生物谷報道：小鼠APC缺失會導(dǎo)致的腸上皮發(fā)生癌變,，敲除小鼠Myc原癌基因能避免這種癌變,。
缺失APC（adenomatous polyposis coli）抑癌蛋白的純合子突變體，易患結(jié)腸癌,。APC的滅活或丟失會導(dǎo)致轉(zhuǎn)錄復(fù)合體 (β-catenin–Tcf4) 組成性核定位（constitutive nuclear localization）和活化,，而β-catenin–Tcf4調(diào)節(jié)原癌基因c-Myc的表達(dá)。最近,，英國卡地夫大學(xué)等單位的研究人員發(fā)現(xiàn)Myc的一種新作用——促進(jìn)APC缺失誘發(fā)的癌變,，這一內(nèi)容刊登于4月5日 Nature 雜志。
缺失APC的小鼠內(nèi)腸細(xì)胞形態(tài)異常且容易發(fā)展出腫瘤,。奇怪的是,，即便在核β-catenin的水平很高的情況下，APC和Myc雙敲除的成年小鼠的腸上皮細(xì)胞表型依舊正常,。這種APC/Myc雙敲除的小鼠細(xì)胞,，增殖、凋亡和遷移能力與野生型細(xì)胞的類似。與早期研究報道一致的是,，APC單敲除的細(xì)胞,，增殖、凋亡和遷移率顯著增加,。
研究人員用微列陣技術(shù)分析野生型腸上皮細(xì)胞,、APC單敲除腸上皮細(xì)胞和APC/Myc雙敲除上皮細(xì)胞的RNA。Wnt信號途徑作用的50個靶基因（先前已知）,，在APC單敲除的RNA樣本中被錯誤調(diào)整,，其中2/3的Wnt靶基因需要Myc激活才能表達(dá)。APC/Myc雙敲除樣本與APC單敲除樣本相比,，axin2,、tcf1、tiam1和Sox17等表達(dá)下調(diào),。這些提示,，Myc在APC缺失引起的癌變中發(fā)揮重要作用，而Myc的活性轉(zhuǎn)換離不開關(guān)鍵基因的介導(dǎo),。
由于腸道完全缺失APC會導(dǎo)致小鼠很快發(fā)生腫瘤和死亡,，研究人員研制出部分腸道細(xì)胞缺失APC和/或Myc的小鼠,，能夠在APC缺失的情況下存活較長時間,。三周后，APC敲除小鼠出現(xiàn)眾多小面積腸損傷和嚴(yán)重腺瘤,，雙敲除小鼠的腸上皮細(xì)胞正常,，沒有一個APC/Myc雙敲除細(xì)胞，沒有β-catenin聚集跡象,，說明野生型細(xì)胞在與雙敲除細(xì)胞的競爭中占上風(fēng),。
這項研究證明Myc在APC介導(dǎo)的小鼠腸上皮細(xì)胞腫瘤發(fā)生事件中發(fā)揮重要作用，評估人類細(xì)胞腫瘤發(fā)生中Myc和APC之間的相互作用,，有必要擴(kuò)展和增加臨床學(xué)證據(jù),。
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: [email protected]).
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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.
