APCmutation is the main driving mechanism of CRC development and leads to constitutively activated WNT signaling, overpopulation of ALDH+ stem cells (SCs), and incomplete differentiation. We previously reported that retinoic acid (RA) receptors are selectively expressed in ALDH+ SCs, which provides a way to target cancer SCs with retinoids to induce differentiation.Hypotheses: A functional link exists between the WNT and RA pathways, andAPCmutation generates a WNT:RA imbalance that decreases retinoid-induced differentiation and increases ALDH+ SCs. Accordingly, to restore parity in WNT:RA signaling, we inducewt-APCexpression inAPC-mutant CRC cells, and we assess the ability of all-trans retinoic acid (ATRA) to induce differentiation. We found that ATRA increased expression of the WNT target gene,CYP26A1, and inducingwt-APCreduced this expression by 50%. Thus, the RA and WNT pathways crosstalk to modulate CYP26A1, which metabolizes retinoids. Moreover, inducingwt-APCaugments ATRA-induced cell differentiation by: (i) decreasing cell proliferation; (ii) suppressingALDH1A1expression; (iii) decreasing ALDH+ SCs; and (iv) increasing neuroendocrine cell differentiation. A novel CYP26A1-based network that links WNT and RA signaling was also identified by NanoString profiling/bioinformatics analysis. Furthermore,CYP26A1inhibitors sensitized CRC cells to the anti-proliferative effect of drugs that downregulate WNT signaling. Notably, inwt-APC-CRCs, decreased CYP26A1 improved patient survival. These findings have strong potential for clinical translation.
APC基因突变是结直肠癌（CRC）发生的主要驱动机制，其导致WNT信号通路持续激活、ALDH+干细胞（SCs）过度增殖以及细胞分化不完全。我们先前报道称，视黄酸（RA）受体在ALDH+ SCs中选择性表达，这为利用类视黄醇靶向癌症SCs以诱导分化提供了途径。假设：WNT与RA通路之间存在功能联系，且APC突变导致WNT:RA信号失衡，从而降低类视黄醇诱导的分化作用并增加ALDH+ SCs数量。为此，我们通过在APC突变型CRC细胞中诱导野生型APC（wt-APC）表达，并评估全反式视黄酸（ATRA）诱导分化的能力，以恢复WNT:RA信号平衡。研究发现，ATRA可上调WNT靶基因CYP26A1的表达，而诱导wt-APC表达使该基因表达降低50%。这表明RA与WNT通路通过交互作用调控代谢类视黄醇的CYP26A1。此外，诱导wt-APC表达通过以下机制增强ATRA诱导的细胞分化：（1）抑制细胞增殖；（2）下调ALDH1A1表达；（3）减少ALDH+ SCs数量；（4）促进神经内分泌细胞分化。通过NanoString谱分析及生物信息学分析，我们还发现了一个连接WNT与RA信号的新型CYP26A1调控网络。值得注意的是，在wt-APC型CRC中，CYP26A1表达降低与患者生存率提高相关。这些发现具有显著的临床转化潜力。
肿瘤(癌症)患者之家