腺瘤性息肉症基因 (APC) 是一个重要的肿瘤抑制因子，主要与 WNT/β-连环素信号通路的调控相联系。APC 突变已被鉴定为80%以上散发性结直肠癌 (CRC) 的早期事件。此外，APC 突变在 CRC 患者中存在预后差异。虽然以往的基因组学研究探讨了共同基因突变在决定 APC 突变瘤体表型的异质性方面的作用，但对于 APC 突变 CRC 患者而言，缺乏有价值的预后决定因素。基于蛋白质组和磷酸化蛋白质组数据，我们对 APC 突变的结肠癌患者进行了分类，揭示了 APC 突变瘤体的基因组学、蛋白质组和磷酸化蛋白质组的异质性。更重要的是，我们确定了 RAI14 作为 APC 突变但非 APC 野生型结肠癌患者的关键预后决定因素。在临床蛋白质组肿瘤分析联盟 (CPTAC) 结肠癌队列中，对 APC 突变瘤体异质性和预后生物标志物的重要性进行了进一步验证。此外，我们发现表达 RAI14 高的结肠癌患者较不敏感于化疗。细胞系中 RAI14 的敲除导致细胞迁移降低和上皮间充质转化相关标志物的改变。机制上，RAI14 的敲除重构了与细胞粘附有关的磷酸化蛋白质组，可能影响 EMT 标志物的表达并促进 F-actin 的降解。综上所述，本研究描述了 APC 突变瘤体的表型异质性，并确定 RAI14 作为 APC 突变结肠癌患者的重要预后决定因素。RAI14 在 APC 突变结肠癌中的预后应用将提供早期警告，增加成功治疗的机会。版权所有©2023年作者。由 Elsevier Inc. 发布。版权所有。

Adenomatous polyposis coli (APC) is an important tumor suppressor and is mostly linked to the regulation of the WNT/β-catenin signaling pathway. APC mutation has been identified as an early event in more than 80% of sporadic colorectal cancers (CRCs). Moreover, prognostic differences are observed in CRC patients with APC mutations. Although previous genomics studies have investigated the roles of concomitant gene mutations in determining the phenotypic heterogeneity of APC-mutant tumors, valuable prognostic determinants for APC-mutant CRC patients are still lacking. Based on the proteome and phosphoproteome data, we classified APC-mutant colon cancer patients and revealed genomic, proteomic and phosphoproteomic heterogeneity in APC-mutant tumors. More importantly, we identified RAI14 as a key prognostic determinant for APC-mutant but not APC-wildtype colon cancer patients. The heterogeneity and the significance of prognostic biomarkers in APC-mutant tumors were further validated in the Clinical Proteomic Tumor Analysis Consortium (CPTAC) colon cancer cohort. In addition, we found that colon cancer patients with high expression of RAI14 were less responsive to chemotherapy. Knockdown of RAI14 in cell lines led to reduced cell migration and changes in epithelial-mesenchymal transition (EMT)-related markers. Mechanistically, knockdown of RAI14 remodeled the phosphoproteome associated with cell adhesion, which might affect EMT marker expression and promote F-actin degradation. Collectively, this work describes the phenotypic heterogeneity of APC-mutant tumors and identifies RAI14 as an important prognostic determinant for APC-mutant colon cancer patients. The prognostic utility of RAI14 in APC-mutant colon cancer will provide early warning and increase the chance of successful treatment.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.