Emerging notion in carcinogenesis ascribes tumor initiation and aggressiveness to cancer stem cells (CSCs). Specifically, colorectal cancer (CRC) development was shown to be compatible with CSCs hypothesis. Mutations in p53 are highly frequent in CRC, and are known to facilitate tumor development and aggressiveness. Yet, the link between mutant p53 and colorectal CSCs is not well-established. In the present study, we set to examine whether oncogenic mutant p53 proteins may augment colorectal CSCs phenotype. By genetic manipulation of mutant p53 in several cellular systems, we demonstrated that mutant p53 enhances colorectal tumorigenesis. Moreover, mutant p53-expressing cell lines harbor larger sub-populations of cells highly expressing the known colorectal CSCs markers: CD44, Lgr5, and ALDH. This elevated expression is mediated by mutant p53 binding to CD44, Lgr5, and ALDH1A1 promoter sequences. Furthermore, ALDH1 was found to be involved in mutant p53-dependent chemotherapy resistance. Finally, analysis of ALDH1 and CD44 in human CRC biopsies indicated a positive correlation between their expression and the presence of oncogenic p53 missense mutations. These findings suggest novel insights pertaining the mechanism by which mutant p53 enhances CRC development, which involves the expansion of CSCs sub-populations within CRC tumors, and underscore the importance of targeting these sub-populations for CRC therapy.

中文翻译：

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突变的p53功能获得是大肠癌干细胞标志物高表达水平的基础。

致癌作用中的新兴概念将肿瘤的起源和侵袭性归因于癌症干细胞（CSC）。具体而言，显示结直肠癌（CRC）的发展与CSC的假设是相容的。p53中的突变在CRC中非常常见，并且已知可促进肿瘤的发展和侵袭性。然而，突变的p53和结直肠CSC之间的联系尚不明确。在本研究中，我们着手检查致癌突变体p53蛋白是否可以增强结直肠CSCs表型。通过在几个细胞系统中突变体p53的遗传操作，我们证明了突变体p53增强了结直肠肿瘤的发生。此外，表达突变型p53的细胞系包含大量亚细胞，这些细胞高度表达已知的结直肠CSCs标记：CD44，Lgr5和ALDH。这种升高的表达是通过突变体p53与CD44，Lgr5和ALDH1A1启动子序列结合而介导的。此外，发现ALDH1与突变型p53依赖的化疗耐药有关。最后，对人类CRC活检组织中ALDH1和CD44的分析表明，它们的表达与致癌性p53错义突变的存在呈正相关。这些发现提示有关突变体p53增强CRC发育的机制的新见解，涉及到CRC肿瘤内CSCs亚群的扩展，并强调了针对CRC治疗靶向这些亚群的重要性。CRC活检中ALDH1和CD44的分析表明，它们的表达与致癌性p53错义突变的存在呈正相关。这些发现提示有关突变体p53增强CRC发育的机制的新见解，涉及到CRC肿瘤内CSCs亚群的扩展，并强调了针对CRC治疗靶向这些亚群的重要性。CRC活检中ALDH1和CD44的分析表明，它们的表达与致癌性p53错义突变的存在呈正相关。这些发现提示有关突变体p53增强CRC发育的机制的新见解，涉及到CRC肿瘤内CSCs亚群的扩展，并强调了针对CRC治疗靶向这些亚群的重要性。