells was successfully decreased while its oncolytic activityto HCC cells was maintained in vitro and in mice with xenograft HCC tumor. Theseresults suggested that SG7011199Tmay be a promising anticancer agent or vector tomediate the expression of therapeutic gene, broadly applicable in the treatment for HCCand other cancers where the miR-199a/b-3p gene is downregulated.
microRNA（miRNA）是生物体内源，长度约为19-25个核苷酸的非编码小RNA，它能通过与靶基因mRNA上的靶序列互补配对结合，在转录后水平对基因表达起负调控作用，导致mRNA的降解或翻译抑制。研究表明，miRNA具有高度的时空表达特异性，一些特定的miRNA常在一类肿瘤细胞（如肝癌）中异常下调，与肿瘤发生发展关系密切。因而，可以根据microRNA的调控方式与表达特点，将miRNA引入溶瘤腺病毒的靶向性调控中，即利用肝癌细胞特异性下调的miRNA调控腺病毒增殖必需基因E1A的表达，使其在相应miRNA高水平表达的正常肝细胞内不增殖（E1A被抑制），而在相应miRNA表达缺失的肝癌细胞内有效增殖（E1A正常表达），从而特异杀伤肝癌细胞，避免对正常肝细胞的毒副作用。
miR-199a/b-3p是正常肝细胞内一种表达量非常高的miRNA（绝对表达量居第三），且在多种类型组织中高水平表达。研究发现，miR-199a/b-3p在肝癌细胞内广谱低水平表达。在本研究中，我们将miR-199a/b-3p靶序列插入E1A的3’非翻译区中，同时将5型腺病毒纤毛替换为5/35型嵌合纤毛，以提高病毒对肿瘤细胞的感染效率，建立基于miR-199调控靶向肝癌细胞的溶瘤腺病毒载体系统。通过Westernblotting、RT-PCR等技术研究在该调控方式作用下，腺病毒E1A的表达情况；通过病毒增殖实验、绿色荧光报告系统等手段检测病毒的增殖特性；应用MTT法检测病毒对肝癌细胞的体外杀伤作用及对正常肝细胞的毒副作用；建立肝癌细胞裸鼠移植瘤模型，研究病毒对移植瘤的抑制作用。
结果表明，包含8个拷贝miR-199a/b-3p靶序列的溶瘤腺病毒SG7035199T能在miR-199a/b-3p低表达的肝癌细胞株（Hep3B与Huh7）中有效增殖并发挥杀伤作用，病毒感染后E1A能正常表达；而在miR-199a/b-3p高表达的正常肝细胞株（L02）及卵巢癌细胞株（SK-OV3）中基本不增殖，基本不发挥杀伤作用，病毒感染后E1A被有效抑制。而对照病毒，如包含5/35型嵌合纤毛，不具有任何调控的增殖型腺病毒WAd5/35以及包含8个拷贝“种子”序列突变后的miR-199a/b-3p靶序列的溶瘤腺病毒SG7035199MT则能在Hep3B、Huh7、L02、SK-OV3中均能有效增殖并发挥杀伤作用。体内方面，SG7035199T能有效抑制Hep3B移植瘤的生长，其抑瘤能力与WAd5/35、SG7035199MT相当；对于SK-OV3移植瘤，SG7035199T基本无抑制作用，而对照病毒WAd5/35、SG7035199MT能有效抑制移植瘤的生长。综上所述，SG7035199T能特异杀伤肝癌细胞，而对正常肝细胞基本无毒性，是一种较为理想的靶向肝癌细胞的溶瘤腺病毒系统。
Hepatocellular carcinoma (HCC) is a widespread cancer in our country，causingmillions deaths every year. The gene-virology therapy is one of promising strategy totreat for HCC. To this end, various viral vectors have been engineered to carryingtransgenes. Among them, oncolytic adenovirus has unique advantages. It can directlydestroy cancer cells, and mediate effective transgenic expression in the process of viralproduction as well. To date, a series of approaches have been developed to ensureoncolytic adenovirus to conditionally kill cancer cells. However, systemic administrationof adenoviruses can cause significant infection of hepatocytes and may lead to livertoxicity. Therefore, it remains a challenge to selectively target the cancer cells andleaving the normal cells, especial normal liver cells unharmed in the therapeutic use ofoncolytic adenovirus for HCC.
MicroRNAs (miRNAs) are versatile, noncoding RNAs, which exertposttranscriptional regulation by targeting mRNAs through specific recognition of shortsequences, leading to decreased protein production. It has been well documented thatmiRNA is expressed in tissue-and differentiation state-specific patterns, and is greatlyassociated with cancer development. Because of its tissue-specific expression profile andshort targeting site, miRNA provides considerable flexibility in the design ofconditionally replicative adenoviruses. By introduction of miRNA target sequence intothe3’-untranslated region (UTR) of a key gene that has an essential role in viral growthand replication (e.g. E1A), the virus replication can be controlled by the tissue-specificendogenous miRNA, thus eliminating the unwanted pathology of wild-type adenovirus.
The miR-199a/b-3p is highly expressed in hepatocytes and several types of tissues.Data have shown that miR-199a/b-3p is downregulated in almost all of primary HCCtissues and HCC cell lines, making it an ideal candidate for adenoviral regulation. In thisstudy, we have engineered an oncolytic adenovirus, SG7011199T, by introducing eightcopies of miR-199a/b-3p target sites into the3’ untranslated region of E1A, a key geneassociated with adenoviral replication, to control the expression of the E1A gene,subsequently the replication and cytotoxicity of the virus. The results showed that theE1A expression (both RNA and protein levels) of the SG7011199Twas tightly regulatedaccording to the endogenous expression level of the miR-199a/b-3p gene. As contrastedwith wild-type adenovirus, the replication of SG7011199Twas distinctly inhibited in normal liver cells lines (i.e. L02) and ovarian cancer cell line (i.e. SK-OV3) expressedhigh level of miR-199a/b-3p, whereas was almost not disturbed in HCC cells (i.e. Hep3Band Huh7) with low level of miR-199a/b-3p. Consequently, the cytotoxicity ofSG7011199Tto normal liver cells was successfully decreased while its oncolytic activityto HCC cells was maintained in vitro and in mice with xenograft HCC tumor. Theseresults suggested that SG7011199Tmay be a promising anticancer agent or vector tomediate the expression of therapeutic gene, broadly applicable in the treatment for HCCand other cancers where the miR-199a/b-3p gene is downregulated.
引文
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