الفهرس 
IntroductionOnly 14 pages are availabe for public view
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Abstract
Human cancers are composed of heterogeneous mixtures of cells with different biological characteristics and various degrees of differentiation and proliferation potential. Based on this heterogeneity, human tumours are thought to have a hierarchical organization whereby a subset of cells with stem-cell properties called cancer stem cells (CSCs) are responsible for maintaining tumour growth and progression. Therefore, understanding CSCs regulation may lead ultimately to the development of new anti-cancer therapies. NANOG1, a transcription factor, and microRNA-302 (miR-302) cluster play an important role in self-renewal and maintenance of pluripotency in embryonic stem cells (ESCs). However, recently several reports have confirmed the expression of NANOG (either NANOG1 or its pseudogene NANOGP8) and miR-302 in a range of tumour cells suggesting they may have a role in tumourigenicity.
Herein, we show differential expression of both NANOG1 and NANOGP8 in human colorectal cancers (CRC), while the majority of the expressed NANOG mRNAs is derived from NANOGP8 loci. Enforced NANOG1 expression increases clonogenic potential and tumour formation in xenograft models, although it is expressed only in a small subpopulation (0.5-2%) of tumour cells and is co-localized with endogenous nuclear β-cateninHigh. Moreover, single NANOG1 CRC cells form spherical aggregates, similar to the embryoid body of ESCs, and express higher levels of stem cells and Wnt-associated target genes. Furthermore, we show that NANOG1 expression is positively regulated by c-JUN and β-catenin/TCF4 in a β-catenin dependent manner. Chromatin immunoprecipitation (ChIP) assays demonstrate that both c-JUN and TCF4 bind to the NANOG1-promoter via the octamer M1 and TCF-DNA binding elements respectively. Moreover, ectopic expression of c-Jun in murine ApcMin/+-ESCs results in the development of larger xenograft tumours with higher cell density compared to controls.