生物谷报道：小鼠APC缺失会导致的肠上皮发生癌变，敲除小鼠Myc原癌基因能避免这种癌变。
缺失APC（adenomatous polyposis coli）抑癌蛋白的纯合子突变体，易患结肠癌。APC的灭活或丢失会导致转录复合体 (β-catenin–Tcf4) 组成性核定位（constitutive nuclear localization）和活化，而β-catenin–Tcf4调节原癌基因c-Myc的表达。最近，英国卡地夫大学等单位的研究人员发现Myc的一种新作用——促进APC缺失诱发的癌变，这一内容刊登于4月5日 Nature 杂志。
缺失APC的小鼠内肠细胞形态异常且容易发展出肿瘤。奇怪的是，即便在核β-catenin的水平很高的情况下，APC和Myc双敲除的成年小鼠的肠上皮细胞表型依旧正常。这种APC/Myc双敲除的小鼠细胞，增殖、凋亡和迁移能力与野生型细胞的类似。与早期研究报道一致的是，APC单敲除的细胞，增殖、凋亡和迁移率显著增加。
研究人员用微列阵技术分析野生型肠上皮细胞、APC单敲除肠上皮细胞和APC/Myc双敲除上皮细胞的RNA。Wnt信号途径作用的50个靶基因（先前已知），在APC单敲除的RNA样本中被错误调整，其中2/3的Wnt靶基因需要Myc激活才能表达。APC/Myc双敲除样本与APC单敲除样本相比，axin2、tcf1、tiam1和Sox17等表达下调。这些提示，Myc在APC缺失引起的癌变中发挥重要作用，而Myc的活性转换离不开关键基因的介导。
由于肠道完全缺失APC会导致小鼠很快发生肿瘤和死亡，研究人员研制出部分肠道细胞缺失APC和/或Myc的小鼠，能够在APC缺失的情况下存活较长时间。三周后，APC敲除小鼠出现众多小面积肠损伤和严重腺瘤，双敲除小鼠的肠上皮细胞正常，没有一个APC/Myc双敲除细胞，没有β-catenin聚集迹象，说明野生型细胞在与双敲除细胞的竞争中占上风。
这项研究证明Myc在APC介导的小鼠肠上皮细胞肿瘤发生事件中发挥重要作用，评估人类细胞肿瘤发生中Myc和APC之间的相互作用，有必要扩展和增加临床学证据。
部分英文原文：
Nature 446, 676-679 (5 April 2007) | doi:10.1038/nature05674; Received 21 September 2006; Accepted 9 February 2007; Published online 21 March 2007
Myc deletion rescues Apc deficiency in the small intestine
Owen J. Sansom1, Valerie S. Meniel2, Vanesa Muncan3, Toby J. Phesse2, Julie A. Wilkins1, Karen R. Reed2, J. Keith Vass1, Dimitris Athineos1, Hans Clevers3 & Alan R. Clarke2
The Beatson Institute, Garscube Estate, Glasgow G61 1BD, UK
Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3US, UK
Hubrecht Laboratory, Nederlands Institute for Developmental Biology, Upsalalaan 8, 3584 CT Utrecht, The Netherlands
Correspondence to: Owen J. Sansom1 Correspondence and requests for materials should be addressed to O.J.S. (Email: o.sansom@beatson.gla.ac.uk).
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Abstract
The APC gene encodes the adenomatous polyposis coli tumour suppressor protein, germline mutation of which characterizes familial adenomatous polyposis (FAP), an autosomal intestinal cancer syndrome1. Inactivation of APC is also recognized as the key early event in the development of sporadic colorectal cancers2, 3, and its loss results in constitutive activity of the -catenin–Tcf4 transcription complex3. The proto-oncogene c-MYC has been identified as a target of the Wnt pathway in colorectal cancer cells in vitro4, in normal crypts in vivo5 and in intestinal epithelial cells acutely transformed on in vivo deletion of the APC gene6; however, the significance of this is unclear. Therefore, to elucidate the role Myc has in the intestine after Apc loss, we have simultaneously deleted both Apc and Myc in the adult murine small intestine. Here we show that loss of Myc rescued the phenotypes of perturbed differentiation, migration, proliferation and apoptosis, which occur on deletion of Apc. Remarkably, this rescue occurred in the presence of high levels of nuclear -catenin. Array analysis revealed that Myc is required for the majority of Wnt target gene activation following Apc loss. These data establish Myc as the critical mediator of the early stages of neoplasia following Apc loss.
