Rationale: Chemoradiation (CRT) is commonly used as an adjuvant or neoadjuvant treatment for colorectal cancer (CRC) patients. However, resistant cells manage to survive and propagate after CRT, increasing the risk of recurrence. Thus, better understanding the mechanism of resistant cancer cells is required to achieve better clinical outcomes. Methods: Here, we explored gene expression profiling of CRC patient tumors to identify therapy resistance genes and discovered that protein tyrosine phosphatase receptor type C (PTPRC), which encodes CD45, was increased in remnant tumor tissues after CRT and correlated with metastasis. Through multiple validations using patient tumors and CRC cell lines, we found for the first time the increase of CD45 expression in CRC (EpCAM+) epithelial cells surviving after CRT. Thus, we investigated the biological role and downstream events of CD45 were explored in human CRC cells and CRC mouse models. Results: Increased CD45 expression in cancer cells in pretreated primary tumors accounts for poor regression and recurrence-free survival in CRT-treated patients. High CD45 expression promotes CRC cell survival upon 5-fluorouracil or radiation treatment, while CD45 depletion sensitizes CRC cells to CRT. Intriguingly, CD45 is preferentially expressed in cancer stem-like cells (CSCs), as determined by spheroid culture and the expression of CSC markers, and is required for the distinct functions of CSCs, such as cancer initiation, repopulation, and metastasis. Mechanistically, CD45 phosphatase activity promotes Wnt transcriptional activity by stabilizing the β-catenin protein, which collectively enhances stemness and the therapy-resistant phenotype. Conclusions: Our results highlight a novel function of CD45 as a mediator of CRT resistance and provide a potential therapy strategy for CRC therapy.

中文翻译：

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CD45-Wnt 信号轴的异常激活促进了结直肠癌细胞的干性和治疗抗性。

理由：放化疗 (CRT) 通常用作结直肠癌 (CRC) 患者的辅助或新辅助治疗。然而，抗性细胞在 CRT 后设法存活和繁殖，增加了复发的风险。因此，需要更好地了解耐药癌细胞的机制以实现更好的临床结果。方法：在这里，我们探索了 CRC 患者肿瘤的基因表达谱以确定治疗抗性基因，发现 CRT 后残余肿瘤组织中编码 CD45 的蛋白酪氨酸磷酸酶受体 C 型 (PTPRC) 增加并与转移相关。通过使用患者肿瘤和 CRC 细胞系进行多次验证，我们首次发现 CRT 后存活的 CRC (EpCAM+) 上皮细胞中 CD45 表达增加。因此，我们研究了 CD45 在人类 CRC 细胞和 CRC 小鼠模型中的生物学作用和下游事件。结果：在预处理的原发性肿瘤中，癌细胞中 CD45 表达增加是 CRT 治疗患者消退和无复发生存率差的原因。高 CD45 表达促进 5-氟尿嘧啶或放射治疗后的 CRC 细胞存活，而 CD45 消耗使 CRC 细胞对 CRT 敏感。有趣的是，CD45 优先在癌症干细胞样细胞 (CSCs) 中表达，这由球体培养和 CSC 标志物的表达确定，并且是 CSCs 的不同功能所必需的，例如癌症起始、再增殖和转移。从机制上讲，CD45 磷酸酶活性通过稳定 β-连环蛋白促进 Wnt 转录活性，这共同增强了干性和抗治疗表型。结论：我们的研究结果突出了 CD45 作为 CRT 抵抗介质的新功能，并为 CRC 治疗提供了潜在的治疗策略。