Intratumoral injection of oligonucleotides to the NFκB binding site inhibits cachexia in a mouse tumor model
Intratumoral injection of oligonucleotides to the NFκB binding site inhibits cachexia in a mouse tumor model
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DOI：
10.1038/sj.gt.3300819
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发表时间：
1999-01-01
期刊：
影响因子：
5.1
通讯作者：
Ogihara, T
中科院分区：
文献类型：
--
作者：
Kawamura, I;Morishita, R;Ogihara, T
癌症恶病质以厌食、体重减轻和进行性组织萎缩为特征，被认为是由多种细胞因子介导的。然而，恶病质诱导的确切机制尚未完全解释。我们已经开发了合成的双链寡脱氧核苷酸（ODN）作为“诱饵”顺式元件，阻断核因子与靶基因启动子区的结合，从而抑制体内和体外的基因反式激活。这种新的分子策略可用于治疗包括癌症在内的多种人类疾病。在这项研究中，我们将靶向转录因子NF-κ B（NF-κ B）结合顺式元件（对细胞因子的基因表达的反式激活至关重要）的诱饵ODN直接注射到小鼠结肠腺癌26的肿瘤中，以检查是否通过抑制细胞因子的作用来减轻恶病质。NF κ B B诱饵ODN转染与乱序诱饵ODN相比，对肿瘤生长无明显影响。然而，转染NF κ B诱饵，而不是乱序诱饵，ODN导致体重，附睾脂肪，腓肠肌质量和食物摄入量的减少，这是由肿瘤的存在引起的衰减。NF kappa B诱饵ODN的转染也明显降低了肿瘤中白细胞介素6 mRNA的表达。已知转录因子E2 F在细胞周期调控基因的协同反式激活中起关键作用。因此，我们推测，在体内引入对E2 F具有高亲和力的合成双链DNA作为“诱饵”顺式元件可能抑制colon 26的肿瘤生长，从而抑制恶病质诱导。然而，注射E2 F诱饵ODN未能抑制肿瘤生长和恶病质诱导，与错配诱饵ODN相比。总之，本研究表明，通过阻断NF κ B B，使用脐分子诱饵策略，结肠腺癌诱导的恶病质26被抑制，而对肿瘤生长没有影响，并且结肠癌模型中的肿瘤生长和恶病质诱导26不受E2 F诱饵ODN的影响。这些结果表明，NF κ B B调节的细胞因子可能在colon 26诱导恶病质中起关键作用，为癌症恶病质的治疗提供了新的策略。
Cancer cachexia, characterized by anorexia, weight loss and progressive tissue wasting, has been postulated to be mediated by Various cytokines. However, the precise mechanism of cachexia induction is not fully explained. We have developed synthetic double-stranded oligodeoxynucleotides (ODN) as 'decoy' cis-elements that block the binding of nuclear factors to promoter regions of targeted genes, resulting in the inhibition of gene transactivation in vivo as well as in vitro. This novel molecular strategy could be useful for treating a broad range of human diseases including cancer. In this study, we injected decoy ODN targeting the transcriptional factor NF-kappaB (NF kappa B) binding cis-elements, which are essential for transactivation of gene expression of cytokines, directly into tumors of adenocarcinoma colon26 in mice, in order to examine whether or not cachexia is alleviated by inhibiting the action of cytokines. Tumor growth was not affected by transfection of NF kappa B decoy ODN as compared with scrambled decoy ODN. Nevertheless, transfection of NF kappa B decoy, but not scrambled decoy, ODN resulted in attenuation of the reductions in body weight, epididymal fat, gastrocnemius muscle mass and food intake, which were induced by the tumor presence. Interleukin 6 mRNA in the tumor was also markedly decreased by the transfection of NF kappa B decoy ODN. It is known that the transcriptional factor E2F plays a pivotal role in the coordinated transactivation of cell cycle regulatory genes. Therefore, we hypothesized that the introduction of synthetic double-stranded DNA with high affinity for E2F in vivo as 'decoy' cis-elements might inhibit the tumor growth of colon26, resulting in turn in inhibition of cachexia induction. However, injection of E2F decoy ODN failed to inhibit tumor growth and cachexia induction, as compared with mismatched decoy ODN. Overall, the present study demonstrated that cachexia induced by adenocarcinoma colon26 was inhibited by blocking of NF kappa B, using a navel molecular decoy strategy, without an effect on tumor growth, and also that tumor growth and cachexia induction in the colon26 model were not affected by E2F decoy ODN. These results suggest that cytokines regulated by NF kappa B may play a pivotal role in the induction of cachexia by colon26, providing a new therapeutic strategy for cancer cachexia.