Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
Department of Oncological Urology and Laboratory Translational Oncology, Division of Imaging and Oncology, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands.
Sci Rep. 2024 Nov 12;14(1):27663. doi: 10.1038/s41598-024-78776-7.
The scaffold protein PEAK1 acts downstream of integrin adhesion complexes and the epidermal growth factor receptor, orchestrating signaling events that control cell proliferation and cytoskeletal remodeling. In this study we investigated the role of PEAK1 in colorectal carcinoma (CRC) progression using various in vitro and in vivo models to replicate the stepwise pathogenesis of CRC. While we observed a cell-type specific role for PEAK1 in the proliferation and in human CRC cell lines in vitro, our in vivo experiments using different CRC mouse models driven by loss of Apc, with or without oncogenic Kras or Pten loss suggest that PEAK1 does not significantly contribute to tumor formation in vivo. However, the survival time of Peak1 mice in the Apc model appeared to be slightly increased. Furthermore, PEAK1 promotes EGF-induced Caco-2 cell proliferation and regulates spheroid polarization and lumenization. Given that the Caco-2 cells harbor mutations in the tumor suppressors APC and β-CATENIN, but not in other tumor suppressors or in proto-oncogenes, we conclude that the PEAK1's impact on colon carcinogenesis is limited, potentially playing a role in the initial stage of the adenoma to carcinoma progression.
支架蛋白 PEAK1 位于整合素黏附复合物和表皮生长因子受体下游，协调控制细胞增殖和细胞骨架重塑的信号事件。在这项研究中，我们使用各种体外和体内模型研究了 PEAK1 在结直肠癌（CRC）进展中的作用，以复制 CRC 的逐步发病机制。虽然我们观察到 PEAK1 在体外对特定细胞类型的增殖和人 CRC 细胞系具有作用，但我们使用不同的 CRC 小鼠模型进行的体内实验表明，这些模型由 APC 缺失驱动，无论是否存在致癌性 Kras 或 Pten 缺失，PEAK1 对体内肿瘤形成没有显著贡献。然而，Peak1 小鼠在 Apc 模型中的存活时间似乎略有增加。此外，PEAK1 促进 EGF 诱导的 Caco-2 细胞增殖，并调节球体极化和管腔化。鉴于 Caco-2 细胞在肿瘤抑制因子 APC 和 β-CATENIN 中存在突变，但在其他肿瘤抑制因子或原癌基因中不存在突变，我们得出结论，PEAK1 对结肠癌发生的影响是有限的，可能在腺瘤到癌进展的初始阶段发挥作用。
