Effect of in vivo administration of reprogramming factors in the mouse liver.
Effect of in vivo administration of reprogramming factors in the mouse liver.
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DOI：
10.3892/ol.2013.1418
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发表时间：
2013-08
期刊：
影响因子：
2.9
通讯作者：
Nagano H
中科院分区：
文献类型：
--
作者：
Tomokuni A;Eguchi H;Hoshino H;Dewi DL;Nishikawa S;Kano Y;Miyoshi N;Tojo A;Kobayashi S;Gotoh N;Hinohara K;Fusaki N;Saito T;Suemizu H;Wada H;Kobayashi S;Marubashi S;Tanemura M;Doki Y;Mori M;Ishii H;Nagano H
癌症是由干细胞或祖细胞通过去分化过程转化而引发的，该过程导致癌症干细胞;然而，该过程涉及促进生长的癌基因的激活和抑制生长的肿瘤抑制基因的失活。在正常体细胞中引入确定的因子，例如由c-Myc、Sox 2、Oct 3/4和Klf 4编码的那些因子，导致它们去分化成诱导多能干（iPS）细胞。我们以前报道过，这些确定的因子通过降低肿瘤侵袭性诱导胃肠道癌细胞发展为诱导多能癌（iPC）细胞。先前的研究表明，虽然p53抑制可能促进重编程，但p53中的功能获得性致癌突变和Kras刺激的致瘤活性中的致癌突变，以及它们在体内的作用还不完全清楚。因此，在本研究中，使用各种背景的转基因和基因敲除小鼠，研究了直接注射仙台病毒（SeV）载体编码的四个定义的因子在体内的效果，并与直接注射的微RNA（miRNA）稀释与阳离子脂质。体内成像数据显示p53缺陷或突变Kras条件激活的转化热点，其大小与免疫缺陷NOD/SCID和uPA-NOG小鼠一致，并且与对照小鼠相比更大。总体而言，目前关于体内重编程的数据表明，Kras激活可能促进正常肝细胞中细胞重编程的效果，并且Kras激活的效果比肿瘤抑制因子p53缺陷的效果更明显。结果还显示，免疫缺陷可能会增加重编程的效果，大概是通过阻断转化细胞的免疫监视。这些发现为进一步研究开发涉及直接体内重编程的治疗方法提供了理论基础。
Cancer is initiated by the transformation of stem cells or progenitor cells via a dedifferentiation process that leads to cancer stem cells; however, the process involves the activation of growth-promoting oncogenes and the inactivation of growth-constraining tumor suppressor genes. The introduction of defined factors, such as those encoded by c-Myc, Sox2, Oct3/4 and Klf4, in normal somatic cells results in their dedifferentiation into induced pluripotent stem (iPS) cells. We previously reported that these defined factors induced the development of induced multipotent cancer (iPC) cells from gastrointestinal cancer cells by reducing tumor aggressiveness. Previous studies indicated that although reprogramming may be facilitated by p53 inhibition, gain-of-function oncogenic mutations in p53 and oncogenic mutations in Kras-stimulated tumorigenic activity, and their roles in vivo are imperfectly understood. Hence, in the present study, the effect of direct injection of a Sendai virus (SeV) vector encoding four defined factors in vivo was studied using various backgrounds of transgenic and knockout mice, and was compared with that of direct injection of microRNAs (miRNAs) diluted with cationic lipid. The in vivo imaging data revealed transformation hot spots for p53 deficiency or conditional activation of mutant Kras, and the sizes were concordant with those in immuno-deficient NOD/SCID and uPA-NOG mice, as well as larger compared with those in the control mice. Overall, the present data on in vivo reprogramming indicated that Kras activation may facilitate the effect of cellular reprogramming in normal liver cells, and the effect of Kras activation is more apparent than that of tumor suppressor p53 deficiency. The results also revealed that immunodeficiency may increase the effect of reprogramming, presumably by blocking the immunosurveillance of transformed cells. These findings provide a rationale for further studies to develop a therapeutic approach involving direct in vivo reprogramming.
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影响因子：
64.5
作者：
Takahashi, Kazutoshi;Yamanaka, Shinya
通讯作者：
Yamanaka, Shinya
影响因子：
64.5
作者：
Takahashi, Kazutoshi;Tanabe, Koji;Yamanaka, Shinya
通讯作者：
Yamanaka, Shinya
影响因子：
11.5
作者：
Prenen, Hans;Tejpar, Sabine;Van Cutsem, Eric
通讯作者：
Van Cutsem, Eric
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.2183/pjab.85.348
发表时间：
2009
期刊：
Proceedings of the Japan Academy. Series B, Physical and biological sciences
影响因子：
--
作者：
Fusaki N;Ban H;Nishiyama A;Saeki K;Hasegawa M
通讯作者：
Hasegawa M