dsRNAs上调若干肿瘤抑制基因及其对膀胱癌治疗作用的研究
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摘要
近年来研究发现序列特异性靶向某些靶基因启动子区的双链小RNAs(dsRNAs)能引起人肿瘤细胞内靶基因转录水平的表达上调,并将此现象命名为RNA诱导的基因激活(RNAa),称这样的dsRNAs为小激活RNAs (saRNAs).随后关于RNAa发生机制方面的研究显示表观遗传学修饰和反义转录产物与RNAa的发生密切相关。然而,目前对RNAa的普遍性、作用机制以及设计原则的了解仍较肤浅,且在RNAa的发生机制方面存在一些争议。
本研究旨在探讨RNAa现象的普遍性、明确其具体发生机制、完善saRNAs的设计规律以及评估其治疗应用的可行性,主要研究内容及成果如下：
1)本文针对肿瘤抑制基因p21、par-4、KAI1和NKX3-1基因启动子区设计了若干对双链小RNAs,利用RT-PCR反应和蛋白印迹验证及挑选了能有效上调靶基因表达的功能性saRNAs:dsP21-306和dsPar4-435;并发现功能性saRNAs的有效性是由dsRNAs的设计位点和细胞本身的遗传背景及特征共同决定的。
2)比较功能性saRNAs邻近位点的dsRNAs与功能性saRNAs在调节靶基因表达方面的异同,发现功能性saRNAs的靶点沿基因启动子区序列向上游或下游位移1～2个碱基能获得1～2对新的功能性saRNAs。同时,结合以往发现的功能性saRNAs,分析总结它们的序列特征,发现其正义链3’端碱基具有一定的规律,可能与其功能有关。
3)利用染色质免疫共沉淀探讨功能性saRNAs对par-4启动子区表观遗传学修饰的影响,发现dsPar4-435作用靶点附近的染色质H3K9二甲基化减少和H3K4二甲基化增加,而H3K9的乙酰化状态无明显改变,提示表观遗传学修饰的变化趋势虽与RNAa现象一致,但是其具体改变可能因基因的不同而存在一定的差异。利用PCR检测提示各种细胞中par-4基因启动子区均存在转录产物,以反义RNA为主,它在dsPar4-435作用后表达略有上升,但确切的作用机制仍需进一步研究探索。
4)利用MTT法、流式细胞术以及蛋白印迹等评估功能性saRNAs对膀胱癌细胞的体外治疗作用和效果,发现dsP21-306和dsPar-435上调靶基因表达后均能有效诱导T24细胞的凋亡,dsP21-306还能诱导G1期细胞周期阻滞,从而抑制膀胱癌细胞的生长,说明saRNAs上调基因表达对膀胱癌具有一定的治疗效果和应用前景。
总之,RNAa现象具有一定的普遍性,其作用机制与表观遗传学修饰和反义转录产物有一定的联系；同时,saRNAs对膀胱癌细胞的体外治疗效果明显,为将来恶性肿瘤及其他疾病的临床治疗应用提供了理论依据。但是,RNAa现象的确切机制、设计规律以及治疗应用的体内实验等工作还需进一步研究完善。
Very recent studies have reported that chemically synthesized small duplex RNAs complementary to the promoters of target genes can up-regulate gene expression in different cancer cell lines and have named this phenomenon as RNA-induced gene activation (RNAa) and such dsRNA molecules as small activating RNAs (saRNAs). Following mechanistic studies on RNAa indicated that epigenetics and antisense transcripts are associated with RNAa. However, it's still confused about the prevalence, exact mechanisms and design rules of RNAa, and there are also some disputations on the mechanisms of RNAa to be solved.
This paper focused on discussing the prevalence of RNAa, identifying its exact mechanisms, improving its design rules, and evaluating its therapeutic potential. The main investigations and results are as follows:
1) Several dsRNAs were designed to target the promoters of p21, par-4, KAI1 and NKX3-1 respectively. The functional saRNAs, dsP21-306 and dsPar4-435, were picked out according to their abilities to induce the target gene expression to more than two times detected by PCR and Western blot. It was suggested that the efficacy of functional saRNAs was dependent on both the target site and the genetic background of target cells.
2) We synthesized several dsRNAs whose target sites were adjacent to the target site of the functional saRNAs and then compared these dsRNAs with the functional saRNAs in regulation of target genes. It was suggested that one or two new functional saRNAs can be obtained by shifting the original target sites to one or two bases nearby along the gene promoters. Meanwhile, all the functional saRNAs including the former ones were analyzed and found that the bases in 3'ends of their sense strands had regularity which might be important to their functions.
