ABSTRACT

The nucleophosmin 1 (NPM1) protein is frequently overexpressed in various cancers compared to normal tissues and represents a potential biomarker for maliganancy. However, its role in colorectal cancer (CRC) is still not fully understood. In this report, we show that NPM1 levels in CRC correlate with prognosis and sensitivity to chemotherapy. NPM1 expression was found to be significantly increased in CRC tumors (P < .001) and was associated with poor overall 5-year survival (P < .05). For individuals with Stage IV disease, this represented a reduction in survival by 11 months (P < .01; HR = 0.38, CI [0.21, 0.69]. In vitro, we show that NPM1 gene silencing enhanced the chemosensitivity of CRC cells and that pharmacological inhibition of NPM1 by NSC348884 triggered the onset of programmed cell death. Our immunofluorescence microscopy and immunoblot analyses also revealed that blocking NPM1 function sensitized CRC cells to chemotherapy-induced apoptosis through a mechanism that involves proteins in the AKT pathway. Consistent with the in vitro data, our patient-derived CRC xenograft model showed that inhibition of NPM1 suppressed tumor growth and attenuated AKT signaling in vivo. Moreover, LY294002, an inhibitor of the PI3K/AKT pathway, restored the chemosensitivity of CRC cells expressing high levels of NPM1. The findings that NPM1’s expression in CRC tissue correlates with prognosis and supports anti-apoptotic activity mediated by AKT signaling, further our understanding of the role of NPM1 in CRC.

摘要

与正常组织相比，核磷蛋白 1 (NPM1) 蛋白在各种癌症中经常过度表达，是恶性肿瘤的潜在生物标志物。然而，它在结直肠癌 (CRC) 中的作用仍未完全了解。在本报告中，我们表明 CRC 中的 NPM1 水平与预后和对化疗的敏感性相关。NPM1 表达在 CRC 肿瘤中显着增加（P < .001），并且与较差的 5 年总生存率相关（P < .05）。对于 IV 期疾病的个体，这意味着生存期减少了 11 个月（P < .01；HR = 0.38，CI [0.21, 0.69]。体外，我们表明 NPM1 基因沉默增强了 CRC 细胞的化学敏感性，并且 NSC348884 对 NPM1 的药理学抑制引发了程序性细胞死亡的发生。我们的免疫荧光显微镜和免疫印迹分析还显示，阻断 NPM1 功能通过涉及 AKT 途径中的蛋白质的机制使 CRC 细胞对化疗诱导的细胞凋亡敏感。与体外数据一致，我们源自患者的 CRC 异种移植模型显示，抑制 NPM1 可抑制肿瘤生长并减弱体内AKT 信号传导. 此外，PI3K/AKT 通路抑制剂 LY294002 可恢复表达高水平 NPM1 的 CRC 细胞的化学敏感性。NPM1 在 CRC 组织中的表达与预后相关并支持 AKT 信号介导的抗凋亡活性的研究结果，进一步了解了 NPM1 在 CRC 中的作用。