Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA.
EMBO J. 2012 Nov 5;31(21):4124-39. doi: 10.1038/emboj.2012.270. Epub 2012 Oct 2.
Cancers and tissue stem cells (SCs) share similar molecular pathways for their self-renewal and differentiation. The race is on to identify unique pathways to specifically target the cancer, while sparing normal SCs. Here, we uncover the transcription factor Runx1/AML1, a known haematopoietic and leukaemia factor, albeit dispensable for normal adult SC homeostasis, as being important for some mouse and human epithelial cancers. We implicate Runx1 as a SC-intrinsic gene in mouse hair follicle and oral epithelia by genetic lineage tracing in adulthood. Runx1-expressing SCs, but not other cells that ectopically upregulate Runx1 by injury and inflammation, are at the skin tumour origin. Runx1 loss impairs tumour initiation and maintenance and the growth of oral, skin, and ovarian epithelial human cancer cells. Runx1 stimulates Stat3 signalling via direct transcriptional repression of SOCS3 and SOCS4 and this is essential for cancer cell growth. Thus, Runx1 is a broader epithelial SC and cancer factor than previously recognized, and qualifies as an attractive potential target for both prevention and therapy of several epithelial cancers.
癌症和组织干细胞 (SCs) 在自我更新和分化方面具有相似的分子途径。目前的研究重点是确定独特的途径，以特异性靶向癌症，同时保留正常的 SCs。在这里，我们发现转录因子 Runx1/AML1 是一种已知的造血和白血病因子，尽管在正常成年 SC 稳态中可有可无，但对一些小鼠和人类上皮癌很重要。我们通过成年后的遗传谱系追踪，将 Runx1 确定为小鼠毛囊和口腔上皮中的 SC 内在基因。表达 Runx1 的 SC 而不是其他通过损伤和炎症异位上调 Runx1 的细胞，是皮肤肿瘤的起源。Runx1 的缺失会损害肿瘤的起始和维持以及口腔、皮肤和卵巢上皮性人类癌细胞的生长。Runx1 通过直接转录抑制 SOCS3 和 SOCS4 来刺激 Stat3 信号通路，这对于癌细胞的生长是必不可少的。因此，Runx1 是一种比以前认识到的更广泛的上皮 SC 和癌症因子，并且是预防和治疗几种上皮癌的有吸引力的潜在靶标。