3) We discussed the relationship between RNAa and the epigenetic changes in par-4 gene promoter by ChIP, and found that H3K9 di-methylation decreased and H3K4 di-methylation increased in the chromatin around the target site after dsPar4-435 transfection, but H3K9 acetylation didn't have evident changes. These results suggested that although the trends of the epigenetic changes were consistent with RNAa, the concrete changes might be different in different genes. Then we detected transcripts existing in par-4 gene promoter in several cells. The transcripts were mainly antisense RNAs and increased when par-4 mRNA was up-regulated by dsPar4-435. The exact mechanisms still need to be investigated in the future.
4) We evaluated the in vitro therapeutics of functional saRNAs on bladder cancer cells by MTT, flow cytometry and Western blot. Both dsP21-306 and dsPar-435 could induce apoptosis in T24 cells effectively and dsP21-306 could also induce G1-phase cell cycle arrest in these cells. Therefore, they could inhibit the growth of bladder cancer cells, suggesting that up-regulation of TSGs expression by saRNAs have therapeutic potential and promise for bladder cancer.
In conclusion, RNAa phenomenon occurs in some genes, and its mechanisms are associated with epigenetics and antisense transcripts. Meanwhile, the in vitro therapeutics of functional saRNAs on bladder cancer cells was effective and provided evidence and basis for the future clinical application in the treatment of cancer or other diseases. However, there are still a lot of problems need to be investigated and improved, including the exact mechanisms, design rules and in vivo therapeutic experiments of RNAa.
本研究旨在探讨RNAa现象的普遍性、明确其具体发生机制、完善saRNAs的设计规律以及评估其治疗应用的可行性,主要研究内容及成果如下：
1)本文针对肿瘤抑制基因p21、par-4、KAI1和NKX3-1基因启动子区设计了若干对双链小RNAs,利用RT-PCR反应和蛋白印迹验证及挑选了能有效上调靶基因表达的功能性saRNAs:dsP21-306和dsPar4-435;并发现功能性saRNAs的有效性是由dsRNAs的设计位点和细胞本身的遗传背景及特征共同决定的。
2)比较功能性saRNAs邻近位点的dsRNAs与功能性saRNAs在调节靶基因表达方面的异同,发现功能性saRNAs的靶点沿基因启动子区序列向上游或下游位移1～2个碱基能获得1～2对新的功能性saRNAs。同时,结合以往发现的功能性saRNAs,分析总结它们的序列特征,发现其正义链3’端碱基具有一定的规律,可能与其功能有关。
3)利用染色质免疫共沉淀探讨功能性saRNAs对par-4启动子区表观遗传学修饰的影响,发现dsPar4-435作用靶点附近的染色质H3K9二甲基化减少和H3K4二甲基化增加,而H3K9的乙酰化状态无明显改变,提示表观遗传学修饰的变化趋势虽与RNAa现象一致,但是其具体改变可能因基因的不同而存在一定的差异。利用PCR检测提示各种细胞中par-4基因启动子区均存在转录产物,以反义RNA为主,它在dsPar4-435作用后表达略有上升,但确切的作用机制仍需进一步研究探索。
4)利用MTT法、流式细胞术以及蛋白印迹等评估功能性saRNAs对膀胱癌细胞的体外治疗作用和效果,发现dsP21-306和dsPar-435上调靶基因表达后均能有效诱导T24细胞的凋亡,dsP21-306还能诱导G1期细胞周期阻滞,从而抑制膀胱癌细胞的生长,说明saRNAs上调基因表达对膀胱癌具有一定的治疗效果和应用前景。
总之,RNAa现象具有一定的普遍性,其作用机制与表观遗传学修饰和反义转录产物有一定的联系；同时,saRNAs对膀胱癌细胞的体外治疗效果明显,为将来恶性肿瘤及其他疾病的临床治疗应用提供了理论依据。但是,RNAa现象的确切机制、设计规律以及治疗应用的体内实验等工作还需进一步研究完善。
Very recent studies have reported that chemically synthesized small duplex RNAs complementary to the promoters of target genes can up-regulate gene expression in different cancer cell lines and have named this phenomenon as RNA-induced gene activation (RNAa) and such dsRNA molecules as small activating RNAs (saRNAs). Following mechanistic studies on RNAa indicated that epigenetics and antisense transcripts are associated with RNAa. However, it's still confused about the prevalence, exact mechanisms and design rules of RNAa, and there are also some disputations on the mechanisms of RNAa to be solved.
