Division of Hematology and Oncology, Department of Medicine, UAB Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama; Birmingham Veterans Affairs Medical Center, Birmingham, Alabama.
Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina.
Gastroenterology. 2022 Jan;162(1):193-208. doi: 10.1053/j.gastro.2021.09.010. Epub 2021 Sep 11.
BACKGROUND & AIMS: Inactivation of the Apc gene is a critical early event in the development of sporadic colorectal cancer (CRC). Expression of serine-threonine kinase receptor-associated protein (STRAP) is elevated in CRCs and is associated with poor outcomes. We investigated the role of STRAP in Apc mutation-induced intestinal tumor initiation and progression.
We generated Strap intestinal epithelial knockout mice (Strap) by crossing mice containing floxed alleles of Strap (Strap) with Villin-Cre mice. Then we generated Apc;Strap;Vill-Cre (Apc;Strap) mice for RNA-sequencing analyses to determine the mechanism of function of STRAP. We used human colon cancer cell lines (DLD1, SW480, and HT29) and human and mouse colon tumor-derived organoids for STRAP knockdown and knockout and overexpression experiments.
Strap deficiency extended the average survival of Apc mice by 80 days and decreased the formation of intestinal adenomas. Expression profiling revealed that the intestinal stem cell signature, the Wnt/β-catenin signaling, and the MEK/ERK pathway are down-regulated in Strap-deficient adenomas and intestinal organoids. Correlation studies suggest that these STRAP-associated oncogenic signatures are conserved across murine and human colon cancer. STRAP associates with MEK1/2, promotes binding between MEK1/2 and ERK1/2, and subsequently induces the phosphorylation of ERK1/2. STRAP activated Wnt/β-catenin signaling through MEK/ERK-induced phosphorylation of LRP6. STRAP was identified as a target of mutated Apc and Wnt/β-catenin signaling as chromatin immunoprecipitation and luciferase assays revealed putative binding sites of the β-catenin/TCF4 complex on the Strap promoter.
STRAP is a target of, and is required in, Apc mutation/deletion-induced intestinal tumorigenesis through a novel feed-forward STRAP/MEK-ERK/Wnt-β-catenin/STRAP regulatory axis.
APC 基因突变是散发性结直肠癌（CRC）发生的早期关键事件。丝氨酸-苏氨酸激酶受体相关蛋白（STRAP）在 CRC 中的表达升高，与不良预后相关。我们研究了 STRAP 在 APC 突变诱导的肠道肿瘤起始和进展中的作用。
我们通过将含有 STRAP 基因 floxed 等位基因的小鼠（Strap）与 Villin-Cre 小鼠杂交，生成 Strap 肠上皮细胞敲除小鼠（Strap）。然后，我们生成 Apc;Strap;Vill-Cre（Apc;Strap）小鼠进行 RNA 测序分析，以确定 STRAP 功能的作用机制。我们使用人结肠癌细胞系（DLD1、SW480 和 HT29）以及人源和鼠源结肠肿瘤衍生的类器官进行 STRAP 敲低和敲除以及过表达实验。
Strap 缺失将 Apc 小鼠的平均存活期延长了 80 天，并减少了肠腺瘤的形成。表达谱分析显示，在 Strap 缺失的腺瘤和肠类器官中，肠道干细胞特征、Wnt/β-catenin 信号通路和 MEK/ERK 通路均下调。相关性研究表明，这些与 STRAP 相关的致癌特征在鼠源和人源结肠肿瘤中是保守的。STRAP 与 MEK1/2 结合，促进 MEK1/2 与 ERK1/2 结合，随后诱导 ERK1/2 的磷酸化。STRAP 通过 MEK/ERK 诱导的 LRP6 磷酸化激活 Wnt/β-catenin 信号通路。染色质免疫沉淀和荧光素酶报告基因检测显示，β-catenin/TCF4 复合物的潜在结合位点位于 Strap 启动子上，证实 STRAP 是突变型 APC 和 Wnt/β-catenin 信号通路的靶标。
通过新型 STRAP/MEK-ERK/Wnt-β-catenin/STRAP 正反馈调节轴，STRAP 是 APC 突变/缺失诱导的肠道肿瘤发生所必需的，也是 APC 突变/缺失诱导的肠道肿瘤发生的靶点。