This paper focused on discussing the prevalence of RNAa, identifying its exact mechanisms, improving its design rules, and evaluating its therapeutic potential. The main investigations and results are as follows:
1) Several dsRNAs were designed to target the promoters of p21, par-4, KAI1 and NKX3-1 respectively. The functional saRNAs, dsP21-306 and dsPar4-435, were picked out according to their abilities to induce the target gene expression to more than two times detected by PCR and Western blot. It was suggested that the efficacy of functional saRNAs was dependent on both the target site and the genetic background of target cells.
2) We synthesized several dsRNAs whose target sites were adjacent to the target site of the functional saRNAs and then compared these dsRNAs with the functional saRNAs in regulation of target genes. It was suggested that one or two new functional saRNAs can be obtained by shifting the original target sites to one or two bases nearby along the gene promoters. Meanwhile, all the functional saRNAs including the former ones were analyzed and found that the bases in 3'ends of their sense strands had regularity which might be important to their functions.
3) We discussed the relationship between RNAa and the epigenetic changes in par-4 gene promoter by ChIP, and found that H3K9 di-methylation decreased and H3K4 di-methylation increased in the chromatin around the target site after dsPar4-435 transfection, but H3K9 acetylation didn't have evident changes. These results suggested that although the trends of the epigenetic changes were consistent with RNAa, the concrete changes might be different in different genes. Then we detected transcripts existing in par-4 gene promoter in several cells. The transcripts were mainly antisense RNAs and increased when par-4 mRNA was up-regulated by dsPar4-435. The exact mechanisms still need to be investigated in the future.
4) We evaluated the in vitro therapeutics of functional saRNAs on bladder cancer cells by MTT, flow cytometry and Western blot. Both dsP21-306 and dsPar-435 could induce apoptosis in T24 cells effectively and dsP21-306 could also induce G1-phase cell cycle arrest in these cells. Therefore, they could inhibit the growth of bladder cancer cells, suggesting that up-regulation of TSGs expression by saRNAs have therapeutic potential and promise for bladder cancer.
In conclusion, RNAa phenomenon occurs in some genes, and its mechanisms are associated with epigenetics and antisense transcripts. Meanwhile, the in vitro therapeutics of functional saRNAs on bladder cancer cells was effective and provided evidence and basis for the future clinical application in the treatment of cancer or other diseases. However, there are still a lot of problems need to be investigated and improved, including the exact mechanisms, design rules and in vivo therapeutic experiments of RNAa.
引文
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1. Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics,2002. CA Cancer J Clin. 2005; 55:74-108.
2. Feldman AR, Kessler L, Myers MH, et al. The prevalence of cancer. Estimates based on the Connecticut Tumor Registry. N Engl J Med.1986; 315:1394-7.
3. Rubben H, Lutzeyer H, Fischer N, et al. Natural history and treatment of low and high risk superfi cial bladder tumors. J Urol.1988; 139:283-5.
4. Sylvester RJ, Oosterlinck W, van der Meijden AP. A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer:a meta-analysis of published results of randomized clinical trials. J Urol.2004; 171:2186-90.
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8. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med.2003; 349:859-66.
9. Splinter TA, Scher HI, Denis L, et al. European Organization for Research on Treatment of Cancer-Genitourinary Group. The prognostic value of the pathological response to combination chemotherapy before cystectomy in patients with invasive bladder cancer. J Urol.1992; 147:606-8.
10. Vaughn DJ. Review and outlook for the role of paclitaxel in urothelial carcinoma. Semin Oncol.1999; 26:117-22.
11. Fire A, Xu S, Montgomery MK, et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature.1998; 391:806-11.
12. Elbashir SM, Harborth J, Lendeckel W, et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature.2001; 411:494-8.
13. Tolia NH, Joshua-Tor L. Slicer and the Argonautes. Nat Chem Biol.2007; 3(1): 36-43.
14. Lee Y, Ahn C, Han J, et al. The nuclear RNase Ⅲ Drosha initiates microRNA processing. Nature.2003; 425:415-9.
15. Lee Y, Jeon K, Lee JT, et al. MicroRNA maturation:stepwise processing and subcellular localization. EMBO J.2002; 21:4663-70.
16. Zeng Y, Cullen BR. Sequence requirements for microRNA processing and function in human cells. RNA.2003; 9:112-3.
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